2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC

Definition of heart failure with preserved (HFpEF), mid-range (HFmrEF) and reduced ejection fraction (HFrEF)

BNP = B-type natriuretic peptide; HF = heart failure; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LAE = left atrial enlargement; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NT-proBNP = N-terminal pro-B type natriuretic peptide.

^aSigns may not be present in the early stages of HF (especially in HFpEF) and in patients treated with diuretics.

^bBNP>35 pg/ml and/or NT-proBNP>125 pg/mL.

The diagnosis of HFpEF is more challenging than the diagnosis of HFrEF. Patients with HFpEF generally do not have a dilated LV, but instead often have an increase in LV wall thickness and/or increased left atrial (LA) size as a sign of increased filling pressures. Most have additional ‘evidence’ of impaired LV filling or suction capacity, also classified as diastolic dysfunction, which is generally accepted as the likely cause of HF in these patients (hence the term ‘diastolic HF’). However, most patients with HFrEF (previously referred to as ‘systolic HF’) also have diastolic dysfunction, and subtle abnormalities of systolic function have been shown in patients with HFpEF. Hence the preference for stating preserved or reduced LVEF over preserved or reduced ‘systolic function’.

In previous guidelines it was acknowledged that a grey area exists between HFrEF and HFpEF.⁷ These patients have an LVEF that ranges from 40 to 49%, hence the term HFmrEF. Identifying HFmrEF as a separate group will stimulate research into the underlying characteristics, pathophysiology and treatment of this group of patients. Patients with HFmrEF most probably have primarily mild systolic dysfunction, but with features of diastolic dysfunction (Table 3.1).

Patients without detectable LV myocardial disease may have other cardiovascular causes for HF (e.g. pulmonary hypertension, valvular heart disease, etc.). Patients with non-cardiovascular pathologies (e.g. anaemia, pulmonary, renal or hepatic disease) may have symptoms similar or identical to those of HF and each may complicate or exacerbate the HF syndrome.

3.2.2 Terminology related to the time course of heart failure

In these guidelines, the term HF is used to describe the symptomatic syndrome, graded according to the New York Heart Association (NYHA) functional classification (see Section 3.2.3 and Web Table 3.2), although a patient can be rendered asymptomatic by treatment. In these guidelines, a patient who has never exhibited the typical symptoms and/or signs of HF and with a reduced LVEF is described as having asymptomatic LV systolic dysfunction. Patients who have had HF for some time are often said to have ‘chronic HF’. A treated patient with symptoms and signs that have remained generally unchanged for at least 1 month is said to be ‘stable’. If chronic stable HF deteriorates, the patient may be described as ‘decompensated’ and this may happen suddenly or slowly, often leading to hospital admission, an event of considerable prognostic importance. New-onset (‘de novo’) HF may also present acutely, for example, as a consequence of acute myocardial infarction (AMI), or in a subacute (gradual) fashion, for example, in patients with a dilated cardiomyopathy (DCM), who often have symptoms for weeks or months before the diagnosis becomes clear. Although symptoms and signs of HF may resolve, the underlying cardiac dysfunction may not, and patients remain at the risk of recurrent ‘decompensation’.

Occasionally, however, a patient may have HF due to a problem that resolves completely (e.g. acute viral myocarditis, takotsubo cardiomyopathy or tachycardiomyopathy). Other patients, particularly those with ‘idiopathic’ DCM, may also show substantial or even complete recovery of LV systolic function with modern disease-modifying therapy [including angiotensin-converting enzyme inhibitor (ACEI), beta-blocker, mineralocorticoid receptor antagonist (MRA), ivabradine and/or CRT]. ‘Congestive HF’ is a term that is sometimes used, and may describe acute or chronic HF with evidence of volume overload. Many or all of these terms may be accurately applied to the same patient at different times, depending upon their stage of illness.

3.2.3 Terminology related to the symptomatic severity of heart failure

The NYHA functional classification (Web Table 3.2) has been used to describe the severity of symptoms and exercise intolerance. However, symptom severity correlates poorly with many measures of LV function; although there is a clear relationship between the severity of symptoms and survival, patients with mild symptoms may still have an increased risk of hospitalization and death.^8–10

Sometimes the term ‘advanced HF’ is used to characterize patients with severe symptoms, recurrent decompensation and severe cardiac dysfunction.¹¹ The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) classification describes stages of HF development based on structural changes and symptoms (Web Table 3.3).¹² The Killip classification may be used to describe the severity of the patient's condition in the acute setting after myocardial infarction (see Section 12).¹³

3.3 Epidemiology, aetiology and natural history of heart failure

The prevalence of HF depends on the definition applied, but is approximately 1–2% of the adult population in developed countries, rising to ≥10% among people >70 years of age.^14–17 Among people >65 years of age presenting to primary care with breathlessness on exertion, one in six will have unrecognized HF (mainly HFpEF).^18,19 The lifetime risk of HF at age 55 years is 33% for men and 28% for women.¹⁶ The proportion of patients with HFpEF ranges from 22 to 73%, depending on the definition applied, the clinical setting (primary care, hospital clinic, hospital admission), age and sex of the studied population, previous myocardial infarction and the year of publication.^{17,18,20–30}

Data on temporal trends based on hospitalized patients suggest that the incidence of HF may be decreasing, more for HFrEF than for HFpEF.^31,32 HFpEF and HFrEF seem to have different epidemiological and aetiological profiles. Compared with HFrEF, patients with HFpEF are older, more often women and more commonly have a history of hypertension and atrial fibrillation (AF), while a history of myocardial infarction is less common.^32,33 The characteristics of patients with HFmrEF are between those with HFrEF and HFpEF,³⁴ but further studies are needed to better characterize this population.

The aetiology of HF is diverse within and among world regions. There is no agreed single classification system for the causes of HF, with much overlap between potential categories (Table 3.4). Many patients will have several different pathologies—cardiovascular and non-cardiovascular—that conspire to cause HF. Identification of these diverse pathologies should be part of the diagnostic workup, as they may offer specific therapeutic opportunities.

Table 3.4

Aetiologies of heart failure

ARVC = arrhythmogenic right ventricular cardiomyopathy; DCM = dilated cardiomyopathy; EMF = endomyocardial fibrosis; GH = growth hormone; HCM = hypertrophic cardiomyopathy; HES = hypereosinophilic syndrome; HIV/AIDS = human immunodeficiency virus/acquired immune deficiency syndrome; LV = left ventricular.

Many patients with HF and ischaemic heart disease (IHD) have a history of myocardial infarction or revascularization. However, a normal coronary angiogram does not exclude myocardial scar (e.g. by CMR imaging) or impaired coronary microcirculation as alternative evidence for IHD.

In clinical practice, a clear distinction between acquired and inherited cardiomyopathies remains challenging. In most patients with a definite clinical diagnosis of HF, there is no confirmatory role for routine genetic testing, but genetic counselling is recommended in patients with hypertrophic cardiomyopathy (HCM), ‘idiopathic’ DCM or arrhythmogenic right ventricular cardiomyopathy (ARVC) (see Section 5.10.1), since the outcomes of these tests may have clinical implications.

Over the last 30 years, improvements in treatments and their implementation have improved survival and reduced the hospitalization rate in patients with HFrEF, although the outcome often remains unsatisfactory. The most recent European data (ESC-HF pilot study) demonstrate that 12-month all-cause mortality rates for hospitalized and stable/ambulatory HF patients were 17% and 7%, respectively, and the 12-month hospitalization rates were 44% and 32%, respectively.³⁵ In patients with HF (both hospitalized and ambulatory), most deaths are due to cardiovascular causes, mainly sudden death and worsening HF. All-cause mortality is generally higher in HFrEF than HFpEF.^35,36 Hospitalizations are often due to non-cardiovascular causes, particularly in patients with HFpEF. Hospitalization for cardiovascular causes did not change from 2000 to 2010, whereas those with non-cardiovascular causes increased.³¹

3.4 Prognosis

Estimation of prognosis for morbidity, disability and death helps patients, their families and clinicians decide on the appropriate type and timing of therapies (in particular, decisions about a rapid transition to advanced therapies) and assists with planning of health and social services and resources.

Numerous prognostic markers of death and/or HF hospitalization have been identified in patients with HF (Web Table 3.5). However, their clinical applicability is limited and precise risk stratification in HF remains challenging.

In recent decades, several multivariable prognostic risk scores have been developed for different populations of patients with HF,^36–41 and some are available as interactive online applications. Multivariable risk scores may help predict death in patients with HF, but remain less useful for the prediction of subsequent HF hospitalizations.^37,38 A systematic review examining 64 prognostic models³⁷ along with a meta-analysis and meta-regression study of 117 prognostic models³⁸ revealed only a moderate accuracy of models predicting mortality, whereas models designed to predict the combined endpoint of death or hospitalization, or only hospitalization, had an even poorer discriminative ability.

4. Diagnosis

4.1 Symptoms and signs

Symptoms are often non-specific and do not, therefore, help discriminate between HF and other problems (Table 4.1).^42–46 Symptoms and signs of HF due to fluid retention may resolve quickly with diuretic therapy. Signs, such as elevated jugular venous pressure and displacement of the apical impulse, may be more specific, but are harder to detect and have poor reproducibility.^18,46,47 Symptoms and signs may be particularly difficult to identify and interpret in obese individuals, in the elderly and in patients with chronic lung disease.^48–50 Younger patients with HF often have a different aetiology, clinical presentation and outcome compared with older patients.^51,52

Table 4.1

Symptoms and signs typical of heart failure

HF = heart failure.

A detailed history should always be obtained. HF is unusual in an individual with no relevant medical history (e.g. a potential cause of cardiac damage), whereas certain features, particularly previous myocardial infarction, greatly increase the likelihood of HF in a patient with appropriate symptoms and signs.^42–45

At each visit, symptoms and signs of HF need to be assessed, with particular attention to evidence of congestion. Symptoms and signs are important in monitoring a patient's response to treatment and stability over time. Persistence of symptoms despite treatment usually indicates the need for additional therapy, and worsening of symptoms is a serious development (placing the patient at risk of urgent hospital admission and death) and merits prompt medical attention.

4.2 Essential initial investigations: natriuretic peptides, electrocardiogram and echocardiography

The plasma concentration of natriuretic peptides (NPs) can be used as an initial diagnostic test, especially in the non-acute setting when echocardiography is not immediately available. Elevated NPs help establish an initial working diagnosis, identifying those who require further cardiac investigation; patients with values below the cut-point for the exclusion of important cardiac dysfunction do not require echocardiography (see also Section 4.3 and Section 12). Patients with normal plasma NP concentrations are unlikely to have HF. The upper limit of normal in the non-acute setting for B-type natriuretic peptide (BNP) is 35 pg/mL and for N-terminal pro-BNP (NT-proBNP) it is 125 pg/mL; in the acute setting, higher values should be used [BNP < 100 pg/mL, NT-proBNP < 300 pg/mL and mid-regional pro A-type natriuretic peptide (MR-proANP) < 120 pmol/L]. Diagnostic values apply similarly to HFrEF and HFpEF; on average, values are lower for HFpEF than for HFrEF.^54,55 At the mentioned exclusionary cut-points, the negative predictive values are very similar and high (0.94–0.98) in both the non-acute and acute setting, but the positive predictive values are lower both in the non-acute setting (0.44–0.57) and in the acute setting (0.66–0.67).^54,56–61 Therefore, the use of NPs is recommended for ruling-out HF, but not to establish the diagnosis.

There are numerous cardiovascular and non-cardiovascular causes of elevated NPs that may weaken their diagnostic utility in HF. Among them, AF, age and renal failure are the most important factors impeding the interpretation of NP measurements.⁵⁵ On the other hand, NP levels may be disproportionally low in obese patients⁶² (see also Section 12.2 and Table 12.3).

An abnormal electrocardiogram (ECG) increases the likelihood of the diagnosis of HF, but has low specificity.^18,46,63,64 Some abnormalities on the ECG provide information on aetiology (e.g. myocardial infarction), and findings on the ECG might provide indications for therapy (e.g. anticoagulation for AF, pacing for bradycardia, CRT if broadened QRS complex) (see Sections 8 and 10). HF is unlikely in patients presenting with a completely normal ECG (sensitivity 89%).⁴³ Therefore, the routine use of an ECG is mainly recommended to rule out HF.

Echocardiography is the most useful, widely available test in patients with suspected HF to establish the diagnosis. It provides immediate information on chamber volumes, ventricular systolic and diastolic function, wall thickness, valve function and pulmonary hypertension.^65–74 This information is crucial in establishing the diagnosis and in determining appropriate treatment (see Sections 5.2–5.4 for details on echocardiography).

The information provided by careful clinical evaluation and the above mentioned tests will permit an initial working diagnosis and treatment plan in most patients. Other tests are generally required only if the diagnosis remains uncertain (e.g. if echocardiographic images are suboptimal or an unusual cause of HF is suspected) (for details see Sections 5.5–5.10).

4.3 Algorithm for the diagnosis of heart failure

4.3.1 Algorithm for the diagnosis of heart failure in the non-acute setting

An algorithm for the diagnosis of HF in the non-acute setting is shown in Figure 4.1. The diagnosis of HF in the acute setting is discussed in Section 12.

Figure 4.1

Diagnostic algorithm for a diagnosis of heart failure of non-acute onset

BNP = B-type natriuretic peptide; CAD = coronary artery disease; HF = heart failure; MI = myocardial infarction; NT-proBNP = N-terminal pro-B type natriuretic peptide. ^aPatient reporting symptoms typical of HF (see Table 4.1).

^bNormal ventricular and atrial volumes and function. ^cConsider other causes of elevated natriuretic peptides (Table 12.3).

For patients presenting with symptoms or signs for the first time, non-urgently in primary care or in a hospital outpatient clinic (Table 4.1), the probability of HF should first be evaluated based on the patient's prior clinical history [e.g. coronary artery disease (CAD), arterial hypertension, diuretic use], presenting symptoms (e.g. orthopnoea), physical examination (e.g. bilateral oedema, increased jugular venous pressure, displaced apical beat) and resting ECG. If all elements are normal, HF is highly unlikely and other diagnoses need to be considered. If at least one element is abnormal, plasma NPs should be measured, if available, to identify those who need echocardiography (an echocardiogram is indicated if the NP level is above the exclusion threshold or if circulating NP levels cannot be assessed).^{55–60,75–78}

4.3.2 Diagnosis of heart failure with preserved ejection fraction

The diagnosis of HFpEF remains challenging. LVEF is normal and signs and symptoms for HF (Table 4.1) are often non-specific and do not discriminate well between HF and other clinical conditions. This section summarizes practical recommendations necessary for proper diagnosis of this clinical entity in clinical practice.

The diagnosis of chronic HFpEF, especially in the typical elderly patient with co-morbidities and no obvious signs of central fluid overload, is cumbersome and a validated gold standard is missing. To improve the specificity of diagnosing HFpEF, the clinical diagnosis needs to be supported by objective measures of cardiac dysfunction at rest or during exercise. The diagnosis of HFpEF requires the following conditions to be fulfilled (see Table 3.1): he initial assessment consists of a clinical diagnosis compatible with the algorithm presented above and the assessment of LVEF by echocardiography. The cut-off of 50% for a diagnosis of HFpEF is arbitrary; patients with an LVEF between 40 and 49% are often classified as HFpEF in clinical trials.⁷⁹ However, in the present guidelines, we define HFpEF as an LVEF ≥50% and consider patients with an LVEF between 40 and 49% as a grey area, which could be indicated as HFmrEF. Clinical signs and symptoms are similar for patients with HFrEF, HFmrEF and HFpEF. Typical demographics and co-morbidities are provided in Web Table 4.2. The resting ECG may reveal abnormalities such as AF, LV hypertrophy and repolarisation abnormalities. A normal ECG and/or plasma concentrations of BNP <35 pg/mL and/or NT-proBNP <125 pg/mL make a diagnosis of HFpEF, HFmrEF or HFrEF unlikely.

The presence of symptoms and/or signs of HF (see Table 4.1)
A ‘preserved’ EF (defined as LVEF ≥50% or 40–49% for HFmrEF)
Elevated levels of NPs (BNP >35 pg/mL and/or NT-proBNP >125 pg/mL)
Objective evidence of other cardiac functional and structural alterations underlying HF (for details, see below)
In case of uncertainty, a stress test or invasively measured elevated LV filling pressure may be needed to confirm the diagnosis (for details, see below).

The next step comprises an advanced workup in case of initial evidence of HFpEF/HFmrEF and consists of objective demonstration of structural and/or functional alterations of the heart as the underlying cause for the clinical presentation. Key structural alterations are a left atrial volume index (LAVI) >34 mL/m² or a left ventricular mass index (LVMI) ≥115 g/m² for males and ≥95 g/m² for females.^65,67,72 Key functional alterations are an E/e′ ≥13 and a mean e' septal and lateral wall <9 cm/s.^{65,67,70,72,80–84} Other (indirect) echocardiographically derived measurements are longitudinal strain or tricuspid regurgitation velocity (TRV).^72,82 An overview of normal and abnormal values for echocardiographic parameters related to diastolic function is presented in Web Table 4.3. Not all of the recommended values are identical to those published in previous guidelines, because of the inclusion of new data published in recent reports, in particular by Cabarello et al.⁷⁰

A diastolic stress test can be performed with echocardiography, typically using a semi-supine bicycle ergometer exercise protocol with assessment of LV (E/e′) and pulmonary artery pressures (TRV), systolic dysfunction (longitudinal strain), stroke volume and cardiac output changes with exercise.^85,86 Different dynamic exercise protocols are available, with semi-supine bicycle ergometry and echocardiography at rest and submaximal exercise being used most often.⁸⁵ Exercise-induced increases in E/e′ beyond diagnostic cut-offs (i.e. >13), but also other indirect measures of systolic and diastolic function, such as longitudinal strain or TRV, are used. Alternatively, invasive haemodynamics at rest with assessment of filling pressures [pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or left ventricular end diastolic pressure (LVEDP) ≥16 mmHg] followed by exercise haemodynamics if below these thresholds, with assessment of changes in filling pressures, pulmonary artery systolic pressure, stroke volume and cardiac output, can be performed.⁸⁷

The diagnosis of HFpEF in patients with AF is difficult. Since AF is associated with higher NP levels, the use of NT-proBNP or BNP for diagnosing HFpEF probably needs to be stratified by the presence of sinus rhythm (with lower cut-offs) vs. AF (higher cut-offs). LAVI is increased by AF, and functional parameters of diastolic dysfunction are less well established in AF, and other cut-off values probably apply. On the other hand, AF might be a sign of the presence of HFpEF, and patients with AF and HFpEF often have similar patient characteristics. In addition, patients with HFpEF and AF might have more advanced HF compared with patients with HFpEF and sinus rhythm.

Patients with HFpEF are a heterogeneous group with various underlying aetiologies and pathophysiological abnormalities. Based on specific suspected causes, additional tests can be performed (Web Table 4.4).^71,88–94 However, they can only be recommended if the results might affect management.

5. Cardiac imaging and other diagnostic tests

Cardiac imaging plays a central role in the diagnosis of HF and in guiding treatment. Of several imaging modalities available, echocardiography is the method of choice in patients with suspected HF, for reasons of accuracy, availability (including portability), safety and cost.^68,69,72 Echocardiography may be complemented by other modalities, chosen according to their ability to answer specific clinical questions and taking account of contraindications to and risks of specific tests.^71,73

In general, imaging tests should only be performed when they have a meaningful clinical consequence. The reliability of the outcomes is highly dependent on the imaging modality, the operator and centre experience and imaging quality. Normal values may vary with age, sex and imaging modality.

5.1 Chest X-ray

A chest X-ray is of limited use in the diagnostic work-up of patients with suspected HF. It is probably most useful in identifying an alternative, pulmonary explanation for a patient's symptoms and signs, i.e. pulmonary malignancy and interstitial pulmonary disease, although computed tomography (CT) of the chest is currently the standard of care. For the diagnosis of asthma or chronic obstructive pulmonary disease (COPD), pulmonary function testing with spirometry is needed. The chest X-ray may, however, show pulmonary venous congestion or oedema in a patient with HF, and is more helpful in the acute setting than in the non-acute setting.^49,64 It is important to note that significant LV dysfunction may be present without cardiomegaly on the chest X-ray.^49,64

5.2 Transthoracic echocardiography

Echocardiography is a term used here to refer to all cardiac ultrasound imaging techniques, including two-dimensional/three-dimensional echocardiography, pulsed and continuous wave Doppler, colour flow Doppler, tissue Doppler imaging (TDI) contrast echocardiography and deformation imaging (strain and strain rate).

Transthoracic echocardiography (TTE) is the method of choice for assessment of myocardial systolic and diastolic function of both left and right ventricles.

5.2.1 Assessment of left ventricular systolic function

For measurement of LVEF, the modified biplane Simpson's rule is recommended. LV end diastolic volume (LVEDV) and LV end systolic volume (LVESV) are obtained from apical four- and two-chamber views. This method relies on accurate tracing of endocardial borders. In case of poor image quality, contrast agents should be used to improve endocardial delineation.⁷² Measurement of regional wall motion abnormalities might be particularly relevant for patients suspected of CAD or myocarditis.

The Teichholz and Quinones methods of calculating LVEF from linear dimensions, as well as a measurement of fractional shortening, are not recommended, as they may result in inaccuracies, particularly in patients with regional LV dysfunction and/or LV remodelling. Three-dimensional echocardiography of adequate quality improves the quantification of LV volumes and LVEF and has the best accuracy compared with values obtained through CMR.⁹⁵

Doppler techniques allow the calculation of haemodynamic variables, such as stroke volume index and cardiac output, based on the velocity time integral at the LV outflow tract area.

In recent years, tissue Doppler parameters (S wave) and deformation imaging techniques (strain and strain rate) have been shown to be reproducible and feasible for clinical use, especially in detecting subtle abnormalities in systolic function in the preclinical stage; however, measurements may vary among vendors and software versions.⁷⁴

5.2.2 Assessment of left ventricular diastolic function

LV diastolic dysfunction is thought to be the underlying pathophysiological abnormality in patients with HFpEF and perhaps HFmrEF, and thus its assessment plays an important role in diagnosis. Although echocardiography is at present the only imaging technique that can allow for the diagnosis of diastolic dysfunction, no single echocardiography variable is sufficiently accurate to be used in isolation to make a diagnosis of LV diastolic dysfunction. Therefore, a comprehensive echocardiography examination incorporating all relevant two-dimensional and Doppler data is recommended (see Section 4.3.2).

5.2.3 Assessment of right ventricular function and pulmonary arterial pressure

An obligatory element of echocardiography examination is the assessment of right ventricle (RV) structure and function, including RV and right atrial (RA) dimensions, an estimation of RV systolic function and pulmonary arterial pressure. Among parameters reflecting RV systolic function, the following measures are of particular importance: tricuspid annular plane systolic excursion (TAPSE; abnormal TAPSE <17 mm indicates RV systolic dysfunction) and tissue Doppler-derived tricuspid lateral annular systolic velocity (s′) (s′ velocity <9.5 cm/s indicates RV systolic dysfunction).^72,96 Systolic pulmonary artery pressure is derived from an optimal recording of maximal tricuspid regurgitant jet and the tricuspid systolic gradient, together with an estimate of RA pressure on the basis of inferior vena cava (IVC) size and its breathing-related collapse.⁹⁷ RV size should be routinely assessed by conventional two-dimensional echocardiography using multiple acoustic windows, and the report should include both qualitative and quantitative parameters. In laboratories with experience in three-dimensional echocardiography, when knowledge of RV volumes may be clinically important, three-dimensional measurement of RV volumes is recommended.⁹⁵ Three-dimensional speckle tracking echocardiography may be an additional quantitative method to assess RV function in specialised centres.⁹⁸

5.3 Transoesophageal echocardiography

Transoesophageal echocardiography (TOE) is not needed in the routine diagnostic assessment of HF; however, it may be valuable in some clinical scenarios of patients with valve disease, suspected aortic dissection, suspected endocarditis or congenital heart disease and for ruling out intracavitary thrombi in AF patients requiring cardioversion. When the severity of mitral or aortic valve disease does not match the patient's symptoms using TTE alone, a TOE examination should be performed.

5.4 Stress echocardiography

Exercise or pharmacological stress echocardiography may be used for the assessment of inducible ischaemia and/or myocardium viability⁹⁹ and in some clinical scenarios of patients with valve disease (e.g. dynamic mitral regurgitation, low-flow–low-gradient aortic stenosis).^99,100 There are also suggestions that stress echocardiography may allow the detection of diastolic dysfunction related to exercise exposure in patients with exertional dyspnoea, preserved LVEF and inconclusive diastolic parameters at rest.^85,86

5.5 Cardiac magnetic resonance

CMR is acknowledged as the gold standard for the measurements of volumes, mass and EF of both the left and right ventricles. It is the best alternative cardiac imaging modality for patients with non-diagnostic echocardiographic studies (particularly for imaging of the right heart) and is the method of choice in patients with complex congenital heart diseases.^91,101,102

CMR is the preferred imaging method to assess myocardial fibrosis using late gadolinium enhancement (LGE) along with T1 mapping and can be useful for establishing HF aetiology.^91,103 For example, CMR with LGE allows differentiation between ischaemic and non-ischaemic origins of HF and myocardial fibrosis/scars can be visualized. In addition, CMR allows the characterization of myocardial tissue of myocarditis, amyloidosis, sarcoidosis, Chagas disease, Fabry disease non-compaction cardiomyopathy and haemochromatosis.^{91,101,103,104}

CMR may also be used for the assessment of myocardial ischaemia and viability in patients with HF and CAD (considered suitable for coronary revascularization). However, limited evidence from RCTs has failed to show that viability assessed by CMR or other means identified patients who obtained clinical benefit from revascularization.^105–107

Clinical limitations of CMR include local expertise, lower availability and higher costs compared with echocardiography, uncertainty about safety in patients with metallic implants (including cardiac devices) and less reliable measurements in patients with tachyarrhythmias. Claustrophobia is an important limitation for CMR. Linear gadolinium-based contrast agents are contraindicated in individuals with a glomerular filtration rate (GFR) <30 mL/min/1.73m², because they may trigger nephrogenic systemic fibrosis (this may be less of a concern with newer cyclic gadolinium-based contrast agents).¹⁰⁸

5.6 Single-photon emission computed tomography and radionuclide ventriculography

Single-photon emission CT (SPECT) may be useful in assessing ischaemia and myocardial viability.¹⁰⁹ Gated SPECT can also yield information on ventricular volumes and function, but exposes the patient to ionizing radiation. 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy may be useful for the detection of transthyretin cardiac amyloidosis.¹¹⁰

5.7 Positron emission tomography

Positron emission tomography (PET) (alone or with CT) may be used to assess ischaemia and viability, but the flow tracers (N-13 ammonia or O-15 water) require an on-site cyclotron.^92,111 Rubidium is an alternative tracer for ischaemia testing with PET, which can be produced locally at relatively low cost. Limited availability, radiation exposure and cost are the main limitations.

5.8 Coronary angiography

Indications for coronary angiography in patients with HF are in concordance with the recommendations of other relevant ESC guidelines.^112–114 Coronary angiography is recommended in patients with HF who suffer from angina pectoris recalcitrant to medical therapy,¹¹⁵ provided the patient is otherwise suitable for coronary revascularization. Coronary angiography is also recommended in patients with a history of symptomatic ventricular arrhythmia or aborted cardiac arrest. Coronary angiography should be considered in patients with HF and intermediate to high pre-test probability of CAD and the presence of ischaemia in non-invasive stress tests in order to establish the ischaemic aetiology and CAD severity.

5.9 Cardiac computed tomography

The main use of cardiac CT in patients with HF is as a non-invasive means to visualize the coronary anatomy in patients with HF with low intermediate pre-test probability of CAD or those with equivocal non-invasive stress tests in order to exclude the diagnosis of CAD, in the absence of relative contraindications. However, the test is only required when its results might affect a therapeutic decision.

The most important clinical indications for the applicability of certain imaging methods in patients with suspected or confirmed HF are shown in the recommendations table.

Recommendations for cardiac imaging in patients with suspected or established heart failure

AHF = acute heart failure; CAD = coronary artery disease; CMR = cardiac magnetic resonance; CRT = cardiac resynchronization therapy; CT = computed tomography; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFmrEF = heart failure with mid-range ejection fraction; HFrEF = heart failure with reduced ejection fraction; ICD = implantable cardioverter-defibrillator; LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction; PET = positron emission tomography; SPECT = single-photon emission computed tomography; TTE = transthoracic echocardiography.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

5.10 Other diagnostic tests

Comprehensive assessment of patients with HF comprises, besides medical history and physical examination, including adequate imaging techniques, a set of additional diagnostic tests, i.e. laboratory variables, ECG, chest X-ray, exercise testing, invasive haemodynamic assessments and endomyocardial biopsy. The major typical indications are summarized in the recommendations table for diagnostic tests in patients with HF. Although there is extensive research on biomarkers in HF (e.g. ST2, galectin 3, copeptin, adrenomedullin), there is no definite evidence to recommend them for clinical practice.

Recommendations for diagnostic tests in patients with heart failure

AHF = acute heart failure; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BNP = B-type natriuretic peptide; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EMB = endomyocardial biopsy; GFR = glomerular filtration rate; GGTP = gamma-glutamyl transpeptidase; HbA1c = glycated haemoglobin; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; QRS = Q, R, and S waves (combination of three of the graphical deflections); TIBC = total iron-binding capacity; TSAT = transferrin saturation; TSH = thyroid-stimulating hormone; WBC = white blood cell.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

5.10.1 Genetic testing in heart failure

Molecular genetic analysis in patients with cardiomyopathies is recommended when the prevalence of detectable mutations is sufficiently high and consistent to justify routine targeted genetic screening. Recommendations for genetic testing in patients with HF are based on the position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.⁹⁴ In most patients with a definite clinical diagnosis of HF, there is no confirmatory role for routine genetic testing to establish the diagnosis. Genetic counselling is recommended in patients with HCM, idiopathic DCM and ARVC. Restrictive cardiomyopathy and isolated non-compaction cardiomyopathies are of a possible genetic origin and should also be considered for genetic testing.

HCM is mostly inherited as an autosomal dominant disease with variable expressivity and age-related penetrance. Currently, more than 20 genes and 1400 mutations have been identified, most of which are located in the sarcomere genes encoding cardiac β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3).^88,122

DCM is idiopathic in 50% of cases, about one-third of which are hereditary. There are already more than 50 genes identified that are associated with DCM. Many genes are related to the cytoskeleton. The most frequent ones are titin (TTN), lamin (LMNA) and desmin (DES).^88,123

ARVC is hereditary in most cases and is caused by gene mutations that encode elements of the desmosome. Desmosomal gene mutations explain 50% of cases and 10 genes are currently associated with the disease.¹²⁴

Counselling should be performed by someone with sufficient knowledge of the specific psychological, social and medical implications of a diagnosis. Determination of the genotype is important, since some forms [e.g. mutations in LMNA and phospholamban (PLN)] are related to a poorer prognosis. DNA analysis could also be of help to establish the diagnosis of rare forms, such as mitochondrial cardiomyopathies. Screening of first-degree relatives for early detection is recommended from early adolescence onwards, although earlier screening may be considered depending on the age of disease onset in other family members.

Recently, the MOGE(S) classification of inherited cardiomyopathies has been proposed, which includes the morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), aetiological annotation (E), including genetic defect or underlying disease/substrate, and the functional status (S) of the disease.¹²⁵

6. Delaying or preventing the development of overt heart failure or preventing death before the onset of symptoms

There is considerable evidence that the onset of HF may be delayed or prevented through interventions aimed at modifying risk factors for HF or treating asymptomatic LV systolic dysfunction (see recommendations table). Many trials show that control of hypertension will delay the onset of HF and some also show that it will prolong life.^126–129 Different antihypertensive drugs [diuretics, ACEIs, angiotensin receptor blockers (ARBs), beta-blockers] have been shown to be effective, especially in older people, both in patients with and without a history of myocardial infarction.^126–128 Along with the ongoing discussion on optimal target blood pressure values in hypertensive non-diabetic subjects, the recent SPRINT study has already demonstrated that treating hypertension to a lower goal [systolic blood pressure (SBP) <120 mmHg vs. <140 mmHg] in older hypertensive subjects (≥75 years of age) or high-risk hypertensive patients reduces the risk of cardiovascular disease, death and hospitalization for HF.¹²⁹

Recently, empaglifozin (an inhibitor of sodium-glucose cotransporter 2), has been shown to improve outcomes (including the reduction of mortality and HF hospitalizations) in patients with type 2 diabetes.¹³⁰ Other hypoglycaemic agents have not been shown convincingly to reduce the risk of cardiovascular events and may increase the risk of HF. Intensification of hypoglycaemic therapy to drive down glycated haemoglobin (HbA1c) with agents other than empagliflozin does not reduce the risk of developing HF (for details see Section 11.6 on diabetes).

Although smoking cessation has not been shown to reduce the risk of developing HF, the epidemiological associations with the development of cardiovascular disease¹³¹ suggest that such advice, if followed, would be beneficial.

The association between alcohol intake and the risk of developing de novo HF is U-shaped, with the lowest risk with modest alcohol consumption (up to 7 drinks/week).^132–134 Greater alcohol intake may trigger the development of toxic cardiomyopathy, and when present, complete abstention from alcohol is recommended.

An inverse relationship between physical activity and the risk of HF has been reported. A recent meta-analysis found that doses of physical activity in excess of the guideline recommended minimal levels may be required for more substantial reductions in HF risk.¹³⁵

It has been shown that among subjects ≥40 years of age with either cardiovascular risk factors or cardiovascular disease (but neither asymptomatic LV dysfunction nor overt HF), BNP-driven collaborative care between the primary care physician and the specialist cardiovascular centre may reduce the combined rates of LV systolic dysfunction and overt HF.¹³⁶

Statins reduce the rate of cardiovascular events and mortality; there is also reasonable evidence that they prevent or delay the onset of HF.^137–140 Neither aspirin nor other antiplatelet agents, nor revascularization, have been shown to reduce the risk of developing HF or mortality in patients with stable CAD. Obesity is also a risk factor for HF,¹⁴¹ but the impact of treatments of obesity on the development of HF is unknown.

In patients with CAD, without LV systolic dysfunction or HF, ACEIs prevent or delay the onset of HF and reduce cardiovascular and all-cause mortality, although the benefit may be small in the contemporary setting, especially in patients receiving aspirin.¹⁴² Up-titration of renin–angiotensin system antagonists and beta-blockers to maximum tolerated dosages may improve outcomes, including HF, in patients with increased plasma concentrations of NPs.^136,143

A primary percutaneous coronary intervention (PCI) at the earliest phase of an ST segment elevation myocardial infarction (STEMI) to reduce infarct size decreases the risk of developing a substantial reduction in LVEF and subsequent development of HFrEF.¹¹² Initiation of an ACEI, a beta-blocker and an MRA immediately after a myocardial infarction, especially when it is associated with LV systolic dysfunction, reduces the rate of hospitalization for HF and mortality,^144–148 as do statins.^137–139

In asymptomatic patients with chronically reduced LVEF, regardless of its aetiology, an ACEI can reduce the risk of HF requiring hospitalization.^5,144,145 This has not yet been shown for beta-blockers or MRAs.

In patients with asymptomatic LV systolic dysfunction (LVEF <30%) of ischaemic origin who are ≥40 days after an AMI, an implantable cardioverter-defibrillator (ICD) is recommended to prolong life.¹⁴⁹

Recommendations to prevent or delay the development of overt heart failure or prevent death before the onset of symptoms

ACEI = angiotensin-converting enzyme inhibitor; CAD = coronary artery disease; HF = heart failure; ICD = implantable cardioverter-defibrillator; LV = left ventricular; LVEF = left ventricular ejection fraction; OMT = optimal medical therapy

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

7. Pharmacological treatment of heart failure with reduced ejection fraction

7.1 Objectives in the management of heart failure

The goals of treatment in patients with HF are to improve their clinical status, functional capacity and quality of life, prevent hospital admission and reduce mortality. The fact that several drugs for HF have shown detrimental effects on long-term outcomes, despite showing beneficial effects on shorter-term surrogate markers, has led regulatory bodies and clinical practice guidelines to seek mortality/morbidity data for approving/recommending therapeutic interventions for HF. However, it is now recognized that preventing HF hospitalization and improving functional capacity are important benefits to be considered if a mortality excess is ruled out.^159–161

Figure 7.1 shows a treatment strategy for the use of drugs (and devices) in patients with HFrEF. The recommendations for each treatment are summarized below.

$Therapeutic algorithm for a patient with symptomatic heart failure with reduced ejection fraction. Green indicates a class I recommendation; yellow indicates a class IIa recommendation. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BNP = B-type natriuretic peptide; CRT = cardiac resynchronization therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; H-ISDN = hydralazine and isosorbide dinitrate; HR = heart rate; ICD = implantable cardioverter defibrillator; LBBB = left bundle branch block; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; MR = mineralocorticoid receptor; NT-proBNP = N-terminal pro-B type natriuretic peptide; NYHA = New York Heart Association; OMT = optimal medical therapy; VF = ventricular fibrillation; VT = ventricular tachycardia. aSymptomatic = NYHA Class II-IV. bHFrEF = LVEF <40%. cIf ACE inhibitor not tolerated/contra-indicated, use ARB. dIf MR antagonist not tolerated/contra-indicated, use ARB. eWith a hospital admission for HF within the last 6 months or with elevated natriuretic peptides (BNP > 250 pg/ml or NTproBNP > 500 pg/ml in men and 750 pg/ml in women). fWith an elevated plasma natriuretic peptide level (BNP ≥ 150 pg/mL or plasma NT-proBNP ≥ 600 pg/mL, or if HF hospitalization within recent 12 months plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL). gIn doses equivalent to enalapril 10 mg b.i.d. hWith a hospital admission for HF within the previous year. iCRT is recommended if QRS ≥ 130 msec and LBBB (in sinus rhythm). jCRT should/may be considered if QRS ≥ 130 msec with non-LBBB (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individualized decision). For further details, see Sections 7 and 8 and corresponding web pages.$

Figure 7.1

Therapeutic algorithm for a patient with symptomatic heart failure with reduced ejection fraction. Green indicates a class I recommendation; yellow indicates a class IIa recommendation. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BNP = B-type natriuretic peptide; CRT = cardiac resynchronization therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; H-ISDN = hydralazine and isosorbide dinitrate; HR = heart rate; ICD = implantable cardioverter defibrillator; LBBB = left bundle branch block; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; MR = mineralocorticoid receptor; NT-proBNP = N-terminal pro-B type natriuretic peptide; NYHA = New York Heart Association; OMT = optimal medical therapy; VF = ventricular fibrillation; VT = ventricular tachycardia. ^aSymptomatic = NYHA Class II-IV. ^bHFrEF = LVEF <40%. ^cIf ACE inhibitor not tolerated/contra-indicated, use ARB. ^dIf MR antagonist not tolerated/contra-indicated, use ARB. ^eWith a hospital admission for HF within the last 6 months or with elevated natriuretic peptides (BNP > 250 pg/ml or NTproBNP > 500 pg/ml in men and 750 pg/ml in women). ^fWith an elevated plasma natriuretic peptide level (BNP ≥ 150 pg/mL or plasma NT-proBNP ≥ 600 pg/mL, or if HF hospitalization within recent 12 months plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL). ^gIn doses equivalent to enalapril 10 mg b.i.d. ^hWith a hospital admission for HF within the previous year. ⁱCRT is recommended if QRS ≥ 130 msec and LBBB (in sinus rhythm). ^jCRT should/may be considered if QRS ≥ 130 msec with non-LBBB (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individualized decision). For further details, see Sections 7 and 8 and corresponding web pages.

Neuro-hormonal antagonists (ACEIs, MRAs and beta-blockers) have been shown to improve survival in patients with HFrEF and are recommended for the treatment of every patient with HFrEF, unless contraindicated or not tolerated. A new compound (LCZ696) that combines the moieties of an ARB (valsartan) and a neprilysin (NEP) inhibitor (sacubitril) has recently been shown to be superior to an ACEI (enalapril) in reducing the risk of death and of hospitalization for HF in a single trial with strict inclusion/exclusion criteria.¹⁶² Sacubitril/valsartan is therefore recommended to replace ACEIs in ambulatory HFrEF patients who remain symptomatic despite optimal therapy and who fit these trial criteria. ARBs have not been consistently proven to reduce mortality in patients with HFrEF and their use should be restricted to patients intolerant of an ACEI or those who take an ACEI but are unable to tolerate an MRA. Ivabradine reduces the elevated heart rate often seen in HFrEF and has also been shown to improve outcomes, and should be considered when appropriate.

The above medications should be used in conjunction with diuretics in patients with symptoms and/or signs of congestion. The use of diuretics should be modulated according to the patient's clinical status.

The key evidence supporting the recommendations in this section is given in Web Table 7.1. The recommended doses of these disease-modifying medications are given in Table 7.2. The recommendations given in Sections 7.5 and 7.6 summarize drugs that should be avoided or used with caution in patients with HFrEF.

Table 7.2

Evidence-based doses of disease-modifying drugs in key randomized trials in heart failure with reduced ejection fraction (or after myocardial infarction)

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker;

ARNI = angiotensin receptor neprilysin inhibitor; b.i.d. = bis in die (twice daily); MRA = mineralocorticoid receptor antagonist; o.d. = omne in die (once daily); t.i.d. = ter in die (three times a day).

^aIndicates an ACE-I where the dosing target is derived from post-myocardial infarction trials.

^bIndicates drugs where a higher dose has been shown to reduce morbidity/mortality compared with a lower dose of the same drug, but there is no substantive randomized, placebo-controlled trial and the optimum dose is uncertain.

^cIndicates a treatment not shown to reduce cardiovascular or all-cause mortality in patients with heart failure (or shown to be non-inferior to a treatment that does).

^dA maximum dose of 50 mg twice daily can be administered to patients weighing over 85 kg.

7.2 Treatments recommended in all symptomatic patients with heart failure with reduced ejection fraction

7.2.1 Angiotensin-converting enzyme inhibitors

ACEIs have been shown to reduce mortality and morbidity in patients with HFrEF^{2,5,163–165} and are recommended unless contraindicated or not tolerated in all symptomatic patients. ACEIs should be up-titrated to the maximum tolerated dose in order to achieve adequate inhibition of the renin–angiotensin–aldosterone system (RAAS). There is evidence that in clinical practice the majority of patients receive suboptimal doses of ACEI.¹⁶⁶ ACEIs are also recommended in patients with asymptomatic LV systolic dysfunction to reduce the risk of HF development, HF hospitalization and death (see Section 6).

Pharmacological treatments indicated in patients with symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction

ACEI = angiotensin-converting enzyme inhibitor; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

^dOr ARB if ACEI is not tolerated/contraindicated

Practical guidance on how to use ACE inhibitors is given in Web Table 7.4.

7.2.2 Beta-blockers

Beta-blockers reduce mortality and morbidity in symptomatic patients with HFrEF, despite treatment with an ACEI and, in most cases, a diuretic,^{167,168,170,172,173} but have not been tested in congested or decompensated patients. There is consensus that beta-blockers and ACEIs are complementary, and can be started together as soon as the diagnosis of HFrEF is made. There is no evidence favouring the initiation of treatment with a beta-blocker before an ACEI has been started.¹⁷⁶ Beta-blockers should be initiated in clinically stable patients at a low dose and gradually up-titrated to the maximum tolerated dose. In patients admitted due to acute HF (AHF) beta-blockers should be cautiously initiated in hospital, once the patient is stabilized.

An individual patient data meta-analysis of all the major beta-blocker trials in HFrEF has shown no benefit on hospital admissions and mortality in the subgroup of patients with HFrEF who are in AF.¹⁷⁷ However, since this is a retrospective subgroup analysis, and because beta-blockers did not increase the risk, the guideline committee decided not to make a separate recommendation according to heart rhythm. Beta-blockers should be considered for rate control in patients with HFrEF and AF, especially in those with high heart rate (see Section 10.1 for details).

Beta-blockers are recommended in patients with a history of myocardial infarction and asymptomatic LV systolic dysfunction to reduce the risk of death (see Section 6).

Practical guidance on how to use beta-blockers is given in Web Table 7.5.

7.2.3 Mineralocorticoid/aldosterone receptor antagonists

MRAs (spironolactone and eplerenone) block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormone (e.g. corticosteroids, androgens) receptors. Spironolactone or eplerenone are recommended in all symptomatic patients (despite treatment with an ACEI and a beta-blocker) with HFrEF and LVEF ≤35%, to reduce mortality and HF hospitalization.^174,175

Caution should be exercised when MRAs are used in patients with impaired renal function and in those with serum potassium levels >5.0 mmol/L. Regular checks of serum potassium levels and renal function should be performed according to clinical status.

Practical guidance on how to use MRAs is given in Web Table 7.6.

7.3 Other treatments recommended in selected symptomatic patients with heart failure with reduced ejection fraction

7.3.1 Diuretics

Diuretics are recommended to reduce the signs and symptoms of congestion in patients with HFrEF, but their effects on mortality and morbidity have not been studied in RCTs. A Cochrane meta-analysis has shown that in patients with chronic HF, loop and thiazide diuretics appear to reduce the risk of death and worsening HF compared with placebo, and compared with an active control, diuretics appear to improve exercise capacity.^178,179

Loop diuretics produce a more intense and shorter diuresis than thiazides, although they act synergistically and the combination may be used to treat resistant oedema. However, adverse effects are more likely and these combinations should only be used with care. The aim of diuretic therapy is to achieve and maintain euvolaemia with the lowest achievable dose. The dose of the diuretic must be adjusted according to the individual needs over time. In selected asymptomatic euvolaemic/hypovolaemic patients, the use of a diuretic drug might be (temporarily) discontinued. Patients can be trained to self-adjust their diuretic dose based on monitoring of symptoms/signs of congestion and daily weight measurements.

Doses of diuretics commonly used to treat HF are provided in Table 7.3. Practical guidance on how to use diuretics is given in Web Table 7.7.

Table 7.3

Doses of diuretics commonly used in patients with heart failure

ACE-I = angiontensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker.

^aOral or intravenous; dose might need to be adjusted according to volume status/weight; excessive doses may cause renal impairment and ototoxicity.

^bDo not use thiazides if estimated glomerular filtration rate <30 mL/min/1.73 m² , except when prescribed synergistically with loop diuretics.

^clndapamide is a non-thiazide sulfonamide.

^dA mineralocorticoid antagonist (MRA) i.e. spironolactone/eplerenone is always preferred. Amiloride and triamterene should not be combined with an MRA.

Other pharmacological treatments recommended in selected patients with symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BNP = B-type natriuretic peptide; bpm = beats per minute; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro-B type natriuretic peptide; NYHA = New York Heart Association; PUFA = polyunsaturated fatty acid. OMT = optimal medical therapy (for HFrEF this mostly comprises an ACEI or sacubitril/valsartan, a beta-blocker and an MRA).

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

^dPatient should have elevated natriuretic peptides (plasma BNP ≥150 pg/mL or plasma NT-proBNP ≥600 pg/mL, or if HF hospitalization within the last 12 months, plasma BNP ≥100 pg/mL or plasma NT-proBNP ≥400 pg/mL) and able to tolerate enalapril 10 mg b.i.d.

^eApplies only to preparation studied in cited trial.

7.3.2 Angiotensin receptor neprilysin inhibitor

A new therapeutic class of agents acting on the RAAS and the neutral endopeptidase system has been developed [angiotensin receptor neprilysin inhibitor (ARNI)]. The first in class is LCZ696, which is a molecule that combines the moieties of valsartan and sacubitril (neprilysin inhibitor) in a single substance. By inhibiting neprilysin, the degradation of NPs, bradykinin and other peptides is slowed. High circulating A-type natriuretic peptide (ANP) and BNP exert physiologic effects through binding to NP receptors and the augmented generation of cGMP, thereby enhancing diuresis, natriuresis and myocardial relaxation and anti-remodelling. ANP and BNP also inhibit renin and aldosterone secretion. Selective AT1-receptor blockade reduces vasoconstriction, sodium and water retention and myocardial hypertrophy.^187,188

A recent trial investigated the long-term effects of sacubitril/valsartan compared with an ACEI (enalapril) on morbidity and mortality in patients with ambulatory, symptomatic HFrEF with LVEF ≤40% (this was changed to ≤35% during the study), elevated plasma NP levels (BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL or, if they had been hospitalized for HF within the previous 12 months, BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL), and an estimated GFR (eGFR) ≥30 mL/min/1.73 m² of body surface area, who were able to tolerate separate treatments periods with enalapril (10 mg b.i.d.) and sacubitril/valsartan (97/103 mg b.i.d.) during a run-in period.¹⁶² In this population, sacubitril/valsartan (97/103 mg b.i.d.) was superior to ACEI (enalapril 10 mg b.i.d.) in reducing hospitalizations for worsening HF, cardiovascular mortality and overall mortality.¹⁶² Sacubitril/valsartan is therefore recommended in patients with HFrEF who fit this profile.

Despite the superiority of sacubitril/valsartan over enalapril in the PARADIGM-HF trial, some relevant safety issues remain when initiating therapy with this drug in clinical practice. Symptomatic hypotension was more often present in the sacubitril/valsartan group (in those ≥75 years of age, it affected 18% in the sacubitril/valsartan group vs. 12% in the enalapril group), although there was no increase in the rate of discontinuation.¹⁶² The risk of angioedema in the trial was reduced by recruiting only those who tolerated therapy with enalapril 10 mg b.i.d. and an sacubitril/valsartan during an active run-in phase of 5–9 weeks (it resulted in a 0.4% rate of angioedema in sacubitril/valsartan group vs. 0.2% in an enalapril group). Also, the number of African American patients, who are at a higher risk of angioedema, was relatively small in this study. To minimize the risk of angioedema caused by overlapping ACE and neprilysin inhibition, the ACEI should be withheld for at least 36 h before initiating sacubitril/valsartan. Combined treatment with an ACEI (or ARB) and sacubitril/valsartan is contraindicated. There are additional concerns about its effects on the degradation of beta-amyloid peptide in the brain, which could theoretically accelerate amyloid deposition.^189–191 However, a recent small 14-day study with healthy subjects showed elevation of the beta-amyloid protein in the soluble rather than the aggregable form, which if confirmed over longer time periods in patients with HFrEF may indicate the cerebral safety of sacubitril/valsartan.¹⁹² Long-term safety needs to be addressed.

7.3.3 I_f-channel inhibitor

Ivabradine slows the heart rate through inhibition of the I_f channel in the sinus node and therefore should only be used for patients in sinus rhythm. Ivabradine reduced the combined endpoint of mortality or hospitalization for HF in patients with symptomatic HFrEF or LVEF ≤35%, in sinus rhythm and with a heart rate ≥70 beats per minute (bpm) who had been hospitalized for HF within the previous 12 months, receiving treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose), an ACEI (or ARB) and an MRA.¹⁸⁰ The European Medicines Agency (EMA) approved ivabradine for use in Europe in patients with HFrEF with LVEF ≤35% and in sinus rhythm with a resting heart rate ≥75 bpm, because in this group ivabradine conferred a survival benefit¹⁹³ based on a retrospective subgroup analysis requested by the EMA.

Practical guidance on how to use ivabradine is given in Web Table 7.8.

Table 11.1

Importance of co-morbidities in patients with heart failure

HF = heart failure; COPD = chronic obstructive pulmonary disease; HFrEF = heart failure with reduced ejection fraction; NSAIDs = non-steroidal anti-inflammatory drugs.

7.3.4 Angiotensin II type I receptor blockers

ARBs are recommended only as an alternative in patients intolerant of an ACEI.¹⁸² Candesartan has been shown to reduce cardiovascular mortality.¹⁸² Valsartan showed an effect on hospitalization for HF (but not on all-cause hospitalizations) in patients with HFrEF receiving background ACEIs.¹⁹⁴

The combination of ACEI/ARB for HFrEF was reviewed by the EMA, which suggested that benefits are thought to outweigh risks only in a select group of patients with HFrEF in whom other treatments are unsuitable. Therefore, ARBs are indicated for the treatment of HFrEF only in patients who cannot tolerate an ACEI because of serious side effects. The combination of ACEI/ARB should be restricted to symptomatic HFrEF patients receiving a beta-blocker who are unable to tolerate an MRA, and must be used under strict supervision.

7.3.5 Combination of hydralazine and isosorbide dinitrate

There is no clear evidence to suggest the use of this fixed-dose combination therapy in all patients with HFrEF. Evidence on the clinical utility of this combination is scanty and comes from one relatively small RCT conducted exclusively in men and before ACEIs or beta-blockers were used to treat HF.¹⁸⁴ A subsequent RCT conducted in self-identified black patients (defined as being of African descent) showed that addition of the combination of hydralazine and isosorbide dinitrate to conventional therapy (ACEI, beta-blocker and MRA) reduced mortality and HF hospitalizations in patients with HFrEF and NYHA Classes III–IV.¹⁸³ The results of this study are difficult to translate to patients of other racial or ethnic origins.

Additionally, a combination of hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who can tolerate neither ACEI nor ARB (or they are contraindicated) to reduce mortality. However, this recommendation is based on the results of the Veterans Administration Cooperative Study, which recruited symptomatic HFrEF patients who received only digoxin and diuretics.¹⁸⁴

7.4 Other treatments with less certain benefits in symptomatic patients with heart failure with reduced ejection fraction

This section describes treatments that have shown benefits in terms of symptomatic improvement, reduction in HF hospitalizations or both, and are useful additional treatments in patients with HFrEF.

7.4.1 Digoxin and other digitalis glycosides

Digoxin may be considered in patients in sinus rhythm with symptomatic HFrEF to reduce the risk of hospitalization (both all-cause and HF hospitalizations),¹⁸⁵ although its effect on top of beta-blockers has never been tested. The effects of digoxin in patients with HFrEF and AF have not been studied in RCTs, and recent studies have suggested potentially higher risk of events (mortality and HF hospitalization) in patients with AF receiving digoxin.^195,196 However, this remains controversial, as another recent meta-analysis concluded on the basis of non-RCTs that digoxin has no deleterious effect on mortality in patients with AF and concomitant HF, most of whom had HFrEF.¹⁹⁷

In patients with symptomatic HF and AF, digoxin may be useful to slow a rapid ventricular rate, but it is only recommended for the treatment of patients with HFrEF and AF with rapid ventricular rate when other therapeutic options cannot be pursued.^{196,198–201} Of note, the optimal ventricular rate for patients with HF and AF has not been well established, but the prevailing evidence suggests that strict rate control might be deleterious. A resting ventricular rate in the range of 70–90 bpm is recommended based on current opinion, although one trial suggested that a resting ventricular rate of up to 110 bpm might still be acceptable.²⁰² This should be tested and refined by further research.

Digitalis should always be prescribed under specialist supervision. Given its distribution and clearance, caution should be exerted in females, in the elderly and in patients with reduced renal function. In the latter patients, digitoxin should be preferred.

7.4.2 n-3 polyunsaturated fatty acids

n-3 polyunsaturated fatty acids (n-3 PUFAs) have shown a small treatment effect in a large RCT.¹⁸⁶ n-3 PUFA preparations differ in composition and dose. Only preparations with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters of at least 85% (850 mg/g) have shown an effect on the cumulative endpoint of cardiovascular death and hospitalization. No effect of n-3 PUFA preparations containing <850 mg/g has been shown in either HFrEF or post-myocardial infarction.²⁰³ n-3 PUFA preparations containing 850–882 mg of EPA and DHA as ethyl esters in the average ratio of 1 : 1.2 may be considered as an adjunctive therapy in patients with symptomatic HFrEF who are already receiving optimized recommended therapy with an ACEI (or ARB), a beta-blocker and an MRA.

7.5 Treatments not recommended (unproven benefit) in symptomatic patients with heart failure with reduced ejection fraction

7.5.1 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (‘statins’)

Although statins reduce mortality and morbidity in patients with atherosclerotic disease, statins are not effective in improving the prognosis in patients with HFrEF. Most statin trials excluded patients with HF (because it was uncertain that they would benefit).²⁰⁴ The two major trials that studied the effect of statin treatment in patients with chronic HF did not demonstrate any evidence of benefit.²⁰⁵ Therefore, evidence does not support the initiation of statins in most patients with chronic HF. However, in patients who already receive a statin because of underlying CAD or/and hyperlipidaemia, a continuation of this therapy should be considered.

7.5.2 Oral anticoagulants and antiplatelet therapy

Other than in patients with AF (both HFrEF and HFpEF), there is no evidence that an oral anticoagulant reduces mortality/morbidity compared with placebo or aspirin.^206,207 Studies testing the non-vitamin K antagonist oral anticoagulants (NOACs) in patients with HFrEF are currently ongoing. Patients with HFrEF receiving oral anticoagulation because of concurrent AF or risk of venous thromboembolism should continue anticoagulation. Detailed information is provided in Section 10.1.

Similarly, there is no evidence on the benefits of antiplatelet drugs (including acetylsalicylic acid) in patients with HF without accompanying CAD, whereas there is a substantial risk of gastrointestinal bleeding, particularly in elderly subjects, related with this treatment.

7.5.3 Renin inhibitors

Aliskiren (direct renin inhibitor) failed to improve outcomes for patients hospitalized for HF at 6 months or 12 months in one study²⁰⁸ and is not presently recommended as an alternative to an ACEI or ARB.

Treatments (or combinations of treatments) that may cause harm in patients with symptomatic (NYHA Class II–IV) heart failure with reduced ejection fraction

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; COX-2 inhibitor = cyclooxygenase-2 inhibitor; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; NSAIDs = non-steroidal anti-inflammatory drugs.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations

7.6 Treatments not recommended (believed to cause harm) in symptomatic patients with heart failure with reduced ejection fraction

7.6.1 Calcium-channel blockers

Non-dihydropyridine calcium-channel blockers (CCBs) are not indicated for the treatment of patients with HFrEF. Diltiazem and verapamil have been shown to be unsafe in patients with HFrEF.²¹⁴

There is a variety of dihydropyridine CCBs; some are known to increase sympathetic tone and they may have a negative safety profile in HFrEF. There is only evidence on safety for amlodipine²¹⁵ and felodipine²¹⁶ in patients with HFrEF, and they can be used only if there is a compelling indication in patients with HFrEF.

8. Non-surgical device treatment of heart failure with reduced ejection fraction

This section provides recommendations on the use of ICDs and CRT. Currently, the evidence is considered insufficient to support specific guideline recommendations for other therapeutic technologies, including baroreflex activation therapy,²¹⁷ vagal stimulation,²¹⁸ diaphragmatic pacing^219,220 and cardiac contractility modulation;^221,222 further research is required. Implantable devices to monitor arrhythmias or haemodynamics are discussed elsewhere in these guidelines.

8.1 Implantable cardioverter-defibrillator

A high proportion of deaths among patients with HF, especially those with milder symptoms, occur suddenly and unexpectedly. Many of these are due to electrical disturbances, including ventricular arrhythmias, bradycardia and asystole, although some are due to coronary, cerebral or aortic vascular events. Treatments that improve or delay the progression of cardiovascular disease will reduce the annual rate of sudden death, but they may have little effect on lifetime risk and will not treat arrhythmic events when they occur. ICDs are effective in preventing bradycardia and correcting potentially lethal ventricular arrhythmias. Some antiarrhythmic drugs might reduce the rate of tachyarrhythmias and sudden death, but they do not reduce overall mortality and may increase it.

Recommendations for implantable cardioverter-defibrillator in patients with heart failure

CAD = coronary artery disease; CRT = cardiac resynchronization therapy; DCM = dilated cardiomyopathy; HF = heart failure; ICD = implantable cardioverter-defibrillator; IHD = ischaemic heart disease; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NYHA = New York Heart Association, OMT = optimal medical therapy.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

8.1.1 Secondary prevention of sudden cardiac death

Compared with amiodarone treatment, ICDs reduce mortality in survivors of cardiac arrest and in patients who have experienced sustained symptomatic ventricular arrhythmias. An ICD is recommended in such patients when the intent is to increase survival; the decision to implant should take into account the patient's view and their quality of life, the LVEF (survival benefit is uncertain when the LVEF is >35%) and the absence of other diseases likely to cause death within the following year.^223–225

8.1.2 Primary prevention of sudden cardiac death

Although amiodarone may have reduced mortality in older trials of HF,^242,243 contemporary studies conducted since the widespread introduction of beta-blockers suggest that it does not reduce mortality in patients with HFrEF.^227,244,245 Dronedarone^246,247 and class I antiarrhythmic agents^246,248 should not be used for prevention of arrhythmias in this population.

Some guideline-recommended therapies, including beta-blockers, MRAs, sacubitril/valsartan and pacemakers with CRT (CRT-Ps), reduce the risk of sudden death (see Section 7).

An ICD reduces the rate of sudden arrhythmic death in patients with HFrEF.^249,250 In patients with moderate or severe HF, a reduction in sudden death may be partially or wholly offset by an increase in death due to worsening HF.²²⁷ In patients with mild HF (NYHA II), an ICD will prevent about two deaths per year for every 100 devices implanted.²²⁷ On average, patients with IHD are at greater risk of sudden death than patients with DCM and therefore, although the relative benefits are similar, the absolute benefit is greater in patients with IHD.²⁴⁹ Patients with longer QRS durations may also receive greater benefit from an ICD, but these patients should often receive a CRT device.^227,251

Two RCTs showed no benefit in patients who had an ICD implanted within 40 days after a myocardial infarction.^158,228 Although sudden arrhythmic deaths were reduced, this was balanced by an increase in non-arrhythmic deaths. Accordingly, an ICD is contraindicated in this time period. A wearable defibrillator may be considered if the patient is deemed to be at high risk of ventricular fibrillation, although evidence from randomized trials is lacking.^239–241

ICD implantation is recommended only after a sufficient trial (minimum 3 months) of optimal medical therapy (OMT) has failed to increase the LVEF to >35%. However, one of the two landmark papers on which these recommendations are based included patients with an LVEF >30%. Fewer than 400 patients with an LVEF of 30–35% were included in the landmark studies, and although there was no statistical interaction between treatment effect and LVEF, the evidence of benefit is less robust in this group of patients.

Conservative programming with long delays²⁵² between detection and the ICD delivering therapy dramatically reduces the risk of both inappropriate (due to artefacts or AF) and appropriate but unnecessary [due to self-terminating ventricular tachycardia (VT)] shocks.^252–254

Patients with a QRS duration ≥130 ms should be considered for a defibrillator with CRT (CRT-D) rather than ICD. See the guideline on CRT for further details (Section 8.2).

ICD therapy is not recommended in patients in NYHA Class IV with severe symptoms refractory to pharmacological therapy who are not candidates for CRT, a ventricular assist device or cardiac transplantation, because such patients have a very limited life expectancy and are likely to die from pump failure.

Patients with serious co-morbidities who are unlikely to survive substantially more than 1 year are unlikely to obtain substantial benefit from an ICD.^229–233

Patients should be counselled as to the purpose of an ICD, complications related to implantation and device activation (predominantly inappropriate shocks) and under what circumstances it might be deactivated (terminal disease) or explanted (infection, recovery of LV function).²⁵⁵

If HF deteriorates, deactivation of a patient's ICD may be considered after appropriate discussion with the patient and caregiver(s).

If the ICD generator reaches its end of life or requires explantation, it should not automatically be replaced.^234–238 Patients should be carefully evaluated by an experienced cardiologist before generator replacement. Treatment goals may have changed and the risk of fatal arrhythmia may be lower or the risk of non-arrhythmic death higher. It is a matter of some controversy whether patients whose LVEF has greatly improved and who have not required device therapy during the lifetime of the ICD should have another device implanted.^234–238

Subcutaneous defibrillators may be as effective as conventional ICDs with a lower risk from the implantation procedure.^256,257 They may be the preferred option for patients with difficult access or who require ICD explantation due to infection. Patients must be carefully selected, as they have limited capacity to treat serious bradyarrhythmia and can deliver neither antitachycardia pacing nor CRT. Substantial RCTs with these devices and more data on safety and efficacy are awaited.^258,259

A wearable ICD (an external defibrillator with leads and electrode pads attached to a wearable vest) that is able to recognize and interrupt VT/ventricular fibrillation may be considered for a limited period of time in selected patients with HF who are at high risk for sudden death but otherwise are not suitable for ICD implantation (e.g. those with poor LVEF after acute myocardial damage until LV function recovers, patients scheduled for heart transplantation).^{239–241,260} However, no prospective RCTs evaluating this device have been reported.

For detailed recommendations on the use/indications of ICD we refer the reader to the ESC/European Heart Rhythm Association (EHRA) guidelines on ventricular tachyarrhythmias and sudden cardiac death.²⁶⁰

8.2 Cardiac resynchronization therapy

Recommendations for cardiac resynchronization therapy implantation in patients with heart failure

AF = atrial fibrillation; AV = atrio-ventricular; CRT = cardiac resynchronization therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; ICD = implantable cardioverter-defibrillator; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; OMT = optimal medical therapy; QRS = Q, R and S waves (combination of three of the graphical deflections); RV = right ventricular.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

^dUse judgement for patients with end-stage HF who might be managed conservatively rather than with treatments to improve symptoms or prognosis.

CRT improves cardiac performance in appropriately selected patients and improves symptoms²⁸⁶ and well-being²⁸⁶ and reduces morbidity and mortality.²⁶⁶ Of the improvement in quality-adjusted life-years (QALYs) with CRT among patients with moderate to severe HF, two-thirds may be attributed to improved quality of life and one-third to increased longevity.²⁸⁷

Only the COMPANION²⁶⁵ and CARE-HF trials^262,263 compared the effect of CRT to guideline-advised medical therapy. Most other trials have compared CRT-D to ICD, and a few have compared CRT-P to backup pacing. The prevention of lethal bradycardia might be an important mechanism of benefit shared by all pacing devices. In CARE-HF, at baseline, 25% of patients had a resting heart rate of ≤60 bpm.^262–264 If prevention of bradycardia is important, the effect of CRT will appear greater in trials where there is no device in the control group.

Most studies of CRT have specified that the LVEF should be <35%, but RAFT²⁶⁷ and MADIT-CRT^268,269 specified an LVEF <30%, while REVERSE^270–272 specified <40% and BLOCK-HF²⁷⁴ <50%. Relatively few patients with an LVEF of 35–40% have been randomized, but an individual participant data (IPD) meta-analysis suggests no diminution of the effect of CRT in this group.²⁶⁶

Not all patients respond favourably to CRT.²⁸⁶ Several characteristics predict improvement in morbidity and mortality, and the extent of reverse remodelling is one of the most important mechanisms of action of CRT. Patients with ischaemic aetiology will have less improvement in LV function due to myocardial scar tissue, which is less likely to undergo favourable remodelling.²⁸⁸ Conversely, women may be more likely to respond than men, possibly due to smaller body and heart size.^273,285,289 QRS width predicts CRT response and was the inclusion criterion in all randomized trials. But QRS morphology has also been related to a beneficial response to CRT. Several studies have shown that patients with left bundle branch block (LBBB) morphology are more likely to respond favourably to CRT, whereas there is less certainty about patients with non-LBBB morphology. However, patients with LBBB morphology often have wider QRS duration, and there is a current debate about whether QRS duration or QRS morphology is the main predictor of a beneficial response to CRT. Evidence from two IPD meta-analyses indicates that after accounting for QRS duration, there is little evidence to suggest that QRS morphology or aetiology of disease influence the effect of CRT on morbidity or mortality.^266,273 In addition, none of the landmark trials selected patients for inclusion according to QRS morphology, sex or ischaemic aetiology, nor were they powered for subgroup analyses.

The Echo-CRT^283,284 trial and an IPD meta-analysis²⁶⁶ suggest possible harm from CRT when QRS duration is <130 ms, thus implantation of CRT is not recommended if QRS duration is <130 ms.^266,283,284

If a patient is scheduled to receive an ICD and is in sinus rhythm with a QRS duration ≥130 ms, CRT-D should be considered if QRS is between 130 and 149 ms and is recommended if QRS is ≥150 ms. However, if the primary reason for implanting a CRT is for the relief of symptoms, then the clinician should choose CRT-P or CRT-D, whichever they consider appropriate. Clinical practice varies widely among countries. The only randomized trial to compare CRT-P and CRT-D²⁶⁵ failed to demonstrate a difference in morbidity or mortality between these technologies.²⁸⁸ If the primary reason for implanting CRT is to improve prognosis, then the majority of evidence lies with CRT-D for patients in NYHA Class II and with CRT-P for patients in NYHA Classes III–IV. It is unclear whether CRT reduces the need for an ICD (by reducing the arrhythmia burden) or increases the benefit from an ICD (by reducing mortality rates from worsening HF, leading to longer exposure to the risk of arrhythmia).

When LVEF is reduced, RV pacing may exacerbate cardiac dyssynchrony. This can be prevented by CRT, which might improve patient outcomes.^{274,275,277,290} However, a difference in outcome was not observed between CRT and RV pacing in a subgroup analysis of RAFT²⁶⁷ or in patients without HFrEF in BioPACE.²⁹¹ On balance, CRT rather than RV pacing is recommended for patients with HFrEF regardless of NYHA class who have an indication for ventricular pacing in order to reduce morbidity, although no clear effect on mortality was observed. Patients with HFrEF who have received a conventional pacemaker or an ICD and subsequently develop worsening HF with a high proportion of RV pacing, despite OMT, may be considered for upgrading to CRT.

Only two small trials have compared pharmacological therapy alone vs. CRT in patients with AF, with conflicting results. Several studies have indicated that CRT is superior to RV pacing in patients undergoing atrio-ventricular (AV) node ablation.^275,277,290 However, CRT is not an indication to carry out AV node ablation except in rare cases when ventricular rate remains persistently high (>110 bpm) despite attempts at pharmacological rate control. A subgroup analysis of patients with AF from the RAFT study found no benefit from CRT-D compared with ICD, although less than half of patients had >90% biventricular capture.²⁷⁶ Observational studies report that when biventricular capture is <98%, the prognosis of patients with CRT declines.²⁷⁷ Whether this association reflects a loss of resynchronization (which might be remedied by device programming), poor placing of the LV lead (which might be avoided at implantation) or greater difficulty in pacing severely diseased myocardium (which might not be amenable to the above) is uncertain. This observation has not been confirmed in a randomized trial.

Imaging tests for dyssynchrony have not yet been shown to be of value in selecting patients for CRT.²⁹² Patients with extensive myocardial scar will have less improvement in LV function with CRT, but this is true of any treatment for HFrEF and does not reliably predict less clinical benefit.²⁹³ Pacing thresholds are higher in scarred myocardium and, if possible, lead placement should avoid such regions.^294,295 Although patients with extensive scarring have an intrinsically worse prognosis, there is little evidence that they obtain less prognostic benefit from CRT.²⁶⁶

The reader is directed to guidelines on pacing and CRT for recommendations on device implantation procedures. The value of trying to optimize AV or VV intervals after implantation using echo- or electrocardiographic criteria or blood pressure response is uncertain, but may be considered for patients who have had a disappointing response to CRT.^296,297

8.3 Other implantable electrical devices

For patients with HFrEF who remain symptomatic despite OMT and do not have an indication for CRT, new device therapies have been proposed and in some cases are approved for clinical use in several European Union (EU) countries but remain under trial evaluation.

Cardiac contractility modulation (CCM) is similar in its mode of insertion to CRT, but it involves non-excitatory electrical stimulation of the ventricle during the absolute refractory period to enhance contractile performance without activating extra systolic contractions. CCM has been evaluated in patients with HFrEF in NYHA Classes II–III with normal QRS duration (<120 ms).^221,222 An individual patient data meta-analysis demonstrated an improvement in exercise tolerance (peak VO₂) and quality of life (Minnesota Living with Heart Failure questionnaire). Thus CCM may be considered in selected patients with HF. The effect of CCM on HF morbidity and mortality remains to be established.

Most other devices under evaluation involve some modification of the activity of the autonomic nervous system (ANS) by targeted electrical stimulation.^298,299 These include vagal nerve stimulation, spinal cord stimulation, carotid body ablation and renal denervation, but so far none of the devices has improved symptoms or outcomes in RCTs.

Devices for remote monitoring are discussed in Section 14.

9. Treatment of heart failure with preserved ejection fraction

While there is clear agreement that the diagnosis of HFrEF requires an LVEF <40%, the exact definition of HFpEF is less clear. According to the definition provided in this document (see Section 3), the diagnosis of HFpEF requires an LVEF ≥50%, whereas patients with LVEF between 40 and 49% are considered to have HFmrEF (for details, please refer to Section 3). Patients with HFmrEF have generally been included in trials of HFpEF. Accordingly, the guidance in this section applies to patients with both HFmrEF and HFpEF. As new data and analyses become available, it might be possible to make recommendations for each phenotype separately.

In clinical practice and clinical trials, compared with HFrEF patients, only slightly fewer patients with HFpEF and HFmrEF currently appear to receive diuretics, beta-blockers, MRAs and ACEIs or ARBs.^{166,300–302} This may reflect treatment of cardiovascular co-morbidities, such as hypertension, CAD and AF, or extrapolation of results from trials conducted for these conditions showing a reduction in new-onset HF,¹²⁷ or failure to distinguish between guideline recommendations for HFrEF and HFmrEF/HFpEF or a belief that existing clinical trials provide some evidence of benefit with these agents.

A summary of phase II and III clinical trials of patients with HFpEF and HFmrEF is presented in Web Table 9.1.

The pathophysiology underlying HFpEF and HFmrEF is heterogeneous, and they are associated with different phenotypes including diverse concomitant cardiovascular diseases (e.g. AF, arterial hypertension, CAD, pulmonary hypertension) and non-cardiovascular diseases [diabetes, chronic kidney disease (CKD), anaemia, iron deficiency, COPD and obesity].^303,304 Compared with HFrEF patients, hospitalizations and deaths in patients with HFmrEF/HFpEF are more likely to be non-cardiovascular.^305,306 Therefore patients should be screened for cardiovascular and non-cardiovascular co-morbidities, which if present should be managed with interventions that have been shown to improve symptoms, well-being or outcome related to that co-morbidity and not to exacerbate HF (see Section 11).

No treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF or HFmrEF. However, since these patients are often elderly and highly symptomatic, and often have a poor quality of life,³⁰⁷ an important aim of therapy may be to alleviate symptoms and improve well-being.³⁰⁸

9.1 Effect of treatment on symptoms in heart failure with preserved ejection fraction

Diuretics will usually improve congestion, if present, thereby improving symptoms and signs of HF. The evidence that diuretics improve symptoms is similar across the spectrum of LVEF.^178,179

Evidence that beta-blockers and MRAs improve symptoms in these patients is lacking. There is inconsistent evidence for an improvement in symptoms in those treated with ARBs (only for candesartan was there an improvement in NYHA class)^309,310 and ACEIs.³¹¹

9.2 Effect of treatment on hospitalization for heart failure in heart failure with preserved ejection fraction

For patients in sinus rhythm, there is some evidence that nebivolol,^173,312,313 digoxin,³¹⁴ spironolactone³⁰¹ and candesartan³¹⁰ might reduce HF hospitalizations. For patients in AF, beta-blockers do not appear to be effective and digoxin has not been studied. The evidence in support of either ARBs³¹⁵ or ACEIs³¹¹ is inconclusive.

9.3 Effect of treatment on mortality in heart failure with preserved ejection fraction

Trials of ACEIs, ARBs, beta-blockers and MRAs have all failed to reduce mortality in patients with HFpEF or HFmrEF. However, in older patients with HFrEF, HFpEF or HFmrEF, nebivolol reduced the combined endpoint of death or cardiovascular hospitalization,^173,312 with no significant interaction between treatment effect and baseline LVEF.³¹³

9.4 Other considerations

Patients in AF should receive an anticoagulant to reduce the risk of thromboembolic events (for details, see the ESC guidelines of AF³¹⁶]. Antiplatelet agents are ineffective for this purpose. Renal dysfunction, which is common in this population, may contraindicate or increase the risk of haemorrhage with NOACs.

The optimal ventricular rate in patients with HFmrEF/HFpEF and AF is uncertain, and aggressive rate control might be deleterious. Whether digoxin, beta-blockers or rate-limiting CCBs, or a combination of these, should be preferred is unknown. Verapamil or diltiazem should not be combined with a beta-blocker. There are insufficient data to recommend ablation strategies (either pulmonary venous or AV node) for HFpEF and HFmrEF.

Circumstantial evidence suggests that treating hypertension, often predominantly systolic, is important in HFmrEF/HFpEF.^127,317 Diuretics, ACEIs, ARBs and MRAs all appear appropriate agents, but beta-blockers may be less effective in reducing SBP. A recent study suggests that patients with hypertension and HFpEF or HFmrEF should not receive an ARB (olmesartan) if they are receiving ACEIs and beta-blockers.³¹⁸

The first-line oral hypoglycaemic drug for patients with HFpEF and HFmrEF should be metformin³¹⁹ (see also Section 11.6). Recently, a trial of empagliflozin showed a reduction in blood pressure and body weight, probably by inducing glycosuria and osmotic diuresis. Its use was associated with a reduction in hospitalization for HF and in cardiovascular mortality.¹³⁰ However, aggressive management of dysglycaemia may be harmful.^153,320

Myocardial ischaemia may contribute to symptoms, morbidity and mortality and should be considered when assessing patients. However, there is only anecdotal evidence that revascularization improves symptoms or outcome. Patients with angina should follow the same management route as patients with HFrEF.¹¹²

Patients with HFpEF and HFmrEF have impaired exercise tolerance, commonly accompanied by an augmented blood pressure response to exercise and chronotropic incompetence. Combined endurance/resistance training appears safe for patients with HFpEF and HFmrEF and improves exercise capacity (as reflected by an increase in peak oxygen consumption), physical functioning score and diastolic function.^307,321

Recommendations for treatment of patients with heart failure with preserved ejection fraction and heart failure with mid-range ejection fraction

HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

10. Arrhythmias and conductance disturbances

Ambulatory electrocardiographic monitoring can be used to investigate symptoms that may be due to arrhythmias,^322–324 but evidence is lacking to support routine, systematic monitoring for all patients with HF to identify tachy- and bradyarrhythmias. There is no evidence that clinical decisions based on routine ambulatory electrocardiographic monitoring improve outcomes for patients with HF.

Ambulatory electrocardiographic recording detects premature ventricular complexes in virtually all patients with HF. Episodes of asymptomatic, non-sustained VT are common, increasing in frequency with the severity of HF and ventricular dysfunction and indicating a poor prognosis in patients with HF, but provide little discrimination between sudden death or death due to progressive HF.^316,325 Bradycardia and pauses are also commonly observed, especially at night when sympathetic activity is often lower and parasympathetic activity higher; sleep apnoea may be a trigger.^326–328 Pauses are associated with a poor prognosis in patients with CAD and left ventricular dysfunction.³²⁹ Bradyarrhythmias may make an important contribution to sudden death in HF.³³⁰

10.1 Atrial fibrillation

AF is the most common arrhythmia in HF irrespective of concomitant LVEF; it increases the risk of thromboembolic complications (particularly stroke) and may impair cardiac function, leading to worsening symptoms of HF.³¹⁶ Incident HF precipitated by AF is associated with a more benign prognosis,³³¹ but new-onset AF in a patient with established HF is associated with a worse outcome, probably because it is both a marker of a sicker patient and because it impairs cardiac function.^332,333 Patients with chronic HF and permanent AF have a worse outcome than those in sinus rhythm, although this is largely explained by more advanced age and HF severity.^332,333 Persistent ventricular rates >150 bpm may cause HFrEF that resolves with rate control or rhythm correction (‘tachycardiomyopathy’).^334,335 AF should be classified and managed according to the current AF guidelines (i.e. first diagnosed episode, paroxysmal, persistent, long-standing persistent or permanent), recognizing the uncertainty about the actual duration of the episode and about previous undetected episodes.³¹⁶

The following issues need to be considered in patients with HF presenting with AF, irrespective of LVEF, especially with a first diagnosed episode of AF or paroxysmal AF:³¹⁶ or details, the reader should refer to the 2016 ESC guidelines on AF.³¹⁶

identification of potentially correctable causes (e.g. hypothyroidism or hyperthyroidism, electrolyte disorders, uncontrolled hypertension, mitral valve disease) and precipitating factors (e.g. recent surgery, chest infection or exacerbation of COPD/asthma, acute myocardial ischaemia, alcohol binge), as this may determine management strategy;
assessment of stroke risk and need for anticoagulation;
assessment of ventricular rate and need for rate control;
evaluation of symptoms of HF and AF.

10.1.1 Prevention of atrial fibrillation in patients with heart failure

Many treatments for HF, including ACEIs,³³⁶ ARBs,³³⁷ beta-blockers^177,338 and MRAs,^339,340 will reduce the incidence of AF, but ivabradine may increase it.³⁴¹ CRT has little effect on the incidence of AF.³⁴²

Amiodarone will reduce the incidence of AF, induce pharmacological cardioversion, maintain more patients in sinus rhythm after cardioversion and may be used to control symptoms in patients with paroxysmal AF if beta-blockers fail to do so.^343–346 Amiodarone should generally be restricted to short-term (<6 months) use in patients with paroxysmal or persistent AF to help attain sinus rhythm and to reduce the high rate of recurrent AF immediately after cardioversion. Dronedarone is contraindicated in patients with HF and AF.^246,247,347

10.1.2 Management of new-onset, rapid atrial fibrillation in patients with heart failure

If the patient has no distressing symptoms of HF, then treatment with oral beta-blockers may be initiated to provide ventricular rate control. For patients with marked congestion who nonetheless have few symptoms at rest, initial treatment with oral or intravenous (i.v.) digoxin is preferred. For patients in haemodynamic instability, an i.v. bolus of digoxin or amiodarone^348,349 should be administered into a peripheral vein with extreme care to avoid extravasation into tissues; where uncertainty exists about venous access, amiodarone must not be given. Longer-term infusion of amiodarone should be given only by central or long-line venous access to avoid peripheral vein phlebitis. In patients with haemodynamic collapse, emergency electrical cardioversion is recommended (see also Section 12).

Recommendations for initial management of a rapid ventricular rate in patients with heart failure and atrial fibrillation in the acute or chronic setting

AF = atrial fibrillation; AHF = acute heart failure; AV = atrio-ventricular; bpm = beats per minute; HF = heart failure; NYHA = New York Heart Association.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

^dThe optimal ventricular rate for patients with HF and AF has not been established, but the prevailing evidence suggests that strict rate control might be deleterious. A resting ventricular rate in the range of 60–100 bpm may be considered based on the current opinion of this Task Force,^350,351 although one trial suggested that a resting ventricular rate of up to 110 bpm might still be acceptable, and this is currently recommended by the ESC guidelines on AF.^198,316 This should be tested and refined by further research.

10.1.3 Rate control

Assessment of ventricular rate control from the radial pulse is not ideal, especially in patients with HF, as ventricular activation may not always generate a palpable pulse. Rate control should be documented electrocardiographically. A wearable device enables ventricular rate to be assessed during rest, exercise and sleep, but the value of routine monitoring has not yet been established. Implanted devices such as pacemakers, CRT or ICDs can also be used to measure ventricular rate.

The optimal resting ventricular rate in patients with AF and HF is uncertain but may be between 60–100 bpm.^{350,352–354} One trial suggested that a resting ventricular rate of up to 110 bpm might still be acceptable,^198,202 and 2016 ESC AF guidelines recommend this threshold as the target for rate control therapy.³¹⁶ However, this Task Force believes that a lower rate for patients with HF may be preferable (60–100 bpm). Ventricular rates <70 bpm are associated with a worse outcome.³⁵¹ This may explain why beta-blockers titrated to guideline-target doses failed to reduce morbidity or mortality in patients with HFrEF and AF,¹⁷⁷ and might also explain the association between digoxin and adverse outcomes reported in some observational studies of AF.^355–357 The optimal ventricular rate during exercise is also uncertain, but may be <110 bpm during light exercise.³⁵⁴ Beta-blockers, digoxin and their combination may be used to control ventricular rate.³⁵⁸ It is uncertain which approach is optimal, but beta-blockers appear safe as the first-line agent even if it is not clear that they reduce morbidity and mortality in patients with AF. Beta-blockers reduce ventricular rate during periods of activity, while digoxin exerts a greater effect at night.³⁵⁸ Persistently high ventricular rates may indicate thyrotoxicosis or excessive sympathetic activity due to congestion, which might respond to diuresis. Although amiodarone and non-dihydropyridine CCBs can reduce ventricular rate, they have more adverse effects and should generally be avoided in patients with HFrEF and, with less certainty, in patients with HFpEF and HFmrEF. Rarely, ventricular rate cannot be reduced below 100–110 bpm by pharmacological means alone and AV node ablation with ventricular pacing may be considered; in this situation, for patients with HFrEF, CRT should be considered instead of conventional RV pacing. There is little evidence, other than from registries, to support a strategy of AV node ablation and CRT compared with pharmacological therapy alone in patients with AF and a resting ventricular rate <100–110 bpm (see Section 8.2).²⁸¹ However, in patients with a fast ventricular rate and intractable symptoms, AV node ablation may be considered. Also, if the patient is indicated for an ICD, AV node ablation with implantation of CRT-D may be a preferred option, especially if the patient has moderate to severe symptoms.

10.1.4 Rhythm control

In patients with chronic HF, a rhythm control strategy (including pharmacological or electrical cardioversion) has not been shown to be superior to a rate control strategy in reducing mortality or morbidity.³⁵⁹ Urgent cardioversion is indicated only if the AF is life threatening, otherwise both HF and ventricular rate should be controlled prior to cardioversion. A rhythm control strategy is probably best reserved for patients with a reversible secondary cause of AF (e.g. hyperthyroidism) or an obvious precipitant (e.g. recent pneumonia) and in patients with troublesome symptoms due to AF after optimization of rate control and HF therapy. The use of class I antiarrhythmic agents and dronedarone increases morbidity and mortality in patients with HF and AF and should be avoided.^246,247,347 Amiodarone will cause some patients with chronic AF to revert to sinus rhythm, may reduce symptomatic paroxysms of AF and will help maintain patients in sinus rhythm after spontaneous or electrical cardioversion.^343–346 When used, the need for continued administration of amiodarone should be regularly reviewed and justified.

The safety and efficacy of catheter ablation in the atria and pulmonary veins (PV) as a rhythm control strategy in HF is at present uncertain except for tachycardia induced cardiomyopathy.³¹⁶ One small study suggested that AF ablation was superior to AV node ablation and CRT.³⁶⁰ Another study, including 203 patients with persistent AF, HF and an ICD or CRT device, showed that AF ablation was superior to amiodarone in correcting AF, and this was associated with fewer hospitalizations for HF and lower mortality. Two small studies of AF ablation compared with rate control met with mixed success in terms of procedural complications and success in improving symptoms.^278,279 The most recent evidence from a meta-analysis that included 914 patients suggests an encouraging success rate of PV ablation of AF in patients with LV dysfunction, with improvements in LVEF and functional capacity.³⁶¹ These results need to be confirmed in ongoing RCTs such as CASTLE AF,³⁶² AMICA and CABANA.

Recommendations for a rhythm control management strategy in patients with atrial fibrillation, symptomatic heart failure (NYHA Class II–IV) and left ventricular systolic dysfunction and no evidence of acute decompensation

AF = atrial fibrillation; HF = heart failure; NYHA = New York Heart Association, OMT = optimal medical therapy.

Patients should generally be anticoagulated for 6 weeks prior to electrical cardioversion.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

10.1.5 Thromboembolism prophylaxis

Patients with HF and AF should generally be anticoagulated and the balance of benefit and risk of bleeding (using CHA₂DS₂-VASc and HAS-BLED scores; for details, please see Web Tables 10.1 and 10.2.) should be evaluated as recommended in the ESC guidelines for AF.³¹⁶ A substantial proportion of patients with HF will have both benefit and risk scores ≥3, indicating that careful consideration should be given before prescribing an oral anticoagulant and that regular review is subsequently needed (and correctable risk factors for bleeding addressed) if an oral anticoagulant is given.

NOACs are preferred for patients with HF with non-valvular AF, as NOACs compared with vitamin K antagonists seem to be at least similarly effective and even safer (less intracranial haemorrhage) in patients with HF than in subjects without HF,^316,366,367 although concerns exist about their safety in older patients with HF and poor renal function^368,369 [for a detailed description of the interaction between NOAC and renal function, see Heidbuchel et al.³⁷⁰]. In patients with HF and AF who have mechanical heart valves or at least moderate mitral stenosis, only oral vitamin K antagonists should be used for prevention of thromboembolic stroke.³⁷⁰

The dabigatran dose should be reduced to 110 mg b.i.d. when creatinine clearance is 30–49 mL/min, rivaroxaban to 15 mg daily and edoxaban to 30 mg daily when creatinine clearance is 30–50 mL/min and apixaban to 2.5 mg twice daily if a patient has two or more of the following: age ≥80 years, serum creatinine ≥1.5 mg/dL or body weight ≤60 kg.^370–375 The summary of the recommendations for the prevention of thromboembolism in patients with symptomatic HF and paroxysmal or persistent/permanent AF is presented in the recommendations table. For further details, please refer to the recent ESC guidelines on AF.³¹⁶

A left atrial occlusion device could be considered in a patient with AF as an alternative to an oral anticoagulant who is at high-risk both of thromboembolism and of bleeding in order to avoid the risk of haemorrhage due to anticoagulation risk.^381,382

Recommendations for the prevention of thrombo-embolism in patients with symptomatic heart failure (NYHA Class II–IV) and paroxysmal or persistent/permanent atrial fibrillation

AF = atrial fibrillation; CHA₂DS₂-VASc = Congestive heart failure or left ventricular dysfunction, Hypertension, Age ≥ 75 (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly (1 point each); HF = heart failure; LMWH = low molecular weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; NYHA = New York Heart Association; TOE = transoesophageal echocardiography.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

10.2 Ventricular arrhythmias

The initial management of asymptomatic ventricular arrhythmias is correction of electrolyte abnormalities, particularly low serum potassium and magnesium, withdrawal of agents that might provoke arrhythmias and, in patients with HFrEF, optimization of pharmacological therapy with ACEIs, beta-blockers and MRAs and sacubitril/valsartan, which all reduce the risk of sudden death.^{174,177,383,384}

The clinical relevance of myocardial ischaemia for the provocation of ventricular arrhythmias is uncertain, although anecdotal cases of ischaemia-induced arrhythmias exist. Randomized trials of revascularization for patients with HFrEF have not reduced overall mortality,^107,385 even in subgroups of patients with angina or myocardial ischaemia,^115,386 but further analysis did suggest a reduction in sudden deaths.³⁸⁷

Amiodarone (often in combination with a beta-blocker) may be used to suppress symptomatic ventricular arrhythmias, but it may adversely affect prognosis, especially in patients with more severe HF.^227,244 Other antiarrhythmic drugs should be avoided.²⁴⁷ Transcatheter radiofrequency modification of the arrhythmogenic substrate may reduce the number of appropriate ICD discharges and may be used to terminate arrhythmic storm in patients with HF and frequent, recurrent ventricular tachyarrhythmias and therefore should be considered in such patients. Seeking the advice of the members of the HF Team with expertise in electrophysiology is recommended in patients with recalcitrant ventricular arrhythmias. For further details we refer the reader to the ESC/EHRA guidelines on ventricular arrhythmias and sudden cardiac death.²⁶⁰

Recommendations for the management of ventricular tachyarrhythmias in heart failure

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CRT = cardiac resynchronization therapy; CRT-D = defibrillator with cardiac resynchronization therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; ICD = implantable cardioverter defibrillator; MRA = mineralocorticoid receptor antagonist.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

10.3 Symptomatic bradycardia, pauses and atrio-ventricular block

The ESC Guidelines on Pacing and CRT recommended intervention when pauses exceed 6 s, even when this is not associated with symptoms.³⁸⁹ However, these recommendations were generated mainly for patients without obvious myocardial dysfunction, and shorter pauses might require intervention in patients with HFrEF.³²⁹ If pauses >3 s are identified on electrocardiographic monitoring, medications should be reviewed and the following agents stopped or reduced in dose, starting with rate-limiting CCBs then amiodarone, digoxin and ivabradine. For patients in AF, a reduction in the dose of beta-blockers allowing the daytime resting ventricular rate to rise to 70–90 bpm may be considered, since evidence that beta-blockers improve outcome in patients with AF is lacking.¹⁷⁷ For patients with pauses but in sinus rhythm, a reduction in the dose of beta-blockers should be avoided unless the pauses are symptomatic, prolonged or frequent, in which case the relative merits of dose reduction, beta-blocker withdrawal and (biventricular) pacing may be considered. However, evidence is lacking to support a strategy of pacing solely to permit initiation or titration of beta-blocker therapy in the absence of a conventional pacing indication; this strategy is not recommended. For patients with HFrEF and high-degree AV block, CRT is preferred over RV pacing (Section 8.2). When the cause of bradycardia or pauses is sinus node disease with intact AV conduction, then therapeutic strategies that avoid inducing ventricular dyssynchrony are preferred, although clinical trial evidence to support this expert opinion for patients with HF is sparse. For other pacing indications, please consult the ESC Guidelines on Pacing and CRT.³⁸⁹

Recommendations for the management of bradyarrhythmias in heart failure

AF = atrial fibrillation; AV = atrio-ventricular; bpm = beats per minute; CRT = cardiac resynchronization therapy; ECG = electrocardiogram; HFrEF = heart failure with reduced ejection fraction; RV = right ventricular.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

11. Co-morbidities

11.1. Heart failure and co-morbidities

Co-morbidities are of great importance in HF (Table 11.1) and may affect the use of treatments for HF (e.g. it may not be possible to use renin–angiotensin system inhibitors is some patients with severe renal dysfunction) (see Section 7). The drugs used to treat co-morbidities may cause worsening of HF (e.g. NSAIDs given for arthritis, some anti-cancer drugs) (see Section 7). Management of co-morbidities is a key component of the holistic care of patients with HF (see Section 14). Many co-morbidities are actively managed by specialists in the field of the co-morbidity, and these physicians will follow their own specialist guidelines. The current guidelines will identify where the presence of HF should change the way a co-morbidity would normally be treated. This may be because either safety or efficacy may be different in the presence of HF (or may simply be unknown) or because of evidence of particular effects in an HF population, either beneficial or detrimental. HFpEF has an even higher prevalence of co-morbidities compared with HFrEF, and many of these may be instrumental in the progression of this syndrome.³⁹⁸

11.2 Angina and coronary artery disease

11.2.1 Pharmacological management

Beta-blockers, and in selected patients ivabradine,¹⁸⁰ are effective agents for angina control, as well as an essential component of HFrEF therapy. In HFpEF patients, they may also be used for angina relief, although this has never been formally tested.³⁹⁹

Trimetazidine has been shown to exert some beneficial effect as an add-on to beta-blockers in patients with HF and angina.^400–406 There are data suggesting that it may improve NYHA functional capacity, exercise duration and LV function in patients with HFrEF.^402–406 Certain other effective anti-anginal drugs have been studied in sizeable numbers of HFrEF/LV dysfunction patients and shown to be safe [e.g. amlodipine,^215,407 nicorandil⁴⁰⁸ and nitrates^183,184,409]. The safety of other anti-anginal agents in HFrEF, such as ranolazine, is uncertain, while other drugs, speciﬁcally diltiazem and verapamil, are thought to be unsafe in patients with HFrEF (although they may be used in HFpEF).²¹⁴ Dihydropyridine CCBs may all increase sympathetic tone, and their safety in HFrEF [except amlodipine²¹⁵ and felodipine²¹⁶] and HFpEF is uncertain.

11.2.2 Myocardial revascularization

For indications for invasive coronary angiography in patients with HF, please refer to Section 5.8.

Percutaneous and surgical revascularization are complementary approaches for symptomatic relief of angina in HFpEF, but whether these interventions improve outcomes is not entirely clear. Recent ESC guidelines on myocardial revascularization recommended coronary artery bypass grafting (CABG) for patients with significant left main stenosis and left main equivalent (proximal stenosis of both the left anterior descending and left circumflex arteries) to improve prognosis.^112,113 However, one needs to be aware of a lack of studies including patients who have well-defined HF, therefore this recommendation is solely based on expert opinion. On the basis of the results of the STICH trial [which excluded patients with left main disease and Canadian Cardiovascular Society (CCS) angina classes III–IV], CABG is also recommended in patients with HFrEF, significant CAD (left anterior descending artery or multivessel disease) and LVEF ≤35% to reduce death and hospitalization for cardiovascular causes.³⁸⁵ Patients with >10% dysfunctional but viable LV myocardium may be more likely to benefit from myocardial revascularization (and those with ≤10% are less likely to benefit), although this approach to patient selection for revascularization is unproven. In the STICH trial, neither the presence of viability nor the severity of LV remodelling identified those who benefited from CABG in terms of a reduction in mortality.¹¹⁸ For the assessment of techniques to assess myocardial viability, please refer to Section 5. Post hoc analyses from the STICH trial revealed that the presence of inducible myocardial ischaemia (either on radionuclide stress test or dobutamine stress echocardiogram) or angina does not identify those with worse prognosis and greater benefit from CABG over OMT.^115,386 However, CABG does improve angina to a greater extent than medical therapy alone.

The choice between CABG and PCI should be made by the Heart Team after careful evaluation of the patient's clinical status and coronary anatomy, expected completeness of revascularization, coexisting valvular disease and co-morbidities.

Recommendations for the treatment of stable angina pectoris with symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction^112,113

bpm = beats per minute; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; NYHA = New York Heart Association.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

11.3 Cachexia and sarcopenia (for frailty, please refer to Section 14)

Cachexia is a generalized wasting process affecting all body compartments [i.e. lean tissue (skeletal muscle), fat tissue (energy reserves) and bone tissue (osteoporosis)]. It may occur in 5–15% of patients with HF, especially those with HFrEF, and more advanced disease status.^414–416 This serious complication is associated with more severe symptoms and reduced functional capacity, more frequent hospitalization and decreased survival. Cachexia in HF can be diagnosed and defined as involuntary non-oedematous weight loss ≥6% of total body weight within the previous 6–12 months.^414–417

The causes are multifactorial, and in individual patients they are difficult to determine. These may include pro-inﬂammatory immune activation, neurohormonal derangements, poor nutrition and malabsorption, impaired calorie and protein balance, anabolic hormone resistance, reduced anabolic drive, prolonged immobilization and physical deconditioning, together characterized by catabolic/anabolic imbalance.⁴¹⁸ Skeletal muscle wasting, when associated with impaired mobility and symptoms (termed sarcopenia or myopenia), occurs in 30–50% of patients with HFrEF.⁴¹⁹ In its most severe form it is associated with frailty and poor morbidity and mortality.⁴²⁰

Potential treatments may include appetite stimulants, exercise training¹²⁰ and anabolic agents, including testosterone, in combination with the application of nutritional supplements and anti-catabolic interventions, although none is of proven beneﬁt and their safety is unknown.⁴²¹

11.4 Cancer

Certain chemotherapeutic agents can cause (or aggravate) LV systolic dysfunction and HF. The best recognized of these are the anthracyclines (e.g. doxorubicin), trastuzumab and tyrosine kinase inhibitors.^397,422 A recent Cochrane review found that dexrazoxane may confer some cardioprotection in patients receiving anthracyclines.⁴²³ Pre- and post-evaluation of LVEF, if available with myocardial strain imaging, is essential in patients receiving cardiotoxic chemotherapy, as detailed elsewhere.^397,422 A risk score for identifying women with breast cancer at risk of developing HF during trastuzumab therapy has been developed based on age, chemotherapy details, baseline cardiovascular status and other co-morbidities, and may be helpful.⁴²⁴ Chemotherapy should be discontinued and HFrEF therapy commenced in patients developing moderate to severe LV systolic dysfunction. If LV function improves, the risks and benefits of further chemotherapy need to be reconsidered.^397,425,426 Mediastinal irradiation can also lead to a variety of long-term cardiac complications. Cardiac biomarkers (NPs and troponins) can be used to identify patients at higher risk of cardiotoxicity and may be helpful in monitoring the use and dosing of cardiotoxic cytotoxics.^397,425,426

11.5 Central nervous system (including depression, stroke and autonomic dysfunction)

Stroke and HF commonly coexist because of an overlap of shared risk factors. Both contribute to a worse prognosis. Stroke may make self-care more difficult for the HF patient. Management of high-risk stroke patients may require balancing the risk of anticoagulant and antiplatelet therapies.

Autonomic dysfunction is common in HFrEF, especially when severe.⁴²⁷ Combined with low blood pressure, it can make fainting and injuries more likely and can interfere with optimal dosing of beta-blockers, ACEIs, ARBs and MRAs. Diuretic dosage may be reduced to reduce the severity of postural hypotension.

Depression is common and is associated with worse clinical status and a poor prognosis in HF.^428–430 It may also contribute to poor adherence and social isolation. A high index of suspicion is needed to make the diagnosis, especially in the elderly. Routine screening using a validated questionnaire is good practice. Until now, the Beck Depression Inventory (BDI) and Cardiac Depression Scale have been formally validated as reliable tools for the assessment of depressive mood in patients with HF,^431,432 but other questionnaires have been broadly used in this group of patients (e.g. Geriatric Depression Scale, Hamilton Depression Scale, Hospital Anxiety and Depression Scale).

Psychosocial intervention and pharmacological treatment are helpful, as well as exercise training, in patients with HFrEF and depression.⁴³³ Cognitive behavioural therapy delivered in patients with HF and major depression beyond standard care and a structured education programme were able to reduce depression severity, anxiety and fatigue symptoms, as well as improve social functioning and mental and HF-related quality of life.⁴³⁴

Selective serotonin reuptake inhibitors are thought to be safe, although the Sertraline Antidepressant Heart Attack Randomized Trial did not confirm that sertraline provides a greater reduction in depressive symptoms or improvement in cardiovascular status compared with placebo in HFrEF patients, but this trial was not powered enough to prove the latter.⁴³⁵ Similarly, escitalopram had no effect on either depression or clinical outcomes during the 24-month follow-up as compared with placebo in patients with HFrEF and depression. Importantly, tricyclic antidepressants should be avoided, because they may cause hypotension, worsening HF and arrhythmias.^429,435

11.6 Diabetes

Dysglycaemia and diabetes are very common in HF, and diabetes is associated with poorer functional status and worse prognosis. In patients with HFrEF, interventions that reduce morbidity and mortality confer similar benefit in the presence or absence of diabetes.³²⁰ For instance, beta-blockers improve outcome similarly, whether or not the patient has diabetes, although different beta-blockers may vary in their effects on glycaemic indices.⁴³⁶

Whether strict glycaemic control alters the risk of cardiovascular events in patients with HF is uncertain.⁴³⁷ Among patients with HF who have not been treated for diabetes, higher HbA1c is associated with greater risk of cardiovascular events,^438,439 but this may not be the case once treatment for diabetes has been commenced.⁴³⁹

In patients with diabetes and HF, glycaemic control should be implemented gradually and moderately, giving preference to those drugs, such as metformin, that have been shown to be safe and effective. In contrast to what was previously believed, metformin is safe to use in patients with HFrEF, and it should be the treatment of choice in patients with HF^440,441 but is contraindicated in patients with severe renal or hepatic impairment, because of the risk of lactic acidosis.

Insulin is required for patients with type 1 diabetes and to treat symptomatic hyperglycaemia in patients with type 2 diabetes and pancreatic islet β cell exhaustion. However, insulin is a powerful sodium-retaining hormone, and when combined with a reduction in glycosuria, may exacerbate fluid retention, leading to HF worsening. Sulphonylurea derivatives have also been associated with an increased risk of worsening HF and should be used with caution.

Thiazolidinediones (glitazones) cause sodium and water retention and increased risk of worsening HF and hospitalization and are not recommended in patients with HF.^209,210 Dipeptidylpeptidase-4 inhibitors (DPP4is; gliptins), which increase incretin secretion, thereby stimulating insulin release, and long-acting glucagon-like peptide 1 (GLP-1) receptor agonists, which act as incretin mimetics, improve glycaemic indices but do not reduce and may increase the risk of cardiovascular events and worsening HF.^320,442,443 Importantly, there are no data on the safety of gliptins and GLP-1 analogues in patients with HF.

Recently, empagliflozin, an inhibitor of sodium-glucose co-transporter 2, reduced hospitalization for HF and mortality, but not myocardial infarction or stroke, in patients with diabetes at high cardiovascular risk, some of whom had HF.¹³⁰ In the absence of other studies with drugs from this group, the results obtained with empaglifozin cannot be considered as a proof of a class effect.

As glycaemic derangement progresses, the judgement on glycaemic control should be made according to cardiac conditions, and if the new anti-diabetic drugs are to be prescribed, they have to be closely monitored by an HF team.

11.7 Erectile dysfunction

Erectile dysfunction is a common and important component of quality of life in men with HF.^444,445 Its treatment should include optimal therapies for underlying cardiovascular diseases and other interfering co-morbidities (e.g. diabetes) and amelioration of anxiety and depressive symptoms. Some drugs applied for HF therapy (e.g. thiazide diuretics, spironolactone and beta-blockers) may augment erectile dysfunction.^444,445 Phosphodiesterase type 5 inhibitors (PDE5Is) have been shown to have favourable haemodynamic and anti-remodelling effects and to improve exercise capacity and quality of life in patients with HFrEF,^446,447 but they are contraindicated in patients taking nitrates.

11.8 Gout and arthritis

Hyperuricaemia and gout are common in HF and may be caused or aggravated by diuretic treatment. Hyperuricaemia is associated with a worse prognosis in HFrEF.⁴⁴⁸ The current European League Against Rheumatism (EULAR) guideline for the management of gout recommends that urate-lowering therapy (ULT) is indicated in patients with recurrent acute flares, arthropathy, tophi or radiographic changes of gout, aiming to maintain a serum urate level below the saturation point for monosodium urate [<357 μmol/L (<6 mg/dL)].⁴⁴⁹

Xanthine oxidase inhibitors (allopurinol, oxypurinol) may be used to prevent gout, although their safety in HFrEF is uncertain.⁴⁵⁰ Gout attacks are better treated with colchicine rather than with NSAIDs (although colchicine should not be used in patients with very severe renal dysfunction and may cause diarrhoea). Intra-articular corticosteroids are an alternative for monoarticular gout, but systemic corticosteroids cause sodium and water retention.

Arthritis is a common co-morbidity and is a common cause of both self-taken and prescribed drugs that can worsen renal function and HF, especially NSAIDs. Rheumatoid arthritis is associated with an increased risk of HFpEF. The safety of disease-modifying drugs commonly given to patients with rheumatoid arthritis has not been established in HF.

11.9 Hypokalaemia and hyperkalaemia

Both hypokalaemia and hyperkalaemia are associated with HF and with many drugs used for HF treatment.⁴⁵¹ Both can aggravate ventricular arrhythmias.

Loop and thiazide diuretics reduce serum potassium, while ACEIs, ARBs and MRAs can all increase serum potassium. Amiloride and triamterene are sometimes used as adjunct diuretics in resistant oedema and to assist in preventing hypokalaemia. The treatment of hypokalaemia can involve recommending high potassium foods or prescribing potassium supplements.

The management of acute hyperkalaemia (>6.0 mmol/L) may require a short-term cessation of potassium-retaining agents and RAAS inhibitors, but this should be minimized and RAAS inhibitors should be carefully reintroduced as soon as possible while monitoring potassium levels. A Cochrane review⁴⁵² found no trial evidence of major outcome benefits for any emergency therapy regimen for hyperkalaemia. Two new potassium binders (patiromer and sodium zirconium cyclosilicate) are currently under consideration for regulatory approval.^453,454 Initial results from patients with HF are available and confirm the efficacy of these therapies in reducing serum potassium⁴⁵⁵ and preventing recurrent hyperkalaemia in patients with HF and CKD in the context of treatment with RAAS inhibitors.⁴⁵⁶

11.10 Hyperlipidaemia

Elevated low-density lipoprotein cholesterol is uncommon in HFrEF; patients with advanced HFrEF often have low concentrations of low-density lipoprotein, which is associated with a worse prognosis. Rosuvastatin did not reduce the primary composite mortality/morbidity endpoints in two large RCTs in patients with HF with or without IHD, but it also did not increase risk, and may have reduced, hospitalizations.^205,457 Therefore there is no evidence to recommend the initiation of statins in most patients with HF. However, in patients who are already receiving a statin for CAD, a continuation of this therapy may be considered.

11.11 Hypertension

Hypertension is associated with an increased risk of developing HF; antihypertensive therapy markedly reduces the incidence of HF (with an exception of α-adrenoceptor blockers, which are less effective than other antihypertensives in preventing HF).⁴⁵⁸ A recent prospective cohort study documented that in a population with incident HF, higher baseline systolic, diastolic and pulse pressure levels were associated with a higher rate of adverse events, which further supports the importance for optimized blood pressure control in this population.⁴⁵⁹ Blood pressure control is an element of the holistic management of patients with HF.

Negatively inotropic CCBs (i.e. diltiazem and verapamil) should not be used to treat hypertension in patients with HFrEF (but are believed to be safe in HFpEF), and moxonidine should also be avoided in patients with HFrEF, as it increased mortality in patients in one RCT.⁴⁶⁰ If blood pressure is not controlled with an ACEI (or an ARB), a beta-blocker, an MRA and a diuretic, then hydralazine and amlodipine²¹⁵ [or felodipine²¹⁶] are additional blood pressure lowering agents that have been shown to be safe in systolic HF. The blood pressure targets recommended in hypertension guidelines³¹⁷ are applicable to HF. Uncontrolled hypertension in patients with HFrEF is very rare, provided they are optimally treated for HF. In contrast, treatment of hypertension is an important issue in patients with HFpEF. In patients with AHF, i.v. nitrates (or sodium nitroprusside) are recommended to lower blood pressure (see Section 12).

Recommendations for the treatment of hypertension in patients with symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; HF = heart failure; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

11.12 Iron deficiency and anaemia

Iron deficiency is common in HF, as it is with other chronic illnesses, and it can lead to anaemia and/or skeletal muscle dysfunction without anaemia.⁴⁶⁶ Within an HF population, iron deficiency is associated with a worse prognosis.^467,468 Intravenous iron has been speciﬁcally studied in two RCTs in patients with HF and iron deficiency (serum ferritin <100 µg/L or ferritin between 100 and 299 µg/L and transferrin saturation <20%)^469,470 both with and without anaemia. Intravenous ferric carboxymaltose (FCM) has been shown to improve self-reported patient global assessment, quality of life and NYHA class (over 6 months) in the FAIR-HF trial⁴⁶⁹ both in anaemic and non-anaemic patients with HF,⁴⁷¹ and in the CONFIRM-HF trial⁴⁷⁰, exercise capacity improved over 24 weeks. In the analysis of secondary endpoints in the CONFIRM-HF trial, i.v. iron reduced the risk of HF hospitalizations in iron-deficient patients with HFrEF.⁴⁷⁰ A meta-analysis of i.v. iron therapy in HFrEF patients with iron deficiency over up to 52 weeks showed reduced hospitalization rates and improved HF symptoms, exercise capacity and quality of life.⁴⁷² Treatment with FCM may therefore result in sustainable improvement in functional capacity, symptoms and quality of life. Treatment was also associated with a significant reduction in hospitalizations for worsening HF. The number of deaths and the incidence of adverse events were similar. Neither i.v. iron trial was powered to test for an effect on major outcomes or to evaluate separately the effects in anaemic and non-anaemic patients. The effect of treating iron deﬁciency in HFpEF/HFmrEF and the long-term safety of iron therapy in either HFrEF, HFmrEF or HFpEF is unknown. The safety of i.v. iron is unknown in patients with HF and haemoglobin >15 g/dL.^469,470 Patients with iron deficiency need to be screened for any potentially treatable/reversible causes (e.g. gastrointestinal sources of bleeding).

Recommendations for the treatment of other co-morbidities in patients with heart failure

FCM = ferric carboxymaltose; HF = heart failure; HFrEF = heart failure with reduced ejection fraction.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

Treatments not recommended for other co-morbidities in patients with heart failure

Treatments not recommended of other co-morbidities in patients with heart failure

COX-2 = cyclooxygenase 2; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; NSAID = non-steroidal anti-inflammatory drug.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

Anaemia (deﬁned as a haemoglobin concentration <13.0 g/dL in men and <12.0 g/dL in women) is common in HF, particularly in hospitalized patients. It is more common in women, the elderly and in patients with renal impairment and is associated with advanced myocardial remodelling, inflammation and volume overload.⁴⁷⁴ Anaemia is associated with advanced symptoms, worse functional status, greater risk of HF hospitalization and reduced survival. A diagnostic workup to seek a cause for any finding of anaemia is indicated (e.g. occult blood loss, iron deficiency, B12/folate deficiency, blood dyscrasias), although in many patients no specific cause is found. The erythropoietin-stimulating agent darbepoetin alfa did not improve clinical outcomes in HFrEF patients with mild to moderate anaemia, but led to an excess of thromboembolic events and is therefore not recommended.⁴⁷⁵

11.13 Kidney dysfunction (including chronic kidney disease, acute kidney injury, cardio-renal syndrome and prostatic obstruction)

HF and CKD frequently coexist, share many risk factors (diabetes, hypertension, hyperlipidaemia) and interact to worsen prognosis.^476,477 CKD is generally defined as an eGFR <60 mL/min/1.73 m² and/or the presence of albuminuria (high 30–300 or very high >300 mg albumin/1 g of urine creatinine). Patients with severe renal dysfunction (eGFR <30 mL/min/1.73m²) have systematically been excluded from randomized clinical trials and therefore there is lack of evidence-based therapies in these patients.

A further deterioration in renal function, termed worsening renal function (WRF), is used to indicate an increase in serum creatinine, usually by >26.5 µmol/L (0.3 mg/dL) and/or a 25% increase or a 20% drop in GFR. The importance of these apparently small changes is that they are frequent, they promote the development and progression of CKD⁴⁷⁸ and, as a consequence, can worsen the prognosis of HF. Increases in creatinine during an AHF hospitalization are not always clinically relevant, especially when they are accompanied by appropriate decongestion, diuresis and haemoconcentration.⁴⁷⁹

Large increases in serum creatinine, termed acute kidney injury (AKI), are relatively rare in HF and are probably associated with the combination of diuretic therapy with other potentially nephrotoxic drugs such as some antibiotics (gentamicin and trimethoprim), contrast media, ACEIs, ARBs, NSAIDs, etc. Of relevance, some of these drugs may accumulate if they are renally excreted. In HF, WRF is relatively common, especially during initiation and up-titration of RAAS inhibitor therapy. Despite the fact that RAAS blockers can frequently cause a decrease in GFR in patients with HF, this reduction is usually small and should not lead to treatment discontinuation unless there is a marked decrease, as the treatment benefit in these patients is probably largely maintained.⁴⁸⁰ When large increases in serum creatinine occur, care should be taken to evaluate the patient thoroughly and should include assessment of a possible renal artery stenosis, excessive hyper- or hypovolaemia, concomitant medication and hyperkalaemia, which frequently coincides with WRF.

Diuretics, especially thiazides, but also loop diuretics, may be less effective in patients with a very low GFR, and if used, should be dosed appropriately (higher doses to achieve similar effects). Renally excreted drugs (e.g. digoxin, insulin and low molecular weight heparin) may accumulate in patients with renal impairment and may need dose adjustment if renal function deteriorates. Patients with HF and coronary or peripheral vascular disease are at risk of acute renal dysfunction when they undergo contrast media enhanced angiography [contrast-induced acute kidney injury (CI-AKI)]. Renal dysfunction and worsening renal function is further discussed in the section about AHF (see Section 12).

Prostatic obstruction is common in older men and can interfere with renal function; it should therefore be ruled out in men with HF with deteriorating renal function. α-adrenoceptor blockers cause hypotension and sodium and water retention, and may not be safe in HFrEF.^458,464,465 For these reasons, 5-α-reductase inhibitors are generally preferred in the medical treatment of prostatic obstruction in patients with HF.

11.14 Lung disease (including asthma and chronic obstructive pulmonary disease)

The diagnosis of COPD and asthma may be difficult in patients with HF, due to overlap in symptoms and signs, but also problems in the interpretation of spirometry, especially in HFpEF.^48,49,391 COPD (and asthma) in patients with HF may be overdiagnosed.⁴⁸¹ Spirometry should be performed when patients have been stable and euvolaemic for at least 3 months, to avoid the confounding effect of pulmonary congestion causing external obstruction of alveoli and bronchioles.⁴⁸² Both correctly and incorrectly labelled COPD are associated with worse functional status and a worse prognosis in HFrEF.

Beta-blockers are only relatively contraindicated in asthma, but not in COPD, although a more selective β1-adrenoceptor antagonist (i.e. bisoprolol, metoprolol succinate, or nebivolol) is preferred.^48,49,391 The contraindication to beta-blockers in asthma, as mentioned on pharmacy leaflets, is based on small case series published in the 1980s and late 1990s with very high initial dosages in young patients with severe asthma. In clinical practice, starting with low doses of cardioselective beta-blockers combined with close monitoring for signs of airway obstruction (wheezing, shortness of breath with lengthening of the expiration) may allow the use of profoundly effective beta-blockers in HFrEF, especially in older people where true severe asthma is uncommon. Therefore, according to the 2015 GINA global strategy report,^395,396 asthma is not an absolute contraindication, but these medications should only be used under close medical supervision by a specialist, with consideration of the risks for and against their use. The long-term safety of cardioactive inhaled pulmonary drugs is uncertain and the need for their use should be reconsidered in patients with HFrEF, especially as their benefit in asthma and COPD may be symptomatic only without a clear effect on mortality. Oral corticosteroids can cause sodium and water retention, potentially leading to worsening of HF, but this is not believed to be a problem with inhaled corticosteroids. Pulmonary hypertension can complicate severe long-standing COPD, which, as a result, makes right-sided HF and congestion more likely. Non-invasive ventilation, added to conventional therapy, improves the outcome of patients with acute respiratory failure due to hypercapnic exacerbation of COPD or HF in situations of acute pulmonary oedema.

11.15 Obesity

Obesity is a risk factor for HF¹⁴¹ and complicates its diagnosis, because it can cause dyspnoea, exercise intolerance and ankle swelling and may result in poor-quality echocardiographic images. Obese individuals also have reduced NP levels.⁶² Obesity is more common in HFpEF than in HFrEF, although it is possible that misdiagnosis may explain at least some of this difference in prevalence. Although obesity is an independent risk factor for developing HF, once HF is diagnosed, it is well established that obesity is associated with lower mortality across a wide range of body mass indexes (BMIs) (see also cachexia in Section 11.3)—the so-called obesity paradox also seen in other chronic illnesses.^414,416 Obesity should be managed as recommended in the ESC guidelines on cardiovascular disease prevention,⁴⁸³ if the aim is to prevent future development of HF. However, these guidelines do not refer to the HF patient in whom higher BMI is not adverse, and, although often recommended for symptom benefit and risk factor control, weight loss as an intervention has never been prospectively shown to be either beneficial or safe in HFrEF. When weight loss is occurring in HF, it is associated with high mortality and morbidity, worse symptom status and poor quality of life. In patients with HF with moderate degrees of obesity (BMI <35 kg/m²), weight loss cannot be recommended. In more advanced obesity (BMI 35–45 kg/m²), weight loss may be considered to manage symptoms and exercise capacity.

11.16 Sleep disturbance and sleep-disordered breathing

Sleep-disordered breathing (SDB) occurs in more than one-third of patients with HF,⁴⁸⁴ being even more prevalent in patients with AHF.⁴⁸⁵ The most common types are: central sleep apnoea (CSA, similar to Cheyne Stokes respiration, CSR), obstructive sleep apnoea (OSA), and a mixed pattern of the two. Other causes of sleep disturbance include anxiety, depression, decubitus or paroxysmal pulmonary congestion (orthopnoea and paroxysmal nocturnal dyspnoea) and diuretic therapy causing nocturnal diuresis. Reviewing sleep history (including asking a partner) is part of the holistic care of patients with HF (see Section 14). CSA and OSA have been shown to be associated with a worse prognosis in HF.^485,486 OSA is associated with an increased risk of incident HF in men.⁴⁸⁷ CSA is the most common form of SDB in HFrEF, and HFrEF is the most common cause of CSA, so they are closely linked. Screening for, and the diagnosis and treatment of, sleep apnoea is discussed in detail elsewhere.^484,488 Diagnosis used to require overnight polysomnography, although advanced home testing equipment which can distinguish the type of sleep apnoea has been developed.

Nocturnal oxygen supplementation, continuous positive airway pressure (CPAP), bi-level positive airway pressure (BiPAP), and adaptive servo-ventilation (ASV) may be considered to treat nocturnal hypoxaemia in OSA as recommended in other guidelines.^489,490 An apnoea/hypopnoea index (AHI) of above 30 per hour can be treated using any of CPAP, BiPAP, ASV and nocturnal oxygen supplementation, which have all been shown to be effective in this regard. It should be noted, however, that none of these interventions has been prospectively shown to be beneficial on major outcomes in HFrEF.

CPAP in HF related CSA has been shown to reduce the frequency of episodes of apnoea and hypopnoea, and improve LVEF and 6 minute walk test distance, but did not improve prognosis or the rate of HF related hospitalizations.⁴⁹¹

The recently published SERVE-HF⁴⁷³ trial has shown that ASV used in patients with HFrEF and a predominantly CSA was neutral regarding the composite primary endpoint (all-cause death, lifesaving cardiovascular intervention, i.e. cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock, or unplanned hospitalization for HF worsening), but more importantly led to an increase in both all-cause and cardiovascular mortality. Therefore ASV is not recommended in patients with HFrEF and predominantly CSA.

The safety and efficacy of alternative approaches to treating CSA in HFrEF patients, such as implantable phrenic nerve stimulation,^219,220,492 are presently undergoing clinical investigation and may require additional long term study.

11.17. Valvular heart disease

Valvular heart disease may cause or aggravate HF. This section briefly addresses problems particularly relevant to HF, and the reader is referred to the recent guidelines on valvular disease for more information.^493,494

Patients with HF and concomitant valvular heart disease constitute a high-risk population. Thus, the whole process of decision-making through a comprehensive evaluation of the risk–benefit ratio of different treatment strategies should be made by a multidisciplinary ‘heart team’ with a particular expertise in valvular heart disease, including cardiologists with expertise in HF, cardiac surgeons, a structural valve interventionist if a catheter-based therapy is being considered, imaging specialists, anaesthetists and, if needed, general practitioners, geriatricians, or intensive care specialists. This may be particularly beneficial in patients with HF being considered for surgery, transcatheter aortic valve implantation or transcatheter mitral valve intervention.

All patients should receive OMT. In those with HFrEF pharmacological therapy should be planned according to a previously described algorithm (see Section 7 for details). Care must be taken using vasodilators (ACEI, ARBs, CCBs, hydralazine, and nitrates) in patients with severe aortic stenosis in order not to cause hypotension.

11.17.1. Aortic stenosis

The main concern in patients with severe aortic stenosis and reduced LVEF is the entity of ‘low-flow, low-gradient’ aortic stenosis (valve area < 1 cm², LVEF < 40%, mean pressure gradient < 40 mmHg). In such individuals, low-dose dobutamine stress echocardiography should be considered to differentiate between patients with moderate aortic stenosis, and those with severe stenosis and low flow across the valve due to low stroke volume, and to evaluate for contractile or flow reserve.

If the mean gradient is > 40 mmHg, there is theoretically no lower LVEF limit for aortic valve replacement in symptomatic patients with severe aortic stenosis.

Transaortic valve implantation (TAVI) is recommended in patients with severe aortic stenosis who are not suitable for surgery as assessed by a ‘heart team’ and have predicted post-TAVI survival > 1 year. TAVI should be also considered in high-risk patients with severe aortic stenosis who may still be suitable for surgery, but in whom TAVI is favoured by a ‘heart team’ based on the individual risk profile and anatomic suitability.^495,496 In a recent trial in patients with severe aortic stenosis, TAVI with a self-expanding transcatheter aortic valve bioprosthesis was associated with a significantly higher rate of survival at 1 year which was sustained at 2 years.^497,498

11.17.2. Aortic regurgitation

In patients with severe aortic regurgitation, aortic valve repair or replacement is recommended in all symptomatic patients and in asymptomatic patients with resting LVEF ≤ 50%, who are otherwise fit for surgery.^499,500

11.17.3. Mitral regurgitation

This section refers to chronic settings while acute settings are discussed in Section 12.

Primary (organic) mitral regurgitation

Surgery is indicated in symptomatic patients with severe organic mitral regurgitation with no contra-indications to surgery. The decision of whether to replace or repair depends mostly on valve anatomy, surgical expertise available, and the patient's condition.

When the LVEF is < 30%, a durable surgical repair may improve symptoms, although its effect on survival is unknown. In this situation, the decision to operate should take account of response to medical therapy, co-morbidities, and the likelihood that the valve can be repaired (rather than replaced).

Secondary mitral regurgitation

This occurs because LV enlargement and remodelling lead to reduced leaflet closing. Effective medical therapy (including CRT in suitable patients) leading to reverse remodelling of the LV may reduce functional mitral regurgitation, and every effort should be made to optimize medical treatment in these patients.

Combined valve and coronary surgery should be considered in symptomatic patients with LV systolic dysfunction (LVEF < 30%), coronary arteries suitable for revascularization, and evidence of viability. Surgery is also recommended in patients with severe mitral regurgitation undergoing CABG with LVEF > 30%.

However, a recent study in patients with moderate, secondary ischaemic mitral regurgitation did not prove that the addition of mitral valve repair to CABG would lead to a higher degree of LV reverse remodelling.⁵⁰¹ Also, there is no evidence favouring mitral valve repair over replacement in the context of better outcomes and magnitude of LV remodelling.⁵⁰² In the presence of AF, atrial ablation and LA appendage closure may be considered at the time of mitral valve surgery.

The role of isolated mitral valve surgery in patients with severe functional mitral regurgitation and severe LV systolic dysfunction (LVEF < 30%) who cannot be revascularized or have non-ischaemic cardiomyopathy is questionable, and in most patients conventional medical and device therapy are preferred. In selected cases, repair may be considered in order to avoid or postpone transplantation. The decision should be based on comprehensive evaluation (including strain echocardiography or magnetic resonance imaging^499,503 and discussed within the ‘heart team’.

In patients with HF with moderate-severe, secondary mitral regurgitation who are judged inoperable or at high surgical risk, percutaneous mitral valve intervention (percutaneous edge-to-edge repair) may be considered in order to improve symptoms and quality of life, although no RCT evidence of improvement has been published, only registry studies.^504–506

11.17.4. Tricuspid regurgitation

Secondary (functional) tricuspid regurgitation (TR) frequently complicates the natural course of HF, due to annular dilatation and increased tricuspid leaflet tethering in relation to RV pressure and/or volume overload. Severe TR causes/deteriorates symptoms and signs of right HF, thus diuretics are used to reduce peripheral oedema. As hepatic congestion is often present in these patients (additionally contributing to hyperaldosteronism), an addition of an MRA (in higher natriuretic doses) may improve decongestion.⁵⁰⁷ Management of HF which underlies secondary TR should be optimized as TR may diminish, following the treatment of its cause. Indications for surgical correction of secondary TR complicating HF are not clearly established.^493,494 The need for correction of TR is usually considered at the time of surgical correction of left-sided valve lesions.^493,494 A recent first report indicated that catheter-based interventions may be possible for TR.⁵⁰⁸

Recommendations for treatment of valvular diseases in patients with heart failure

HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; LVEF = left ventricular ejection fraction; TAVI = transaortic valve implantation.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

12. Acute heart failure

12.1 Definition and classification

AHF refers to rapid onset or worsening of symptoms and/or signs of HF. It is a life-threatening medical condition requiring urgent evaluation and treatment, typically leading to urgent hospital admission.

AHF may present as a first occurrence (de novo) or, more frequently, as a consequence of acute decompensation of chronic HF, and may be caused by primary cardiac dysfunction or precipitated by extrinsic factors, often in patients with chronic HF. Acute myocardial dysfunction (ischaemic, inflammatory or toxic), acute valve insufficiency or pericardial tamponade are among the most frequent acute primary cardiac causes of AHF. Decompensation of chronic HF can occur without known precipitant factors, but more often with one or more factors, such as infection, uncontrolled hypertension, rhythm disturbances or non-adherence with drugs/diet (Table 12.1).

Table 12.1

Factors triggering acute heart failure

ACS = acute coronary syndromes; NSAIDs = non-steroidal anti-inflammatory drugs.

A large number of overlapping classifications of AHF based on different criteria have been proposed.^510–513 In practice the most useful classifications are those based on clinical presentation at admission, allowing clinicians to identify patients at high risk of complications and to direct management at specific targets, which creates a pathway for personalized care in the AHF setting. In most cases, patients with AHF present with either preserved (90–140 mmHg) or elevated (>140 mmHg; hypertensive AHF) systolic blood pressure (SBP). Only 5–8% of all patients present with low SBP (i.e. <90 mmHg; hypotensive AHF), which is associated with poor prognosis, particularly when hypoperfusion is also present.^514,515

Another approach is to classify patients according to the presence of the following precipitants/causes leading to decompensation, which need to be treated/corrected urgently (see Section 12.3.1): ACS, hypertensive emergency, rapid arrhythmias or severe bradycardia/conduction disturbance, acute mechanical cause underlying AHF or acute pulmonary embolism.

Clinical classification can be based on bedside physical examination in order to detect the presence of clinical symptoms/signs of congestion (‘wet’ vs. ‘dry’ if present vs. absent) and/or peripheral hypoperfusion (‘cold’ vs. ‘warm’ if present vs. absent) (Figure 12.1).^514,515 The combination of these options identifies four groups: warm and wet (well perfused and congested) —most commonly present; cold and wet (hypoperfused and congested); cold and dry (hypoperfused without congestion); and warm and dry (compensated, well perfused without congestion). This classification may be helpful to guide therapy in the initial phase and carries prognostic information.^510,514,515

Figure 12.1

Clinical profiles of patients with acute heart failure based on the presence/absence of congestion and/or hypoperfusion

Patients with HF complicating AMI can be classified according to Killip and Kimball¹³ into class I, no clinical signs of HF; class II, HF with rales and S₃ gallop; class III, with frank acute pulmonary oedema; class IV, cardiogenic shock, hypotension (SBP <90 mmHg) and evidence of peripheral vasoconstriction such as oliguria, cyanosis and diaphoresis.

Definitions of the terms used in this section related to clinical presentation of patients with AHF are provided in Table 12.2.

Table 12.2

Definitions of the terms used in Section 12 on acute heart failure

BP = blood pressure; bpm = beats per minute; PaCO₂ = partial pressure of carbon dioxide in arterial blood; PaO₂ = partial pressure of oxygen in arterial blood; SaO₂ = oxygen saturation.

12.2 Diagnosis and initial prognostic evaluation

The diagnostic workup needs to be started in the pre-hospital setting and continued in the emergency department (ED) in order to establish the diagnosis in a timely manner and initiate appropriate management. The greater benefit of early treatment is well established in ACS and now needs to be considered in the setting of AHF.^516,517 In parallel, coexisting life-threatening clinical conditions and/or precipitants that require urgent treatment/correction need to be immediately identified and managed (Figure 12.2). Typically, an initial step in the diagnostic workup of AHF is to rule out alternative causes for the patient's symptoms and signs (i.e. pulmonary infection, severe anaemia, acute renal failure).

Figure 12.2

Initial management of a patient with acute heart failure. ^aAcute mechanical cause: myocardial rupture complicating acute coronary syndrome (free wall rupture, ventricular septal defect, acute mitral regurgitation), chest trauma or cardiac intervention, acute native or prosthetic valve incompetence secondary to endocarditis, aortic dissection or thrombosis, see above.

When AHF is confirmed clinical evaluation is mandatory to select further management.

It is recommended that initial diagnosis of AHF should be based on a thorough history assessing symptoms, prior cardiovascular history and potential cardiac and non-cardiac precipitants, as well as on the assessment of signs/symptoms of congestion and/or hypoperfusion by physical examination and further confirmed by appropriate additional investigations such as ECG, chest X-ray, laboratory assessment (with specific biomarkers) and echocardiography.

In patients presenting with AHF, early initiation of appropriate therapy (along with relevant investigations) is of key importance.^516–518

Typically, symptoms and signs of AHF reflect fluid overload (pulmonary congestion and/or peripheral oedema) or, less often, reduced cardiac output with peripheral hypoperfusion (Table 12.2). Since the sensitivity and specificity of symptoms and signs are often not satisfactory, careful clinical evaluation needs to be followed by these additional investigations:

Chest X-ray can be a useful test for the diagnosis of AHF. Pulmonary venous congestion, pleural effusion, interstitial or alveolar oedema and cardiomegaly are the most specific findings for AHF, although in up to 20% of patients with AHF, chest X-ray is nearly normal.⁵¹⁹ Supine chest radiographs are of limited value in AHF. Chest X-ray is also useful to identify alternative non-cardiac diseases that may cause or contribute to the patient's symptoms (i.e. pneumonia, non-consolidative pulmonary infections).
ECG is rarely normal in AHF (high negative predictive value).⁵²⁰ It is also helpful in identifying underlying cardiac disease and potential precipitants (rapid AF, acute myocardial ischaemia).
Immediate echocardiography is mandatory only in patients with haemodynamic instability (particularly in cardiogenic shock) and in patients suspected of acute life-threatening structural or functional cardiac abnormalities (mechanical complications, acute valvular regurgitation, aortic dissection). Early echocardiography should be considered in all patients with de novo AHF and in those with unknown cardiac function; however, the optimal timing is unknown (preferably within 48 h from admission, if the expertise is available). Pocket-size echocardiography may be used as an extension of the clinical examination in the first instance where available. Repeated echocardiography is usually not needed unless there is relevant deterioration in clinical status. Bedside thoracic ultrasound for signs of interstitial oedema and pleural effusion may be useful in detecting AHF if the expertise is available.
Laboratory tests:
- – Natriuretic peptides.
- – Upon presentation to the ED or CCU/ICU, a plasma NP level (BNP, NT-proBNP or MR-proANP) should be measured in all patients with acute dyspnoea and suspected AHF to help in the differentiation of AHF from non-cardiac causes of acute dyspnoea. NPs have high sensitivity, and normal levels in patients with suspected AHF makes the diagnosis unlikely (thresholds: BNP <100 pg/mL, NT-proBNP <300 pg/mL, MR-proANP <120 pg/mL).^{57–61,77,78,521} However, elevated levels of NPs do not automatically confirm the diagnosis of AHF, as they may also be associated with a wide variety of cardiac and non-cardiac causes (Table 12.3). Unexpectedly low levels of NPs can be detected in some patients with decompensated end-stage HF, flash pulmonary oedema or right sided AHF.
- Other laboratory tests at presentation.
- – The following laboratory assessments should be performed at admission on the blood of all patients with AHF: cardiac troponin, blood urea nitrogen (BUN) (or urea), creatinine, electrolytes (sodium, potassium), liver function tests, thyroid-stimulating hormone (TSH), glucose and complete blood count; D-dimer is indicated in patients with a suspicion of acute pulmonary embolism.
  - ○ Routine arterial blood gas is not needed and should be restricted to patients in whom oxygenation cannot be readily assessed by pulse oximetry. However, arterial blood gas may be useful when a precise measurement of O₂ and CO₂ partial pressures is needed. A venous sample might acceptably indicate pH and CO₂.
  - ○ Of note, measurement of cardiac troponins is useful for detection of ACS as the underlying cause of AHF. However, elevated concentrations of circulating cardiac troponins are detected in the vast majority of patients with AHF, often without obvious myocardial ischaemia or an acute coronary event, suggesting ongoing myocyte injury or necrosis in these patients.⁵²⁵ Also in patients with acute pulmonary embolism as the underlying cause of acute decompensation, elevated troponins are useful for risk stratification and decision-making.⁵²⁶
  - ○ It is recommended to measure creatinine, BUN and electrolytes every 1–2 days while in the hospital and before discharge from the hospital. Of note, more frequent testing might be justified according to the severity of the case. Pre-discharge assessment of NPs may be considered for prognostic evaluation.
  - ○ Assessment of procalcitonin levels may be considered in patients with AHF with suspected coexisting infection, particularly for the differential diagnosis of pneumonia and to guide antibiotic therapy,⁵²⁷ if considered.
  - ○ Liver function tests are often impaired in patients with AHF due to haemodynamic derangements (both reduced output and increased venous congestion). Abnormal liver function tests identify patients at risk of poor prognosis and may be useful for optimal management.^528–530
  - ○ Since both hypothyroidism and hyperthyroidism may precipitate AHF, TSH should be assessed in newly diagnosed AHF.
  - ○ Multiple other biomarkers, including those reflecting inflammation, oxidative stress, neurohormonal disarray and myocardial and matrix remodelling, have been investigated for their diagnostic and prognostic value in AHF; however, none has reached the stage of being recommended for routine clinical use.
Routine invasive haemodynamic evaluation with a pulmonary artery catheter is not indicated for the diagnosis of AHF. It may be helpful in selected cases of haemodynamically unstable patients with an unknown mechanism of deterioration. Also, routine use of an arterial line or central venous line for diagnostic purposes is not indicated.

Table 12.3

Causes of elevated concentrations of natriuretic peptides^522–524

HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ICD = implantable cardioverter defibrillator.

Numerous clinical and laboratory variables are independent predictors of in-hospital complications and longer-term outcomes in AHF syndromes, but their impact on management has not been adequately established.

Recommendations regarding applied diagnostic measurements

AHF = acute heart failure; BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; ECG = electrocardiogram; MR-proANP = mid-regional pro A-type natriuretic peptide; NT-proBNP = N-terminal pro-B type natriuretic peptide; TSH = thyroid-stimulating hormone

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

12.3 Management

AHF is a life-threatening medical condition, thus rapid transfer to the nearest hospital should be pursued, preferably to a site with a cardiology department and/or a coronary care/intensive care unit (CCU/ICU).

Early diagnosis is important in AHF. Therefore, all patients with suspected AHF should have a diagnostic workup and appropriate pharmacological and non-pharmacological treatment should be started promptly and in parallel.

Initial evaluation and continued non-invasive monitoring of the patient's vital cardiorespiratory functions, including pulse oximetry, blood pressure, respiratory rate and a continuous ECG instituted within minutes, is essential to evaluate whether ventilation, peripheral perfusion, oxygenation, heart rate and blood pressure are adequate. Urine output should also be monitored, although routine urinary catheterization is not recommended.

Patients with respiratory distress/failure or haemodynamic compromise should be triaged to a location where immediate respiratory and cardiovascular support can be provided (Figure 12.2).

12.3.1 Identification of precipitants/causes leading to decompensation that needs urgent management

The next step should comprise the identification of major precipitants/causes leading to decompensation, which should be managed urgently to avoid further deterioration (Figure 12.2). These include the following: dentification of acute aetiologies/precipitants with subsequent initiation of specific treatments should be done within the immediate phase of AHF management (initial 60–120 min) (Figure 12.2).

Acute coronary syndrome. Patients presenting with ACS should be managed according to the ESC guidelines on non-ST elevation ACS (NSTE-ACS) and STEMI.^114,535 Coexistence of these two clinical conditions (ACS and AHF) always identifies a very-high-risk group where an immediate (i.e. <2 h from hospital admission in patients with NSTEMI, analogous to STEMI management) invasive strategy with intent to perform revascularization is recommended, irrespective of ECG or biomarker findings.^114,535 See below for patients presenting with persistent haemodynamic instability due to mechanical ACS complication.
Hypertensive emergency. AHF precipitated by rapid and excessive increase in arterial blood pressure typically manifests as acute pulmonary oedema. A prompt reduction in blood pressure should be considered as a primary therapeutic target and initiated as soon as possible. Aggressive blood pressure reduction (in the range of 25% during the first few hours and cautiously thereafter) with i.v. vasodilators in combination with loop diuretics is recommended.^317,536,537
Rapid arrhythmias or severe bradycardia/conduction disturbance. Severe rhythm disturbances in patients with AHF and unstable conditions should be corrected urgently with medical therapy, electrical cardioversion or temporary pacing^260,316,389 (see also Section 10.1 for AF management).
Electrical cardioversion is recommended if an atrial or ventricular arrhythmia is thought to be contributing to the patient's haemodynamic compromise in order to restore sinus rhythm and improve the patient's clinical condition.
Patients with AHF and incessant ventricular arrhythmias present a challenging scenario, as arrhythmias and haemodynamic instability operate in a vicious circle, perpetuating each other. In selected cases, immediate angiography (with resultant revascularization, if needed) and electrophysiological testing with radiofrequency ablation may be considered.²⁶⁰
Acute mechanical cause underlying AHF. This may present as a mechanical complication of ACS (free wall rupture, ventricular septal defect, acute mitral regurgitation), chest trauma or cardiac intervention, or as acute native or prosthetic valve incompetence secondary to endocarditis, aortic dissection or thrombosis and comprise rare causes of obstruction (e.g. cardiac tumours). Echocardiography is essential for diagnosis, and treatment typically requires circulatory support with surgical or percutaneous intervention.
Acute pulmonary embolism. When acute pulmonary embolism is confirmed as the cause of shock or hypotension, immediate specific treatment is recommended with primary reperfusion either with thrombolysis, catheter-based approach or surgical embolectomy.⁵²⁶ Patients presenting with acute pulmonary embolism should be managed according to the appropriate guidelines.⁵²⁶

12.3.2 Criteria for hospitalization in ward vs. intensive care/coronary care unit

Patients with persistent, significant dyspnoea or haemodynamic instability should be triaged to a location where immediate resuscitative support can be provided if needed.
For high-risk patients (i.e. with persistent, significant dyspnoea, haemodynamic instability, recurrent arrhythmias, AHF and associated ACS), initial care should be provided in a high-dependency setting (ICU/CCU). Clinical risk algorithms developed to predict in-hospital mortality of patients with AHF can assist in determining which patients in the ED need the highest level of inpatient care.^538,539
The criteria for ICU/CCU admission include any of the following:
- – need for intubation (or already intubated)
- – signs/symptoms of hypoperfusion
- – oxygen saturation (SpO₂) <90% (despite supplemental oxygen)
- – use of accessory muscles for breathing, respiratory rate >25/min
- – heart rate <40 or >130 bpm, SBP <90 mmHg.⁵⁴⁰
The remaining patients with AHF usually need hospitalization on an ordinary ward. Only a few patients admitted to the ED with AHF (mainly as exacerbation of HF symptoms with subtle signs of congestion) after a small dose of diuretics and some adjustments of oral therapy can be discharged directly home from the ED with advice to be clinically followed in an outpatient clinic.
Step-down care from the ICU/CCU is dictated by clinical stabilization and resolution of morbid conditions. Further treatment will be continued with the involvement of a multidisciplinary team and discharge planning.

12.3.3 Management of the early phase

Oxygen therapy and/or ventilatory support

Recommendations for the management of patients with acute heart failure: oxygen therapy and ventilatory support

AHF = acute heart failure; BiPAP = bilevel positive airway pressure; COPD = chronic obstructive pulmonary disease; CPAP = continuous positive airway pressure; PaCO₂ = partial pressure of carbon dioxide in arterial blood; PaO₂ = partial pressure of oxygen in arterial blood; SpO₂ = transcutaneous oxygen saturation.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

In AHF, oxygen should not be used routinely in non-hypoxaemic patients, as it causes vasoconstriction and a reduction in cardiac output.^546,547 In COPD, hyperoxygenation may increase ventilation–perfusion mismatch, suppressing ventilation and leading to hypercapnia. During oxygen therapy, acid–base balance and transcutaneous SpO₂ should be monitored.

Non-invasive positive pressure ventilation includes both CPAP and bi-level positive pressure ventilation (PPV). Bi-level PPV also allows inspiratory pressure support that improves minute ventilation and is especially useful in patients with hypercapnia, most typically COPD patients.

Congestion affects lung function and increases intrapulmonary shunting, resulting in hypoxaemia. The fraction of inspired oxygen (FiO₂) should be increased up to 100% if necessary, according to SpO₂, unless contraindicated. Hyperoxia, however, should be avoided.^546,547 Non-invasive positive pressure ventilation reduces respiratory distress^541–545 and may decrease intubation and mortality rates,⁵⁴³ although data regarding mortality are less conclusive. CPAP is a feasible technique in the pre-hospital setting, because it is simpler than pressure support positive end-expiratory pressure (PS-PEEP) and requires minimal training and equipment. On hospital arrival, patients who still show signs of respiratory distress should continue with non-invasive ventilation, preferably PS-PEEP, in case of acidosis and hypercapnia, particularly in those with a previous history of COPD or signs of fatigue.⁵⁴⁰

Caution should be exercised with regard to side effects of anaesthetic drugs, among which propofol can induce hypotension and have cardiodepressive side effects. In contrast, midazolam may have fewer cardiac side effects and thus is preferred in patients with AHF or cardiogenic shock.

A management algorithm for patients with AHF based on the clinical profile during an early phase is presented in Figure 12.3.

Figure 12.3

Management of patients with acute heart failure based on clinical profile during an early phase ^aSymptoms/signs of congestion: orthopnoea, paroxysmal nocturnal dyspnoea, breathlessness, bi-basilar rales, an abnormal blood pressure response to the Valsalva maneuver (left-sided); symptoms of gut congestion, jugular venous distension, hepatojugular reflux, hepatomegaly, ascites, and peripheral oedema (right-sided).

Pharmacological therapy

Recommendations for the management of patients with acute heart failure: pharmacotherapy

AHF = acute heart failure; ECG = electrocardiogram; HF = heart failure; i.v. = intravenous; LMWH = low molecular weight heparin; SBP = systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

^dBeta-blockers should be used cautiously, if the patient is hypotensive.

Diuretics

Diuretics are a cornerstone in the treatment of patients with AHF and signs of fluid overload and congestion. Diuretics increase renal salt and water excretion and have some vasodilatory effect. In patients with AHF and signs of hypoperfusion, diuretics should be avoided before adequate perfusion is attained.

The initial approach to congestion management involves i.v. diuretics with the addition of vasodilators for dyspnoea relief if blood pressure allows. To enhance diuresis or overcome diuretic resistance, options include dual nephron blockade by loop diuretics (i.e. furosemide or torasemide) with thiazide diuretics or natriuretic doses of MRAs.^570,571 However, this combination requires careful monitoring to avoid hypokalaemia, renal dysfunction and hypovolaemia.

Data defining optimal dosing, timing and method of delivery are incomplete. In the ‘high-dose’ arm of the DOSE study, administration of furosemide at 2.5 times the previous oral dose resulted in greater improvement in dyspnoea, larger weight change and fluid loss at the cost of transient worsening in renal function.⁵⁴⁸ In AHF, i.v. furosemide is the most commonly used first-line diuretic. The dose should be limited to the smallest amount to provide adequate clinical effect and modified according to previous renal function and previous dose of diuretics. The initial i.v. dose should be at least equal to the pre-existing oral dose used at home. Consequently, patients with new-onset AHF or those with chronic HF without a history of renal failure and previous use of diuretics may respond to i.v. boluses of 20–40 mg, whereas those with previous use of diuretics usually require higher doses. A bolus of 10–20 mg i.v. torasemide may be considered as an alternative.

Vasodilators

Intravenous vasodilators (Table 12.4) are the second most often used agents in AHF for symptomatic relief; however, there is no robust evidence confirming their beneficial effects.

They have dual benefit by decreasing venous tone (to optimize preload) and arterial tone (decrease afterload). Consequently, they may also increase stroke volume. Vasodilators are especially useful in patients with hypertensive AHF, whereas in those with SBP <90 mmHg (or with symptomatic hypotension) they should be avoided. Dosing should be carefully controlled to avoid excessive decreases in blood pressure, which is related to poor outcome. Vasodilators should be used with caution in patients with significant mitral or aortic stenosis.

Use of an inotrope (Table 12.5) should be reserved for patients with a severe reduction in cardiac output resulting in compromised vital organ perfusion, which occurs most often in hypotensive AHF. Inotropic agents are not recommended in cases of hypotensive AHF where the underlying cause is hypovolaemia or other potentially correctable factors before elimination of these causes. Levosimendan is preferable over dobutamine to reverse the effect of beta-blockade if beta-blockade is thought to be contributing to hypoperfusion.⁵⁷² However, levosimendan is a vasodilator, thus it is not suitable for treatment of patients with hypotension (SBP <85 mmHg) or cardiogenic shock unless in combination with other inotropes or vasopressors.^559,573,574 Inotropes, especially those with adrenergic mechanisms, can cause sinus tachycardia and may induce myocardial ischaemia and arrhythmias, thus ECG monitoring is required. There is long-standing concern that they may increase mortality, which derives from studies in which intermittent or continuous infusions of inotropes were given.^{559–563,575} In any case, inotropes have to be used with caution starting from rather low doses and up-titrating with close monitoring.

Vasopressors

Drugs with prominent peripheral arterial vasoconstrictor action such as norepinephrine or dopamine in higher doses (>5 μg/kg/min) are given to patients with marked hypotension. These agents are given to raise blood pressure and redistribute blood to the vital organs. However, this is at the expense of an increase in LV afterload.

Dopamine was compared with norepinephrine in the treatment of various shock patients. A subgroup analysis suggested that norepinephrine would have fewer side effects and lower mortality.⁵⁵⁸ Epinephrine (adrenaline) should be restricted to patients with persistent hypotension despite adequate cardiac filling pressures and the use of other vasoactive agents, as well as for resuscitation protocols.⁵⁷⁶

Thromboembolism prophylaxis

Thromboembolism prophylaxis with heparin or another anticoagulant is recommended unless contraindicated or unnecessary (because of existing treatment with oral anticoagulants).

Table 12.4

Intravenous vasodilators used to treat acute heart failure

^aNot available in many European countries.

Table 12.5

Positive inotropes and/or vasopressors used to treat acute heart failure

i.v. = intravenous.

^aAlso a vasodilator.

^bNot recommended in acutely worsened ischaemic heart failure.

^cBolus not recommended in hypotensive patients.

Digoxin

Digoxin is mostly indicated in patients with AF and rapid ventricular rate (>110 bpm) and given in boluses of 0.25–0.5 mg i.v. if not used previously (0.0625–0.125 mg may be an adequate dose in patients with moderate to severe renal dysfunction). However, in patients with co-morbidities or other factors affecting digoxin metabolism (including other drugs) and/or the elderly, the maintenance dose may be difficult to estimate theoretically, and in this situation it should be established empirically, based on the measurements of digoxin concentration in peripheral blood.

Vasopressin antagonists

Vasopressin antagonists such as tolvaptan block the action of arginine vasopressin (AVP) at the V₂ receptor in renal tubules and promote aquaresis. Tolvaptan may be used to treat patients with volume overload and resistant hyponatraemia (thirst and dehydration are recognized adverse effects).⁵⁷⁷

Opiates

Opiates relieve dyspnoea and anxiety. In AHF, routine use of opiates is not recommended and they may only be cautiously considered in patients with severe dyspnoea, mostly with pulmonary oedema. Dose-dependent side effects include nausea, hypotension, bradycardia and respiratory depression (potentially increasing the need for invasive ventilation). There are controversies regarding the potentially elevated mortality risk in patients receiving morphine.^568,569

Anxiolytics and sedatives

Anxiolytics or sedatives may be needed in a patient with agitation or delirium. Cautious use of benzodiazepines (diazepam or lorazepam) may be the safest approach.

Device therapy

Recommendations regarding renal replacement therapy in patients with acute heart failure

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

Renal replacement therapy

Ultrafiltration involves the removal of plasma water across a semipermeable membrane in response to a transmembrane pressure gradient. There is no evidence favouring ultrafiltration over loop diuretics as first-line therapy in patients with AHF.^571,578 At the present time, routine use of ultrafiltration is not recommended and should be confined to patients who fail to respond to diuretic-based strategies.

The following criteria may indicate the need for initiation of renal replacement therapy in patients with refractory volume overload: oliguria unresponsive to fluid resuscitation measures, severe hyperkalaemia (K⁺ >6.5 mmol/L), severe acidaemia (pH <7.2), serum urea level >25 mmol/L (150 mg/dL) and serum creatinine >300 µmol/L (>3.4 mg/dL).

Mechanical assist devices

Intra-aortic balloon pump

The conventional indications for an intra-aortic balloon pump (IABP) are to support the circulation before surgical correction of specific acute mechanical problems (e.g. interventricular septal rupture and acute mitral regurgitation), during severe acute myocarditis and in selected patients with acute myocardial ischaemia or infarction before, during and after percutaneous or surgical revascularization. There is no good evidence that an IABP is of benefit in other causes of cardiogenic shock (for details see below).

Ventricular assist devices

Ventricular assist devices and other forms of mechanical circulatory support (MCS) may be used as a ‘bridge to decision’ or longer term in selected patients (see Section 13).

Other interventions

In patients with AHF and pleural effusion, pleurocentesis with fluid evacuation may be considered if feasible in order to alleviate dyspnoea.

In patients with ascites, ascitic paracentesis with fluid evacuation may be considered in order to alleviate symptoms. This procedure, through reduction in intra-abdominal pressure, may also partially normalize the transrenal pressure gradient, thus improving renal filtration.⁵⁸¹

12.3.4 Management of patients with cardiogenic shock

Cardiogenic shock is defined as hypotension (SBP <90 mmHg) despite adequate filling status with signs of hypoperfusion (Table 12.2). The pathogenetic scenarios of cardiogenic shock range from low-output advanced end-stage chronic HF to acute-onset de novo cardiogenic shock most often caused by STEMI, but also by various aetiologies other than ACS. A patient in cardiogenic shock should undergo immediate comprehensive assessment. ECG and echocardiography are required immediately in all patients with suspected cardiogenic shock. In patients with cardiogenic shock complicating ACS, an immediate coronary angiography is recommended (within 2 h from hospital admission) with an intent to perform coronary revascularization.^114,535 Invasive monitoring with an arterial line should be also considered.

There is no agreement on the optimal method of haemodynamic monitoring in assessing and treating patients in cardiogenic shock, including pulmonary artery catheterization.

Pharmacologic therapy aims to improve organ perfusion by increasing cardiac output and blood pressure. After fluid challenge, pharmacologic management consists of an inotropic agent and a vasopressor as needed. Treatment is guided by the continuous monitoring of organ perfusion and haemodynamics. Pulmonary artery catheterization may be considered. As a vasopressor, norepinephrine is recommended when mean arterial pressure needs pharmacologic support. Dobutamine is the most commonly used adrenergic inotrope. Levosimendan may also be used in combination with a vasopressor.^582,583 Levosimendan infusion in cardiogenic shock following AMI on top of dobutamine and norepinephrine improved cardiovascular haemodynamics without leading to hypotension.^582,583 PDE3 inhibitors may be another option, especially in non-ischaemic patients.^561,584

However, rather than combining several inotropes, device therapy has to be considered when there is an inadequate response. Recently the IABP-SHOCK II trial showed that the use of an IABP did not improve outcomes in patients suffering from AMI and cardiogenic shock.^585,586 Therefore, routine use of an IABP cannot be recommended.

Recommendations regarding management of patients with cardiogenic shock

ACS = acute coronary syndrome; CCU = coronary care unit; ECG = electrocardiogram; IABP = intra-aortic balloon pump; ICU = intensive care unit; SBP = systolic blood pressure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting recommendations.

12.4 Management of evidence-based oral therapies

Recommendations regarding oral evidence-based disease-modifying therapies in patients with acute heart failure

AHF = acute heart failure; HFrEF = heart failure with reduced ejection fraction.

^aClass of recommendation.

^bLevel of evidence.

Oral disease-modifying HF therapy should be continued on admission with AHF, except in the presence of haemodynamic instability (symptomatic hypotension, hypoperfusion, bradycardia), hyperkalaemia or severely impaired renal function. In these cases, the daily dosage of oral therapy may be reduced or stopped temporarily until the patient is stabilized. In particular, beta-blockers can be safely continued during AHF presentations except in cardiogenic shock. A recent meta-analysis demonstrated that discontinuation of beta-blockers in patients hospitalized with AHF was associated with significantly increased in-hospital mortality, short-term mortality and the combined endpoint of short-term rehospitalization or mortality.⁵⁸⁷

12.5 Monitoring of clinical status of patients hospitalized due to acute heart failure

Recommendations regarding monitoring of clinical status of patients hospitalized due to acute heart failure

HF = heart failure; i.v. = intravenous.

^aClass of recommendation.

^bLevel of evidence.

Patients should be weighed daily and an accurate fluid balance chart should be maintained. Renal function should preferably be monitored with daily measurement of BUN/urea, creatinine and electrolytes. Routine use of a urinary catheter is not recommended.

Renal function is commonly impaired at admission, but may improve or deteriorate with diuresis. Routine monitoring of pulse, respiratory rate and blood pressure should continue. There is no study showing the usefulness of invasive haemodynamic monitoring in patients with AHF excluding those with cardiogenic shock. There is evidence that measuring NPs during the hospital admission may help with discharge planning. Patients whose NP concentrations fall during admission have lower cardiovascular mortality and readmission rates at 6 months.^588–590

12.6 Criteria for discharge from hospital and follow-up in high-risk period

Patients admitted with AHF are medically fit for discharge⁵⁵² atients should preferably be atients with chronic HF should be followed up within a multiprofessional HF service. Pre- and post-discharge management should follow the standards of care of the HFA.^540,591,592

when haemodynamically stable, euvolaemic, established on evidence-based oral medication and with stable renal function for at least 24 hours before discharge;
once provided with tailored education and advice about self-care.

enrolled in a disease management programme; follow-up plans must be in place prior to discharge and clearly communicated to the primary care team;
reviewed by their general practitioner within 1 week of discharge;
seen by the hospital cardiology team within 2 weeks of discharge if feasible.

12.7 Goals of treatment during the different stages of management of acute heart failure

During the treatment of patients with AHF, one can distinguish subsequent stages that require different therapeutic approaches (described in the previous sections of this chapter). Importantly, the goals of treatment during the different stages of management of patients with AHF also differ, and are summarized in Table 12.6.

Table 12.6

Goals of treatment in acute heart failure

CCU = coronary care unit; ED = emergency department; ICU = intensive care unit.

13. Mechanical circulatory support and heart transplantation

13.1 Mechanical circulatory support

For patients with either chronic or acute HF who cannot be stabilized with medical therapy, MCS systems can be used to unload the failing ventricle and maintain sufficient end-organ perfusion. Patients in acute cardiogenic shock are initially treated with short-term assistance using extracorporeal, non-durable life support systems so that more definitive therapy may be planned. Patients with chronic, refractory HF despite medical therapy can be treated with a permanent implantable left ventricular assist device (LVAD). Table 13.1 lists the current indications for the use of mechanical circulatory assist devices.⁵⁹³

Table 13.1

Terms describing various indications for mechanical circulatory support

BiVAD = biventricular assist device; BTB = bridge to bridge; BTC = bridge to candidacy; BTD = bridge to decision; BTR = bridge to recovery; BTT = bridge to transplantation; DT = destination therapy; ECLS = extracorporeal life support; ECMO = extracorporeal membrane oxygenation; HF = heart failure; LVAD = left ventricular assist device; MCS = mechanical circulatory support; VAD = ventricular assist device.

13.1.1 Mechanical circulatory support in acute heart failure

To manage patients with AHF or cardiogenic shock (INTERMACS level 1), short-term mechanical support systems, including percutaneous cardiac support devices, extracorporeal life support (ECLS) and extracorporeal membrane oxygenation (ECMO) may be used to support patients with left or biventricular failure until cardiac and other organ function have recovered. Typically the use of these devices is restricted to a few days to weeks. The Survival After Veno-arterial ECMO (SAVE) score can help to predict survival for patients receiving ECMO for refractory cardiogenic shock (online calculator at http://www.save-score.com).⁵⁹⁴

In addition, MCS systems, particularly ECLS and ECMO, can be used as a ‘bridge to decision’ (BTD) in patients with acute and rapidly deteriorating HF or cardiogenic shock to stabilize haemodynamics, recover end-organ function and allow for a full clinical evaluation for the possibility of either heart transplant or a more durable MCS device.⁵⁹⁵

Evidence regarding the benefits of temporary percutaneous MCS in patients not responding to standard therapy, including inotropes, is limited. In a meta-analysis of three randomized clinical trials comparing a percutaneous MCS vs. IABP in a total of 100 patients in cardiogenic shock, percutaneous MCS appeared safe and demonstrated better haemodynamics, but did not improve 30-day mortality and was associated with more bleeding complications.⁵⁹⁶ In a randomized trial on high-risk PCI in patients with impaired LV function (PROTECT II trial), the 30-day incidence of major adverse events was not different for patients with IABP or a haemodynamic support device.⁵⁹⁷ Based on these results, temporary percutaneous MCS cannot be recommended as a proven or efficacious treatment for acute cardiogenic shock. In selected patients it may serve as a bridge to definite therapy. A difficult decision to withdraw MCS may need to be made when the patient has no potential for cardiac recovery and is not eligible for longer-term MCS support or heart transplant.

13.1.2 Mechanical circulatory support in end-stage chronic heart failure

Heart transplantation has always been a limited therapeutic option for patients with end-stage chronic HF. The increasing number of patients with refractory, chronic HF and the declining willingness for organ donation have resulted in expanded waiting lists and prolonged waiting times for patients listed for heart transplantation (median 16 months in the region covered by Eurotransplant).⁵⁹⁸ More than 60% of patients are transplanted in high-urgency status, leaving little chance for patients listed for less urgent transplantation. Three times more patients are listed for heart transplantation annually than are actually transplanted, and the mortality rate on the Eurotransplant waiting list in 2013 was 21.7%.⁵⁹⁸

More recent data suggest that patients with ongoing LVAD support may have an improved survival on the transplant waiting list.⁵⁹⁹ Accordingly, MCS devices, particularly continuous-flow LVADs, are increasingly seen as an alternative to heart transplantation. Initially LVADs were developed for use as a short-term BTT approach (Table 13.1),⁶⁰⁰ but they are now being used for months to years in patients who will either face a long-term wait on the transplant list (currently only 10% of patients with an MCS device implanted with a BTT indication will receive an organ within 1 year of listing) or in patients who are not eligible for transplantation as permanent therapy or destination therapy. The number of patients with a permanent LVAD who are considered neither too old nor ineligible for transplantation is constantly growing. For a majority of these patients, lifelong LVAD therapy, despite eligibility for transplantation, has become a clinical reality. Current 2–3-year survival rates in carefully selected patients receiving the latest continuous flow devices are excellent, and comparable to early survival after heart transplantation.⁵⁹⁵ However, fewer data are available for longer-term outcomes. Among patients with continuous-flow LVADs, actuarial survival is 80% at 1 year and 70% at 2 years in predominantly non-transplant-eligible patients. Notably, survival of 85% at 2 years was recorded for patients up to 70 years of age without diabetes, renal impairment or cardiogenic shock.^601,602 Patients receiving LVAD devices as BTT have a post-transplant survival rate similar or better than those not requiring or receiving bridging.⁵⁹⁹ Despite technological improvements, bleeding, thromboembolism (both of which can cause stroke), pump thrombosis, driveline infections and device failure remain significant problems and affect the long-term outcome of patients on MCS.^{599,603–606} It is recommended that such devices should only be implanted and managed at centres with appropriately trained specialist HF physicians and surgeons and an outpatient LVAD clinic with trained nursing staff.⁶⁰⁷

In some patients, LV reverse remodelling and functional improvement during MCS may permit removal of the LVAD [‘bridge to recovery’ (BTR)]. This outcome is more likely in younger patients with an acute fulminant but reversible cause of HF, such as acute myocarditis or peripartum cardiomyopathy.^608,609 LVADs may also be used as a ‘bridge to candidacy’ (BTC) in order to permit recovery of end-organ dysfunction, improve RV function and relieve pulmonary hypertension, which may allow initially ineligible patients to become eligible for heart transplantation.

Earlier ventricular assist device (VAD) implantation in less severely ill patients, e.g. those not yet on inotropic support, was tested in a recent trial that revealed better outcomes than in those patients continuing on medical therapy.⁶⁰⁵ The INTERMACS registry likewise shows better outcomes in patients implanted with a higher INTERMACS class, although the majority of VAD implants are done at INTERMACS levels 1–3.^604,610 Additionally, it needs to be remembered that no RCTs exist comparing medical therapy vs. MCS devices in these transplant-eligible patients (Table 13.2).

Table 13.2

INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) stages for classifying patients with advanced heart failure

ECLS = extracorporeal life support; ECMO = extracorporeal membrane oxygenation; INTERMACS = Interagency Registry for Mechanically Assisted Circulatory Support; LVAD = left ventricular assist device; NYHA = New York Heart Association.

^aKaplan-Meier estimates with standard error of the mean for 1 year survival with LVAD therapy. Patients were censored at time of last contact, recovery or heart transplantation.

Due to small numbers outcomes for INTERMACS levels 5, 6, 7 were combined⁶¹⁰.

Typically, patients with end-stage HF considered for MCS exhibit many clinical hallmarks of declining cardiovascular function⁵⁹³ and may already be on continuous inotropic support or manifest a decline in end-organ function. Markers of liver and renal dysfunction, haematologic and coagulation abnormalities and lower serum albumin levels are associated with worse outcome.^611,612

Evaluation of RV function is crucial since postoperative RV failure greatly increases perioperative mortality and reduces survival to, and after, transplantation. There are, however, multiple approaches to assessment of the RV (see Section 5.2.3). If RV failure is expected to be potentially reversible, temporary (days to weeks) extracorporeal right ventricular assist device (RVAD) support using a centrifugal pump in addition to LVAD implantation may be considered. For patients with chronic biventricular failure or a high risk for persisting RV failure after LVAD implantation, implantation of a biventricular assist device (BiVAD) may be necessary. Patients requiring long-term BiVAD support must be transplant-eligible, as BiVAD therapy is not suitable for destination therapy. The outcomes of BiVAD therapy are inferior to those for LVAD therapy and therefore the indication for VAD therapy should be discussed before RV function deteriorates. The implantation of a total artificial heart with removal of the native heart should be restricted to selected patients who cannot be treated with an LVAD (unrepairable ventricular septal defect, cardiac rupture).

Patients with active infection, severe renal, pulmonary or hepatic dysfunction or uncertain neurological status after cardiac arrest or due to cardiogenic shock are not usually candidates for BTT or DT but may be candidates for BTC (Table 13.3).

Table 13.3

Patients potentially eligible for implantation of a left ventricular assist device

CI = cardiac index; HF = heart failure; i.v. = intravenous; LVEF = left ventricular ejection fraction; PCWP = pulmonary capillary wedge pressure; SBP = systolic blood pressure; VO₂ = oxygen consumption.

Recommendations for implantation of mechanical circulatory support in patients with refractory heart failure

HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVAD = left ventricular assist device.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

13.2 Heart transplantation

Heart transplantation is an accepted treatment for end-stage HF.^614,615 Although controlled trials have never been conducted, there is a consensus that transplantation—provided that proper selection criteria are applied—significantly increases survival, exercise capacity, quality of life and return to work compared with conventional treatment.

Apart from the shortage of donor hearts, the main challenges in transplantation are the consequences of the limited effectiveness and complications of immunosuppressive therapy in the long term (i.e. antibody-mediated rejection, infection, hypertension, renal failure, malignancy and coronary artery vasculopathy). The indications for and contraindications to heart transplantation have recently been updated and are summarized in Table 13.4.⁶¹⁶ It needs to be considered that some contraindications are transient and treatable. While an active infection remains a relative contraindication to heart transplantation, patients with HIV, hepatitis, Chagas disease and tuberculosis can be considered as suitable candidates provided certain strict management principles are adhered to by the teams. In patients with cancer requiring heart transplantation, a close collaboration with oncology specialists should occur to stratify each patient as to their risk of tumour recurrence.⁶¹⁶

Table 13.4

Heart transplantation: indications and contra-indications

BMI = body mass index; HF = heart failure; LVAD = left ventricular assist device.

The use of mechanical circulatory support, particularly LVAD, should be considered for patients with potentially reversible or treatable co-morbidities, such as cancer, obesity, renal failure, tobacco use and pharmacologically irreversible pulmonary hypertension, with a subsequent re-evaluation to establish candidacy.

14. Multidisciplinary team management

Non-pharmacological non-device/surgical interventions used in the management of HF (both HFrEF and HFpEF) are summarized in Tables 14.1 and 14.2 and detailed practical recommendations on their use have been published by the HFA of the ESC.^591,592 There is no evidence that these on their own improve mortality, morbidity or quality of life. For this reason, these interventions have not been given a recommendation with an evidence level. The exceptions are implementation of care in a multidisciplinary framework, monitoring and exercise training (see recommendations table), all of which are discussed below.

Table 14.1

Characteristics and components of management programmes for patients with heart failure

Table 14.2

Key topics and self-care skills to include in patient education and the professional behaviours to optimize learning and facilitate shared decision making

Table 14.2

Key topics and self-care skills to include in patient education and the professional behaviours to optimize learning and facilitate shared decision making (continued)

HF = heart failure; ICD = implantable cardioverter defibrillator.

Recommendations for exercise, multidisciplinary management and monitoring of patients with heart failure

HF = heart failure; HFrEF = heart failure with reduced ejection fraction; ICD = implantable cardioverter-defibrillator; LVEF = left ventricular ejection fraction, IN-TIME = Implant-based multiparameter telemonitoring of patients with heart failure.

^aClass of recommendation.

^bLevel of evidence.

^cReference(s) supporting levels of evidence.

14.1 Organization of care

The goal of management of HF is to provide a ‘seamless’ system of care that embraces both the community and hospital throughout the health care journey. The standards of care that patients with HF should expect have been published by the ESC HFA.⁵⁹¹ To achieve this goal, other services, such as cardiac rehabilitation and palliative care, must be integrated into the overall provision for patients with HF. Fundamental to the delivery of this complete package of care are multidisciplinary management programmes designed to improve outcomes through structured follow-up with patient education, optimization of medical treatment, psychosocial support and improved access to care (Table 14.1). Such strategies reduce HF hospitalization and mortality in patients discharged from the hospital.^624,625

Key to the success of these programmes is coordination of care along the continuum of HF and throughout the chain of care delivered by the various services within the health care system. This necessitates close collaboration between HF practitioners (primarily cardiologists, HF nurses and general practitioners) and other experts, including pharmacists, dieticians, physiotherapists, psychologists, palliative care providers and social workers. The content and structure of HF management programmes may vary in different countries and health care settings. The components shown in Table 14.1 are recommended. HF services should be easily accessible to the patient and his/her family and care providers. A telephone helpline may facilitate access to professional advice.

The website http://ww.heartfailurematters.org is an option for professional information for those patients and families with Internet access.

14.2 Discharge planning

Early readmission after hospital discharge is common and may be addressed through coordinated discharge planning. The standards of care that patients should expect have been published by the HFA and the Acute Cardiac Care Association.^540,631 Discharge planning should commence as soon as the patient's condition is stable. During hospital admission, providing patients with information and education for self-care improves outcome. Discharge should be arranged for when the patient is euvolaemic and any precipitants of the admission have been treated. Hospitals with early physician follow-up after discharge show reduced 30-day readmission, and those that initiated programmes to discharge patients with an outpatient follow-up appointment already scheduled experienced a greater reduction in readmissions than those not taking up this strategy.⁶³²

14.3 Lifestyle advice

There is little evidence that specific lifestyle advice improves quality of life or prognosis; however, providing this information has become a key component of education for self-care. Patients should be provided with sufficient up-to-date information to make decisions on lifestyle adjustment and self-care. Ideally for those patients admitted to the hospital, lifestyle advice should begin prior to discharge. Information should be individually tailored to need and take into account relevant co-morbidities that may influence retention of information (such as cognitive impairment and depression). Practical recommendations have been published by the HFA.⁵⁹¹ Key topics to include are recommended in Table 14.2.

14.4 Exercise training

Several systematic reviews and meta-analyses of small studies have shown that physical conditioning by exercise training improves exercise tolerance, health-related quality of life and HF hospitalization rates in patients with HF. A single large RCT⁶¹⁸ showed a modest and non-significant reduction in the primary composite outcome of all-cause mortality or all-cause hospitalization. There was no reduction in mortality and no safety concerns were raised.^618,633 The most recent Cochrane review of exercise training⁶¹⁹ included 33 trials with 4740 patients with HF (predominantly HFrEF). There was a trend towards a reduction in mortality with exercise in trials with >1 year of follow-up. Compared with the control group, exercise training reduced the rate of overall and HF-specific hospitalization and improved quality of life. Practical recommendations on exercise training have been published by the HFA.¹²⁰

There is evidence that in patients with HFpEF, exercise training has several benefits, including improvements in exercise capacity, as measured objectively using peak oxygen consumption, quality of life and diastolic function, assessed by echocardiography.^{321,620,621,634}

Patients with HF, regardless of LVEF, are recommended to perform properly designed exercise training (see the recommendations table).

14.5 Follow-up and monitoring

Patients with HF benefit from regular follow-up and monitoring of biomedical parameters to ensure the safety and optimal dosing of medicines and detect the development of complications or disease progression that may require a change in management (e.g. the onset of AF or development of anaemia). Monitoring may be undertaken by the patients themselves during home visits, in community or hospital clinics, by remote monitoring with or without implanted devices or by structured telephone support (STS). The optimal method of monitoring will depend on local organizations and resources and will vary among patients. For example, more frequent monitoring will be required during periods of instability or optimization of medication. Older adults may also benefit from more frequent monitoring. Some patients will be keen and able to participate in self-monitoring.

High circulating NPs predict unfavourable outcomes in patients with HF, and a decrease in NP levels during recovery from circulatory decompensation is associated with a better prognosis.^588–590 Although it is plausible to monitor clinical status and tailor treatment based on changes in circulating NPs in patients with HF, published studies have provided differing results.^635–638 This does not enable us to recommend a broad application of such an approach.

Telemedicine in HF, which is also termed remote patient management, has variable clinical trial results.⁶³⁹ Several meta-analyses suggest clinical benefits, but numerous prospectively initiated clinical trials including >3700 patients have not confirmed this. These clinical trials include Tele-HF,⁶⁴⁰ TIM-HF,⁶⁴¹ INH,⁶⁴² WISH⁶⁴³ and TEHAF.⁶⁴⁴ It is clear that there is not just one type of telemedicine, and each approach needs to be assessed on its individual merit.

Recently, two individual approaches were shown to be successful in improving clinical outcome when used in patients with HFpEF or HFrEF. These approaches include the CardioMems system (tested in 550 patients with both HFrEF and HFpEF)⁶²⁸ and the IN-TIME approach (tested in 664 HFrEF patients)⁶³⁰, which may be considered for use in selected patients with HF (see the recommendations table).

14.6 The older adult, frailty and cognitive impairment

HF management and self-care behaviour are complicated by ageing, co-morbid conditions, cognitive impairment, frailty and limited social support. HF is also a leading cause of hospital admission in the older adult, where it is associated with increased hospital length of stay and risk of mortality.⁶⁴⁵

Frailty is common in older adults with HF, with a recent study suggesting it may be present in >70% of patients with HF and >80 years of age.⁶⁴⁵ Frailty scoring systems provide an objective assessment and identify the presence of or change in the level of frailty. Patients with a high frailty score will benefit from closer contact with the HF specialist team, more frequent follow-up and monitoring and individualized self-care support.

Frailty scores include⁶⁴⁶ walking speed (gait speed test), timed up-and-go test, PRISMA 7 questionnaire, Frail Score,⁶⁴⁷ Fried Score^647,648 and Short Physical Performance Battery (SPPB).

Cognitive impairment and HF frequently coexist. Acute delirium is also associated with decompensated HF and may be present on hospital admission. Cognitive function can be assessed using the Mini-Mental State Examination⁶⁴⁹ or the Montreal cognitive assessment.⁶⁵⁰ The presence of delirium and HF is found more commonly in older adults and is associated with increased mortality and poorer self-care ability and increases any hospital length of stay.⁶⁵¹ There is currently no clinical evidence that HF medication worsens or improves cognitive function. However, its effect on HF outcome suggests such medication should be used. Support from a multidisciplinary HF team in collaboration with specialist dementia support teams, alongside medication compliance aids, tailored self-care advice and involvement of family and caregivers, may improve adherence with complex HF medication and self-care regimens (see Table 14.2 on patient education) (Table 14.3).

Table 14.3

Specific recommendations regarding monitoring and follow-up of the older adult with heart failure

14.7 Palliative and end-of-life care

Palliative care approaches include a focus on symptom management, emotional support and communication between the patient and his/her family. Ideally this should be introduced early in the disease trajectory and increased as the disease progresses. A decision to alter the focus of care from modifying disease progression to optimising quality of life should be made in discussion with the patient, cardiologist, nurse and general practitioner. The patient's family should be involved in such discussions if requested by the patient^652,653 (Table 14.4).

Table 14.4

Patients with heart failure in whom end of life care should be considered

Key components of a palliative care service are recommended in Table 14.5. Palliative care has been discussed in detail in a position paper from the ESC HFA.⁶⁵⁴

Table 14.5

Key components of palliative care service in patients with heart failure

Liaison between the specialist palliative care services and the HF team and/or the primary care physician, using a shared care approach, is required in order to address and optimally coordinate the patient's care. Recent pilot studies have suggested an improvement in symptom burden and quality of life,^653,655 but these data are too limited to provide a recommendation.

Specific therapies and actions may provide palliation of symptoms and improve quality of life but have a limited evidence base: deally these therapies should be delivered in the patient's home. In the majority of cases the whole family should receive social support.⁶⁵²

Morphine (with an antiemetic when high doses are needed) can be used to reduce breathlessness, pain and anxiety.⁶⁵⁶
Increasing the inspired oxygen concentration may provide relief of dyspnoea.
Diuretic management can be used to relieve severe congestion or optimize symptom control (congestion and thirst).
Reduce HF drugs that reduce blood pressure to maintain sufficient oxygenation and reduce the risk of falls.

A management plan should be developed through discussion with the patient and family. It should include learly, symptoms and quality of life change over time and regular reassessment is recommended. Palliative scores provide an objective assessment of the patient's symptoms and needs and may help establish the effectiveness of therapy.

A discussion about stopping medication that does not have an immediate effect on symptom management or health-related quality of life, such as agents to lower cholesterol or treat osteoporosis
Documentation of the patient's decision regarding resuscitation attempts
Deactivation of an ICD at end-of-life (according to local legal regulations)
Preferred place for care and death
Emotional support to the patient and family/caregiver with appropriate referral for psychological or spiritual support

Palliative outcome scores include the Palliative Care Outcome Scale,⁶⁵⁷ Karnofsky Performance Status⁶⁵⁸ and Functional Assessment of Chronic Illness Therapy – Palliative Care (FACIT-Pal).⁶⁵⁹

15. Gaps in evidence

Clinicians responsible for managing patients with HF must frequently make treatment decisions without adequate evidence or a consensus of expert opinion. The following is a short list of selected, common issues that deserve to be addressed in future clinical research.

1. Definition, diagnosis, epidemiology . Strategies aimed at prevention and screening of HF . Pharmacological therapy . Devices and interventions . Co-morbidities . Acute heart failure . Other/remaining aspects

• For HFmrEF/HFpEF, research into the underlying characteristics, pathophysiology and diagnosis (with new modalities)
• Updated epidemiology on HF incidence and prevalence including patients from all continents
• For imaging and biomarkers, studies on effects of specific imaging modalities and biomarkers to improve clinical outcome (e.g. biomarker-guided therapies, detection of CAD/myocardial ischaemia, late-gadolinium enhancement CMR, echocardiographic strain measurements, stress echocardiography, etc.)
• Increasing awareness of HF in the medical community, lay public and among policy makers.

• Evaluate the comparative clinical effectiveness and cost-effectiveness of different strategies to screen for HF.

• Identification of non-responders to current guideline-advised medical treatment
• Targeted therapies for specific aetiologies of HFrEF (e.g. myocarditis, peripartum cardiomyopathy)
• Therapies directly improving cardiomyocyte function (e.g. acto-myosin cross-bridge activation, sarco/endoplasmic reticulum Ca²⁺-ATPase activation, ryanodine receptor stabilization, energetic modulation) or targeting non-myocytic compartment (e.g. anti-fibrosis/matrix remodelling)
• Therapies for HFmrEF/HFpEF (ARNIs, beta-blockers, soluble guanyl cyclase inhibitors, i.v. iron)

• Indications for ICDs in specific subgroups (e.g. ARVC and HFmrEF/HFpEF) and optimal selection of ICD candidates
• QRS morphology or duration as a predictor of response to CRT
• CRT in patients with AF
• Efficacy of PV ablation as a rhythm-control strategy in patients with AF
• Interventional approach to recurrent, life-threatening ventricular tachyarrhythmias
• The role of remote monitoring strategies in HF
• Non-surgical (percutaneous) correction of functional mitral and tricuspid regurgitations
• Identification of indications for coronary angiography/revascularization in patients with HF and chronic stable CAD
• Effects of novel LVADs as destination therapy and bridge to transplantation

• A better understanding of pathophysiology and potential treatments in specific HF populations, including the
- • very elderly,
- • young patients,
- • eGFR <30 mL/min,
- • diabetic patients,
- • cardiotoxic chemotherapy-induced HF,
- • muscular dystrophies,
- • cachexia and depression.
• Therapies for HF-related sleep-disordered breathing in HFrEF/HFpEF/HFmrEF.

• Prospective evaluation of the ‘time-to-treatment’ concept in AHF
• Evaluation of whether inadequate phenotyping is responsible for the failure of treatments to improve outcome in AHF
• Better definition and treatment of diuretic resistance
• Role of nitrates in the management of AHF
• Treatments improving mortality and morbidity
• Strategies and therapies to prevent early rehospitalization after discharge for a hospital admission for AHF.

• Treatment algorithms for patients with HF excluded by pivotal clinical trials
• Palliative and end-of-life care management and assessment of outcome
• Optimal integration of multidisciplinary care, self-management of patients and their adherence.

16. To do and not to do messages from the Guidelines

To do and not to do messages from the Guidelines (continued)

ACE-I = angiotensin-converting enzyme inhibitor; AHF = acute heart failure;; ARB = angiotensin receptor blocker; AST = aspartate aminotransferase; AV = atrio-ventricular; BNP = B-type natriuretic peptide; CCU = coronary care unit; COX-2 = cyclooxygenase 2; CRT = cardiac resynchronization therapy; CT = computed tomography; DCM = dilated cardiomyopathy; ECG = electrocardiogram; HF = heart failure; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ICD = implantable cardioverter-defibrillator; ICU = intensive care unit; i.v. = intravenous; LBBB = left bundle branch block; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR-proANP = mid-regional pro A-type natriuretic peptide; NSAIDs = non-steroidal anti-inflammatory drugs; NT-proBNP = N-terminal pro-B type natriuretic peptide; NYHA = New York Heart Association; OMT = optimal medical therapy; QRS = Q, R, and S waves (combination of three of the graphical deflections); RV = right ventricular; TTE = transthoracic echocardiography.

^aClass of recommendation.

^bLevel of evidence

^cOr ARB if ACEI is not tolerated/contra-indicated.

17. Web Addenda

All Web figures and Web tables are available in the Supplementary Data, available at European Heart Journal online and also via the ESC website.

18. Appendix

ESC Committee for Practice Guidelines (CPG): Jose Luis Zamorano (Chairperson) (Spain), Victor Aboyans (France), Stephan Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon (Spain), Gonzalo Barón-Esquivias (Spain), Helmut Baumgartner (Germany), Jeroen J. Bax (The Netherlands), Héctor Bueno (Spain), Scipione Carerj (Italy), Veronica Dean (France), Çetin Erol (Turkey), Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Paulus Kirchhof (UK/Germany), Philippe Kolh (Belgium), Patrizio Lancellotti (Belgium), Gregory Y. H. Lip (UK), Petros Nihoyannopoulos (UK), Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Marco Roffi (Switzerland), Adam Torbicki (Poland), António Vaz Carneiro (Portugal), Stephan Windecker (Switzerland).

ESC National Cardiac Societies actively involved in the review process of the 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

Armenia: Armenian Cardiologists Association, Hamayak S. Sisakian; Azerbaijan: Azerbaijan Society of Cardiology, Elnur Isayev; Belarus: Belorussian Scientific Society of Cardiologists, Alena Kurlianskaya; Belgium: Belgian Society of Cardiology, Wilfried Mullens; Bulgaria: Bulgarian Society of Cardiology, Mariya Tokmakova; Cyprus: Cyprus Society of Cardiology, Petros Agathangelou; Czech Republic: Czech Society of Cardiology, Vojtech Melenovsky; Denmark: Danish Society of Cardiology, Henrik Wiggers; Egypt: Egyptian Society of Cardiology, Mahmoud Hassanein; Estonia: Estonian Society of Cardiology, Tiina Uuetoa; Finland: Finnish Cardiac Society, Jyri Lommi; Former Yugoslav Republic of Macedonia: Macedonian FYR Society of Cardiology, Elizabeta Srbinovska Kostovska; France: French Society of Cardiology, Yves Juillière; Georgia: Georgian Society of Cardiology, Alexander Aladashvili; Germany: German Cardiac Society, Andreas Luchner; Greece: Hellenic Cardiological Society, Christina Chrysohoou; Hungary: Hungarian Society of Cardiology, Noémi Nyolczas; Iceland: Icelandic Society of Cardiology, Gestur Thorgeirsson; Israel: Israel Heart Society, Jean Marc Weinstein; Italy: Italian Federation of Cardiology, Andrea Di Lenarda; Kazakhstan: Association of Cardiologists of Kazakhstan, Nazipa Aidargaliyeva; Kosovo: Kosovo Society of Cardiology, Gani Bajraktari; Kyrgyzstan: Kyrgyz Society of Cardiology, Medet Beishenkulov; Latvia: Latvian Society of Cardiology, Ginta Kamzola; Lebanon: Lebanese Society of Cardiology, Tony Abdel-Massih; Lithuania: Lithuanian Society of Cardiology, Jelena Čelutkienė; Luxembourg: Luxembourg Society of Cardiology, Stéphanie Noppe; Malta: Maltese Cardiac Society, Andrew Cassar; Moldova: Moldavian Society of Cardiology, Eleonora Vataman; Morocco: Moroccan Society of Cardiology, Saadia Abir-Khalil; The Netherlands: Netherlands Society of Cardiology, Petra van Pol; Norway: Norwegian Society of Cardiology, Rune Mo; Poland: Polish Cardiac Society, Ewa Straburzyńska-Migaj; Portugal: Portuguese Society of Cardiology, Cândida Fonseca; Romania: Romanian Society of Cardiology, Ovidiu Chioncel; Russian Federation: Russian Society of Cardiology, Evgeny Shlyakhto; San Marino: San Marino Society of Cardiology, Marco Zavatta; Serbia: Cardiology Society of Serbia, Petar Otasevic; Slovakia: Slovak Society of Cardiology, Eva Goncalvesová; Slovenia: Slovenian Society of Cardiology, Mitja Lainscak; Spain: Spanish Society of Cardiology, Beatriz Díaz Molina; Sweden: Swedish Society of Cardiology, Maria Schaufelberger; Switzerland: Swiss Society of Cardiology, Thomas Suter; Turkey: Turkish Society of Cardiology, Mehmet Birhan Yılmaz; Ukraine: Ukrainian Association of Cardiology, Leonid Voronkov; United Kingdom: British Cardiovascular Society, Ceri Davies.

19. References

1

Filippatos

G

,

Khan

SS

,

Ambrosy

AP

,

Cleland

JGF

,

Collins

SP

,

Lam

CSP

,

Angermann

CE

,

Ertl

G

,

Dahlström

U

,

Hu

D

,

Dickstein

K

,

Perrone

S V

,

Ghadanfar

M

,

Bermann

G

,

Noe

A

,

Schweizer

A

,

Maier

T

,

Gheorghiade

M

.

International REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure (REPORT-HF): rationale for and design of a global registry

.

Eur J Heart Fail

2015

;

17

:

527

–

533

.

2

The CONSENSUS Trial Study Group

.

Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)

.

N Engl J Med

1987

;

316

:

1429

–

1435

.

3

McMurray

JJJ V

.

Improving outcomes in heart failure: a personal perspective

.

Eur Heart J

2015

;

36

:

3467

–

3470

.

4

Wang

TJ

.

Natural history of asymptomatic left ventricular systolic dysfunction in the community

.

Circulation

2003

;

108

:

977

–

982

.

5

The SOLVD Investigators

.

Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions

.

N Engl J Med

1992

;

327

:

685

–

691

.

6

Butler

J

,

Fonarow

GC

,

Zile

MR

,

Lam

CS

,

Roessig

L

,

Schelbert

EB

,

Shah

SJ

,

Ahmed

A

,

Bonow

RO

,

Cleland

JGF

,

Cody

RJ

,

Chioncel

O

,

Collins

SP

,

Dunnmon

P

,

Filippatos

G

,

Lefkowitz

MP

,

Marti

CN

,

McMurray

JJ

,

Misselwitz

F

,

Nodari

S

,

O'Connor

C

,

Pfeffer

MA

,

Pieske

B

,

Pitt

B

,

Rosano

G

,

Sabbah

HN

,

Senni

M

,

Solomon

SD

,

Stockbridge

N

,

Teerlink

JR

,

Georgiopoulou

VV

,

Gheorghiade

M

.

Developing therapies for heart failure with preserved ejection fraction: current state and future directions

.

JACC Heart Fail

2014

;

2

:

97

–

112

.

7

McMurray

JJ V

,

Adamopoulos

S

,

Anker

SD

,

Auricchio

A

,

Böhm

M

,

Dickstein

K

,

Falk

V

,

Filippatos

G

,

Fonseca

C

,

Gomez-Sanchez

MA

,

Jaarsma

T

,

Køber

L

,

Lip

GYH

,

Maggioni

A Pietro

,

Parkhomenko

A

,

Pieske

BM

,

Popescu

BA

,

Rønnevik

PK

,

Rutten

FH

,

Schwitter

J

,

Seferovic

P

,

Stepinska

J

,

Trindade

PT

,

Voors

AA

,

Zannad

F

,

Zeiher

A

,

Bax

JJ

,

Baumgartner

H

,

Ceconi

C

,

Dean

V

,

Deaton

C

,

Fagard

R

,

Funck-Brentano

C

,

Hasdai

D

,

Hoes

A

,

Kirchhof

P

,

Knuuti

J

,

Kolh

P

,

McDonagh

T

,

Moulin

C

,

Reiner

Z

,

Sechtem

U

,

Sirnes

PA

,

Tendera

M

,

Torbicki

A

,

Vahanian

A

,

Windecker

S

,

Bonet

LA

,

Avraamides

P

,

Ben Lamin

HA

,

Brignole

M

,

Coca

A

,

Cowburn

P

,

Dargie

H

,

Elliott

P

,

Flachskampf

FA

,

Guida

GF

,

Hardman

S

,

Iung

B

,

Merkely

B

,

Mueller

C

,

Nanas

JN

,

Nielsen

OW

,

Orn

S

,

Parissis

JT

,

Ponikowski

P

,

Members

AF

,

McMurray

JJ V

,

Adamopoulos

S

,

Anker

SD

,

Auricchio

A

,

Böhm

M

,

Dickstein

K

,

Falk

V

,

Filippatos

G

,

Fonseca

C

,

Gomez-Sanchez

MA

,

Jaarsma

T

,

Køber

L

,

Lip

GYH

,

Maggioni

A Pietro

,

Parkhomenko

A

,

Pieske

BM

,

Popescu

BA

,

Rønnevik

PK

,

Rutten

FH

,

Schwitter

J

,

Seferovic

P

,

Stepinska

J

,

Trindade

PT

,

Voors

AA

,

Zannad

F

,

Zeiher

A

,

Guidelines ESCC for P, Reviewers D

.

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart

.

Eur J Heart Fail

2012

;

14

:

803

–

869

.

8

McMurray

JJ V

.

Clinical practice

.

Systolic heart failure. N Engl J Med

2010

;

3623

:

228

–

238

.

9

Chen

J

,

Normand

S-LT

,

Wang

Y

,

Krumholz

HM

.

National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998–2008

.

JAMA

2011

;

306

:

1669

–

1678

.

10

Dunlay

SM

,

Redfield

MM

,

Weston

SA

,

Therneau

TM

,

Hall Long

K

,

Shah

ND

,

Roger

VL

.

Hospitalizations after heart failure diagnosis a community perspective

.

J Am Coll Cardiol

2009

;

54

:

1695

–

1702

.

11

Metra

M

,

Ponikowski

P

,

Dickstein

K

,

McMurray

JJ V

,

Gavazzi

A

,

Bergh

C-H,

,

Fraser

AG

,

Jaarsma

T

,

Pitsis

A

,

Mohacsi

P

,

Böhm

M

,

Anker

S

,

Dargie

H

,

Brutsaert

D

,

Komajda

M

.

Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology

.

Eur J Heart Fail

9

:

684

–

694

.

12

Yancy

CW

,

Jessup

M

,

Bozkurt

B

,

Butler

J

,

Casey

DE

,

Drazner

MH

,

Fonarow

GC

,

Geraci

SA

,

Horwich

T

,

Januzzi

JL

,

Johnson

MR

,

Kasper

EK

,

Levy

WC

,

Masoudi

FA

,

McBride

PE

,

McMurray

JJ V

,

Mitchell

JE

,

Peterson

PN

,

Riegel

B

,

Sam

F

,

Stevenson

LW

,

Tang

WHW

,

Tsai

EJ

,

Wilkoff

BL

.

2013 ACCF/AHA Guideline for the Management of Heart Failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

.

Circulation

2013

;

128

:

1810

–

1852

.

13

Killip

T

3rd ,

Kimball

JT

.

Treatment of myocardial infarction in a coronary care unit

.

A two year experience with 250 patients. Am J Cardiol

1967

;

20

:

457

–

464

.

14

Mosterd

A

,

Hoes

AW

.

Clinical epidemiology of heart failure

.

Heart

2007

;

93

:

1137

–

1146

.

15

Redfield

MM

,

Jacobsen

SJ

,

Burnett

JC

,

Mahoney

DW

,

Bailey

KR

,

Rodeheffer

RJ

.

Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic

.

JAMA

2003

;

289

:

194

–

202

.

16

Bleumink

GS

,

Knetsch

AM

,

Sturkenboom

MCJM

,

Straus

SMJM

,

Hofman

A

,

Deckers

JW

,

Witteman

JCM

,

Stricker

BHC

.

Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study

.

Eur Heart J England;

2004

;

25

:

1614

–

1619

.

17

Ceia

F

,

Fonseca

C

,

Mota

T

,

Morais

H

,

Matias

F

,

De Sousa

A

,

Oliveira

AG

.

Prevalence of chronic heart failure in Southwestern Europe: the EPICA study

.

Eur J Heart Fail

2002

;

4

:

531

–

539

.

18

van Riet

EES

,

Hoes

AW

,

Limburg

A

,

Landman

MAJ

,

van der Hoeven

H

,

Rutten

FH

.

Prevalence of unrecognized heart failure in older persons with shortness of breath on exertion

.

Eur J Heart Fail

2014

;

16

:

772

–

777

.

19

Filippatos

G

,

Parissis

JT

.

Heart failure diagnosis and prognosis in the elderly: the proof of the pudding is in the eating

.

Eur J Heart Fail

2011

;

13

:

467

–

471

.

20

Rutten

FH

,

Cramer

M-JM

,

Grobbee

DE

,

Sachs

APE

,

Kirkels

JH

,

Lammers

J-WJ

,

Hoes

AW

.

Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease

.

Eur Heart J

2005

;

26

:

1887

–

1894

.

21

Boonman-de Winter

LJM

,

Rutten

FH

,

Cramer

MJM

,

Landman

MJ

,

Liem

AH

,

Rutten

GEHM

,

Hoes

AW

.

High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes

.

Diabetologia

2012

;

55

:

2154

–

2162

.

22

van Riet

EES

,

Hoes

AW

,

Wagenaar

KP

,

Limburg

A

,

Landman

MAJ

,

Rutten

FH

.

Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review

.

Eur J Heart Fail

2016

;

23

Abhayaratna

WP

,

Smith

WT

,

Becker

NG

,

Marwick

TH

,

Jeffery

IM

,

McGill

DA

.

Prevalence of heart failure and systolic ventricular dysfunction in older Australians: the Canberra Heart Study

.

Med J Aust

2006

;

184

:

151

–

154

.

24

Tiller

D

,

Russ

M

,

Greiser

KH

,

Nuding

S

,

Ebelt

H

,

Kluttig

A

,

Kors

JA

,

Thiery

J

,

Bruegel

M

,

Haerting

J

,

Werdan

K

.

Prevalence of symptomatic heart failure with reduced and with normal ejection fraction in an elderly general population—the CARLA study

.

PLoS One

2013

;

8

:

e59225

.

25

Mureddu

GF

,

Agabiti

N

,

Rizzello

V

,

Forastiere

F

,

Latini

R

,

Cesaroni

G

,

Masson

S

,

Cacciatore

G

,

Colivicchi

F

,

Uguccioni

M

,

Perucci

CA

,

Boccanelli

A

.

Prevalence of preclinical and clinical heart failure in the elderly

.

A population-based study in Central Italy. Eur J Heart Fail

2012

;

14

:

718

–

729

.

26

Badano

LP

,

Albanese

MC

,

De Biaggio

P

,

Rozbowsky

P

,

Miani

D

,

Fresco

C

,

Fioretti

PM

.

Prevalence, clinical characteristics, quality of life, and prognosis of patients with congestive heart failure and isolated left ventricular diastolic dysfunction

.

J Am Soc Echocardiogr

2004

;

17

:

253

–

261

.

27

Philbin

EF

,

Rocco

TA

,

Lindenmuth

NW

,

Ulrich

K

,

Jenkins

PL

.

Systolic versus diastolic heart failure in community practice: clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors

.

Am J Med

2000

;

109

:

605

–

613

.

28

Magaña-Serrano

JA

,

Almahmeed

W

,

Gomez

E

,

Al-Shamiri

M

,

Adgar

D

,

Sosner

P

,

Herpin

D

.

Prevalence of heart failure with preserved ejection fraction in Latin American, Middle Eastern, and North African Regions in the I PREFER study (Identification of Patients With Heart Failure and PREserved Systolic Function: an epidemiological regional study

.

Am J Cardiol

2011

;

108

:

1289

–

1296

.

29

Peyster

E

,

Norman

J

,

Domanski

M

.

Prevalence and predictors of heart failure with preserved systolic function: community hospital admissions of a racially and gender diverse elderly population

.

J Card Fail

2004

;

10

:

49

–

54

.

30

Hellermann

JP

,

Jacobsen

SJ

,

Reeder

GS

,

Lopez-Jimenez

F

,

Weston

SA

,

Roger

VL

.

Heart failure after myocardial infarction: prevalence of preserved left ventricular systolic function in the community

.

Am Heart J

2003

;

145

:

742

–

748

.

31

Gerber

Y

,

Weston

SA

,

Redfield

MM

,

Chamberlain

AM

,

Manemann

SM

,

Jiang

R

,

Killian

JM

,

Roger

VL

.

A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010

.

JAMA Intern Med

2015

;

175

:

996

–

1004

.

32

Owan

TE

,

Hodge

DO

,

Herges

RM

,

Jacobsen

SJ

,

Roger

VL

,

Redfield

MM

.

Trends in prevalence and outcome of heart failure with preserved ejection fraction

.

N Engl J Med

2006

;

355

:

251

–

259

.

33

Meta-analysis Global Group in Chronic Heart Failure (MAGGIC)

.

The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis

.

Eur Heart J

2012

;

33

:

1750

–

1757

.

34

Lam

CSP

,

Solomon

SD

.

The middle child in heart failure: heart failure with mid-range ejection fraction (40–50%)

.

Eur J Heart Fail

2014

;

16

:

1049

–

1055

.

35

Maggioni

AP

,

Dahlström

U

,

Filippatos

G

,

Chioncel

O

,

Leiro

MC

,

Drozdz

J

,

Fruhwald

F

,

Gullestad

L

,

Logeart

D

,

Fabbri

G

,

Urso

R

,

Metra

M

,

Parissis

J

,

Persson

H

,

Ponikowski

P

,

Rauchhaus

M

,

Voors

AA

,

Nielsen

OW

,

Zannad

F

,

Tavazzi

L

,

Crespo Leiro

M

,

Drozdz

J

,

Fruhwald

F

,

Gullestad

L

,

Logeart

D

,

Fabbri

G

,

Urso

R

,

Metra

M

,

Parissis

J

,

Persson

H

,

Ponikowski

P

,

Rauchhaus

M

,

Voors

AA

,

Nielsen

OW

,

Zannad

F

,

Tavazzi

L

.

EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot)

.

Eur J Heart Fail

2013

;

15

:

808

–

817

.

36

Pocock

SJ

,

Ariti

CA

,

McMurray

JJV

,

Maggioni

A

,

Køber

L

,

Squire

IB

,

Swedberg

K

,

Dobson

J

,

Poppe

KK

,

Whalley

GA

,

Doughty

RN

.

Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies

.

Eur Heart J

2013

;

34

:

1404

–

1413

.

37

Rahimi

K

,

Bennett

D

,

Conrad

N

,

Williams

TM

,

Basu

J

,

Dwight

J

,

Woodward

M

,

Patel

A

,

McMurray

J

,

MacMahon

S

.

Risk prediction in patients with heart failure

.

JACC Heart Fail

2014

;

2

:

440

–

446

.

38

Ouwerkerk

W

,

Voors

AA

,

Zwinderman

AH

.

Factors influencing the predictive power of models for predicting mortality and/or heart-failure hospitalization in patients with heart failure

.

JACC Heart Fail

2014

;

2

:

429

–

436

.

39

Lupón

J

,

de Antonio

M

,

Vila

J

,

Peñafiel

J

,

Galán

A

,

Zamora

E

,

Urrutia

A

,

Bayes-Genis

A

.

Development of a novel heart failure risk tool: the Barcelona bio-heart failure risk calculator (BCN bio-HF calculator)

.

PLoS One

2014

;

9

:

e85466

.

40

Levy

WC

.

The Seattle Heart Failure Model: prediction of survival in heart failure

.

Circulation

2006

;

113

:

1424

–

1433

.

41

Mozaffarian

D

,

Anker

SD

,

Anand

I

,

Linker

DT

,

Sullivan

MD

,

Cleland

JGF

,

Carson

PE

,

Maggioni

AP

,

Mann

DL

,

Pitt

B

,

Poole-Wilson

PA

,

Levy

WC

.

Prediction of mode of death in heart failure: the Seattle Heart Failure Model

.

Circulation

2007

;

116

:

392

–

398

.

42

Davie

P

,

Francis

CM

,

Caruana

L

,

Sutherland

GR

,

McMurray

JJ

.

Assessing diagnosis in heart failure: which features are any use

?

QJM

1997

;

90

:

335

–

339

.

43

Mant

J

,

Doust

J

,

Roalfe

A

,

Barton

P

,

Cowie

MR

,

Glasziou

P

,

Mant

D

,

McManus

RJ

,

Holder

R

,

Deeks

J

,

Fletcher

K

,

Qume

M

,

Sohanpal

S

,

Sanders

S

,

Hobbs

FDR

.

Systematic review and individual patient data meta-analysis of diagnosis of heart failure, with modelling of implications of different diagnostic strategies in primary care

.

Health Technol Assess

2009

;

13

:

1

–

207

,

iii

.

44

Oudejans

I

,

Mosterd

A

,

Bloemen

JA

,

Valk

MJ

,

Van Velzen

E

,

Wielders

JP

,

Zuithoff

NP

,

Rutten

FH

,

Hoes

AW

.

Clinical evaluation of geriatric outpatients with suspected heart failure: value of symptoms, signs, and additional tests

.

Eur J Heart Fail

2011

;

13

:

518

–

527

.

45

Fonseca

C

.

Diagnosis of heart failure in primary care

.

Heart Fail Rev

2006

;

11

:

95

–

107

.

46

Kelder

JC

,

Cramer

MJ

,

van Wijngaarden

J

,

van Tooren

R

,

Mosterd

A

,

Moons

KGM

,

Lammers

JW

,

Cowie

MR

,

Grobbee

DE

,

Hoes

AW

.

The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure

.

Circulation

2011

;

124

:

2865

–

2873

.

47

Boonman-de Winter

LJM

,

Rutten

FH

,

Cramer

MJ

,

Landman

MJ

,

Zuithoff

NPA

,

Liem

AH

,

Hoes

AW

.

Efficiently screening heart failure in patients with type 2 diabetes

.

Eur J Heart Fail

2015

;

17

:

187

–

195

.

48

Rutten

FH

,

Moons

KGM

,

Cramer

M-JM

,

Grobbee

DE

,

Zuithoff

NPA

,

Lammers

J-WJ

,

Hoes

AW

.

Recognising heart failure in elderly patients with stable chronic obstructive pulmonary disease in primary care: cross sectional diagnostic study

.

BMJ

2005

;

331

:

1379

.

49

Hawkins

NM

,

Petrie

MC

,

Jhund

PS

,

Chalmers

GW

,

Dunn

FG

,

McMurray

JJV

.

Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology

.

Eur J Heart Fail

2009

;

11

:

130

–

139

.

50

Daniels

LB

,

Clopton

P

,

Bhalla

V

,

Krishnaswamy

P

,

Nowak

RM

,

McCord

J

,

Hollander

JE

,

Duc

P

,

Omland

T

,

Storrow

AB

,

Abraham

WT

,

Wu

AHB

,

Steg

PG

,

Westheim

A

,

Knudsen

CW

,

Perez

A

,

Kazanegra

R

,

Herrmann

HC

,

McCullough

PA

,

Maisel

AS

.

How obesity affects the cut-points for B-type natriuretic peptide in the diagnosis of acute heart failure. Results from the Breathing Not Properly Multinational Study

.

Am Heart J

2006

;

151

:

999

–

1005

.

51

Wong

CM

,

Hawkins

NM

,

Jhund

PS

,

MacDonald

MR

,

Solomon

SD

,

Granger

CB

,

Yusuf

S

,

Pfeffer

MA

,

Swedberg

K

,

Petrie

MC

,

McMurray

JJ V

.

Clinical characteristics and outcomes of young and very young adults with heart failure: the CHARM programme (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity)

.

J Am Coll Cardiol

2013

;

62

:

1845

–

1854

.

52

Wong

CM

,

Hawkins

NM

,

Petrie

MC

,

Jhund

PS

,

Gardner

RS

,

Ariti

CA

,

Poppe

KK

,

Earle

N

,

Whalley

GA

,

Squire

IB

,

Doughty

RN

,

McMurray

JJV

.

Heart failure in younger patients: the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC)

.

Eur Heart J

2014

;

35

:

2714

–

2721

.

53

Thibodeau

JT

,

Turer

AT

,

Gualano

SK

,

Ayers

CR

,

Velez-Martinez

M

,

Mishkin

JD

,

Patel

PC

,

Mammen

PPA

,

Markham

DW

,

Levine

BD

,

Drazner

MH

.

Characterization of a novel symptom of advanced heart failure: bendopnea

.

JACC Heart Fail

2014

;

2

:

24

–

31

.

54

Roberts

E

,

Ludman

AJ

,

Dworzynski

K

,

Al-Mohammad

A

,

Cowie

MR

,

McMurray

JJV

,

Mant

J

.

The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting

.

BMJ

2015

;

350

:

h910

.

55

Maisel

A

,

Mueller

C

,

Adams

K

,

Anker

SD

,

Aspromonte

N

,

Cleland

JGF

,

Cohen-Solal

A

,

Dahlstrom

U

,

DeMaria

A

,

DiSomma

S

,

Filippatos

GS

,

Fonarow

GC

,

Jourdain

P

,

Komajda

M

,

Liu

PP

,

McDonagh

T

,

McDonald

K

,

Mebazaa

A

,

Nieminen

MS

,

Peacock

WF

,

Tubaro

M

,

Valle

R

,

Vanderhyden

M

,

Yancy

CW

,

Zannad

F

,

Braunwald

E

.

State of the art: using natriuretic peptide levels in clinical practice

.

Eur J Heart Fail

2008

;

10

:

824

–

839

.

56

Zaphiriou

A

,

Robb

S

,

Murray-Thomas

T

,

Mendez

G

,

Fox

K

,

McDonagh

T

,

Hardman

SMC

,

Dargie

HJ

,

Cowie

MR

.

The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study

.

Eur J Heart Fail

2005

;

7

:

537

–

541

.

57

Fuat

A

,

Murphy

JJ

,

Hungin

APS

,

Curry

J

,

Mehrzad

AA

,

Hetherington

A

,

Johnston

JI

,

Smellie

WSA

,

Duffy

V

,

Cawley

P

.

The diagnostic accuracy and utility of a B-type natriuretic peptide test in a community population of patients with suspected heart failure

.

Br J Gen Pract

2006

;

56

:

327

–

333

.

58

Yamamoto

K

,

Burnett

JC

,

Bermudez

EA

,

Jougasaki

M

,

Bailey

KR

,

Redfield

MM

.

Clinical criteria and biochemical markers for the detection of systolic dysfunction

.

J Card Fail

2000

;

6

:

194

–

200

.

59

Cowie

MR

,

Struthers

AD

,

Wood

DA

,

Coats

AJ

,

Thompson

SG

,

Poole-Wilson

PA

,

Sutton

GC

.

Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care

.

Lancet

1997

;

350

:

1349

–

1353

.

60

Krishnaswamy

P

,

Lubien

E

,

Clopton

P

,

Koon

J

,

Kazanegra

R

,

Wanner

E

,

Gardetto

N

,

Garcia

A

,

DeMaria

A

,

Maisel

AS

.

Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction

.

Am J Med

2001

;

111

:

274

–

279

.

61

Kelder

JC

,

Cramer

MJ

,

Verweij

WM

,

Grobbee

DE

,

Hoes

AW

.

Clinical utility of three B-type natriuretic peptide assays for the initial diagnostic assessment of new slow-onset heart failure

.

J Card Fail

2011

;

17

:

729

–

734

.

62

Madamanchi

C

,

Alhosaini

H

,

Sumida

A

,

Runge

MS

.

Obesity and natriuretic peptides, BNP and NT-proBNP: Mechanisms and diagnostic implications for heart failure

.

Int J Cardiol

2014

;

176

:

611

–

617

.

63

Davie

AP

,

Francis

CM

,

Love

MP

,

Caruana

L

,

Starkey

IR

,

Shaw

TR

,

Sutherland

GR

,

McMurray

JJ

.

Value of the electrocardiogram in identifying heart failure due to left ventricular systolic dysfunction

.

BMJ

1996

;

312

:

222

.

64

Thomas

JT

,

Kelly

RF

,

Thomas

SJ

,

Stamos

TD

,

Albasha

K

,

Parrillo

JE

,

Calvin

JE

.

Utility of history, physical examination, electrocardiogram, and chest radiograph for differentiating normal from decreased systolic function in patients with heart failure

.

Am J Med

2002

;

112

:

437

–

445

.

65

Paulus

WJ

,

Tschope

C

,

Sanderson

JE

,

Rusconi

C

,

Flachskampf

FA

,

Rademakers

FE

,

Marino

P

,

Smiseth

OA

,

De Keulenaer

G

,

Leite-Moreira

AF

,

Borbely

A

,

Edes

I

,

Handoko

ML

,

Heymans

S

,

Pezzali

N

,

Pieske

B

,

Dickstein

K

,

Fraser

AG

,

Brutsaert

DL

.

How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology

.

Eur Heart J

2007

;

28

:

2539

–

2550

.

66

Marwick

TH

,

Raman

SV

,

Carrió

I

,

Bax

JJ

.

Recent developments in heart failure imaging

.

JACC Cardiovasc Imaging

2010

;

3

:

429

–

439

.

67

Dokainish

H

,

Nguyen

JS

,

Bobek

J

,

Goswami

R

,

Lakkis

NM

.

Assessment of the American Society of Echocardiography-European Association of Echocardiography guidelines for diastolic function in patients with depressed ejection fraction: an echocardiographic and invasive haemodynamic study

.

Eur J Echocardiogr

2011

;

12

:

857

–

864

.

68

Kirkpatrick

JN

,

Vannan

MA

,

Narula

J

,

Lang

RM

.

Echocardiography in heart failure: applications, utility, and new horizons

.

J Am Coll Cardiol

2007

;

50

:

381

–

396

.

69

Nagueh

SF

,

Bhatt

R

,

Vivo

RP

,

Krim

SR

,

Sarvari

SI

,

Russell

K

,

Edvardsen

T

,

Smiseth

OA

,

Estep

JD

.

Echocardiographic evaluation of hemodynamics in patients with decompensated systolic heart failure

.

Circ Cardiovasc Imaging

2011

;

4

:

220

–

227

.

70

Caballero

L

,

Kou

S

,

Dulgheru

R

,

Gonjilashvili

N

,

Athanassopoulos

GD

,

Barone

D

,

Baroni

M

,

Cardim

N

,

Gomez de Diego

JJ

,

Oliva

MJ

,

Hagendorff

A

,

Hristova

K

,

Lopez

T

,

Magne

J

,

Martinez

C

,

de la Morena

G

,

Popescu

BA

,

Penicka

M

,

Ozyigit

T

,

Rodrigo Carbonero

JD

,

Salustri

A

,

Van De Veire

N

,

Von Bardeleben

RS

,

Vinereanu

D

,

Voigt

J-U

,

Zamorano

JL

,

Bernard

A

,

Donal

E

,

Lang

RM

,

Badano

LP

,

Lancellotti

P

.

Echocardiographic reference ranges for normal cardiac Doppler data: results from the NORRE Study

.

Eur Heart J Cardiovasc Imaging

2015

;

16

:

1031

–

1041

.

71

Garbi

M

,

McDonagh

T

,

Cosyns

B

,

Bucciarelli-Ducci

C

,

Edvardsen

T

,

Kitsiou

A

,

Nieman

K

,

Lancellotti

P

.

Appropriateness criteria for cardiovascular imaging use in heart failure: report of literature review

.

Eur Heart J Cardiovasc Imaging

2015

;

16

:

147

–

153

.

72

Lang

RM

,

Badano

LP

,

Mor-Avi

V

,

Afilalo

J

,

Armstrong

A

,

Ernande

L

,

Flachskampf

FA

,

Foster

E

,

Goldstein

SA

,

Kuznetsova

T

,

Lancellotti

P

,

Muraru

D

,

Picard

MH

,

Rietzschel

ER

,

Rudski

L

,

Spencer

KT

,

Tsang

W

,

Voigt

J-U

.

Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

.

Eur Heart J Cardiovasc Imaging

2015

;

16

:

233

–

270

.

73

Gimelli

A

,

Lancellotti

P

,

Badano

LP

,

Lombardi

M

,

Gerber

B

,

Plein

S

,

Neglia

D

,

Edvardsen

T

,

Kitsiou

A

,

Scholte

AJHA

,

Schroder

S

,

Cosyns

B

,

Gargiulo

P

,

Zamorano

JL

,

Perrone-Filardi

P

.

Non-invasive cardiac imaging evaluation of patients with chronic systolic heart failure: a report from the European Association of Cardiovascular Imaging (EACVI)

.

Eur Heart J

2014

;

35

:

3417

–

3425

.

74

Voigt

J-U

,

Pedrizzetti

G

,

Lysyansky

P

,

Marwick

TH

,

Houle

H

,

Baumann

R

,

Pedri

S

,

Ito

Y

,

Abe

Y

,

Metz

S

,

Song

JH

,

Hamilton

J

,

Sengupta

PP

,

Kolias

TJ

,

d'Hooge

J

,

Aurigemma

GP

,

Thomas

JD

,

Badano

LP

.

Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging

.

Eur Heart J Cardiovasc Imaging

2015

;

16

:

1

–

11

.

75

Ewald

B

,

Ewald

D

,

Thakkinstian

A

,

Attia

J

.

Meta-analysis of B type natriuretic peptide and N-terminal pro B natriuretic peptide in the diagnosis of clinical heart failure and population screening for left ventricular systolic dysfunction

.

Intern Med J

2008

;

38

:

101

–

113

.

76

Doust

JA

,

Glasziou

PP

,

Pietrzak

E

,

Dobson

AJ

.

A systematic review of the diagnostic accuracy of natriuretic peptides for heart failure

.

Arch Intern Med

2004

;

164

:

1978

–

1984

.

77

Gustafsson

F

,

Steensgaard-Hansen

F

,

Badskjaer

J

,

Poulsen

AH

,

Corell

P

,

Hildebrandt

P

.

Diagnostic and prognostic performance of N-terminal ProBNP in primary care patients with suspected heart failure

.

J Card Fail

2005

;

11

:

S15

–

S20

.

78

Nielsen

OW

,

Rasmussen

V

,

Christensen

NJ

,

Hansen

JF

.

Neuroendocrine testing in community patients with heart disease: plasma N-terminal proatrial natriuretic peptide predicts morbidity and mortality stronger than catecholamines and heart rate variability

.

Scand J Clin Lab Invest

2004

;

64

:

619

–

628

.

79

Kelly

JP

,

Mentz

RJ

,

Mebazaa

A

,

Voors

AA

,

Butler

J

,

Roessig

L

,

Fiuzat

M

,

Zannad

F

,

Pitt

B

,

O'Connor

CM

,

Lam

CSP

.

Patient selection in heart failure with preserved ejection fraction clinical trials

.

J Am Coll Cardiol

2015

;

65

:

1668

–

1682

.

80

Cohen

GI

,

Pietrolungo

JF

,

Thomas

JD

,

Klein

AL

.

A practical guide to assessment of ventricular diastolic function using Doppler echocardiography

.

J Am Coll Cardiol

1996

;

27

:

1753

–

1760

.

81

Gilman

G

,

Nelson

TA

,

Hansen

WH

,

Khandheria

BK

,

Ommen

SR

.

Diastolic function: a sonographer's approach to the essential echocardiographic measurements of left ventricular diastolic function

.

J Am Soc Echocardiogr

2007

;

20

:

199

–

209

.

82

Nagueh

SF

,

Appleton

CP

,

Gillebert

TC

,

Marino

PN

,

Oh

JK

,

Smiseth

OA

,

Waggoner

AD

,

Flachskampf

FA

,

Pellikka

PA

,

Evangelisa

A

.

Recommendations for the evaluation of left ventricular diastolic function by echocardiography

.

Eur J Echocardiogr

2009

;

10

:

165

–

193

.

83

Nishimura

RA

,

Appleton

CP

,

Redfield

MM

,

Ilstrup

DM

,

Holmes

DR

,

Tajik

AJ

.

Noninvasive doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: a simultaneous Doppler echocardiographic and cardiac catheterization study

.

J Am Coll Cardiol

1996

;

28

:

1226

–

1233

.

84

Ommen

SR

,

Nishimura

RA

,

Appleton

CP

,

Miller

FA

,

Oh

JK

,

Redfield

MM

,

Tajik

AJ

.

Clinical utility of Doppler echocardiography and tissue doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study

.

Circulation

2000

;

102

:

1788

–

1794

.

85

Erdei

T

,

Smiseth

OA

,

Marino

P

,

Fraser

AG

.

A systematic review of diastolic stress tests in heart failure with preserved ejection fraction, with proposals from the EU-FP7 MEDIA study group

.

Eur J Heart Fail

2014

;

16

:

1345

–

1361

.

86

Donal

E

,

Lund

LH

,

Oger

E

,

Reynaud

A

,

Schnell

F

,

Persson

H

,

Drouet

E

,

Linde

C

,

Daubert

C

,

KaRen investigators

.

Value of exercise echocardiography in heart failure with preserved ejection fraction: a substudy from the KaRen study

.

Eur Heart J Cardiovasc Imaging

2016

;

17

:

106

–

113

.

87

Borlaug

BA

,

Nishimura

RA

,

Sorajja

P

,

Lam

CSP

,

Redfield

MM

.

Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction

.

Circ Heart Fail

2010

;

3

:

588

–

595

.

88

Elliott

PM

,

Anastasakis

A

,

Borger

MA

,

Borggrefe

M

,

Cecchi

F

,

Charron

P

,

Hagege

AA

,

Lafont

A

,

Limongelli

G

,

Mahrholdt

H

,

McKenna

WJ

,

Mogensen

J

,

Nihoyannopoulos

P

,

Nistri

S

,

Pieper

PG

,

Pieske

B

,

Rapezzi

C

,

Rutten

FH

,

Tillmanns

C

,

Watkins

H

.

2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC)

.

Eur Heart J

2014

;

35

:

2733

–

2779

.

89

Cosyns

B

,

Plein

S

,

Nihoyanopoulos

P

,

Smiseth

O

,

Achenbach

S

,

Andrade

MJ

,

Pepi

M

,

Ristic

A

,

Imazio

M

,

Paelinck

B

,

Lancellotti

P

.

European Association of Cardiovascular Imaging (EACVI) position paper: multimodality imaging in pericardial disease

.

Eur Heart J Cardiovasc Imaging

2015

;

16

:

12

–

31

.

90

Caforio

ALP

,

Pankuweit

S

,

Arbustini

E

,

Basso

C

,

Gimeno-Blanes

J

,

Felix

SB

,

Fu

M

,

Helio

T

,

Heymans

S

,

Jahns

R

,

Klingel

K

,

Linhart

A

,

Maisch

B

,

McKenna

W

,

Mogensen

J

,

Pinto

YM

,

Ristic

A

,

Schultheiss

H-P

,

Seggewiss

H

,

Tavazzi

L

,

Thiene

G

,

Yilmaz

A

,

Charron

P

,

Elliott

PM

.

Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

.

Eur Heart J

2013

;

34

:

2636

–

2648

.

91

Gonzalez

JA

,

Kramer

CM

.

Role of imaging techniques for diagnosis, prognosis and management of heart failure patients: cardiac magnetic resonance

.

Curr Heart Fail Rep

2015

;

12

:

276

–

283

.

92

Peix

A

,

Mesquita

CT

,

Paez

D

,

Pereira

CC

,

Felix

R

,

Gutierrez

C

,

Jaimovich

R

,

Ianni

BM

,

Soares

J

,

Olaya

P

,

Rodriguez

MV

,

Flotats

A

,

Giubbini

R

,

Travin

M

,

Garcia

E V

.

Nuclear medicine in the management of patients with heart failure: guidance from an expert panel of the International Atomic Energy Agency (IAEA)

.

Nucl Med Commun

2014

;

35

:

818

–

823

.

93

Cooper

LT

,

Baughman

KL

,

Feldman

AM

,

Frustaci

A

,

Jessup

M

,

Kuhl

U

,

Levine

GN

,

Narula

J

,

Starling

RC

,

Towbin

J

,

Virmani

R

.

The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology

.

Eur Heart J

2007

;

28

:

3076

–

3093

.

94

Charron

P

,

Arad

M

,

Arbustini

E

,

Basso

C

,

Bilinska

Z

,

Elliott

P

,

Helio

T

,

Keren

A

,

McKenna

WJ

,

Monserrat

L

,

Pankuweit

S

,

Perrot

A

,

Rapezzi

C

,

Ristic

A

,

Seggewiss

H

,

Van Langen

I

,

Tavazzi

L

.

Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

.

Eur Heart J

2010

;

31

:

2715

–

2728

.

95

Lang

RM

,

Badano

LP

,

Tsang

W

,

Adams

DH

,

Agricola

E

,

Buck

T

,

Faletra

FF

,

Franke

A

,

Hung

J

,

Pérez de Isla

L

,

Kamp

O

,

Kasprzak

JD

,

Lancellotti

P

,

Marwick

TH

,

McCulloch

ML

,

Monaghan

MJ

,

Nihoyannopoulos

P

,

Pandian

NG

,

Pellikka

PA

,

Pepi

M

,

Roberson

DA

,

Shernan

SK

,

Shirali

GS

,

Sugeng

L

,

Ten Cate

FJ

,

Vannan

MA

,

Zamorano

JL

,

Zoghbi

WA

.

EAE/ASE recommendations for image acquisition and display using three-dimensional echocardiography

.

J Am Soc Echocardiogr

2012

;

25

:

3

–

46

.

96

Rudski

LG

,

Lai

WW

,

Afilalo

J

,

Hua

L

,

Handschumacher

MD

,

Chandrasekaran

K

,

Solomon

SD

,

Louie

EK

,

Schiller

NB

.

Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography. Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography

.

J Am Soc Echocardiogr

2010

;

23

:

685

–

713

.

97

Galiè

N

,

Humbert

M

,

Vachiery

J-L

,

Gibbs

S

,

Lang

I

,

Torbicki

A

,

Simonneau

G

,

Peacock

A

,

Vonk Noordegraaf

A

,

Beghetti

M

,

Ghofrani

A

,

Gomez Sanchez

MA

,

Hansmann

G

,

Klepetko

W

,

Lancellotti

P

,

Matucci

M

,

McDonagh

T

,

Pierard

LA

,

Trindade

PT

,

Zompatori

M

,

Hoeper

M

.

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

.

Eur Heart J

2015

;

37

:

ehv317

.

98

Smith

BCF

,

Dobson

G

,

Dawson

D

,

Charalampopoulos

A

,

Grapsa

J

,

Nihoyannopoulos

P

.

Three-dimensional speckle tracking of the right ventricle: toward optimal quantification of right ventricular dysfunction in pulmonary hypertension

.

J Am Coll Cardiol

2014

;

64

:

41

–

51

.

99

Sicari

R

,

Nihoyannopoulos

P

,

Evangelista

A

,

Kasprzak

J

,

Lancellotti

P

,

Poldermans

D

,

Voigt

JU

,

Zamorano

JL

.

Stress Echocardiography Expert Consensus Statement—Executive Summary: European Association of Echocardiography (EAE) (a registered branch of the ESC)

.

Eur Heart J

2009

;

30

:

278

–

289

.

100

Garnier

F

,

Eicher

J-C

,

Jazayeri

S

,

Bertaux

G

,

Bouchot

O

,

Aho

L-S

,

Wolf

J-E

,

Laurent

G

.

Usefulness and limitations of contractile reserve evaluation in patients with low-flow, low-gradient aortic stenosis eligible for cardiac resynchronization therapy

.

Eur J Heart Fail

2014

;

16

:

648

–

654

.

101

Hundley

WG

,

Bluemke

DA

,

Finn

JP

,

Flamm

SD

,

Fogel

MA

,

Friedrich

MG

,

Ho

VB

,

Jerosch-Herold

M

,

Kramer

CM

,

Manning

WJ

,

Patel

M

,

Pohost

GM

,

Stillman

AE

,

White

RD

,

Woodard

PK

,

Harrington

RA

,

Anderson

JL

,

Bates

ER

,

Bridges

CR

,

Eisenberg

MJ

,

Ferrari

VA

,

Grines

CL

,

Hlatky

MA

,

Jacobs

AK

,

Kaul

S

,

Lichtenberg

RC

,

Lindner

JR

,

Moliterno

DJ

,

Mukherjee

D

,

Rosenson

RS

,

Schofield

RS

,

Shubrooks

SJ

,

Stein

JH

,

Tracy

CM

,

Weitz

HH

,

Wesley

DJ

.

ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the american college of cardiology foundation task force on expert consensus documents

.

Circulation

2010

;

121

:

2462

–

2508

.

102

Kilner

PJ

,

Geva

T

,

Kaemmerer

H

,

Trindade

PT

,

Schwitter

J

,

Webb

GD

.

Recommendations for cardiovascular magnetic resonance in adults with congenital heart disease from the respective working groups of the European Society of Cardiology

.

Eur Heart J

2010

;

31

:

794

–

805

.

103

Moon

JC

,

Messroghli

DR

,

Kellman

P

,

Piechnik

SK

,

Robson

MD

,

Ugander

M

,

Gatehouse

PD

,

Arai

AE

,

Friedrich

MG

,

Neubauer

S

,

Schulz-Menger

J

,

Schelbert

EB

.

Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement

.

J Cardiovasc Magn Reson

2013

;

15

:

92

.

104

Yoshida

A

,

Ishibashi-Ueda

H

,

Yamada

N

,

Kanzaki

H

,

Hasegawa

T

,

Takahama

H

,

Amaki

M

,

Asakura

M

,

Kitakaze

M

.

Direct comparison of the diagnostic capability of cardiac magnetic resonance and endomyocardial biopsy in patients with heart failure

.

Eur J Heart Fail

2013

;

15

:

166

–

175

.

105

Bonow

RO

,

Castelvecchio

S

,

Panza

JA

,

Berman

DS

,

Velazquez

EJ

,

Michler

RE

,

She

L

,

Holly

TA

,

Desvigne-Nickens

P

,

Kosevic

D

,

Rajda

M

,

Chrzanowski

L

,

Deja

M

,

Lee

KL

,

White

H

,

Oh

JK

,

Doenst

T

,

Hill

JA

,

Rouleau

JL

,

Menicanti

L

.

Severity of remodeling, myocardial viability, and survival in ischemic LV dysfunction after surgical revascularization

.

JACC Cardiovasc Imaging

2015

;

8

:

1121

–

1129

.

106

McDiarmid

AK

,

Loh

H

,

Nikitin

N

,

Cleland

JG

,

Ball

SG

,

Greenwood

JP

,

Plein

S

,

Sparrow

P

.

Predictive power of late gadolinium enhancement for myocardial recovery in chronic ischaemic heart failure: a HEART sub-study

.

ESC Heart Fail

2014

;

1

:

146

–

153

.

107

Cleland

JGF

,

Calvert

M

,

Freemantle

N

,

Arrow

Y

,

Ball

SG

,

Bonser

RS

,

Chattopadhyay

S

,

Norell

MS

,

Pennell

DJ

,

Senior

R

.

The heart failure revascularisation trial (HEART)

.

Eur J Heart Fail

2011

;

13

:

227

–

233

.

108

Haneder

S

,

Kucharczyk

W

,

Schoenberg

SO

,

Michaely

HJ

.

Safety of magnetic resonance contrast media: a review with special focus on nephrogenic systemic fibrosis

.

Top Magn Reson Imaging

2015

;

24

:

57

–

65

.

109

Beller

GA

,

Heede

RC

.

SPECT imaging for detecting coronary artery disease and determining prognosis by noninvasive assessment of myocardial perfusion and myocardial viability

.

J Cardiovasc Transl Res

2011

;

4

:

416

–

424

.

110

González-López

E

,

Gallego-Delgado

M

,

Guzzo-Merello

G

,

de Haro-Del Moral

FJ

,

Cobo-Marcos

M

,

Robles

C

,

Bornstein

B

,

Salas

C

,

Lara-Pezzi

E

,

Alonso-Pulpon

L

,

Garcia-Pavia

P

.

Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction

.

Eur Heart J

2015

;

36

:

2585

–

2594

.

111

Beanlands

RSB

,

Nichol

G

,

Huszti

E

,

Humen

D

,

Racine

N

,

Freeman

M

,

Gulenchyn

KY

,

Garrard

L

,

deKemp

R

,

Guo

A

,

Ruddy

TD

,

Benard

F

,

Lamy

A

,

Iwanochko

RM

.

F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2)

.

J Am Coll Cardiol

2007

;

50

:

2002

–

2012

.

112

Windecker

S

,

Kolh

P

,

Alfonso

F

,

Collet

J-P

,

Cremer

J

,

Falk

V

,

Filippatos

G

,

Hamm

C

,

Head

SJ

,

Juni

P

,

Kappetein

AP

,

Kastrati

A

,

Knuuti

J

,

Landmesser

U

,

Laufer

G

,

Neumann

F-J

,

Richter

DJ

,

Schauerte

P

,

Sousa Uva

M

,

Stefanini

GG

,

Taggart

DP

,

Torracca

L

,

Valgimigli

M

,

Wijns

W

.

2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI)

.

Eur Heart J

2014

;

35

:

2541

–

2619

.

113

Montalescot

G

,

Sechtem

U

,

Achenbach

S

,

Andreotti

F

,

Arden

C

,

Budaj

A

,

Bugiardini

R

,

Crea

F

,

Cuisset

T

,

Di Mario

C

,

Ferreira

JR

,

Gersh

BJ

,

Gitt

AK

,

Hulot

J-S

,

Marx

N

,

Opie

LH

,

Pfisterer

M

,

Prescott

E

,

Ruschitzka

F

,

Sabaté

M

,

Senior

R

,

Taggart

DP

,

van der Wall

EE

,

Vrints

CJM

,

Zamorano

JL

,

Baumgartner

H

,

Bax

JJ

,

Bueno

H

,

Dean

V

,

Deaton

C

,

Erol

C

,

Fagard

R

,

Ferrari

R

,

Hasdai

D

,

Hoes

AW

,

Kirchhof

P

,

Knuuti

J

,

Kolh

P

,

Lancellotti

P

,

Linhart

A

,

Nihoyannopoulos

P

,

Piepoli

MF

,

Ponikowski

P

,

Sirnes

PA

,

Tamargo

JL

,

Tendera

M

,

Torbicki

A

,

Wijns

W

,

Windecker

S

,

Valgimigli

M

,

Claeys

MJ

,

Donner-Banzhoff

N

,

Frank

H

,

Funck-Brentano

C

,

Gaemperli

O

,

Gonzalez-Juanatey

JR

,

Hamilos

M

,

Husted

S

,

James

SK

,

Kervinen

K

,

Kristensen

SD

,

Maggioni

A Pietro

,

Pries

AR

,

Romeo

F

,

Rydén

L

,

Simoons

ML

,

Steg

PG

,

Timmis

A

,

Yildirir

A

.

2013 ESC guidelines on the management of stable coronary artery disease

.

Eur Heart J

2013

;

34

:

2949

–

3003

.

114

Roffi

M

,

Patrono

C

,

Collet

J-P

,

Mueller

C

,

Valgimigli

M

,

Andreotti

F

,

Bax

JJ

,

Borger

MA

,

Brotons

C

,

Chew

DP

,

Gencer

B

,

Hasenfuss

G

,

Kjeldsen

K

,

Lancellotti

P

,

Landmesser

U

,

Mehilli

J

,

Mukherjee

D

,

Storey

RF

,

Windecker

S

.

2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

.

Eur Heart J

2015

;

ehv320

.

115

Jolicœur

EM

,

Dunning

A

,

Castelvecchio

S

,

Dabrowski

R

,

Waclawiw

MA

,

Petrie

MC

,

Stewart

R

,

Jhund

PS

,

Desvigne-Nickens

P

,

Panza

JA

,

Bonow

RO

,

Sun

B

,

San

TR

,

Al-Khalidi

HR

,

Rouleau

JL

,

Velazquez

EJ

,

Cleland

JGF

.

Importance of angina in patients with coronary disease, heart failure, and left ventricular systolic dysfunction: insights from STICH

.

J Am Coll Cardiol

2015

;

66

:

2092

–

2100

.

116

Allman

KC

,

Shaw

LJ

,

Hachamovitch

R

,

Udelson

JE

.

Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis

.

J Am Coll Cardiol

2002

;

39

:

1151

–

1158

.

117

Ling

LF

,

Marwick

TH

,

Flores

DR

,

Jaber

WA

,

Brunken

RC

,

Cerqueira

MD

,

Hachamovitch

R

.

Identification of therapeutic benefit from revascularization in patients with left ventricular systolic dysfunction inducible ischemia versus hibernating myocardium

.

Circ Cardiovasc Imaging

2013

;

6

:

363

–

372

.

118

Bonow

RO

,

Maurer

G

,

Lee

KL

,

Holly

TA

,

Binkley

PF

,

Desvigne-Nickens

P

,

Drozdz

J

,

Farsky

PS

,

Feldman

AM

,

Doenst

T

,

Michler

RE

,

Berman

DS

,

Nicolau

JC

,

Pellikka

PA

,

Wrobel

K

,

Alotti

N

,

Asch

FM

,

Favaloro

LE

,

She

L

,

Velazquez

EJ

,

Jones

RH

,

Panza

JA

.

Myocardial viability and survival in ischemic left ventricular dysfunction

.

N Engl J Med

2011

;

364

:

1617

–

1625

.

119

Corrà

U

,

Piepoli

MF

,

Adamopoulos

S

,

Agostoni

P

,

Coats

AJS

,

Conraads

V

,

Lambrinou

E

,

Pieske

B

,

Piotrowicz

E

,

Schmid

J-P

,

Seferović

PM

,

Anker

SD

,

Filippatos

G

,

Ponikowski

PP

.

Cardiopulmonary exercise testing in systolic heart failure in 2014: the evolving prognostic role: a position paper from the committee on exercise physiology and training of the heart failure association of the ESC

.

Eur J Heart Fail

2014

;

16

:

929

–

941

.

120

Piepoli

MF

,

Conraads

V

,

Corrà

U

,

Dickstein

K

,

Francis

DP

,

Jaarsma

T

,

McMurray

J

,

Pieske

B

,

Piotrowicz

E

,

Schmid

J-P

,

Anker

SD

,

Solal

AC

,

Filippatos

GS

,

Hoes

AW

,

Gielen

S

,

Giannuzzi

P

,

Ponikowski

PP

.

Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation

.

Eur J Heart Fail

2011

;

13

:

347

–

357

.

121

Volpicelli

G

,

Elbarbary

M

,

Blaivas

M

,

Lichtenstein

DA

,

Mathis

G

,

Kirkpatrick

AW

,

Melniker

L

,

Gargani

L

,

Noble

VE

,

Via

G

,

Dean

A

,

Tsung

JW

,

Soldati

G

,

Copetti

R

,

Bouhemad

B

,

Reissig

A

,

Agricola

E

,

Rouby

J-J

,

Arbelot

C

,

Liteplo

A

,

Sargsyan

A

,

Silva

F

,

Hoppmann

R

,

Breitkreutz

R

,

Seibel

A

,

Neri

L

,

Storti

E

,

Petrovic

T

.

International evidence-based recommendations for point-of-care lung ultrasound

.

Intensive Care Med

2012

;

38

:

577

–

591

.

122

Roma-Rodrigues

C

,

Fernandes

AR

.

Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy

.

Appl Clin Genet

2014

;

7

:

195

–

208

.

123

McNally

EM

,

Golbus

JR

,

Puckelwartz

MJ

.

Genetic mutations and mechanisms in dilated cardiomyopathy

.

J Clin Invest

2013

;

123

:

19

–

26

.

124

Priori

SG

,

Wilde

AA

,

Horie

M

,

Cho

Y

,

Behr

ER

,

Berul

C

,

Blom

N

,

Brugada

J

,

Chiang

CE

,

Huikuri

H

,

Kannankeril

P

,

Krahn

A

,

Leenhardt

A

,

Moss

A

,

Schwartz

PJ

,

Shimizu

W

,

Tomaselli

G

,

Tracy

C

.

HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013

.

Heart Rhythm

2013

;

10

:

1932

–

1963

.

125

Arbustini

E

,

Narula

N

,

Tavazzi

L

,

Serio

A

,

Grasso

M

,

Favalli

V

,

Bellazzi

R

,

Tajik

JA

,

Bonow

RD

,

Fuster

V

,

Narula

J

.

The MOGE(S) classification of cardiomyopathy for clinicians

.

J Am Coll Cardiol

2014

;

64

:

304

–

318

.

126

Kostis

JB

,

Davis

BR

,

Cutler

J

,

Grimm

RH

,

Berge

KG

,

Cohen

JD

,

Lacy

CR

,

Perry

HM

,

Blaufox

MD

,

Wassertheil-Smoller

S

,

Black

HR

,

Schron

E

,

Berkson

DM

,

Curb

JD

,

Smith

WM

,

McDonald

R

,

Applegate

WB

,

SHEP Cooperative Research Group

.

Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension

.

JAMA

1997

;

278

:

212

–

216

.

127

Beckett

NS

,

Peters

R

,

Fletcher

AE

,

Staessen

JA

,

Liu

L

,

Dumitrascu

D

,

Stoyanovsky

V

,

Antikainen

RL

,

Nikitin

Y

,

Anderson

C

,

Belhani

A

,

Forette

F

,

Rajkumar

C

,

Thijs

L

,

Banya

W

,

Bulpitt

CJ

.

Treatment of hypertension in patients 80 years of age or older

.

N Engl J Med

2008

;

358

:

1887

–

1898

.

128

Sciarretta

S

,

Palano

F

,

Tocci

G

,

Baldini

R

,

Volpe

M

.

Antihypertensive treatment and development of heart failure in hypertension

.

Arch Intern Med

2011

;

171

:

384

–

394

.

129

Wright

JT

,

Williamson

JD

,

Whelton

PK

,

Snyder

JK

,

Sink

KM

,

Rocco

M V

,

Reboussin

DM

,

Rahman

M

,

Oparil

S

,

Lewis

CE

,

Kimmel

PL

,

Johnson

KC

,

Goff

DC

,

Fine

LJ

,

Cutler

JA

,

Cushman

WC

,

Cheung

AK

,

Ambrosius

WT

,

SPRINT Research Group

.

A randomized trial of intensive versus standard blood-pressure control

.

N Engl J Med

2015

;

373

:

2103

–

2116

.

130

Zinman

B

,

Wanner

C

,

Lachin

JM

,

Fitchett

D

,

Bluhmki

E

,

Hantel

S

,

Mattheus

M

,

Devins

T

,

Johansen

OE

,

Woerle

HJ

,

Broedl

UC

,

Inzucchi

SE

,

EMPA-REG OUTCOME Investigators

.

Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes

.

N Engl J Med

2015

;

373

:

2117

–

2128

.

131

Suskin

N

,

Sheth

T

,

Negassa

A

,

Yusuf

S

.

Relationship of current and past smoking to mortality and morbidity in patients with left ventricular dysfunction

.

J Am Coll Cardiol

2001

;

37

:

1677

–

1682

.

132

Dorans

KS

,

Mostofsky

E

,

Levitan

EB

,

Håkansson

N

,

Wolk

A

,

Mittleman

MA

.

Alcohol and incident heart failure among middle-aged and elderly men: the cohort of Swedish men

.

Circ Heart Fail

2015

;

8

:

422

–

427

.

133

Goncalves

A

,

Claggett

B

,

Jhund

PS

,

Rosamond

W

,

Deswal

A

,

Aguilar

D

,

Shah

AM

,

Cheng

S

,

Solomon

SD

.

Alcohol consumption and risk of heart failure: the Atherosclerosis Risk in Communities Study

.

Eur Heart J

2015

;

36

:

939

–

945

.

134

Larsson

SC

,

Orsini

N

,

Wolk

A

.

Alcohol consumption and risk of heart failure: a dose-response meta-analysis of prospective studies

.

Eur J Heart Fail

2015

;

17

:

367

–

373

.

135

Pandey

A

,

Garg

S

,

Khunger

M

,

Darden

D

,

Ayers

C

,

Kumbhani

DJ

,

Mayo

HG

,

de Lemos

JA

,

Berry

JD

.

Dose-response relationship between physical activity and risk of heart failure: a meta-analysis

.

Circulation

2015

;

132

:

1786

–

1794

.

136

Ledwidge

M

,

Gallagher

J

,

Conlon

C

,

Tallon

E

,

O'Connell

E

,

Dawkins

I

,

Watson

C

,

O'Hanlon

R

,

Bermingham

M

,

Patle

A

,

Badabhagni

MR

,

Murtagh

G

,

Voon

V

,

Tilson

L

,

Barry

M

,

McDonald

L

,

Maurer

B

,

McDonald

K

.

Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial

.

JAMA

2013

;

310

:

66

–

74

.

137

Scirica

BM

,

Morrow

DA

,

Cannon

CP

,

Ray

KK

,

Sabatine

MS

,

Jarolim

P

,

Shui

A

,

McCabe

CH

,

Braunwald

E

.

Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study

.

J Am Coll Cardiol

2006

;

47

:

2326

–

2331

.

138

Afilalo

J

,

Majdan

AA

,

Eisenberg

MJ

.

Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials

.

Heart

2007

;

93

:

914

–

921

.

139

Kjekshus

J

,

Pedersen

TR

,

Olsson

AG

,

Faergeman

O

,

Pyörälä

K

.

The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease

.

J Card Fail

1997

;

3

:

249

–

254

.

140

Protection

H

,

Collaborative

S

,

Emberson

JR

,

Ng

LL

,

Armitage

J

,

Bowman

L

,

Parish

S

,

Collins

R

.

N-terminal pro-B-type natriuretic peptide, vascular disease risk, and cholesterol reduction among 20,536 patients in the MRC/BHF Heart Protection Study

.

J Am Coll Cardiol

2007

;

49

:

311

–

319

.

141

Kenchaiah

S

,

Evans

JC

,

Levy

D

,

Wilson

PWF

,

Benjamin

EJ

,

Larson

MG

,

Kannel

WB

,

Vasan

RS

.

Obesity and the risk of heart failure

.

N Engl J Med

2002

;

347

:

305

–

313

.

142

Dagenais

GR

,

Pogue

J

,

Fox

K

,

Simoons

ML

,

Yusuf

S

.

Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials

.

Lancet

2006

;

368

:

581

–

588

.

143

Huelsmann

M

,

Neuhold

S

,

Resl

M

,

Strunk

G

,

Brath

H

,

Francesconi

C

,

Adlbrecht

C

,

Prager

R

,

Luger

A

,

Pacher

R

,

Clodi

M

.

PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial

.

J Am Coll Cardiol

2013

;

62

:

1365

–

1372

.

144

Jong

P

,

Yusuf

S

,

Rousseau

MF

,

Ahn

SA

,

Bangdiwala

SI

.

Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study

.

Lancet

2003

;

361

:

1843

–

1848

.

145

Pfeffer

MA

,

Braunwald

E

,

Moyé

LA

,

Basta

L

,

Brown

EJ

,

Cuddy

TE

,

Davis

BR

,

Geltman

EM

,

Goldman

S

,

Flaker

GC

,

Klein

M

,

Lamas

GA

,

Packer

M

,

Rouleau

JLJ

,

Rouleau

JLJ

,

Rutherford

J

,

Wertheimer

JH

,

Hawkins

CM

.

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction

.

N Engl J Med

1992

;

327

:

669

–

677

.

146

Dargie

HJ

.

Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial

.

Lancet

2001

;

357

:

1385

–

1390

.

147

Montalescot

G

,

Pitt

B

,

Lopez de Sa

E

,

Hamm

CW

,

Flather

M

,

Verheugt

F

,

Shi

H

,

Turgonyi

E

,

Orri

M

,

Vincent

J

,

Zannad

F

,

Noll

G

,

Weir

R

,

O'Neill

B

,

Bohm

M

,

Hillis

WS

,

Grieve

A

,

Rouleau

J-L

,

Gerasimos

F

,

Fitchett

D

,

Lepage

S

,

Madan

M

,

Sussex

B

,

Tremblay

G

,

Welsh

R

,

Wong

G

,

Hutyra

M

,

Kettner

J

,

Ostadal

P

,

Spinar

J

,

Vojacek

J

,

Barboteu

M

,

Collet

J-P

,

Coste

P

,

Cottin

Y

,

Ducos

D

,

Galinier

M

,

Teiger

E

,

Zemour

G

,

Bauersachs

J

,

Hambrecht

R

,

Hauf

G

,

Heuer

H

,

Mudra

H

,

Munzel

T

,

Steiner

S

,

Strasser

R

,

Sydow

K

,

Tschope

C

,

Wachter

R

,

Werner

N

,

Alexopoulos

D

,

Babalis

D

,

Pyrgakis

V

,

Dezsi

C

,

Lupkovics

G

,

Polgar

P

,

Tomcsanyi

J

,

Herrman

J

,

ten Berg

JM

,

Gorny

J

,

Kubica

J

,

Lewczuk

J

,

Zmuda

W

,

Hranai

M

,

Kovar

F

,

Margoczy

R

,

Micko

K

,

Sumbal

J

,

Genover

XB

,

Ortiz

AF

,

Sala

MF

,

Garcia

CG

,

Munoz

CP

,

Rey Blas

JR

,

Soriano

FR

,

Adamson

D

,

Alamgir

F

,

Chauhan

A

,

Lip

G

,

Martin

T

,

McCann

G

,

Newby

D

,

Smith

D

.

Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the Randomized Double-Blind Reminder Study

.

Eur Heart J

2014

;

35

:

2295

–

2302

.

148

Pitt

B

,

Remme

W

,

Zannad

F

,

Neaton

J

,

Martinez

F

,

Roniker

B

,

Bittman

R

,

Hurley

S

,

Kleiman

J

,

Gatlin

M

.

Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction

.

N Engl J Med

2003

;

348

:

1309

–

1321

.

149

Moss

AJ

,

Zareba

W

,

Hall

WJ

,

Klein

H

,

Wilber

DJ

,

Cannom

DS

,

Daubert

JP

,

Higgins

SL

,

Brown

MW

,

Andrews

ML

.

Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction

.

N Engl J Med

2002

;

346

:

877

–

883

.

150

Beckett

NS

,

Peters

R

,

Fletcher

AE

,

Staessen

JA

,

Liu

L

,

Dumitrascu

D

,

Stoyanovsky

V

,

Antikainen

RL

,

Nikitin

Y

,

Anderson

C

,

Belhani

A

,

Forette

F

,

Rajkumar

C

,

Thijs

L

,

Banya

W

,

Bulpitt

CJ

.

Treatment of hypertension in patients 80 years of age or older

.

N Engl J Med

2008

;

358

:

1887

–

1898

.

151

Sciarretta

S

,

Palano

F

,

Tocci

G

,

Baldini

R

,

Volpe

M

.

Antihypertensive treatment and development of heart failure in hypertension: a Bayesian network meta-analysis of studies in patients with hypertension and high cardiovascular risk

.

Arch Intern Med

2011

;

171

:

384

–

394

.

152

Preiss

D

,

Campbell

RT

,

Murray

HM

,

Ford

I

,

Packard

CJ

,

Sattar

N

,

Rahimi

K

,

Colhoun

HM

,

Waters

DD

,

LaRosa

JC

,

Amarenco

P

,

Pedersen

TR

,

Tikkanen

MJ

,

Koren

MJ

,

Poulter

NR

,

Sever

PS

,

Ridker

PM

,

MacFadyen

JG

,

Solomon

SD

,

Davis

BR

,

Simpson

LM

,

Nakamura

H

,

Mizuno

K

,

Marfisi

RM

,

Marchioli

R

,

Tognoni

G

,

Athyros

VG

,

Ray

KK

,

Gotto

AM

,

Clearfield

MB

,

Downs

JR

,

McMurray

JJ

.

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials

.

Eur Heart J

2015

;

36

:

1536

–

1546

.

153

Udell

JA

,

Cavender

MA

,

Bhatt

DL

,

Chatterjee

S

,

Farkouh

ME

,

Scirica

BM

.

Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials

.

Lancet Diabetes Endocrinol

2015

;

3

:

356

–

366

.

154

Padwal

R

,

McAlister

F a

,

McMurray

JJ V

,

Cowie

MR

,

Rich

M

,

Pocock

S

,

Swedberg

K

,

Maggioni

A

,

Gamble

G

,

Ariti

C

,

Earle

N

,

Whalley

G

,

Poppe

KK

,

Doughty

RN

,

Bayes-Genis

A

.

The obesity paradox in heart failure patients with preserved versus reduced ejection fraction: a meta-analysis of individual patient data

.

Int J Obes

2014

;

38

:

1110

–

1114

.

155

Held

C

,

Gerstein

HC

,

Yusuf

S

,

Zhao

F

,

Hilbrich

L

,

Anderson

C

,

Sleight

P

,

Teo

K

,

ONTARGET/TRANSCEND Investigators

.

Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk

.

Circulation

2007

;

115

:

1371

–

1375

.

156

Desai

AS

,

Fang

JC

,

Maisel

WH

,

Baughman

KL

.

Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials

.

JAMA

2004

;

292

:

2874

–

2879

.

157

Kadish

A

,

Dyer

A

,

Daubert

JP

,

Quigg

R

,

Estes

NAM

,

Anderson

KP

,

Calkins

H

,

Hoch

D

,

Goldberger

J

,

Shalaby

A

,

Sanders

WE

,

Schaechter

A

,

Levine

JH

,

Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators

.

Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy

.

N Engl J Med

2004

;

350

:

2151

–

2158

.

158

Hohnloser

SH

,

Kuck

KH

,

Dorian

P

,

Roberts

RS

,

Hampton

JR

,

Hatala

R

,

Fain

E

,

Gent

M

,

Connolly

SJ

.

Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction

.

N Engl J Med

2004

;

351

:

2481

–

2488

.

159

Stewart

S

,

Jenkins

A

,

Buchan

S

,

McGuire

A

,

Capewell

S

,

McMurray

JJJV

.

The current cost of heart failure to the National Health Service in the UK

.

Eur J Heart Fail

2002

;

4

:

361

–

371

.

160

Gheorghiade

M

,

Shah

AN

,

Vaduganathan

M

,

Butler

J

,

Bonow

RO

,

Rosano

GMC

,

Taylor

S

,

Kupfer

S

,

Misselwitz

F

,

Sharma

A

,

Fonarow

GC

.

Recognizing hospitalized heart failure as an entity and developing new therapies to improve outcomes: academics’, clinicians’, industry's, regulators’, and payers’ perspectives

.

Heart Fail Clin

2013

;

9

:

285

–

290

,

v–vi

.

161

Ambrosy

AP

,

Fonarow

GC

,

Butler

J

,

Chioncel

O

,

Greene

SJ

,

Vaduganathan

M

,

Nodari

S

,

Lam

CSP

,

Sato

N

,

Shah

AN

,

Gheorghiade

M

.

The global health and economic burden of hospitalizations for heart failure

.

J Am Coll Cardiol

2014

;

63

:

1123

–

1133

.

162

McMurray

JJ

,

Packer

M

,

Desai

AS

,

Gong

J

,

Lefkowitz

MP

,

Rizkala

AR

,

Rouleau

JL

,

Shi

VC

,

Solomon

SD

,

Swedberg

K

,

Zile

MR

,

PARADIGM-HF Investigators and Committees

.

Angiotensin-neprilysin inhibition versus enalapril in heart failure

.

N Engl J Med

2014

;

371

:

993

–

1004

.

163

Garg

R

,

Yusuf

S

.

Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure

.

JAMA

1995

;

273

:

1450

–

1456

.

164

Packer

M

,

Poole-Wilson

PA

,

Armstrong

PW

,

Cleland

JGF

,

Horowitz

JD

,

Massie

BM

,

Ryden

L

,

Thygesen

K

,

Uretsky

BF

,

Rydén

L

,

Thygesen

K

,

Uretsky

BF

,

ATLAS Study Group

.

Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure

.

Circulation

1999

;

100

:

2312

–

2318

.

165

SOLVD Investigattors

.

Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure

.

N Engl J Med

1991

;

325

:

293

–

302

.

166

Maggioni

AP

,

Anker

SD

,

Dahlström

U

,

Filippatos

G

,

Ponikowski

P

,

Zannad

F

,

Amir

O

,

Chioncel

O

,

Leiro

MC

,

Drozdz

J

,

Erglis

A

,

Fazlibegovic

E

,

Fonseca

C

,

Fruhwald

F

,

Gatzov

P

,

Goncalvesova

E

,

Hassanein

M

,

Hradec

J

,

Kavoliuniene

A

,

Lainscak

M

,

Logeart

D

,

Merkely

B

,

Metra

M

,

Persson

H

,

Seferovic

P

,

Temizhan

A

,

Tousoulis

D

,

Tavazzi

L

.

Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12 440 patients of the ESC Heart Failure Long-Term Registry

.

Eur J Heart Fail

2013

;

15

:

1173

–

1184

.

167

Hjalmarson

A

,

Goldstein

S

,

Fagerberg

B

,

Wedel

H

,

Waagstein

F

,

Kjekshus

J

,

Wikstrand

J

,

ElAllaf

D

,

Vítovec

J

,

Aldershvile

J

,

Halinen

M

,

Dietz

R

,

Neuhaus

KL

,

Jánosi

A

,

Thorgeirsson

G

,

Dunselman

PH

,

Gullestad

L

,

Kuch

J

,

Herlitz

J

,

Rickenbacher

P

,

Ball

S

,

Gottlieb

S

,

Deedwania

P

.

MERIT-HF Study Group. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF)

.

JAMA

2000

;

283

:

1295

–

1302

.

168

Packer

M

,

Coats

AJ

,

Fowler

MB

,

Katus

HA

,

Krum

H

,

Mohacsi

P

,

Rouleau

JL

,

Tendera

M

,

Castaigne

A

,

Roecker

EB

,

Schultz

MK

,

DeMets

DL

.

Effect of carvedilol on survival in severe chronic heart failure

.

N Engl J Med

2001

;

344

:

1651

–

1658

.

169

Packer

M

,

Bristow

MR

,

Cohn

JN

,

Colucci

WS

,

Fowler

MB

,

Gilbert

EM

,

Shusterman

NH

.

The effect of carvedilol on morbidity and mortality in patients with chronic heart failure

.

N Engl J Med

1996

;

334

:

1349

–

1355

.

170

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)

.

Lancet

1999

;

353

:

2001

–

2007

.

171

Packer

M

.

Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study

.

Circulation

2002

;

106

:

2194

–

2199

.

172

CIBIS-II Investigators and Committees

.

The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial

.

Lancet

1999

;

353

:

9

–

13

.

173

Flather

MD

,

Shibata

MC

,

Coats

AJS

,

Van Veldhuisen

DJ

,

Parkhomenko

A

,

Borbola

J

,

Cohen-Solal

A

,

Dumitrascu

D

,

Ferrari

R

,

Lechat

P

,

Soler-Soler

J

,

Tavazzi

L

,

Spinarova

L

,

Toman

J

,

Böhm

M

,

Anker

SD

,

Thompson

SG

,

Poole-Wilson

PA

,

SENIORS Investigators

.

Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)

.

Eur Heart J

2005

;

26

:

215

–

225

.

174

Pitt

B

,

Zannad

F

,

Remme

WJ

,

Cody

R

,

Castaigne

A

,

Perez

A

,

Palensky

J

,

Wittes

J

.

The effect of spironolactone on morbidity and mortality in patients with severe heart failure

.

N Engl J Med

1999

;

341

:

709

–

717

.

175

Zannad

F

,

McMurray

JJV

,

Krum

H

,

Van Veldhuisen

DJ

,

Swedberg

K

,

Shi

H

,

Vincent

J

,

Pocock

SJ

,

Pitt

B

.

Eplerenone in patients with systolic heart failure and mild symptoms

.

N Engl J Med

2011

;

364

:

11

–

21

.

176

Willenheimer

R

,

van Veldhuisen

DJ

,

Silke

B

,

Erdmann

E

,

Follath

F

,

Krum

H

,

Ponikowski

P

,

Skene

A

,

van de Ven

L

,

Verkenne

P

,

Lechat

P

,

CIBIS III Investigators

.

Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III

.

Circulation

2005

;

112

:

2426

–

2435

.

177

Kotecha

D

,

Holmes

J

,

Krum

H

,

Altman

DG

,

Manzano

L

,

Cleland

JGF

,

Lip

GYH

,

Coats

AJS

,

Andersson

B

,

Kirchhof

P

,

von Lueder

TG

,

Wedel

H

,

Rosano

G

,

Shibata

MC

,

Rigby

A

,

Flather

MD

.

Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis

.

Lancet

2014

;

384

:

2235

–

2243

.

178

Faris

RF

,

Flather

M

,

Purcell

H

,

Poole-Wilson

PA

,

Coats

AJ

.

Diuretics for heart failure

.

Cochrane Database Syst Rev

2012

;

2

:

CD003838

.

179

Faris

R

,

Flather

M

,

Purcell

H

,

Henein

M

,

Poole-Wilson

P

,

Coats

A

.

Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials

.

Int J Cardiol

2002

;

82

:

149

–

158

.

180

Swedberg

K

,

Komajda

M

,

Böhm

M

,

Borer

JS

,

Ford

I

,

Dubost-Brama

A

,

Lerebours

G

,

Tavazzi

L

.

Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study

.

Lancet

2010

;

376

:

875

–

885

.

181

Swedberg

K

,

Komajda

M

,

Böhm

M

,

Borer

J

,

Robertson

M

,

Tavazzi

L

,

Ford

I

.

Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study

.

J Am Coll Cardiol

2012

;

59

:

1938

–

1945

.

182

Granger

CB

,

McMurray

JJV

,

Yusuf

S

,

Held

P

,

Michelson

EL

,

Olofsson

B

,

Ostergren

J

,

Pfeffer

MA

,

Swedberg

K

.

Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial

.

Lancet

2003

;

362

:

772

–

776

.

183

Taylor

AL

,

Ziesche

S

,

Yancy

C

,

Carson

P

,

D'Agostino

R

,

Ferdinand

K

,

Taylor

M

,

Adams

K

,

Sabolinski

M

,

Worcel

M

,

Cohn

JN

.

Combination of isosorbide dinitrate and hydralazine in blacks with heart failure

.

N Engl J Med

2004

;

351

:

2049

–

2057

.

184

Cohn

JN

,

Archibald

DG

,

Ziesche

S

,

Franciosa

JA

,

Harston

WE

,

Tristani

FE

,

Dunkman

WB

,

Jacobs

W

,

Francis

GS

,

Flohr

KH

,

Goldman

S

,

Cobb

FR

,

Shah

PM

,

Saunders

R

,

Fletcher

RD

,

Loeb

HS

,

Hughes

VC

,

Baker

B

.

Effect of vasodilator therapy on mortality in chronic congestive heart failure

.

N Engl J Med

1986

;

314

:

1547

–

1552

.

185

Digitalis Investigation Group

.

The effect of digoxin on mortality and morbidity in patients with heart failure

.

N Engl J Med

1997

;

336

:

525

–

533

.

186

Tavazzi

L

,

Maggioni

AP

,

Marchioli

R

,

Barlera

S

,

Franzosi

MG

,

Latini

R

,

Lucci

D

,

Nicolosi

GL

,

Porcu

M

,

Tognoni

G

.

Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial

.

Lancet

2008

;

372

:

1223

–

1230

.

187

King

JB

,

Bress

AP

,

Reese

AD

,

Munger

MA

.

Neprilysin inhibition in heart failure with reduced ejection fraction: a clinical review

.

Pharmacother J Hum Pharmacol Drug Ther

2015

;

35

:

823

–

837

.

188

Mangiafico

S

,

Costello-Boerrigter

LC

,

Andersen

IA

,

Cataliotti

A

,

Burnett

JC

.

Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

.

Eur Heart J

2013

;

34

:

886

–

893

.

189

Vodovar

N

,

Paquet

C

,

Mebazaa

A

,

Launay

J-M

,

Hugon

J

,

Cohen-Solal

A

.

Neprilysin, cardiovascular, and Alzheimer's diseases: the therapeutic split

?

Eur Heart J

2015

;

36

:

902

–

905

.

190

Yasojima

K

,

McGeer

EG

,

McGeer

PL

.

Relationship between beta amyloid peptide generating molecules and neprilysin in Alzheimer disease and normal brain

.

Brain Res

2001

;

919

:

115

–

121

.

191

Vepsalainen

S

,

Helisalmi

S

,

Mannermaa

A

,

Pirttila

T

,

Soininen

H

,

Hiltunen

M

,

Vepsäläinen

S

,

Helisalmi

S

,

Mannermaa

A

,

Pirttilä

T

,

Soininen

H

,

Hiltunen

M

.

Combined risk effects of IDE and NEP gene variants on Alzheimer disease

.

J Neurol Neurosurg Psychiatry

2009

;

80

:

1268

–

1270

.

192

Langenickel

TH

,

Tsubouchi

C

,

Ayalasomayajula

S

,

Pal

P

,

Valentin

M-A

,

Hinder

M

,

Jhee

S

,

Gevorkyan

H

,

Rajman

I

.

The effect of LCZ696 on amyloid-β concentrations in cerebrospinal fluid in healthy subjects

.

Br J Clin Pharmacol

2015 Dec 12. [Epub ahead of print]

10.1111/bcp.12861

193

Böhm

M

,

Borer

J

,

Ford

I

,

Gonzalez-Juanatey

JR

,

Komajda

M

,

Lopez-Sendon

J

,

Reil

J-C

,

Swedberg

K

,

Tavazzi

L

.

Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study

.

Clin Res Cardiol

2013

;

102

:

11

–

22

.

194

Cohn

JN

,

Tognoni

G

.

A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure

.

N Engl J Med

2001

;

345

:

1667

–

1675

.

195

Ouyang

A-J

,

Lv

Y-N

,

Zhong

H-L

,

Wen

J-H

,

Wei

X-H

,

Peng

H-W

,

Zhou

J

,

Liu

L-L

.

Meta-analysis of digoxin use and risk of mortality in patients with atrial fibrillation

.

Am J Cardiol

2015

;

115

:

901

–

906

.

196

Vamos

M

,

Erath

JW

,

Hohnloser

SH

.

Digoxin-associated mortality: a systematic review and meta-analysis of the literature

.

Eur Heart J

2015

;

36

:

1831

–

1838

.

197

Ziff

OJ

,

Lane

DA

,

Samra

M

,

Griffith

M

,

Kirchhof

P

,

Lip

GYH

,

Steeds

RP

,

Townend

J

,

Kotecha

D

.

Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data

.

BMJ

2015

;

351

:

h4451

.

198

Van Gelder

IC

,

Groenveld

HF

,

Crijns

HJGM

,

Tuininga

YS

,

Tijssen

JGP

,

Alings

AM

,

Hillege

HL

,

Bergsma-Kadijk

JA

,

Cornel

JH

,

Kamp

O

,

Tukkie

R

,

Bosker

HA

,

Van Veldhuisen

DJ

,

Van den Berg

MP

,

RACE II Investigators

.

Lenient versus strict rate control in patients with atrial fibrillation

.

N Engl J Med

2010

;

362

:

1363

–

1373

.

199

Bavishi

C

,

Khan

AR

,

Ather

S

.

Digoxin in patients with atrial fibrillation and heart failure: a meta-analysis

.

Int J Cardiol

2015

;

188

:

99

–

101

.

200

Freeman

JV

,

Reynolds

K

,

Fang

M

,

Udaltsova

N

,

Steimle

A

,

Pomernacki

NK

,

Borowsky

LH

,

Harrison

TN

,

Singer

DE

,

Go

AS

.

Digoxin and risk of death in adults with atrial fibrillation: the ATRIA-CVRN Study

.

Circ Arrhythmia Electrophysiol

2015

;

8

:

49

–

58

.

201

Washam

JB

,

Stevens

SR

,

Lokhnygina

Y

,

Halperin

JL

,

Breithardt

G

,

Singer

DE

,

Mahaffey

KW

,

Hankey

GJ

,

Berkowitz

SD

,

Nessel

CC

,

Fox

KAA

,

Califf

RM

,

Piccini

JP

,

Patel

MR

.

Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)

.

Lancet

2015

;

385

:

2363

–

2370

.

202

Mulder

BA

,

Van Veldhuisen

DJ

,

Crijns

HJGM

,

Tijssen

JGP

,

Hillege

HL

,

Alings

M

,

Rienstra

M

,

Groenveld

HF

,

Van den Berg

MP

,

Van Gelder

IC

,

RACE II investigators

.

Lenient vs. strict rate control in patients with atrial fibrillation and heart failure: a post-hoc analysis of the RACE II study

.

Eur J Heart Fail

2013

;

15

:

1311

–

1318

.

203

Lucas

M

,

Kimmig

M

,

Karalis

G

.

Do omega-3 polyunsaturated fatty acids prevent cardiovascular disease? A review of the randomized clinical trials

.

Lipid Insights

2013

;

6

:

13

–

20

.

204

Reiner

Z

,

Catapano

AL

,

De Backer

G

,

Graham

I

,

Taskinen

M-R

,

Wiklund

O

,

Agewall

S

,

Alegria

E

,

Chapman

MJ

,

Durrington

P

,

Erdine

S

,

Halcox

J

,

Hobbs

R

,

Kjekshus

J

,

Filardi

PP

,

Riccardi

G

,

Storey

RF

,

Wood

D

,

Bax

J

,

Vahanian

A

,

Auricchio

A

,

Baumgartner

H

,

Ceconi

C

,

Dean

V

,

Deaton

C

,

Fagard

R

,

Filippatos

G

,

Funck-Brentano

C

,

Hasdai

D

,

Hobbs

R

,

Hoes

A

,

Kearney

P

,

Knuuti

J

,

Kolh

P

,

McDonagh

T

,

Moulin

C

,

Poldermans

D

,

Popescu

BA

,

Reiner

Z

,

Sechtem

U

,

Sirnes

PA

,

Tendera

M

,

Torbicki

A

,

Vardas

P

,

Widimsky

P

,

Windecker

S

,

Reviewers:

D

,

Funck-Brentano

C

,

Poldermans

D

,

Berkenboom

G

,

De Graaf

J

,

Descamps

O

,

Gotcheva

N

,

Griffith

K

,

Guida

GF

,

Gulec

S

,

Henkin

Y

,

Huber

K

,

Kesaniemi

YA

,

Lekakis

J

,

Manolis

AJ

,

Marques-Vidal

P

,

Masana

L

,

McMurray

J

,

Mendes

M

,

Pagava

Z

,

Pedersen

T

,

Prescott

E

,

Rato

Q

,

Rosano

G

,

Sans

S

,

Stalenhoef

A

,

Tokgozoglu

L

,

Viigimaa

M

,

Wittekoek

ME

,

Zamorano

JL

.

ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)

.

Eur Heart J

2011

;

32

:

1769

–

1818

.

205

Kjekshus

J

,

Apetrei

E

,

Barrios

V

,

Böhm

M

,

Cleland

JGF

,

Cornel

JH

,

Dunselman

P

,

Fonseca

C

,

Goudev

A

,

Grande

P

,

Gullestad

L

,

Hjalmarson

Å

,

Hradec

J

,

Jánosi

A

,

Kamenský

G

,

Komajda

M

,

Korewicki

J

,

Kuusi

T

,

Mach

F

,

Mareev

V

,

McMurray

JJV

,

Ranjith

N

,

Schaufelberger

M

,

Vanhaecke

J

,

van Veldhuisen

DJ

,

Waagstein

F

,

Wedel

H

,

Wikstrand

J

.

Rosuvastatin in older patients with systolic heart failure

.

N Engl J Med

2007

;

357

:

2248

–

2261

.

206

Homma

S

,

Thompson

JLP

,

Pullicino

PM

,

Levin

B

,

Freudenberger

RS

,

Teerlink

JR

,

Ammon

SE

,

Graham

S

,

Sacco

RL

,

Mann

DL

,

Mohr

JP

,

Massie

BM

,

Labovitz

AJ

,

Anker

SD

,

Lok

DJ

,

Ponikowski

P

,

Estol

CJ

,

Lip

GYH

,

Di Tullio

MR

,

Sanford

AR

,

Mejia

V

,

Gabriel

AP

,

del Valle

ML

,

Buchsbaum

R

,

Shunichi

H

,

Thompson

JLP

,

Pullicino

PM

,

Levin

B

,

Freudenberger

RS

,

Teerlink

JR

,

Ammon

SE

,

Graham

S

,

Sacco

RL

,

Mann

DL

,

Mohr

JP

,

Massie

BM

,

Labovitz

AJ

,

Lip

GYH

,

Tullio

MR

,

Di, Sanford

AR

,

Mejia

V

,

Gabriel

AP

,

Valle

ML

,

Buchsbaum

R

,

Investigators

W

.

Warfarin and aspirin in patients with heart failure and sinus rhythm

.

N Engl J Med

2012

;

366

:

1859

–

1869

.

207

Lip

GYH

,

Ponikowski

P

,

Andreotti

F

,

Anker

SD

,

Filippatos

G

,

Homma

S

,

Morais

J

,

Pullicino

P

,

Rasmussen

LH

,

Marin

F

,

Lane

DA

.

Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm. A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis

.

Eur J Heart Fail

2012

;

14

:

681

–

695

.

208

Gheorghiade

M

,

Böhm

M

,

Greene

SJ

,

Fonarow

GC

,

Lewis

EF

,

Zannad

F

,

Solomon

SD

,

Baschiera

F

,

Botha

J

,

Hua

TA

,

Gimpelewicz

CR

,

Jaumont

X

,

Lesogor

A

,

Maggioni

AP

,

ASTRONAUT Investigators and Coordinators

.

Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial

.

JAMA

2013

;

309

:

1125

–

1135

.

209

Hernandez

AV

,

Usmani

A

,

Rajamanickam

A

,

Moheet

A

.

Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials

.

Am J Cardiovasc Drugs

2011

;

11

:

115

–

128

.

210

Komajda

M

,

McMurray

JJV

,

Beck-Nielsen

H

,

Gomis

R

,

Hanefeld

M

,

Pocock

SJ

,

Curtis

PS

,

Jones

NP

,

Home

PD

.

Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial

.

Eur Heart J

2010

;

31

:

824

–

831

.

211

Mamdani

M

,

Juurlink

DN

,

Lee

DS

,

Rochon

PA

,

Kopp

A

,

Naglie

G

,

Austin

PC

,

Laupacis

A

,

Stukel

TA

.

Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study

.

Lancet

2004

;

363

:

1751

–

1756

.

212

Huerta

C

,

Varas-Lorenzo

C

,

Castellsague

J

,

García Rodríguez

LA

.

Non-steroidal anti-inflammatory drugs and risk of first hospital admission for heart failure in the general population

.

Heart

2006

;

92

:

1610

–

1615

.

213

Scott

P a

,

Kingsley

GH

,

Scott

DL

.

Non-steroidal anti-inflammatory drugs and cardiac failure: meta-analyses of observational studies and randomised controlled trials

.

Eur J Heart Fail

2008

;

10

:

1102

–

1107

.

214

Goldstein

RE

,

Boccuzzi

SJ

,

Cruess

D

,

Nattel

S

.

Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee and the Multicenter Diltiazem Postinfarction Research Group

.

Circulation

1991

;

83

:

52

–

60

.

215

Packer

M

,

O'Connor

CM

,

Ghali

JK

,

Pressler

ML

,

Carson

PE

,

Belkin

RN

,

Miller

AB

,

Neuberg

GW

,

Frid

D

,

Wertheimer

JH

,

Cropp

AB

,

DeMets

DL

,

Prospective Randomized Amlodipine Survival Evaluation Study Group

.

Effect of amlodipine on morbidity and mortality in severe chronic heart failure

.

N Engl J Med

1996

;

335

:

1107

–

1114

.

216

Cohn

JN

,

Ziesche

S

,

Smith

R

,

Anand

I

,

Dunkman

WB

,

Loeb

H

,

Cintron

G

,

Boden

W

,

Baruch

L

,

Rochin

P

,

Loss

L

.

Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III

.

Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation

1997

;

96

:

856

–

863

.

217

Abraham

WT

,

Zile

MR

,

Weaver

FA

,

Butter

C

,

Ducharme

A

,

Halbach

M

,

Klug

D

,

Lovett

EG

,

Muller-Ehmsen

J

,

Schafer

JE

,

Senni

M

,

Swarup

V

,

Wachter

R

,

Little

WC

.

Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction

.

JACC Heart Fail

2015

;

3

:

487

–

496

.

218

Zannad

F

,

De Ferrari

GM

,

Tuinenburg

AE

,

Wright

D

,

Brugada

J

,

Butter

C

,

Klein

H

,

Stolen

C

,

Meyer

S

,

Stein

KM

,

Ramuzat

A

,

Schubert

B

,

Daum

D

,

Neuzil

P

,

Botman

C

,

Castel

MA

,

D'Onofrio

A

,

Solomon

SD

,

Wold

N

,

Ruble

SB

.

Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial

.

Eur Heart J

2015

;

36

:

425

–

433

.

219

Ponikowski

P

,

Javaheri

S

,

Michalkiewicz

D

,

Bart

BA

,

Czarnecka

D

,

Jastrzebski

M

,

Kusiak

A

,

Augostini

R

,

Jagielski

D

,

Witkowski

T

,

Khayat

RN

,

Oldenburg

O

,

Gutleben

K-J

,

Bitter

T

,

Karim

R

,

Iber

C

,

Hasan

A

,

Hibler

K

,

Germany

R

,

Abraham

WT

.

Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure

.

Eur Heart J

2012

;

33

:

889

–

894

.

220

Abraham

WT

,

Jagielski

D

,

Oldenburg

O

,

Augostini

R

,

Krueger

S

,

Kolodziej

A

,

Gutleben

K-J

,

Khayat

R

,

Merliss

A

,

Harsch

MR

,

Holcomb

RG

,

Javaheri

S

,

Ponikowski

P

.

Phrenic nerve stimulation for the treatment of central sleep apnea

.

JACC Heart Fail

2015

;

3

:

360

–

369

.

221

Kadish

A

,

Nademanee

K

,

Volosin

K

,

Krueger

S

,

Neelagaru

S

,

Raval

N

,

Obel

O

,

Weiner

S

,

Wish

M

,

Carson

P

,

Ellenbogen

K

,

Bourge

R

,

Parides

M

,

Chiacchierini

RP

,

Goldsmith

R

,

Goldstein

S

,

Mika

Y

,

Burkhoff

D

,

Abraham

WT

.

A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure

.

Am Heart J

2011

;

161

:

329

–

337

.e2.

222

Borggrefe

MM

,

Lawo

T

,

Butter

C

,

Schmidinger

H

,

Lunati

M

,

Pieske

B

,

Misier

AR

,

Curnis

A

,

Böcker

D

,

Remppis

A

,

Kautzner

J

,

Stühlinger

M

,

Leclerq

C

,

Táborský

M

,

Frigerio

M

,

Parides

M

,

Burkhoff

D

,

Hindricks

G

.

Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure

.

Eur Heart J

2008

;

29

:

1019

–

1028

.

223

Wyse

DG

,

Friedman

PL

,

Epstein

AE

.

A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators

.

N Engl J Med

1997

;

337

:

1576

–

1583

.

224

Connolly

SJ

,

Hallstrom

AP

,

Cappato

R

,

Schron

EB

,

Kuck

KH

,

Zipes

DP

,

Greene

HL

,

Boczor

S

,

Domanski

M

,

Follmann

D

,

Gent

M

,

Roberts

RS

.

Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study

.

Eur Heart J

2000

;

21

:

2071

–

2078

.

225

Connolly

SJ

,

Gent

M

,

Roberts

RS

,

Dorian

P

,

Roy

D

,

Sheldon

RS

,

Mitchell

LB

,

Green

MS

,

Klein

GJ

,

O'Brien

B

.

Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone

.

Circulation

2000

;

101

:

1297

–

1302

.

226

Kuck

KH

,

Cappato

R

,

Siebels

J

,

Rüppel

R

.

Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH)

.

Circulation

2000

;

102

:

748

–

754

.

227

Bardy

GH

,

Lee

KL

,

Mark

DB

,

Poole

JE

,

Packer

DL

,

Boineau

R

,

Domanski

M

,

Troutman

C

,

Anderson

J

,

Johnson

G

,

McNulty

SE

,

Clapp-Channing

N

,

Davidson-Ray

LD

,

Fraulo

ES

,

Fishbein

DP

,

Luceri

RM

,

Ip

JH

.

Amiodarone or an implantable cardioverter–defibrillator for congestive heart failure

.

N Engl J Med

2005

;

352

:

225

–

237

.

228

Steinbeck

G

,

Andresen

D

,

Seidl

K

,

Brachmann

J

,

Hoffmann

E

,

Wojciechowski

D

,

Kornacewicz-Jach

Z

,

Sredniawa

B

,

Lupkovics

G

,

Hofgärtner

F

,

Lubinski

A

,

Rosenqvist

M

,

Habets

A

,

Wegscheider

K

,

Senges

J

.

Defibrillator implantation early after myocardial infarction

.

N Engl J Med

2009

;

361

:

1427

–

1436

.

229

Sanders

GD

,

Hlatky

MA

,

Owens

DK

.

Cost-effectiveness of implantable cardioverter-defibrillators

.

N Engl J Med

2005

;

353

:

1471

–

1480

.

230

Steinberg

BA

,

Al-Khatib

SM

,

Edwards

R

,

Han

J

,

Bardy

GH

,

Bigger

JT

,

Buxton

AE

,

Moss

AJ

,

Lee

KL

,

Steinman

R

,

Dorian

P

,

Hallstrom

A

,

Cappato

R

,

Kadish

AH

,

Kudenchuk

PJ

,

Mark

DB

,

Inoue

LYT

,

Sanders

GD

.

Outcomes of implantable cardioverter-defibrillator use in patients with comorbidities: results from a combined analysis of 4 randomized clinical trials

.

JACC Heart Fail

2014

;

2

:

623

–

629

.

231

Raphael

CE

,

Finegold

JA

,

Barron

AJ

,

Whinnett

ZI

,

Mayet

J

,

Linde

C

,

Cleland

JGF

,

Levy

WC

,

Francis

DP

.

The effect of duration of follow-up and presence of competing risk on lifespan-gain from implantable cardioverter defibrillator therapy: who benefits the most

?

Eur Heart J

2015

;

36

:

1676

–

1688

.

232

Miller

RJH

,

Howlett

JG

,

Exner

DV

,

Campbell

PM

,

Grant

ADM

,

Wilton

SB

.

Baseline functional class and therapeutic efficacy of common heart failure interventions: a systematic review and meta-analysis

.

Can J Cardiol

2015

;

31

:

792

–

799

.

233

Hess

PL

,

Al-Khatib

SM

,

Han

JY

,

Edwards

R

,

Bardy

GH

,

Bigger

JT

,

Buxton

A

,

Cappato

R

,

Dorian

P

,

Hallstrom

A

,

Kadish

AH

,

Kudenchuk

PJ

,

Lee

KL

,

Mark

DB

,

Moss

AJ

,

Steinman

R

,

Inoue

LYT

,

Sanders

G

.

Survival benefit of the primary prevention implantable cardioverter-defibrillator among older patients: does age matter? An analysis of pooled data from 5 clinical trials

.

Circ Cardiovasc Qual Outcomes

2015

;

8

:

179

–

186

.

234

Merchant

FM

,

Jones

P

,

Wehrenberg

S

,

Lloyd

MS

,

Saxon

LA

.

Incidence of defibrillator shocks after elective generator exchange following uneventful first battery life

.

J Am Heart Assoc

2014

;

3

:

e001289

.

235

Yap

S-C

,

Schaer

BA

,

Bhagwandien

RE

,

Kuhne

M

,

Dabiri Abkenari

L

,

Osswald

S

,

Szili-Torok

T

,

Sticherling

C

,

Theuns

DA

.

Evaluation of the need of elective implantable cardioverter-defibrillator generator replacement in primary prevention patients without prior appropriate ICD therapy

.

Heart

2014

;

100

:

1188

–

1192

.

236

Kini

V

,

Soufi

MK

,

Deo

R

,

Epstein

AE

,

Bala

R

,

Riley

M

,

Groeneveld

PW

,

Shalaby

A

,

Dixit

S

.

Appropriateness of primary prevention implantable cardioverter-defibrillators at the time of generator replacement: are indications still met

?

J Am Coll Cardiol

2014

;

63

:

2388

–

2394

.

237

Erkapic

D

,

Sperzel

J

,

Stiller

S

,

Meltendorf

U

,

Mermi

J

,

Wegscheider

K

,

Hügl

B

.

Long-term benefit of implantable cardioverter/defibrillator therapy after elective device replacement: Results of the INcidence free SUrvival after ICD REplacement (INSURE) trial—a prospective multicentre study

.

Eur Heart J

2013

;

34

:

130

–

137

.

238

Alsheikh-Ali

AA

,

Homer

M

,

Maddukuri

PV

,

Kalsmith

B

,

Estes

NAM

,

Link

MS

.

Time-dependence of appropriate implantable defibrillator therapy in patients with ischemic cardiomyopathy

.

J Cardiovasc Electrophysiol

2008

;

19

:

784

–

789

.

239

Opreanu

M

,

Wan

C

,

Singh

V

,

Salehi

N

,

Ahmad

J

,

Szymkiewicz

SJ

,

Thakur

RK

.

Wearable cardioverter-defibrillator as a bridge to cardiac transplantation: a national database analysis

.

J Heart Lung Transplant

2015

;

34

:

1305

–

1309

.

240

Zishiri

ET

,

Williams

S

,

Cronin

EM

,

Blackstone

EH

,

Ellis

SG

,

Roselli

EE

,

Smedira

NG

,

Gillinov

AM

,

Glad

JA

,

Tchou

PJ

,

Szymkiewicz

SJ

,

Chung

MK

.

Early risk of mortality after coronary artery revascularization in patients with left ventricular dysfunction and potential role of the wearable cardioverter defibrillator

.

Circ Arrhythm Electrophysiol

2013

;

6

:

117

–

128

.

241

Chung

MK

,

Szymkiewicz

SJ

,

Shao

M

,

Zishiri

E

,

Niebauer

MJ

,

Lindsay

BD

,

Tchou

PJ

.

Aggregate national experience with the wearable cardioverter-defibrillator

.

J Am Coll Cardiol

2010

;

56

:

194

–

203

.

242

Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators

.

Lancet

1997

;

350

:

1417

–

1424

.

243

Andrey

JL

,

Gomez-Soto

FM

,

Romero

SP

,

Escobar

MA

,

García-Egido

AA

,

Garcia-Arjona

R

,

Gomez

F

,

GAMIC (Grupo para Atencion Medica Integrada de Cadiz)

.

Mortality of newly diagnosed heart failure treated with amiodarone: a propensity-matched study

.

Int J Cardiol

2011

;

151

:

175

–

181

.

244

Torp-Pedersen

C

,

Metra

M

,

Spark

P

,

Lukas

MA

,

Moullet

C

,

Scherhag

A

,

Komajda

M

,

Cleland

JGF

,

Remme

W

,

Di Lenarda

A

,

Swedberg

K

,

Poole-Wilson

PA

.

The safety of amiodarone in patients with heart failure

.

J Card Fail

2007

;

13

:

340

–

345

.

245

Piepoli

M

,

Villani

GQ

,

Ponikowski

P

,

Wright

A

,

Flather

MD

,

Coats

AJ

.

Overview and meta-analysis of randomised trials of amiodarone in chronic heart failure

.

Int J Cardiol

1998

;

66

:

1

–

10

.

246

Chatterjee

S

,

Ghosh

J

,

Lichstein

E

,

Aikat

S

,

Mukherjee

D

.

Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure

.

Am J Cardiol

2012

;

110

:

607

–

613

.

247

Køber

L

,

Torp-Pedersen

C

,

McMurray

JJV

,

Gøtzsche

O

,

Lévy

S

,

Crijns

H

,

Amlie

J

,

Carlsen

J

.

Increased mortality after dronedarone therapy for severe heart failure

.

N Engl J Med

2008

;

358

:

2678

–

2687

.

248

Echt

DS

,

Liebson

PR

,

Mitchell

LB

,

Peters

RW

,

Obias-Manno

D

,

Barker

AH

,

Arensberg

D

,

Baker

A

,

Friedman

L

,

Greene

HL

,

Huther

ML

,

Richardson

DW

.

Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial

.

N Engl J Med

1991

;

324

:

781

–

788

.

249

Theuns

DAMJ

,

Smith

T

,

Hunink

MGM

,

Bardy

GH

,

Jordaens

L

.

Effectiveness of prophylactic implantation of cardioverter-defibrillators without cardiac resynchronization therapy in patients with ischaemic or non-ischaemic heart disease: a systematic review and meta-analysis

.

Europace

2010

;

12

:

1564

–

1570

.

250

Cook

NR

,

Ridker

PM

.

Advances in measuring the effect of individual predictors of cardiovascular risk: the role of reclassification measures

.

Ann Intern Med

2009

;

150

:

795

–

802

.

251

Moss

AJ

,

Hall

WJ

,

Cannom

DS

,

Daubert

JP

,

Higgins

SL

,

Klein

H

,

Levine

JH

,

Saksena

S

,

Waldo

AL

,

Wilber

D

,

Brown

MW

,

Heo

M

.

Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators

.

N Engl J Med

1996

;

335

:

1933

–

1940

.

252

Moss

AJ

,

Schuger

C

,

Beck

CA

,

Brown

MW

,

Cannom

DS

,

Daubert

JP

,

Estes

NAM

,

Greenberg

H

,

Hall

WJ

,

Huang

DT

,

Kautzner

J

,

Klein

H

,

McNitt

S

,

Olshansky

B

,

Shoda

M

,

Wilber

D

,

Zareba

W

.

Reduction in inappropriate therapy and mortality through ICD programming

.

N Engl J Med

2012

;

367

:

2275

–

2283

.

253

Gasparini

M

,

Proclemer

A

,

Klersy

C

,

Kloppe

A

,

Lunati

M

,

Ferrer

JBM

,

Hersi

A

,

Gulaj

M

,

Wijfels

MCEF

,

Santi

E

,

Manotta

L

,

Arenal

A

.

Effect of long-detection interval vs standard-detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: the ADVANCE III randomized clinical trial

.

JAMA

2013

;

309

:

1903

–

1911

.

254

Cleland

JGF

,

Buga

L

.

Device therapy: defibrillators—a shocking therapy for cardiomyopathy

?

Nat Rev Cardiol

2010

;

7

:

69

–

70

.

255

Stewart

GC

,

Weintraub

JR

,

Pratibhu

PP

,

Semigran

MJ

,

Camuso

JM

,

Brooks

K

,

Tsang

SW

,

Anello

MS

,

Nguyen

VT

,

Lewis

EF

,

Nohria

A

,

Desai

AS

,

Givertz

MM

,

Stevenson

LW

.

Patient expectations from implantable defibrillators to prevent death in heart failure

.

J Card Fail

2010

;

16

:

106

–

113

.

256

Bardy

GH

,

Smith

WM

,

Hood

M a

,

Crozier

IG

,

Melton

IC

,

Jordaens

L

,

Theuns

D

,

Park

RE

,

Wright

DJ

,

Connelly

DT

,

Fynn

SP

,

Murgatroyd

FD

,

Sperzel

J

,

Neuzner

J

,

Spitzer

SG

,

Ardashev

AV

,

Oduro

A

,

Boersma

L

,

Maass

AH

,

Van Gelder

IC

,

Wilde

AA

,

van Dessel

PF

,

Knops

RE

,

Barr

CS

,

Lupo

P

,

Cappato

R

,

Grace

AA

.

An entirely subcutaneous implantable cardioverter-defibrillator

.

N Engl J Med

2010

;

363

:

36

–

44

.

257

Aziz

S

,

Leon

AR

,

El-Chami

MF

.

The subcutaneous defibrillator

.

J Am Coll Cardiol

2014

;

63

:

1473

–

1479

.

258

Olde Nordkamp

LRA

,

Knops

RE

,

Bardy

GH

,

Blaauw

Y

,

Boersma

LVA

,

Bos

JS

,

Delnoy

PPHM

,

van Dessel

PFHM

,

Driessen

AHG

,

de Groot

JR

,

Herrman

JPR

,

Jordaens

LJLM

,

Kooiman

KM

,

Maass

AH

,

Meine

M

,

Mizusawa

Y

,

Molhoek

SG

,

van Opstal

J

,

Tijssen

JGP

,

Wilde

AAM

.

Rationale and design of the PRAETORIAN trial: a Prospective, RAndomizEd comparison of subcuTaneOus and tRansvenous ImplANtable cardioverter-defibrillator therapy

.

Am Heart J

2012

;

163

:

753

–

760.e2

.

259

Burke

MC

,

Gold

MR

,

Knight

BP

,

Barr

CS

,

Theuns

DAMJ

,

Boersma

LVA

,

Knops

RE

,

Weiss

R

,

Leon

AR

,

Herre

JM

,

Husby

M

,

Stein

KM

,

Lambiase

PD

.

Safety and efficacy of the totally subcutaneous implantable defibrillator: 2-year results from a pooled analysis of the IDE Study and EFFORTLESS Registry

.

J Am Coll Cardiol

2015

;

65

:

1605

–

1615

.

260

Priori

SG

,

Blomström-Lundqvist

C

,

Mazzanti

A

,

Blom

N

,

Borggrefe

M

,

Camm

J

,

Elliott

PM

,

Fitzsimons

D

,

Hatala

R

,

Hindricks

G

,

Kirchhof

P

,

Kjeldsen

K

,

Kuck

K-H

,

Hernandez-Madrid

A

,

Nikolaou

N

,

Norekvål

TM

,

Spaulding

C

,

Van Veldhuisen

DJ

.

2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the Europe

.

Eur Heart J

2015

;

36

:

2793

–

2867

.

261

Cazeau

S

,

Leclercq

C

,

Lavergne

T

,

Walker

S

,

Varma

C

,

Linde

C

,

Garrigue

S

,

Kappenberger

L

,

Haywood

GA

,

Santini

M

,

Bailleul

C

,

Mabo

P

,

Lazarus

A

,

Ritter

P

,

Levy

T

,

McKenna

W

,

Daubert

J-C

.

Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay

.

N Engl J Med

2001

;

344

:

873

–

880

.

262

Cleland

J

,

Daubert

J

,

Erdmann

E

,

Freemantle

N

,

Gras

D

,

Kappenberger

L

,

Tavazzi

L

.

The effect of cardiac resynchronization on morbidity and mortality in heart failure

.

N Engl J Med

2005

;

352

:

1539

–

1549

.

263

Cleland

JGF

,

Daubert

J-C

,

Erdmann

E

,

Freemantle

N

,

Gras

D

,

Kappenberger

L

,

Tavazzi

L

.

Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase]

.

Eur Heart J

2006

;

27

:

1928

–

1932

.

264

Cleland

JGF

,

Freemantle

N

,

Erdmann

E

,

Gras

D

,

Kappenberger

L

,

Tavazzi

L

,

Daubert

J-CC

.

Long-term mortality with cardiac resynchronization therapy in the Cardiac Resynchronization–Heart Failure (CARE-HF) trial

.

Eur J Heart Fail

2012

;

14

:

628

–

634

.

265

Bristow

MR

,

Saxon

LA

,

Boehmer

J

,

Krueger

S

,

Kass

DA

,

De Marco

T

,

Carson

P

,

DiCarlo

L

,

DeMets

D

,

White

BG

,

DeVries

DW

,

Feldman

AM

.

Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure

.

N Engl J Med

2004

;

350

:

2140

–

2150

.

266

Cleland

JG

,

Abraham

WT

,

Linde

C

,

Gold

MR

,

Young

JB

,

Claude Daubert

J

,

Sherfesee

L

,

Wells

GA

,

Tang

ASL

.

An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure

.

Eur Heart J

2013

;

34

:

3547

–

3556

.

267

Tang

ASL

,

Wells

GA

,

Talajic

M

,

Arnold

MO

,

Sheldon

R

,

Connolly

S

,

Hohnloser

SH

,

Nichol

G

,

Birnie

DH

,

Sapp

JL

,

Yee

R

,

Healey

JS

,

Rouleau

JL

.

Cardiac-resynchronization therapy for mild-to-moderate heart failure

.

N Engl J Med

2010

;

363

:

2385

–

2395

.

268

Moss

AJ

,

Hall

WJ

,

Cannom

DS

,

Klein

H

,

Brown

MW

,

Daubert

JP

,

Estes

NAM

,

Foster

E

,

Greenberg

H

,

Higgins

SL

,

Pfeffer

MA

,

Solomon

SD

,

Wilber

D

,

Zareba

W

.

Cardiac-resynchronization therapy for the prevention of heart-failure events

.

N Engl J Med

2009

;

361

:

1329

–

1338

.

269

Goldenberg

I

,

Kutyifa

V

,

Klein

HU

,

Cannom

DS

,

Brown

MW

,

Dan

A

,

Daubert

JP

,

Estes

NAM

,

Foster

E

,

Greenberg

H

,

Kautzner

J

,

Klempfner

R

,

Kuniss

M

,

Merkely

B

,

Pfeffer

MA

,

Quesada

A

,

Viskin

S

,

McNitt

S

,

Polonsky

B

,

Ghanem

A

,

Solomon

SD

,

Wilber

D

,

Zareba

W

,

Moss

AJ

.

Survival with cardiac-resynchronization therapy in mild heart failure

.

N Engl J Med

2014

;

370

:

1694

–

1701

.

270

Linde

C

,

Abraham

WT

,

Gold

MR

,

St John Sutton

M

,

Ghio

S

,

Daubert

C

.

Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms

.

J Am Coll Cardiol

2008

;

52

:

1834

–

1843

.

271

Daubert

C

,

Gold

MR

,

Abraham

WT

,

Ghio

S

,

Hassager

C

,

Goode

G

,

Szili-Török

T

,

Linde

C

,

REVERSE Study Group

.

Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE trial

.

J Am Coll Cardiol

2009

;

54

:

1837

–

1846

.

272

Linde

C

,

Gold

MR

,

Abraham

WT

,

St John Sutton

M

,

Ghio

S

,

Cerkvenik

J

,

Daubert

C

.

Long-term impact of cardiac resynchronization therapy in mild heart failure: 5-year results from the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study

.

Eur Heart J

2013

;

34

:

2592

–

2599

.

273

Woods

B

,

Hawkins

N

,

Mealing

S

,

Sutton

A

,

Abraham

WT

,

Beshai

JF

,

Klein

H

,

Sculpher

M

,

Plummer

CJ

,

Cowie

MR

.

Individual patient data network meta-analysis of mortality effects of implantable cardiac devices

.

Heart

2015

;

101

:

1800

–

1806

.

274

Curtis

AB

,

Worley

SJ

,

Adamson

PB

,

Chung

ES

,

Niazi

I

,

Sherfesee

L

,

Shinn

T

,

St John Sutton

M

.

Biventricular pacing for atrioventricular block and systolic dysfunction

.

N Engl J Med

2013

;

368

:

1585

–

1593

.

275

Brignole

M

,

Botto

G

,

Mont

L

,

Iacopino

S

,

De Marchi

G

,

Oddone

D

,

Luzi

M

,

Tolosana

JM

,

Navazio

A

,

Menozzi

C

.

Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial

.

Eur Heart J

2011

;

32

:

2420

–

2429

.

276

Leclercq

C

,

Walker

S

,

Linde

C

,

Clementy

J

,

Marshall

AJ

,

Ritter

P

,

Djiane

P

,

Mabo

P

,

Levy

T

,

Gadler

F

,

Bailleul

C

,

Daubert

J-C

.

Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation

.

Eur Heart J

2002

;

23

:

1780

–

1787

.

277

Stavrakis

S

,

Garabelli

P

,

Reynolds

DW

.

Cardiac resynchronization therapy after atrioventricular junction ablation for symptomatic atrial fibrillation: a meta-analysis

.

Europace

2012

;

14

:

1490

–

1497

.

278

MacDonald

MR

,

Connelly

DT

,

Hawkins

NM

,

Steedman

T

,

Payne

J

,

Shaw

M

,

Denvir

M

,

Bhagra

S

,

Small

S

,

Martin

W

,

McMurray

JJ

,

Petrie

MC

.

Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a randomised controlled trial

.

Heart

2011

;

97

:

740

–

747

.

279

Jones

DG

,

Haldar

SK

,

Hussain

W

,

Sharma

R

,

Francis

DP

,

Rahman-Haley

SL

,

McDonagh

TA

,

Underwood

SR

,

Markides

V

,

Wong

T

.

A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure

.

J Am Coll Cardiol

2013

;

61

:

1894

–

1903

.

280

Upadhyay

GA

,

Choudhry

NK

,

Auricchio

A

,

Ruskin

J

,

Singh

JP

.

Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies

.

J Am Coll Cardiol

2008

;

52

:

1239

–

1246

.

281

Gasparini

M

,

Leclercq

C

,

Lunati

M

,

Landolina

M

,

Auricchio

A

,

Santini

M

,

Boriani

G

,

Lamp

B

,

Proclemer

A

,

Curnis

A

,

Klersy

C

,

Leyva

F

.

Cardiac resynchronization therapy in patients with atrial fibrillation. The CERTIFY Study (Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry)

.

JACC Heart Fail

2013

;

1

:

500

–

507

.

282

Gage

RM

,

Burns

KV

,

Bank

AJ

.

Echocardiographic and clinical response to cardiac resynchronization therapy in heart failure patients with and without previous right ventricular pacing

.

Eur J Heart Fail

2014

;

16

:

1199

–

1205

.

283

Ruschitzka

F

,

Abraham

WT

,

Singh

JP

,

Bax

JJ

,

Borer

JS

,

Brugada

J

,

Dickstein

K

,

Ford

I

,

Gorcsan

J

,

Gras

D

,

Krum

H

,

Sogaard

P

,

Holzmeister

J

.

Cardiac-resynchronization therapy in heart failure with a narrow QRS complex

.

N Engl J Med

2013

;

369

:

1395

–

1405

.

284

Steffel

J

,

Robertson

M

,

Singh

JP

,

Abraham

WT

,

Bax

JJ

,

Borer

JS

,

Dickstein

K

,

Ford

I

,

Gorcsan

J

,

Gras

D

,

Krum

H

,

Sogaard

P

,

Holzmeister

J

,

Brugada

J

,

Ruschitzka

F

.

The effect of QRS duration on cardiac resynchronization therapy in patients with a narrow QRS complex: a subgroup analysis of the EchoCRT trial

.

Eur Heart J

2015

;

36

:

1983

–

1989

.

285

Zusterzeel

R

,

Selzman

KA

,

Sanders

WE

,

Caños

DA

,

O'Callaghan

KM

,

Carpenter

JL

,

Piña

IL

,

Strauss

DG

.

Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patient-level data

.

JAMA Intern Med

2014

;

174

:

1340

–

1348

.

286

Sohaib

SMMA

,

Finegold

JA

,

Nijjer

SS

,

Hossain

R

,

Linde

C

,

Levy

WC

,

Sutton

R

,

Kanagaratnam

P

,

Francis

DP

,

Whinnett

ZI

.

Opportunity to increase life span in narrow QRS cardiac resynchronization therapy recipients by deactivating ventricular pacing: evidence from randomized controlled trials

.

JACC Heart Fail

2015

;

3

:

327

–

336

.

287

Cleland

JGF

,

Calvert

MJ

,

Verboven

Y

,

Freemantle

N

.

Effects of cardiac resynchronization therapy on long-term quality of life: an analysis from the Cardiac Resynchronisation-Heart Failure (CARE-HF) study

.

Am Heart J

2009

;

157

:

457

–

466

.

288

Cleland

JGF

,

Mareev

Y

,

Linde

C

.

Reflections on EchoCRT: sound guidance on QRS duration and morphology for CRT?

Eur Heart J

2015

;

36

:

1948

–

1951

.

289

Linde

C

,

Stahlberg

M

,

Benson

L

,

Braunschweig

F

,

Edner

M

,

Dahlstrom

U

,

Alehagen

U

,

Lund

LH

.

Gender, underutilization of cardiac resynchronization therapy, and prognostic impact of QRS prolongation and left bundle branch block in heart failure

.

Europace

2015

;

17

:

424

–

431

.

290

Doshi

RN

,

Daoud

EG

,

Fellows

C

,

Turk

K

,

Duran

A

,

Hamdan

MH

,

Pires

LA

,

PAVE Study Group

.

Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study)

.

J Cardiovasc Electrophysiol

2005

;

16

:

1160

–

1165

.

291

Funck

RC

,

Mueller

H-H

,

Lunati

M

,

Piorkowski

C

,

De Roy

L

,

Paul

V

,

Wittenberg

M

,

Wuensch

D

,

Blanc

J-J

.

Characteristics of a large sample of candidates for permanent ventricular pacing included in the Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization Study (BioPace)

.

Europace

2014

;

16

:

354

–

362

.

292

Chung

ES

,

Leon

AR

,

Tavazzi

L

,

Sun

J-P

,

Nihoyannopoulos

P

,

Merlino

J

,

Abraham

WT

,

Ghio

S

,

Leclercq

C

,

Bax

JJ

,

Yu

C-M

,

Gorcsan

J

,

StJohn Sutton

M

,

De Sutter

J

,

Murillo

J

.

Results of the Predictors of Response to CRT (PROSPECT) Trial

.

Circulation

2008

;

117

:

2608

–

2616

.

293

Wikstrom

G

,

Blomström-Lundqvist

C

,

Andren

B

,

Lönnerholm

S

,

Blomström

P

,

Freemantle

N

,

Remp

T

,

Cleland

JGF

.

The effects of aetiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial

.

Eur Heart J

2009

;

30

:

782

–

788

.

294

Khan

FZ

,

Virdee

MS

,

Palmer

CR

,

Pugh

PJ

,

O'Halloran

D

,

Elsik

M

,

Read

P a

,

Begley

D

,

Fynn

SP

,

Dutka

DP

.

Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial

.

J Am Coll Cardiol

2012

;

59

:

1509

–

1518

.

295

Saba

S

,

Marek

J

,

Schwartzman

D

,

Jain

S

,

Adelstein

E

,

White

P

,

Oyenuga

OA

,

Onishi

T

,

Soman

P

,

Gorcsan

J

.

Echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy: results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region Trial

.

Circ Heart Fail

2013

;

6

:

427

–

434

.

296

Kosmala

W

,

Marwick

TH

.

Meta-analysis of effects of optimization of cardiac resynchronization therapy on left ventricular function, exercise capacity, and quality of life in patients with heart failure

.

Am J Cardiol

2014

;

113

:

988

–

994

.

297

Whinnett

ZI

,

Francis

DP

,

Denis

A

,

Willson

K

,

Pascale

P

,

Van Geldorp

I

,

De Guillebon

M

,

Ploux

S

,

Ellenbogen

K

,

Haïssaguerre

M

,

Ritter

P

,

Bordachar

P

.

Comparison of different invasive hemodynamic methods for AV delay optimization in patients with cardiac resynchronization therapy: Implications for clinical trial design and clinical practice

.

Int J Cardiol

2013

;

168

:

2228

–

2237

.

298

Kuck

K-H

,

Bordachar

P

,

Borggrefe

M

,

Boriani

G

,

Burri

H

,

Leyva

F

,

Schauerte

P

,

Theuns

D

,

Thibault

B

,

Kirchhof

P

,

Hasenfuss

G

,

Dickstein

K

,

Leclercq

C

,

Linde

C

,

Tavazzi

L

,

Ruschitzka

F

.

New devices in heart failure: an European Heart Rhythm Association report: developed by the European Heart Rhythm Association; endorsed by the Heart Failure Association

.

Europace

2014

;

16

:

109

–

128

.

299

Singh

JP

,

Kandala

J

,

Camm

AJ

.

Non-pharmacological modulation of the autonomic tone to treat heart failure

.

Eur Heart J

2014

;

35

:

77

–

85

.

300

Solomon

SD

,

Zile

M

,

Pieske

B

,

Voors

A

,

Shah

A

,

Kraigher-Krainer

E

,

Shi

V

,

Bransford

T

,

Takeuchi

M

,

Gong

J

,

Lefkowitz

M

,

Packer

M

,

McMurray

JJ

.

The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial

.

Lancet

2012

;

380

:

1387

–

1395

.

301

Pitt

B

,

Pfeffer

MA

,

Assmann

SF

,

Boineau

R

,

Anand

IS

,

Claggett

B

,

Clausell

N

,

Desai

AS

,

Diaz

R

,

Fleg

JL

,

Gordeev

I

,

Harty

B

,

Heitner

JF

,

Kenwood

CT

,

Lewis

EF

,

O'Meara

E

,

Probstfield

JL

,

Shaburishvili

T

,

Shah

SJ

,

Solomon

SD

,

Sweitzer

NK

,

Yang

S

,

McKinlay

SM

.

Spironolactone for heart failure with preserved ejection fraction

.

N Engl J Med

2014

;

370

:

1383

–

1392

.

302

Redfield

MM

,

Chen

HH

,

Borlaug

BA

,

Semigran

MJ

,

Lee

KL

,

Lewis

G

,

LeWinter

MM

,

Rouleau

JL

,

Bull

DA

,

Mann

DL

,

Deswal

A

,

Stevenson

LW

,

Givertz

MM

,

Ofili

EO

,

O'Connor

CM

,

Felker

GM

,

Goldsmith

SR

,

Bart

BA

,

McNulty

SE

,

Ibarra

JC

,

Lin

G

,

Oh

JK

,

Patel

MR

,

Kim

RJ

,

Tracy

RP

,

Velazquez

EJ

,

Anstrom

KJ

,

Hernandez

AF

,

Mascette

AM

,

Braunwald

E

,

RELAX Trial

.

Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial

.

JAMA

2013

;

309

:

1268

–

1277

.

303

Senni

M

,

Paulus

WJ

,

Gavazzi

A

,

Fraser

AG

,

Diez

J

,

Solomon

SD

,

Smiseth

OA

,

Guazzi

M

,

Lam

CSP

,

Maggioni

AP

,

Tschope

C

,

Metra

M

,

Hummel

SL

,

Edelmann

F

,

Ambrosio

G

,

Stewart Coats

AJ

,

Filippatos

GS

,

Gheorghiade

M

,

Anker

SD

,

Levy

D

,

Pfeffer

MA

,

Stough

WG

,

Pieske

BM

.

New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes

.

Eur Heart J

2014

;

35

:

2797

–

2815

.

304

Ferrari

R

,

Böhm

M

,

Cleland

JGF

,

Paulus

WJS

,

Pieske

B

,

Rapezzi

C

,

Tavazzi

L

.

Heart failure with preserved ejection fraction: uncertainties and dilemmas

.

Eur J Heart Fail

2015

;

17

:

665

–

671

.

305

Ather

S

,

Chan

W

,

Bozkurt

B

,

Aguilar

D

,

Ramasubbu

K

,

Zachariah

AA

,

Wehrens

XHT

,

Deswal

A

.

Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction

.

J Am Coll Cardiol

2012

;

59

:

998

–

1005

.

306

Henkel

DM

,

Redfield

MM

,

Weston

SA

,

Gerber

Y

,

Roger

VL

.

Death in heart failure: a community perspective

.

Circ Heart Fail

2008

;

1

:

91

–

97

.

307

Fukuta

H

,

Goto

T

,

Wakami

K

,

Ohte

N

.

Effects of drug and exercise intervention on functional capacity and quality of life in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials

.

Eur J Prev Cardiol

2016

;

23

:

78

–

85

.

308

Lewis

EF

,

Lamas

GA

,

O'Meara

E

,

Granger

CB

,

Dunlap

ME

,

McKelvie

RS

,

Probstfield

JL

,

Young

JB

,

Michelson

EL

,

Halling

K

,

Carlsson

J

,

Olofsson

B

,

McMurray

JJV

,

Yusuf

S

,

Swedberg

K

,

Pfeffer

MA

.

Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM

.

Eur J Heart Fail

2007

;

9

:

83

–

91

.

309

Massie

BM

,

Carson

PE

,

McMurray

JJ

,

Komajda

M

,

McKelvie

R

,

Zile

MR

,

Anderson

S

,

Donovan

M

,

Iverson

E

,

Staiger

C

,

Ptaszynska

A

.

Irbesartan in patients with heart failure and preserved ejection fraction

.

N Engl J Med

2008

;

359

:

2456

–

2467

.

310

Yusuf

S

,

Pfeffer

MA

,

Swedberg

K

,

Granger

CB

,

Held

P

,

McMurray

JJ V

,

Michelson

EL

,

Olofsson

B

,

Ostergren

J

.

Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial

.

Lancet

2003

;

362

:

777

–

781

.

311

Cleland

JGF

,

Tendera

M

,

Adamus

J

,

Freemantle

N

,

Polonski

L

,

Taylor

J

.

The perindopril in elderly people with chronic heart failure (PEP-CHF) study

.

Eur Heart J

2006

;

27

:

2338

–

2345

.

312

Mulder

BA

,

van Veldhuisen

DJ

,

Crijns

HJGM

,

Böhm

M

,

Cohen-Solal

A

,

Babalis

D

,

Roughton

M

,

Flather

MD

,

Coats

AJS

,

Van Gelder

IC

.

Effect of nebivolol on outcome in elderly patients with heart failure and atrial fibrillation: insights from SENIORS

.

Eur J Heart Fail

2012

;

14

:

1171

–

1178

.

313

van Veldhuisen

DJ

,

Cohen-Solal

A

,

Böhm

M

,

Anker

SD

,

Babalis

D

,

Roughton

M

,

Coats

AJS

,

Poole-Wilson

PA

,

Flather

MD

.

Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction

.

J Am Coll Cardiol

2009

;

53

:

2150

–

2158

.

314

Ahmed

A

,

Rich

MW

,

Fleg

JL

,

Zile

MR

,

Young

JB

,

Kitzman

DW

,

Love

TE

,

Aronow

WS

,

Adams

KF

,

Gheorghiade

M

.

Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial

.

Circulation

2006

;

114

:

397

–

403

.

315

McMurray

JJ V

,

Ostergren

J

,

Swedberg

K

,

Granger

CB

,

Held

P

,

Michelson

EL

,

Olofsson

B

,

Yusuf

S

,

Pfeffer

MA

.

Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial

.

Lancet

2003

;

362

:

767

–

771

.

316

Kirchof

P

,

Benussi

S

et al. .

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

.

Eur Heart J

.

2016

.

. Forthcoming

10.1093/eurheartj/ehw210

.

317

Mancia

G

,

Fagard

R

,

Narkiewicz

K

,

Redon

J

,

Zanchetti

A

,

Böhm

M

,

Christiaens

T

,

Cifkova

R

,

De Backer

G

,

Dominiczak

A

,

Galderisi

M

,

Grobbee

DE

,

Jaarsma

T

,

Kirchhof

P

,

Kjeldsen

SE

,

Laurent

S

,

Manolis

AJ

,

Nilsson

PM

,

Ruilope

LM

,

Schmieder

RE

,

Sirnes

PA

,

Sleight

P

,

Viigimaa

M

,

Waeber

B

,

Zannad

F

,

Redon

J

,

Dominiczak

A

,

Narkiewicz

K

,

Nilsson

PM

,

Burnier

M

,

Viigimaa

M

,

Ambrosioni

E

,

Caufield

M

,

Coca

A

,

Olsen

MH

,

Schmieder

RE

,

Tsioufis

C

,

van de Borne

P

,

Zamorano

JL

,

Achenbach

S

,

Baumgartner

H

,

Bax

JJ

,

Bueno

H

,

Dean

V

,

Deaton

C

,

Erol

C

,

Fagard

R

,

Ferrari

R

,

Hasdai

D

,

Hoes

AW

,

Kirchhof

P

,

Knuuti

J

,

Kolh

P

,

Lancellotti

P

,

Linhart

A

,

Nihoyannopoulos

P

,

Piepoli

MF

,

Ponikowski

P

,

Sirnes

PA

,

Tamargo

JL

,

Tendera

M

,

Torbicki

A

,

Wijns

W

,

Windecker

S

,

Clement

DL

,

Coca

A

,

Gillebert

TC

,

Tendera

M

,

Rosei

EA

,

Ambrosioni

E

,

Anker

SD

,

Bauersachs

J

,

Hitij

JB

,

Caulfield

M

,

De Buyzere

M

,

De Geest

S

,

Derumeaux

GA

,

Erdine

S

,

Farsang

C

,

Funck-Brentano

C

,

Gerc

V

,

Germano

G

,

Gielen

S

,

Haller

H

,

Hoes

AW

,

Jordan

J

,

Kahan

T

,

Komajda

M

,

Lovic

D

,

Mahrholdt

H

,

Olsen

MH

,

Ostergren

J

,

Parati

G

,

Perk

J

,

Polonia

J

,

Popescu

BA

,

Reiner

Z

,

Rydén

L

,

Sirenko

Y

,

Stanton

A

,

Struijker-Boudier

H

,

Tsioufis

C

,

van de Borne

P

,

Vlachopoulos

C

,

Volpe

M

,

Wood

DA

.

2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

.

Eur Heart J

2013

;

34

:

2159

–

2219

.

318

Sakata

Y

,

Shiba

N

,

Takahashi

J

,

Miyata

S

,

Nochioka

K

,

Miura

M

,

Takada

T

,

Saga

C

,

Shinozaki

T

,

Sugi

M

,

Nakagawa

M

,

Sekiguchi

N

,

Komaru

T

,

Kato

A

,

Fukuchi

M

,

Nozaki

E

,

Hiramoto

T

,

Inoue

K

,

Goto

T

,

Ohe

M

,

Tamaki

K

,

Ibayashi

S

,

Ishide

N

,

Maruyama

Y

,

Tsuji

I

,

Shimokawa

H

.

Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial

.

Eur Heart J

2015

;

36

:

915

–

923

.

319

Rydén

L

,

Grant

PJ

,

Anker

SD

,

Berne

C

,

Cosentino

F

,

Danchin

N

,

Deaton

C

,

Escaned

J

,

Hammes

H-P

,

Huikuri

H

,

Marre

M

,

Marx

N

,

Mellbin

L

,

Ostergren

J

,

Patrono

C

,

Seferovic

P

,

Uva

MS

,

Taskinen

M-R

,

Tendera

M

,

Tuomilehto

J

,

Valensi

P

,

Zamorano

JL

,

Achenbach

S

,

Baumgartner

H

,

Bax

JJ

,

Bueno

H

,

Dean

V

,

Erol

C

,

Fagard

R

,

Ferrari

R

,

Hasdai

D

,

Hoes

AW

,

Kirchhof

P

,

Knuuti

J

,

Kolh

P

,

Lancellotti

P

,

Linhart

A

,

Nihoyannopoulos

P

,

Piepoli

MF

,

Ponikowski

P

,

Sirnes

PA

,

Tamargo

JL

,

Torbicki

A

,

Wijns

W

,

Windecker

S

,

De Backer

G

,

Ezquerra

EA

,

Avogaro

A

,

Badimon

L

,

Baranova

E

,

Betteridge

J

,

Ceriello

A

,

Funck-Brentano

C

,

Gulba

DC

,

Kjekshus

JK

,

Lev

E

,

Mueller

C

,

Neyses

L

,

Nilsson

PM

,

Perk

J

,

Reiner

Z

,

Sattar

N

,

Schächinger

V

,

Scheen

A

,

Schirmer

H

,

Strömberg

A

,

Sudzhaeva

S

,

Viigimaa

M

,

Vlachopoulos

C

,

Xuereb

RG

.

ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD

.

Eur Heart J

2013

;

34

:

3035

–

3087

.

320

Gilbert

RE

,

Krum

H

.

Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy

.

Lancet

2015

;

385

:

2107

–

2117

.

321

Edelmann

F

,

Gelbrich

G

,

Düngen

H-D

,

Fröhling

S

,

Wachter

R

,

Stahrenberg

R

,

Binder

L

,

Töpper

A

,

Lashki

DJ

,

Schwarz

S

,

Herrmann-Lingen

C

,

Löffler

M

,

Hasenfuss

G

,

Halle

M

,

Pieske

B

.

Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction

.

J Am Coll Cardiol

2011

;

58

:

1780

–

1791

.

322

Katritsis

DG

,

Siontis

GCM

,

Camm

AJ

.

Prognostic significance of ambulatory ECG monitoring for ventricular arrhythmias

.

Prog Cardiovasc Dis

2013

;

56

:

133

–

142

.

323

Camm

AJ

,

Corbucci

G

,

Padeletti

L

.

Usefulness of continuous electrocardiographic monitoring for atrial fibrillation

.

Am J Cardiol

2012

;

110

:

270

–

276

.

324

Turakhia

MP

,

Ullal

AJ

,

Hoang

DD

,

Than

CT

,

Miller

JD

,

Friday

KJ

,

Perez

M V

,

Freeman

JV

,

Wang

PJ

,

Heidenreich

PA

.

Feasibility of extended ambulatory electrocardiogram monitoring to identify silent atrial fibrillation in high-risk patients: the Screening Study for Undiagnosed Atrial Fibrillation (STUDY-AF)

.

Clin Cardiol

2015

;

38

:

285

–

292

.

325

Camm

AJ

,

Kirchhof

P

,

Lip

GYH

,

Schotten

U

,

Savelieva

I

,

Ernst

S

,

Van Gelder

IC

,

Al-Attar

N

,

Hindricks

G

,

Prendergast

B

,

Heidbuchel

H

,

Alfieri

O

,

Angelini

A

,

Atar

D

,

Colonna

P

,

De Caterina

R

,

De Sutter

J

,

Goette

A

,

Gorenek

B

,

Heldal

M

,

Hohloser

SH

,

Kolh

P

,

Le Heuzey

JY

,

Ponikowski

P

,

Rutten

FH

,

Vahanian

A

,

Auricchio

A

,

Bax

J

,

Ceconi

C

,

Dean

V

,

Filippatos

G

,

Funck-Brentano

C

,

Hobbs

R

,

Kearney

P

,

McDonagh

T

,

Popescu

BA

,

Reiner

Z

,

Sechtem

U

,

Sirnes

PA

,

Tendera

M

,

Vardas

PE

,

Widimsky

P

,

Agladze

V

,

Aliot

E

,

Balabanski

T

,

Blomstrom-Lundqvist

C

,

Capucci

A

,

Crijns

H

,

Dahlof

B

,

Folliguet

T

,

Glikson

M

,

Goethals

M

,

Gulba

DC

,

Ho

SY

,

Klautz

RJM

,

Kose

S

,

McMurray

J

,

PerroneFilardi

P

,

Raatikainen

P

,

Salvador

MJ

,

Schalij

MJ

,

Shpektor

A

,

Sousa

J

,

Stepinska

J

,

Uuetoa

H

,

Zamorano

JL

,

Zupan

I

.

Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)

.

Eur Heart J

2010

;

31

:

2369

–

2429

.

326

Cintra

FD

,

Leite

RP

,

Storti

LJ

,

Bittencourt

LA

,

Poyares

D

,

Castro

L de S

,

Tufik

S

,

Paola

A de

.

Sleep apnea and nocturnal cardiac arrhythmia: a populational study

.

Arq Bras Cardiol

2014

;

103

:

368

–

374

.

327

Gilat

H

,

Vinker

S

,

Buda

I

,

Soudry

E

,

Shani

M

,

Bachar

G

.

Obstructive sleep apnea and cardiovascular comorbidities: a large epidemiologic study

.

Medicine (Baltimore)

2014

;

93

:

e45

.

328

Vizzardi

E

,

Sciatti

E

,

Bonadei

I

,

D'Aloia

A

,

Curnis

A

,

Metra

M

.

Obstructive sleep apnoea–hypopnoea and arrhythmias

.

J Cardiovasc Med

2014

;

1

.

329

Bloch Thomsen

PE

,

Jons

C

,

Raatikainen

MJP

,

MoerchJoergensen

R

,

Hartikainen

J

,

Virtanen

V

,

Boland

J

,

Anttonen

O

,

Gang

UJ

,

Hoest

N

,

Boersma

LVA

,

Platou

ES

,

Becker

D

,

Messier

MD

,

Huikuri

HV

.

Long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction: the Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) study

.

Circulation

2010

;

122

:

1258

–

1264

.

330

Faggiano

P

,

D'Aloia

A

,

Gualeni

A

,

Gardini

A

,

Giordano

A

.

Mechanisms and immediate outcome of in-hospital cardiac arrest in patients with advanced heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

.

Am J Cardiol

2001

;

87

:

655

–

657

,

A10–A11

.

331

Smit

MD

,

Moes

ML

,

Maass

AH

,

Achekar

ID

,

Van Geel

PP

,

Hillege

HL

,

van Veldhuisen

DJ

,

Van Gelder

IC

.

The importance of whether atrial fibrillation or heart failure develops first

.

Eur J Heart Fail

2012

;

14

:

1030

–

1040

.

332

Swedberg

K

,

Olsson

LG

,

Charlesworth

A

,

Cleland

J

,

Hanrath

P

,

Komajda

M

,

Metra

M

,

Torp-Pedersen

C

,

Poole-Wilson

P

.

Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET

.

Eur Heart J

2005

;

26

:

1303

–

1308

.

333

Hoppe

UC

,

Casares

JM

,

Eiskjaer

H

,

Hagemann

A

,

Cleland

JGF

,

Freemantle

N

,

Erdmann

E

.

Effect of cardiac resynchronization on the incidence of atrial fibrillation in patients with severe heart failure

.

Circulation

2006

;

114

:

18

–

25

.

334

Calvo

N

,

Bisbal

F

,

Guiu

E

,

Ramos

P

,

Nadal

M

,

Tolosana

JM

,

Arbelo

E

,

Berruezo

A

,

Sitges

M

,

Brugada

J

,

Mont

L

.

Impact of atrial fibrillation-induced tachycardiomyopathy in patients undergoing pulmonary vein isolation

.

Int J Cardiol

2013

;

168

:

4093

–

4097

.

335

Morris

PD

,

Robinson

T

,

Channer

KS

.

Reversible heart failure: toxins, tachycardiomyopathy and mitochondrial abnormalities

.

Postgrad Med J

2012

;

88

:

706

–

712

.

336

Pedersen

OD

,

Bagger

H

,

Køber

L

,

Torp-Pedersen

C

.

Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction

.

Circulation

1999

;

100

:

376

–

380

.

337

Ducharme

A

,

Swedberg

K

,

Pfeffer

MA

,

Cohen-Solal

A

,

Granger

CB

,

Maggioni

AP

,

Michelson

EL

,

McMurray

JJ V

,

Olsson

L

,

Rouleau

JL

,

Young

JB

,

Olofsson

B

,

Puu

M

,

Yusuf

S

.

Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program

.

Am Heart J

2006

;

152

:

86

–

92

.

338

McMurray

J

,

Køber

L

,

Robertson

M

,

Dargie

H

,

Colucci

W

,

Lopez-Sendon

J

,

Remme

W

,

Sharpe

DN

,

Ford

I

.

Antiarrhythmic effect of carvedilol after acute myocardial infarction

.

J Am Coll Cardiol

2005

;

45

:

525

–

530

.

339

Swedberg

K

,

Zannad

F

,

McMurray

JJV

,

Krum

H

,

van Veldhuisen

DJ

,

Shi

H

,

Vincent

J

,

Pitt

B

.

Eplerenone and atrial fibrillation in mild systolic heart failure

.

J Am Coll Cardiol

2012

;

59

:

1598

–

1603

.

340

Han

M

,

Zhang

Y

,

Sun

S

,

Wang

Z

,

Wang

J

,

Xie

X

,

Gao

M

,

Yin

X

,

Hou

Y

.

Renin–angiotensin system inhibitors prevent the recurrence of atrial fibrillation

.

J Cardiovasc Pharmacol

2013

;

62

:

405

–

415

.

341

Martin

RIR

,

Pogoryelova

O

,

Koref

MS

,

Bourke

JP

,

Teare

MD

,

Keavney

BD

.

Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomised controlled trials

.

Heart

2014

;

100

:

1506

–

1510

.

342

Hess

PL

,

Jackson

KP

,

Hasselblad

V

,

Al-Khatib

SM

.

Is cardiac resynchronization therapy an antiarrhythmic therapy for atrial fibrillation? A systematic review and meta-analysis

.

Curr Cardiol Rep

2013

;

15

:

330

.

343

Brodsky

MA

,

Allen

BJ

,

Walker

CJ

,

Casey

TP

,

Luckett

CR

,

Henry

WL

.

Amiodarone for maintenance of sinus rhythm after conversion of atrial fibrillation in the setting of a dilated left atrium

.

Am J Cardiol

1987

;

60

:

572

–

575

.

344

Deedwania

PC

,

Singh

BN

,

Ellenbogen

K

,

Fisher

S

,

Fletcher

R

,

Singh

SN

.

Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHF-STAT). The Department of Veterans Affairs CHF-STAT Investigators

.

Circulation

1998

;

98

:

2574

–

2579

.

345

Shelton

RJ

,

Clark

AL

,

Goode

K

,

Rigby

AS

,

Houghton

T

,

Kaye

GC

,

Cleland

JGF

.

A randomised, controlled study of rate versus rhythm control in patients with chronic atrial fibrillation and heart failure: (CAFE-II Study)

.

Heart

2009

;

95

:

924

–

930

.

346

Capucci

A

,

Villani

GQ

,

Aschieri

D

,

Rosi

A

,

Piepoli

MF

.

Oral amiodarone increases the efficacy of direct-current cardioversion in restoration of sinus rhythm in patients with chronic atrial fibrillation

.

Eur Heart J

2000

;

21

:

66

–

73

.

347

Connolly

SJ

,

Camm

AJ

,

Halperin

JL

,

Joyner

C

,

Alings

M

,

Amerena

J

,

Atar

D

,

Avezum

Á

,

Blomström

P

,

Borggrefe

M

,

Budaj

A

,

Chen

S-A

,

Ching

CK

,

Commerford

P

,

Dans

A

,

Davy

J-M

,

Delacrétaz

E

,

Di Pasquale

G

,

Diaz

R

,

Dorian

P

,

Flaker

G

,

Golitsyn

S

,

Gonzalez-Hermosillo

A

,

Granger

CB

,

Heidbüchel

H

,

Kautzner

J

,

Kim

JS

,

Lanas

F

,

Lewis

BS

,

Merino

JL

,

Morillo

C

,

Murin

J

,

Narasimhan

C

,

Paolasso

E

,

Parkhomenko

A

,

Peters

NS

,

Sim

K-H

,

Stiles

MK

,

Tanomsup

S

,

Toivonen

L

,

Tomcsányi

J

,

Torp-Pedersen

C

,

Tse

H-F

,

Vardas

P

,

Vinereanu

D

,

Xavier

D

,

Zhu

J-R

,

Zhu

J-R

,

Baret-Cormel

L

,

Weinling

E

,

Staiger

C

,

Yusuf

S

,

Chrolavicius

S

,

Afzal

R

,

Hohnloser

SH

.

Dronedarone in high-risk permanent atrial fibrillation

.

N Engl J Med

2011

;

365

:

2268

–

2276

.

348

Hofmann

R

,

Steinwender

C

,

Kammler

J

,

Kypta

A

,

Leisch

F

.

Effects of a high dose intravenous bolus amiodarone in patients with atrial fibrillation and a rapid ventricular rate

.

Int J Cardiol

2006

;

110

:

27

–

32

.

349

Hofmann

R

,

Wimmer

G

,

Leisch

F

.

Intravenous amiodarone bolus immediately controls heart rate in patients with atrial fibrillation accompanied by severe congestive heart failure

.

Heart

2000

;

84

:

635

.

350

Li

S-J

,

Sartipy

U

,

Lund

LH

,

Dahlström

U

,

Adiels

M

,

Petzold

M

,

Fu

M

.

Prognostic significance of resting heart rate and use of β-blockers in atrial fibrillation and sinus rhythm in patients with heart failure and reduced ejection fraction: findings from the Swedish Heart Failure Registry

.

Circ Heart Fail

2015

;

8

:

871

–

879

.

351

Mareev

Y

,

Cleland

JGF

.

Should β-blockers be used in patients with heart failure and atrial fibrillation

?

Clin Ther

2015

;

37

:

2215

–

2224

.

352

Hagens

VE

,

Crijns

HJGM

,

Van Veldhuisen

DJ

,

Van Den Berg

MP

,

Rienstra

M

,

Ranchor

AV

,

Bosker

HA

,

Kamp

O

,

Tijssen

JGP

,

Veeger

NJGM

,

Van Gelder

IC

.

Rate control versus rhythm control for patients with persistent atrial fibrillation with mild to moderate heart failure: results from the RAte Control versus Electrical cardioversion (RACE) study

.

Am Heart J

2005

;

149

:

1106

–

1111

.

353

Van Gelder

IC

,

Hagens

VE

,

Bosker

HA

,

Kingma

JH

,

Kamp

O

,

Kingma

T

,

Said

SA

,

Darmanata

JI

,

Timmermans

AJM

,

Tijssen

JGP

,

Crijns

HJGM

.

A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation

.

N Engl J Med

2002

;

347

:

1834

–

1840

.

354

Van Gelder

IC

,

Wyse

DG

,

Chandler

ML

,

Cooper

HA

,

Olshansky

B

,

Hagens

VE

,

Crijns

HJGM

,

RACE and AFFIRM Investigators

.

Does intensity of rate-control influence outcome in atrial fibrillation? An analysis of pooled data from the RACE and AFFIRM studies

.

Europace

2006

;

8

:

935

–

942

.

355

Allen

LA

,

Fonarow

GC

,

Simon

DN

,

Thomas

LE

,

Marzec

LN

,

Pokorney

SD

,

Gersh

BJ

,

Go

AS

,

Hylek

EM

,

Kowey

PR

,

Mahaffey

KW

,

Chang

P

,

Peterson

ED

,

Piccini

JP

.

Digoxin use and subsequent outcomes among patients in a contemporary atrial fibrillation cohort

.

J Am Coll Cardiol

2015

;

65

:

2691

–

2698

.

356

Gheorghiade

M

,

Fonarow

GC

,

van Veldhuisen

DJ

,

Cleland

JGF

,

Butler

J

,

Epstein

AE

,

Patel

K

,

Aban

IB

,

Aronow

WS

,

Anker

SD

,

Ahmed

A

.

Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial

.

Eur Heart J

2013

;

34

:

1489

–

1497

.

357

Turakhia

MP

,

Santangeli

P

,

Winkelmayer

WC

,

Xu

X

,

Ullal

AJ

,

Than

CT

,

Schmitt

S

,

Holmes

TH

,

Frayne

SM

,

Phibbs

CS

,

Yang

F

,

Hoang

DD

,

Ho

PM

,

Heidenreich

PA

.

Increased mortality associated with digoxin in contemporary patients with atrial fibrillation

.

J Am Coll Cardiol

2014

;

64

:

660

–

668

.

358

Khand

AU

,

Rankin

AC

,

Martin

W

,

Taylor

J

,

Gemmell

I

,

Cleland

JGF

.

Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure?

J Am Coll Cardiol

2003

;

42

:

1944

–

1951

.

359

Roy

D

,

Talajic

M

,

Nattel

S

,

Wyse

DG

,

Dorian

P

,

Lee

KL

,

Bourassa

MG

,

Arnold

JMO

,

Buxton

AE

,

Camm

AJ

,

Connolly

SJ

,

Dubuc

M

,

Ducharme

A

,

Guerra

PG

,

Hohnloser

SH

,

Lambert

J

,

Le Heuzey

J-Y

,

O'Hara

G

,

Pedersen

OD

,

Rouleau

J-L

,

Singh

BN

,

Stevenson

LW

,

Stevenson

WG

,

Thibault

B

,

Waldo

AL

.

Rhythm control versus rate control for atrial fibrillation and heart failure

.

N Engl J Med

2008

;

358

:

2667

–

2677

.

360

Khan

MN

,

Jais

P

,

Cummings

J

,

Di Biase

L

,

Sanders

P

,

Martin

DO

,

Kautzner

J

,

Hao

S

,

Themistoclakis

S

,

Fanelli

R

,

Potenza

D

,

Massaro

R

,

Wazni

O

,

Schweikert

R

,

Saliba

W

,

Wang

P

,

Al-Ahmad

A

,

Beheiry

S

,

Santarelli

P

,

Starling

RC

,

Dello Russo

A

,

Pelargonio

G

,

Brachmann

J

,

Schibgilla

V

,

Bonso

A

,

Casella

M

,

Raviele

A

,

Haissaguerre

M

,

Natale

A

.

Pulmonary-vein isolation for atrial fibrillation in patients with heart failure

.

N Engl J Med

2008

;

359

:

1778

–

1785

.

361

Ganesan

AN

,

Nandal

S

,

Lüker

J

,

Pathak

RK

,

Mahajan

R

,

Twomey

D

,

Lau

DH

,

Sanders

P

.

Catheter ablation of atrial fibrillation in patients with concomitant left ventricular impairment: a systematic review of efficacy and effect on ejection fraction

.

Heart Lung Circ

2015

;

24

:

270

–

280

.

362

Marrouche

NF

,

Brachmann

J

.

Catheter ablation versus standard conventional treatment in patients with left ventricular dysfunction and atrial fibrillation (CASTLE-AF) – study design

.

Pacing Clin Electrophysiol

2009

;

32

:

987

–

994

.

363

Khan

AR

,

Khan

S

,

Sheikh

MA

,

Khuder

S

,

Grubb

B

,

Moukarbel

GV

.

Catheter ablation and antiarrhythmic drug therapy as first- or second-line therapy in the management of atrial fibrillation: systematic review and meta-analysis

.

Circ Arrhythm Electrophysiol

2014

;

7

:

853

–

860

.

364

Lafuente-Lafuente

C

,

Valembois

L

,

Bergmann

J-F

,

Belmin

J

.

Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation

.

Cochrane Database Syst Rev

2012

;

5

:

CD005049

.

365

A multicentre, randomized trial on the benefit/risk profile of amiodarone, flecainide and propafenone in patients with cardiac disease and complex ventricular arrhythmias. Antiarrhythmic Drug Evaluation Group (A.D.E.G.)

.

Eur Heart J

1992

;

13

:

1251

–

1258

.

366

Ruff

CT

,

Giugliano

RP

,

Braunwald

E

,

Hoffman

EB

,

Deenadayalu

N

,

Ezekowitz

MD

,

Camm

AJ

,

Weitz

JI

,

Lewis

BS

,

Parkhomenko

A

,

Yamashita

T

,

Antman

EM

.

Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials

.

Lancet

2014

;

383

:

955

–

962

.

367

Xiong

Q

,

Lau

YC

,

Senoo

K

,

Lane

DA

,

Hong

K

,

Lip

GYH

.

Non-vitamin K antagonist oral anticoagulants (NOACs) in patients with concomitant atrial fibrillation and heart failure: a systemic review and meta-analysis of randomized trials

.

Eur J Heart Fail

2015

;

17

:

1192

–

1200

.

368

Sardar

P

,

Chatterjee

S

,

Lavie

CJ

,

Giri

JS

,

Ghosh

J

,

Mukherjee

D

,

Lip

GYH

.

Risk of major bleeding in different indications for new oral anticoagulants: insights from a meta-analysis of approved dosages from 50 randomized trials

.

Int J Cardiol

2015

;

179

:

279

–

287

.

369

Sardar

P

,

Chatterjee

S

,

Chaudhari

S

,

Lip

GYH

.

New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials

.

J Am Geriatr Soc

2014

;

62

:

857

–

864

.

370

Heidbuchel

H

,

Verhamme

P

,

Alings

M

,

Antz

M

,

Diener

H-C

,

Hacke

W

,

Oldgren

J

,

Sinnaeve

P

,

Camm

AJ

,

Kirchhof

P

.

Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation

.

Europace

2015

;

17

:

1467

–

1507

.

371

Connolly

SJ

,

Ezekowitz

MD

,

Yusuf

S

,

Eikelboom

J

,

Oldgren

J

,

Parekh

A

,

Pogue

J

,

Reilly

PA

,

Themeles

E

,

Varrone

J

,

Wang

S

,

Alings

M

,

Xavier

D

,

Zhu

J

,

Diaz

R

,

Lewis

BS

,

Darius

H

,

Diener

H-C

,

Joyner

CD

,

Wallentin

L

.

Dabigatran versus warfarin in patients with atrial fibrillation

.

N Engl J Med

2009

;

361

:

1139

–

1151

.

372

Patel

MR

,

Mahaffey

KW

,

Garg

J

,

Pan

G

,

Singer

DE

,

Hacke

W

,

Breithardt

G

,

Halperin

JL

,

Hankey

GJ

,

Piccini

JP

,

Becker

RC

,

Nessel

CC

,

Paolini

JF

,

Berkowitz

SD

,

Fox

KAA

,

Califf

RM

.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation

.

N Engl J Med

2011

;

365

:

883

–

891

.

373

Giugliano

RP

,

Ruff

CT

,

Braunwald

E

,

Murphy

SA

,

Wiviott

SD

,

Halperin

JL

,

Waldo

AL

,

Ezekowitz

MD

,

Weitz

JI

,

Špinar

J

,

Ruzyllo

W

,

Ruda

M

,

Koretsune

Y

,

Betcher

J

,

Shi

M

,

Grip

LT

,

Patel

SP

,

Patel

I

,

Hanyok

JJ

,

Mercuri

M

,

Antman

EM

.

Edoxaban versus warfarin in patients with atrial fibrillation

.

N Engl J Med

2013

;

369

:

2093

–

2104

.

374

Granger

CB

,

Alexander

JH

,

McMurray

JJ V

,

Lopes

RD

,

Hylek

EM

,

Hanna

M

,

Al-Khalidi

HR

,

Ansell

J

,

Atar

D

,

Avezum

A

,

Bahit

MC

,

Diaz

R

,

Easton

JD

,

Ezekowitz

JA

,

Flaker

G

,

Garcia

D

,

Geraldes

M

,

Gersh

BJ

,

Golitsyn

S

,

Goto

S

,

Hermosillo

AG

,

Hohnloser

SH

,

Horowitz

J

,

Mohan

P

,

Jansky

P

,

Lewis

BS

,

Lopez-Sendon

JL

,

Pais

P

,

Parkhomenko

A

,

Verheugt

FWA

,

Zhu

J

,

Wallentin

L

.

Apixaban versus warfarin in patients with atrial fibrillation

.

N Engl J Med

2011

;

365

:

981

–

992

.

375

Connolly

SJ

,

Eikelboom

J

,

Joyner

C

,

Diener

H-C

,

Hart

R

,

Golitsyn

S

,

Flaker

G

,

Avezum

A

,

Hohnloser

SH

,

Diaz

R

,

Talajic

M

,

Zhu

J

,

Pais

P

,

Budaj

A

,

Parkhomenko

A

,

Jansky

P

,

Commerford

P

,

Tan

RS

,

Sim

K-H

,

Lewis

BS

,

Van Mieghem

W

,

Lip

GYH

,

Kim

JH

,

Lanas-Zanetti

F

,

Gonzalez-Hermosillo

A

,

Dans

AL

,

Munawar

M

,

O'Donnell

M

,

Lawrence

J

,

Lewis

G

,

Afzal

R

,

Yusuf

S

.

Apixaban in patients with atrial fibrillation

.

N Engl J Med

2011

;

364

:

806

–

817

.

376

Lip

GYH

,

Nieuwlaat

R

,

Pisters

R

,

Lane

DA

,

Crijns

HJGM

.

Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation

.

Chest

2010

;

137

:

263

–

272

.

377

Pisters

R

,

Lane

DA

,

Nieuwlaat

R

.

A novel user-friendly score (HAS BLED) to asses 1-year risk of major bleeding in patients with atrial fibrillation

.

Chest J

2010

;

138

:

1093

–

1100

.

378

Connolly

SJ

,

Ezekowitz

MD

,

Yusuf

S

,

Reilly

PA

,

Wallentin

L

.

Newly identified events in the RE-LY trial

.

N Engl J Med

2010

;

363

:

1875

–

1876

.

379

Hart

RG

,

Pearce

LA

,

Aguilar

MI

.

Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation

.

Ann Intern Med

2007

;

146

:

857

–

867

.

380

Eikelboom

JW

,

Connolly

SJ

,

Brueckmann

M

,

Granger

CB

,

Kappetein

AP

,

Mack

MJ

,

Blatchford

J

,

Devenny

K

,

Friedman

J

,

Guiver

K

,

Harper

R

,

Khder

Y

,

Lobmeyer

MT

,

Maas

H

,

Voigt

J-U

,

Simoons

ML

,

Van de Werf

F

.

Dabigatran versus warfarin in patients with mechanical heart valves

.

N Engl J Med

2013

;

369

:

1206

–

1214

.

381

Holmes

DR

,

Doshi

SK

,

Kar

S

,

Price

MJ

,

Sanchez

JM

,

Sievert

H

,

Valderrabano

M

,

Reddy

VY

.

Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis

.

J Am Coll Cardiol

2015

;

65

:

2614

–

2623

.

382

Price

MJ

,

Reddy

VY

,

Valderrábano

M

,

Halperin

JL

,

Gibson

DN

,

Gordon

N

,

Huber

KC

,

Holmes

DR

.

Bleeding outcomes after left atrial appendage closure compared with long-term warfarin: a pooled, patient-level analysis of the WATCHMAN randomized trial experience

.

JACC Cardiovasc Interv

2015

;

8

:

1925

–

1932

.

383

Cleland

JG

,

Massie

BM

,

Packer

M

.

Sudden death in heart failure: vascular or electrical

?

Eur J Heart Fail

1999

;

1

:

41

–

45

.

384

Desai

AS

,

McMurray

JJ V

,

Packer

M

,

Swedberg

K

,

Rouleau

JL

,

Chen

F

,

Gong

J

,

Rizkala

AR

,

Brahimi

A

,

Claggett

B

,

Finn

P V

,

Hartley

LH

,

Liu

J

,

Lefkowitz

M

,

Shi

V

,

Zile

MR

,

Solomon

SD

.

Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients

.

Eur Heart J

2015

;

36

:

1990

–

1997

.

385

Velazquez

EJ

,

Lee

KL

,

Deja

MA

,

Jain

A

,

Sopko

G

,

Marchenko

A

,

Ali

IS

,

Pohost

G

,

Gradinac

S

,

Abraham

WT

,

Yii

M

,

Prabhakaran

D

,

Szwed

H

,

Ferrazzi

P

,

Petrie

MC

,

O'Connor

CM

,

Panchavinnin

P

,

She

L

,

Bonow

RO

,

Rankin

GR

,

Jones

RH

,

Rouleau

J-L

,

STICH Investigators

.

Coronary-artery bypass surgery in patients with left ventricular dysfunction

.

N Engl J Med

2011

;

364

:

1607

–

1616

.

386

Panza

JA

,

Holly

TA

,

Asch

FM

,

She

L

,

Pellikka

PA

,

Velazquez

EJ

,

Lee

KL

,

Borges-Neto

S

,

Farsky

PS

,

Jones

RH

,

Berman

DS

,

Bonow

RO

.

Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction

.

J Am Coll Cardiol

2013

;

61

:

1860

–

1870

.

387

Carson

P

,

Wertheimer

J

,

Miller

A

,

O'Connor

CM

,

Pina

IL

,

Selzman

C

,

Sueta

C

,

She

L

,

Greene

D

,

Lee

KL

,

Jones

RH

,

Velazquez

EJ

.

The STICH trial (Surgical Treatment for Ischemic Heart Failure): mode-of-death results

.

JACC Heart Fail

2013

;

1

:

400

–

408

.

388

Oseroff

O

,

Retyk

E

,

Bochoeyer

A

.

Subanalyses of secondary prevention implantable cardioverter-defibrillator trials: antiarrhythmics versus implantable defibrillators (AVID), Canadian Implantable Defibrillator Study (CIDS), and Cardiac Arrest Study Hamburg (CASH)

.

Curr Opin Cardiol

2004

;

19

:

26

–

30

.

389

Brignole

M

,

Auricchio

A

,

Baron-Esquivias

G

,

Bordachar

P

,

Boriani

G

,

Breithardt

O-A

,

Cleland

J

,

Deharo

J-C

,

Delgado

V

,

Elliott

PM

,

Gorenek

B

,

Israel

CW

,

Leclercq

C

,

Linde

C

,

Mont

L

,

Padeletti

L

,

Sutton

R

,

Vardas

PE

,

Zamorano

JL

,

Achenbach

S

,

Baumgartner

H

,

Bax

JJ

,

Bueno

H

,

Dean

V

,

Deaton

C

,

Erol

C

,

Fagard

R

,

Ferrari

R

,

Hasdai

D

,

Hoes

AW

,

Kirchhof

P

,

Knuuti

J

,

Kolh

P

,

Lancellotti

P

,

Linhart

A

,

Nihoyannopoulos

P

,

Piepoli

MF

,

Ponikowski

P

,

Sirnes

PA

,

Tamargo

JL

,

Tendera

M

,

Torbicki

A

,

Wijns

W

,

Windecker

S

,

Blomstrom-Lundqvist

C

,

Badano

LP

,

Aliyev

F

,

Bänsch

D

,

Bsata

W

,

Buser

P

,

Charron

P

,

Daubert

J-C

,

Dobreanu

D

,

Faerestrand

S

,

Le Heuzey

J-Y

,

Mavrakis

H

,

McDonagh

T

,

Merino

JL

,

Nawar

MM

,

Nielsen

JC

,

Pieske

B

,

Poposka

L

,

Ruschitzka

F

,

Van Gelder

IC

,

Wilson

CM

.

2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association

.

Eur Heart J

2013

;

34

:

2281

–

2329

.

390

Blondé-Cynober

F

,

Morineau

G

,

Estrugo

B

,

Fillie

E

,

Aussel

C

,

Vincent

J-P

.

Diagnostic and prognostic value of brain natriuretic peptide (BNP) concentrations in very elderly heart disease patients: specific geriatric cut-off and impacts of age, gender, renal dysfunction, and nutritional status

.

Arch Gerontol Geriatr

2011

;

52

:

106

–

110

.

391

Hawkins

NM

,

Virani

S

,

Ceconi

C

.

Heart failure and chronic obstructive pulmonary disease: the challenges facing physicians and health services

.

Eur Heart J

2013

;

34

:

2795

–

2807

.

392

Enjuanes

C

,

Klip

IT

,

Bruguera

J

,

Cladellas

M

,

Ponikowski

P

,

Banasiak

W

,

van Veldhuisen

DJ

,

van der Meer

P

,

Jankowska

EA

,

Comín-Colet

J

.

Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study

.

Int J Cardiol

2014

;

174

:

268

–

275

.

393

Braunstein

JB

,

Anderson

GF

,

Gerstenblith

G

,

Weller

W

,

Niefeld

M

,

Herbert

R

,

Wu

AW

.

Noncardiac comorbidity increases preventable hospitalizations and mortality among Medicare beneficiaries with chronic heart failure

.

J Am Coll Cardiol

2003

;

42

:

1226

–

1233

.

394

Muzzarelli

S

,

Leibundgut

G

,

Maeder

MT

,

Rickli

H

,

Handschin

R

,

Gutmann

M

,

Jeker

U

,

Buser

P

,

Pfisterer

M

,

Brunner-La Rocca

H-P

.

Predictors of early readmission or death in elderly patients with heart failure

.

Am Heart J

2010

;

160

:

308

–

314

.

395

Reddel

HK

,

Bateman

ED

,

Becker

A

,

Boulet

L-P

,

Cruz

AA

,

Drazen

JM

,

Haahtela

T

,

Hurd

SS

,

Inoue

H

,

de Jongste

JC

,

Lemanske

RF

,

Levy

ML

,

O'Byrne

PM

,

Paggiaro

P

,

Pedersen

SE

,

Pizzichini

E

,

Soto-Quiroz

M

,

Szefler

SJ

,

Wong

GWK

,

FitzGerald

JM

.

A summary of the new GINA strategy: a roadmap to asthma control

.

Eur Respir J

2015

;

46

:

622

–

639

.

396

Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, Available at http://ginasthma.org/gina-report-global-strategy-for-asthma-management-and-prevention (date last accessed 12 February 2016)

.

397

Eschenhagen

T

,

Force

T

,

Ewer

MS

,

De Keulenaer

GW

,

Suter

TM

,

Anker

SD

,

Avkiran

M

,

De Azambuja

E

,

Balligand

JL

,

Brutsaert

DL

,

Condorelli

G

,

Hansen

A

,

Heymans

S

,

Hill

J a

,

Hirsch

E

,

Hilfiker-Kleiner

D

,

Janssens

S

,

De Jong

S

,

Neubauer

G

,

Pieske

B

,

Ponikowski

P

,

Pirmohamed

M

,

Rauchhaus

M

,

Sawyer

D

,

Sugden

PH

,

Wojta

J

,

Zannad

F

,

Shah

AM

.

Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology

.

Eur J Heart Fail

2011

;

13

:

1

–

10

.

398

Paulus

WJ

,

Tschöpe

C

.

A novel paradigm for heart failure with preserved ejection fraction

.

J Am Coll Cardiol

2013

;

62

:

263

–

271

.

399

Fox

K

,

Ford

I

,

Steg

PG

,

Tardif

J-C

,

Tendera

M

,

Ferrari

R

.

Ivabradine in stable coronary artery disease without clinical heart failure

.

N Engl J Med

2014

;

371

:

1091

–

1099

.

400

Marazzi

G

,

Wajngarten

M

,

Vitale

C

,

Patrizi

R

,

Pelliccia

F

,

Gebara

O

,

Pierri

H

,

Ramires

JAF

,

Volterrani

M

,

Fini

M

,

Rosano

GMC

.

Effect of free fatty acid inhibition on silent and symptomatic myocardial ischemia in diabetic patients with coronary artery disease

.

Int J Cardiol

2007

;

120

:

79

–

84

.

401

Vitale

C

,

Spoletini

I

,

Malorni

W

,

Perrone-Filardi

P

,

Volterrani

M

,

Rosano

GMC

.

Efficacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina—the VASCO-angina study

.

Int J Cardiol

2013

;

168

:

1078

–

1081

.

402

Vitale

C

,

Wajngaten

M

,

Sposato

B

,

Gebara

O

,

Rossini

P

,

Fini

M

,

Volterrani

M

,

Rosano

GMC

.

Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease

.

Eur Heart J

2004

;

25

:

1814

–

1821

.

403

Gao

D

,

Ning

N

,

Niu

X

,

Hao

G

,

Meng

Z

.

Trimetazidine: a meta-analysis of randomised controlled trials in heart failure

.

Heart

2011

;

97

:

278

–

286

.

404

Tuunanen

H

,

Engblom

E

,

Naum

A

,

Någren

K

,

Scheinin

M

,

Hesse

B

,

Juhani Airaksinen

KE

,

Nuutila

P

,

Iozzo

P

,

Ukkonen

H

,

Opie

LH

,

Knuuti

J

.

Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy

.

Circulation

2008

;

118

:

1250

–

1258

.

405

Marazzi

G

,

Gebara

O

,

Vitale

C

,

Caminiti

G

,

Wajngarten

M

,

Volterrani

M

,

Ramires

JAF

,

Rosano

G

,

Fini

M

.

Effect of trimetazidine on quality of life in elderly patients with ischemic dilated cardiomyopathy

.

Adv Ther

2009

;

26

:

455

–

461

.

406

Rosano

G

,

Vitale

C

,

Sposato

B

,

Mercuro

G

,

Fini

M

.

Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study

.

Cardiovasc Diabetol

2003

;

2

:

16

.

407

Wijeysundera

HC

,

Hansen

MS

,

Stanton

E

,

Cropp

a. S

,

Hall

C

,

Dhalla

NS

,

Ghali

J

,

Rouleau

JL

.

Neurohormones and oxidative stress in nonischemic cardiomyopathy: Relationship to survival and the effect of treatment with amlodipine

.

Am Heart J

2003

;

146

:

291

–

297

.

408

IONA Study Group

.

Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial

.

Lancet

2002

;

359

:

1269

–

1275

.

409

Cohn

JN

,

Johnson

G

,

Ziesche

S

,

Cobb

F

,

Francis

G

,

Tristani

F

,

Smith

R

,

Dunkman

WB

,

Loeb

H

,

Wong

M

,

Bhat

G

,

Goldman

S

,

Fletcher

RD

,

Doherty

J

,

Hughes

CV

,

Carson

P

,

Cintron

G

,

Shabetai

R

,

Haakenson

C

.

A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure

.

N Engl J Med

1991

;

325

:

303

–

310

.

410

Fox

K

,

Ford

I

,

Steg

PG

,

Tendera

M

,

Ferrari

R

.

Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial

.

Lancet

2008

;

372

:

807

–

816

.

411

Fox

K

,

Ford

I

,

Steg

PG

,

Tendera

M

,

Robertson

M

,

Ferrari

R

.

Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial

.

Eur Heart J

2009

;

30

:

2337

–

2345

.

412

Pursnani

S

,

Korley

F

,

Gopaul

R

,

Kanade

P

,

Chandra

N

,

Shaw

RE

,

Bangalore

S

.

Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials

.

Circ Cardiovasc Interv

2012

;

5

:

476

–

490

.

413

Trikalinos

TA

,

Alsheikh-Ali

AA

,

Tatsioni

A

,

Nallamothu

BK

,

Kent

DM

.

Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis

.

Lancet

2009

;

373

:

911

–

918

.

414

von Haehling

S

,

Anker

SD

.

Prevalence, incidence and clinical impact of cachexia: facts and numbers—update 2014

.

J Cachexia Sarcopenia Muscle

2014

;

5

:

261

–

263

.

415

von Haehling

S

,

Lainscak

M

,

Springer

J

,

Anker

SD

.

Cardiac cachexia: a systematic overview

.

Pharmacol Ther

2009

;

121

:

227

–

252

.

416

Evans

WJ

,

Morley

JE

,

Argilés

J

,

Bales

C

,

Baracos

V

,

Guttridge

D

,

Jatoi

A

,

Kalantar-Zadeh

K

,

Lochs

H

,

Mantovani

G

,

Marks

D

,

Mitch

WE

,

Muscaritoli

M

,

Najand

A

,

Ponikowski

P

,

Rossi Fanelli

F

,

Schambelan

M

,

Schols

A

,

Schuster

M

,

Thomas

D

,

Wolfe

R

,

Anker

SD

.

Cachexia: a new definition

.

Clin Nutr

2008

;

27

:

793

–

799

.

417

Akashi

YJ

,

Springer

J

,

Anker

SD

.

Cachexia in chronic heart failure: prognostic implications and novel therapeutic approaches

.

Curr Heart Fail Rep

2005

;

2

:

198

–

203

.

418

Anker

SD

,

Chua

TP

,

Ponikowski

P

,

Harrington

D

,

Swan

JW

,

Kox

WJ

,

Poole-Wilson

PA

,

Coats

AJ

.

Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia

.

Circulation

1997

;

96

:

526

–

534

.

419

Fülster

S

,

Tacke

M

,

Sandek

A

,

Ebner

N

,

Tschöpe

C

,

Doehner

W

,

Anker

SD

,

Von Haehling

S

.

Muscle wasting in patients with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF)

.

Eur Heart J

2013

;

34

:

512

–

519

.

420

Morley

JE

,

Anker

SD

,

von Haehling

S

.

Prevalence, incidence, and clinical impact of sarcopenia: facts, numbers, and epidemiology-update 2014

.

J Cachexia Sarcopenia Muscle

2014

;

5

:

253

–

259

.

421

von Haehling

S

,

Anker

SD

.

Treatment of cachexia: an overview of recent developments

.

J Am Med Dir Assoc

2014

;

15

:

866

–

872

.

422

Jones

AL

,

Barlow

M

,

Barrett-Lee

PJ

,

Canney

PA

,

Gilmour

IM

,

Robb

SD

,

Plummer

CJ

,

Wardley

AM

,

Verrill

MW

.

Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring

.

Br J Cancer

2009

;

100

:

684

–

692

.

423

van Dalen

EC

,

Caron

HN

,

Dickinson

HO

,

Kremer

LCM

.

Cardioprotective interventions for cancer patients receiving anthracyclines

.

Cochrane Database Syst Rev

2005

;

6

:

CD003917

.

424

Ezaz

G

,

Long

JB

,

Gross

CP

,

Chen

J

.

Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer

.

J Am Heart Assoc

2014

;

3

:

e000472

.

425

Suter

TM

,

Ewer

MS

.

Cancer drugs and the heart: Importance and management

.

Eur Heart J

2013

;

34

:

1102

–

1111

.

426

Zamorano

J-L

,

Lancelotti

P

et al. .

2016 Position paper on anticancer treatments and cardiovascular toxicity

.

Eur Heart J

.

2016

.

. Forthcoming

10.1093/eurheartj/ehw211

.

427

Tjeerdsma

G

,

Szabó

BM

,

van Wijk

LM

,

Brouwer

J

,

Tio

RA

,

Crijns

HJ

,

van Veldhuisen

DJ

.

Autonomic dysfunction in patients with mild heart failure and coronary artery disease and the effects of add-on beta-blockade

.

Eur J Heart Fail

2001

;

3

:

33

–

39

.

428

Fan

H

,

Yu

W

,

Zhang

Q

,

Cao

H

,

Li

J

,

Wang

J

,

Shao

Y

,

Hu

X

.

Depression after heart failure and risk of cardiovascular and all-cause mortality: a meta-analysis

.

Prev Med

2014

;

63

:

36

–

42

.

429

Diez-Quevedo

C

,

Lupón

J

,

González

B

,

Urrutia

A

,

Cano

L

,

Cabanes

R

,

Altimir

S

,

Coll

R

,

Pascual

T

,

de Antonio

M

,

Bayes-Genis

A

.

Depression, antidepressants, and long-term mortality in heart failure

.

Int J Cardiol

2013

;

167

:

1217

–

1225

.

430

Newhouse

A

,

Jiang

W

.

Heart failure and depression

.

Heart Fail Clin

2014

;

10

:

295

–

304

.

431

Lahlou-Laforêt

K

,

Ledru

F

,

Niarra

R

,

Consoli

SM

.

Validity of beck depression inventory for the assessment of depressive mood in chronic heart failure Patients

.

J Affect Disord

2015

;

184

:

256

–

260

.

432

Ski

CF

,

Thompson

DR

,

Hare

DL

,

Stewart

AG

,

Watson

R

.

Cardiac Depression Scale: Mokken scaling in heart failure patients

.

Health Qual Life Outcomes

2012

;

10

:

141

.

433

Tu

R-H

,

Zeng

Z-Y

,

Zhong

G-Q

,

Wu

W-F

,

Lu

Y-J

,

Bo

Z-D

,

He

Y

,

Huang

W-Q

,

Yao

L-M

.

Effects of exercise training on depression in patients with heart failure: a systematic review and meta-analysis of randomized controlled trials

.

Eur J Heart Fail

2014

;

16

:

749

–

757

.

434

Blumenthal

JA

,

Babyak

MA

,

O'Connor

C

,

Keteyian

S

,

Landzberg

J

,

Howlett

J

,

Kraus

W

,

Gottlieb

S

,

Blackburn

G

,

Swank

A

,

Whellan

DJ

.

Effects of exercise training on depressive symptoms in patients with chronic heart failure: the HF-ACTION randomized trial

.

JAMA

2012

;

308

:

465

–

474

.

435

O'Connor

CM

,

Jiang

W

,

Kuchibhatla

M

,

Silva

SG

,

Cuffe

MS

,

Callwood

DD

,

Zakhary

B

,

Stough

WG

,

Arias

RM

,

Rivelli

SK

,

Krishnan

R

.

Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial

.

J Am Coll Cardiol

2010

;

56

:

692

–

699

.

436

Bakris

GL

,

Fonseca

V

,

Katholi

RE

,

McGill

JB

,

Messerli

FH

,

Phillips

RA

,

Raskin

P

,

Wright

JT

,

Oakes

R

,

Lukas

MA

,

Anderson

KM

,

Bell

DSH

,

GEMINI Investigators for the

.

Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial

.

JAMA

2004

;

292

:

2227

–

2236

.

437

Aguilar

D

,

Bozkurt

B

,

Ramasubbu

K

,

Deswal

A

.

Relationship of hemoglobin A1C and mortality in heart failure patients with diabetes

.

J Am Coll Cardiol

2009

;

54

:

422

–

428

.

438

Gerstein

HC

,

Swedberg

K

,

Carlsson

J

,

McMurray

JJ V

,

Michelson

EL

,

Olofsson

B

,

Pfeffer

MA

,

Yusuf

S

.

The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program

.

Arch Intern Med

2008

;

168

:

1699

–

1704

.

439

Goode

KM

,

John

J

,

Rigby

AS

,

Kilpatrick

ES

,

Atkin

SL

,

Bragadeesh

T

,

Clark

AL

,

Cleland

JGF

.

Elevated glycated haemoglobin is a strong predictor of mortality in patients with left ventricular systolic dysfunction who are not receiving treatment for diabetes mellitus

.

Heart

2009

;

95

:

917

–

923

.

440

MacDonald

MR

,

Eurich

DT

,

Majumdar

SR

,

Lewsey

JD

,

Bhagra

S

,

Jhund

PS

,

Petrie

MC

,

McMurray

JJ V

,

Petrie

JR

,

McAlister

FA

.

Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K

.

General Practice Research Database. Diabetes Care

2010

;

33

:

1213

–

1218

.

10.1016/j.ijcard.2015.08.089

441

Boussageon

R

,

Supper

I

,

Bejan-Angoulvant

T

,

Kellou

N

,

Cucherat

M

,

Boissel

J-P

,

Kassai

B

,

Moreau

A

,

Gueyffier

F

,

Cornu

C

.

Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials

.

PLoS Med

2012

;

9

:

e1001204

.

442

Monami

M

,

Dicembrini

I

,

Mannucci

E

.

Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials

.

Nutr Metab Cardiovasc Dis

2014

;

24

:

689

–

697

.

443

Savarese

G

,

Perrone-Filardi

P

,

D'Amore

C

,

Vitale

C

,

Trimarco

B

,

Pani

L

,

Rosano

GMC

.

Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: a meta-analysis

.

Int J Cardiol

2015

;

181

:

239

–

244

.

444

Giagulli

VA

,

Moghetti

P

,

Kaufman

JM

,

Guastamacchia

E

,

Iacoviello

M

,

Triggiani

V

.

Managing erectile dysfunction in heart failure

.

Endocr Metab Immune Disord Drug Targets

2013

;

13

:

125

–

134

.

445

Vlachopoulos

C

,

Jackson

G

,

Stefanadis

C

,

Montorsi

P

.

Erectile dysfunction in the cardiovascular patient

.

Eur Heart J

2013

;

34

:

2034

–

2046

.

446

Guazzi

M

,

Vicenzi

M

,

Arena

R

,

Guazzi

MD

.

PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study

.

Circ Heart Fail

2011

;

4

:

8

–

17

.

447

Giannetta

E

,

Feola

T

,

Gianfrilli

D

,

Pofi

R

,

Dall'Armi

V

,

Badagliacca

R

,

Barbagallo

F

,

Lenzi

A

,

Isidori

AM

,

Dall'Armi

V

,

Badagliacca

R

,

Barbagallo

F

,

Lenzi

A

,

Isidori

AM

.

Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials

.

BMC Med

2014

;

12

:

185

.

448

Anker

SD

.

Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging

.

Circulation

2003

;

107

:

1991

–

1997

.

449

Zhang

W

.

EULAR evidence-based recommendations for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT)

.

Ann Rheum Dis

2006

;

65

:

1312

–

1324

.

450

Uric acid and xanthine oxidase in heart failure - Emerging data and therapeutic implications. Doehner W, Jankowska EA, Springer J, Lainscak M, Anker SD. Int J Cardiol. 2015 Aug 11. pii: S0167-5273(15)30319-3. . [Epub ahead of print]

451

Desai

AS

.

Hyperkalemia in patients with heart failure: incidence, prevalence, and management

.

Curr Heart Fail Rep

2009

;

6

:

272

–

280

.

452

Mahoney

BA

,

Smith

WA

,

Lo

D

,

Tsoi

K

,

Tonelli

M

,

Clase

C

.

Emergency interventions for hyperkalaemia

.

Cochrane Database Syst Rev

2005

;

2

:

CD003235

.

453

Packham

DK

,

Rasmussen

HS

,

Lavin

PT

,

El-Shahawy

MA

,

Roger

SD

,

Block

G

,

Qunibi

W

,

Pergola

P

,

Singh

B

.

Sodium zirconium cyclosilicate in hyperkalemia

.

N Engl J Med

2015

;

372

:

222

–

231

.

454

Weir

MR

,

Bakris

GL

,

Bushinsky

DA

,

Mayo

MR

,

Garza

D

,

Stasiv

Y

,

Wittes

J

,

Christ-Schmidt

H

,

Berman

L

,

Pitt

B

.

Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors

.

N Engl J Med

2015

;

372

:

211

–

221

.

455

Anker

SD

,

Kosiborod

M

,

Zannad

F

,

Piña

IL

,

McCullough

PA

,

Filippatos

G

,

van der Meer

P

,

Ponikowski

P

,

Rasmussen

HS

,

Lavin

PT

,

Singh

B

,

Yang

A

,

Deedwania

P

.

Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial

.

Eur J Heart Fail

2015

;

17

:

1050

–

1056

.

456

Pitt

B

,

Bakris

GL

,

Bushinsky

DA

,

Garza

D

,

Mayo

MR

,

Stasiv

Y

,

Christ-Schmidt

H

,

Berman

L

,

Weir

MR

.

Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors

.

Eur J Heart Fail

2015

;

17

:

1057

–

1065

.

457

Tavazzi

L

,

Maggioni

AP

,

Marchioli

R

,

Barlera

S

,

Franzosi

MG

,

Latini

R

,

Lucci

D

,

Nicolosi

GL

,

Porcu

M

,

Tognoni

G

.

Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial

.

Lancet

2008

;

372

:

1231

–

1239

.

458

Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. ALLHAT Collaborative Research Group

.

JAMA

2000

;

283

:

1967

–

1975

.

459

Lip

GYH

,

Skjøth

F

,

Overvad

K

,

Rasmussen

LH

,

Larsen

TB

.

Blood pressure and prognosis in patients with incident heart failure: the Diet, Cancer and Health (DCH) cohort study

.

Clin Res Cardiol

2015

;

104

:

1088

–

1096

.

460

Cohn

JN

,

Pfeffer

MA

,

Rouleau

J

,

Sharpe

N

,

Swedberg

K

,

Straub

M

,

Wiltse

C

,

Wright

TJ

,

MOXCON Investigators

.

Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON)

.

Eur J Heart Fail

2003

;

5

:

659

–

667

.

461

Maggioni

AP

,

Anand

I

,

Gottlieb

SO

,

Latini

R

,

Tognoni

G

,

Cohn

JN

.

Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors

.

J Am Coll Cardiol

2002

;

40

:

1414

–

1421

.

462

Pitt

B

,

Anker

SD

,

Bushinsky

DA

,

Kitzman

DW

,

Zannad

F

,

Huang

I-Z

.

Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial

.

Eur Heart J

2011

;

32

:

820

–

828

.

463

Packer

M

,

Bristow

MR

,

Cohn

JN

,

Colucci

WS

,

Fowler

MB

,

Gilbert

EM

,

Shusterman

NH

,

U.S. Carvedilol Heart Failure Study Group

.

The effect of carvedilol on morbidity and mortality in patients with chronic heart failure

.

N Engl J Med

1996

;

334

:

1349

–

1355

.

464

Dorszewski

A

,

Göhmann

E

,

Dorsźewski

B

,

Werner

GS

,

Kreuzer

H

,

Figulla

HR

.

Vasodilation by urapidil in the treatment of chronic congestive heart failure in addition to angiotensin-converting enzyme inhibitors is not beneficial: results of a placebo-controlled, double-blind study

.

J Card Fail

1997

;

3

:

91

–

96

.

465

Bayliss

J

,

Norell

MS

,

Canepa-Anson

R

,

Reid

C

,

Poole-Wilson

P

,

Sutton

G

.

Clinical importance of the renin-angiotensin system in chronic heart failure: double blind comparison of captopril and prazosin

.

Br Med J (Clin Res Ed)

1985

;

290

:

1861

–

1865

.

466

Jankowska

EA

,

von Haehling

S

,

Anker

SD

,

Macdougall

IC

,

Ponikowski

P

.

Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives

.

Eur Heart J

2013

;

34

:

816

–

826

.

467

Jankowska

EA

,

Kasztura

M

,

Sokolski

M

,

Bronisz

M

,

Nawrocka

S

,

Oleśkowska-Florek

W

,

Zymliński

R

,

Biegus

J

,

Siwołowski

P

,

Banasiak

W

,

Anker

SD

,

Filippatos

G

,

Cleland

JGF

,

Ponikowski

P

.

Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure

.

Eur Heart J

2014

;

35

:

2468

–

2476

.

468

Jankowska

EA

,

Malyszko

J

,

Ardehali

H

,

Koc-Zorawska

E

,

Banasiak

W

,

von Haehling

S

,

Macdougall

IC

,

Weiss

G

,

McMurray

JJV

,

Anker

SD

,

Gheorghiade

M

,

Ponikowski

P

.

Iron status in patients with chronic heart failure

.

Eur Heart J

2013

;

34

:

827

–

834

.

469

Anker

SD

,

Comin Colet

J

,

Filippatos

G

,

Willenheimer

R

,

Dickstein

K

,

Drexler

H

,

Luscher

TF

,

Bart

B

,

Banasiak

W

,

Niegowska

J

,

Kirwan

BA

,

Mori

C

,

von Eisenhart Rothe

B

,

Pocock

SJ

,

Poole-Wilson

PA

,

Ponikowski

P

.

Ferric carboxymaltose in patients with heart failure and iron deficiency

.

N Engl J Med

2009

;

361

:

2436

–

2448

.

470

Ponikowski

P

,

van Veldhuisen

DJ

,

Comin-Colet

J

,

Ertl

G

,

Komajda

M

,

Mareev

V

,

McDonagh

T

,

Parkhomenko

A

,

Tavazzi

L

,

Levesque

V

,

Mori

C

,

Roubert

B

,

Filippatos

G

,

Ruschitzka

F

,

Anker

SD

.

Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency

.

Eur Heart J

2015

;

36

:

657

–

668

.

471

Filippatos

G

,

Farmakis

D

,

Colet

JC

,

Dickstein

K

,

Lüscher

TF

,

Willenheimer

R

,

Parissis

J

,

Gaudesius

G

,

Mori

C

,

von Eisenhart Rothe

B

,

Greenlaw

N

,

Ford

I

,

Ponikowski

P

,

Anker

SD

.

Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial

.

Eur J Heart Fail

2013

;

15

:

1267

–

1276

.

472

Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Jankowska EA, Tkaczyszyn M, Suchocki T, Drozd M, von Haehling S, Doehner W, Banasiak W, Filippatos G, Anker SD, Ponikowski P. Eur J Heart Fail. 2016 Jan 28. . [Epub ahead of print].

10.1002/ejhf.473

473

Angermann

C

,

Pia

M

,

Erdmann

E

,

Levy

P

,

Simonds

AK

,

Somers

VK

,

Zannad

F

,

Cowie

MR

,

Woehrle

H

,

Wegscheider

K

,

Angermann

C

,

D'Ortho

M-P

,

Erdmann

E

,

Levy

P

,

Simonds

AK

,

Somers

VK

,

Zannad

F

,

Teschler

H

.

Adaptive servo-ventilation for central sleep apnea in systolic heart failure

.

N Engl J Med

2015

;

373

:

1095

–

1105

.

474

O'Meara

E

,

Rouleau

JL

,

White

M

,

Roy

K

,

Blondeau

L

,

Ducharme

A

,

Neagoe

P-E

,

Sirois

MG

,

Lavoie

J

,

Racine

N

,

Liszkowski

M

,

Madore

F

,

Tardif

J-C

,

de Denus

S

,

ANCHOR Investigators

.

Heart failure with anemia: novel findings on the roles of renal disease, interleukins, and specific left ventricular remodeling processes

.

Circ Heart Fail

2014

;

7

:

773

–

781

.

475

Swedberg

K

,

Young

JB

,

Anand

IS

,

Cheng

S

,

Desai

AS

,

Diaz

R

,

Maggioni

AP

,

McMurray

JJV

,

O'Connor

C

,

Pfeffer

MA

,

Solomon

SD

,

Sun

Y

,

Tendera

M

,

van Veldhuisen

DJ

.

Treatment of anemia with darbepoetin alfa in systolic heart failure

.

N Engl J Med

2013

;

368

:

1210

–

1219

.

476

Damman

K

,

Valente

MAE

,

Voors

AA

,

O'Connor

CM

,

van Veldhuisen

DJ

,

Hillege

HL

.

Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis

.

Eur Heart J

2014

;

35

:

455

–

469

.

477

Filippatos

G

,

Farmakis

D

,

Parissis

J

.

Renal dysfunction and heart failure: things are seldom what they seem

.

Eur Heart J

2014

;

35

:

416

–

418

.

478

Chawla

LS

,

Eggers

PW

,

Star

RA

,

Kimmel

PL

.

Acute kidney injury and chronic kidney disease as interconnected syndromes

.

N Engl J Med

2014

;

371

:

58

–

66

.

479

Damman

K

,

Testani

JM

.

The kidney in heart failure: an update

.

Eur Heart J

2015

;

36

:

1437

–

1444

.

480

Clark

H

,

Krum

H

,

Hopper

I

.

Worsening renal function during renin-angiotensin-aldosterone system inhibitor initiation and long-term outcomes in patients with left ventricular systolic dysfunction

.

Eur J Heart Fail

2014

;

16

:

41

–

48

.

481

Brenner

S

,

Güder

G

,

Berliner

D

,

Deubner

N

,

Fröhlich

K

,

Ertl

G

,

Jany

B

,

Angermann

CE

,

Störk

S

.

Airway obstruction in systolic heart failure – COPD or congestion?

Int J Cardiol

2013

;

168

:

1910

–

1916

.

482

Güder

G

,

Brenner

S

,

Störk

S

,

Hoes

A

,

Rutten

FH

.

Chronic obstructive pulmonary disease in heart failure: accurate diagnosis and treatment

.

Eur J Heart Fail

2014

;

16

:

1

–

10

.

483

Perk

J

,

De Backer

G

,

Gohlke

H

,

Graham

I

,

Reiner

Z

,

Verschuren

M

,

Albus

C

,

Benlian

P

,

Boysen

G

,

Cifkova

R

,

Deaton

C

,

Ebrahim

S

,

Fisher

M

,

Germano

G

,

Hobbs

R

,

Hoes

A

,

Karadeniz

S

,

Mezzani

A

,

Prescott

E

,

Ryden

L

,

Scherer

M

,

Syvänne

M

,

Scholte

op

,

Reimer

WJM

,

Vrints

C

,

Wood

D

,

Zamorano

JL

,

Zannad

F

,

European Association for Cardiovascular Prevention & Rehabilitation (EACPR), ESC Committee for Practice Guidelines (CPG)

.

European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice

.

Eur Heart J

2012

;

33

:

1635

–

1701

.

484

McKelvie

RS

,

Moe

GW

,

Cheung

A

,

Costigan

J

,

Ducharme

A

,

Estrella-Holder

E

,

Ezekowitz

JA

,

Floras

J

,

Giannetti

N

,

Grzeslo

A

,

Harkness

K

,

Heckman

GA

,

Howlett

JG

,

Kouz

S

,

Leblanc

K

,

Mann

E

,

O'Meara

E

,

Rajda

M

,

Rao

V

,

Simon

J

,

Swiggum

E

,

Zieroth

S

,

Arnold

JMO

,

Ashton

T

,

D'Astous

M

,

Dorian

P

,

Haddad

H

,

Isaac

DL

,

Leblanc

M-H

,

Liu

P

,

Sussex

B

,

Ross

HJ

.

The 2011 Canadian Cardiovascular Society heart failure management guidelines update: focus on sleep apnea, renal dysfunction, mechanical circulatory support, and palliative care

.

Can J Cardiol

2011

;

27

:

319

–

338

.

485

Khayat

R

,

Jarjoura

D

,

Porter

K

,

Sow

A

,

Wannemacher

J

,

Dohar

R

,

Pleister

A

,

Abraham

WT

.

Sleep disordered breathing and post-discharge mortality in patients with acute heart failure

.

Eur Heart J

2015

;

36

:

1463

–

1469

.

486

Nakamura

S

,

Asai

K

,

Kubota

Y

,

Murai

K

,

Takano

H

,

Tsukada

YT

,

Shimizu

W

.

Impact of sleep-disordered breathing and efficacy of positive airway pressure on mortality in patients with chronic heart failure and sleep-disordered breathing: a meta-analysis

.

Clin Res Cardiol

2015

;

104

:

208

–

216

.

487

Gottlieb

DJ

,

Yenokyan

G

,

Newman

AB

,

O'Connor

GT

,

Punjabi

NM

,

Quan

SF

,

Redline

S

,

Resnick

HE

,

Tong

EK

,

Diener-West

M

,

Shahar

E

.

Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the Sleep Heart Health Study

.

Circulation

2010

;

122

:

352

–

360

.

488

Imadojemu

VA

,

Sinoway

LI

,

Leuenberger

UA

.

Vascular dysfunction in sleep apnea

.

Am J Respir Crit Care Med

2004

;

169

:

328

–

329

.

489

Randerath

WJ

,

Nothofer

G

,

Priegnitz

C

,

Anduleit

N

,

Treml

M

,

Kehl

V

,

Galetke

W

.

Long-term auto-servoventilation or constant positive pressure in heart failure and coexisting central with obstructive sleep apnea

.

Chest

2012

;

142

:

440

–

447

.

490

Yumino

D

,

Kasai

T

,

Kimmerly

D

,

Amirthalingam

V

,

Floras

JS

,

Bradley

TD

.

Differing effects of obstructive and central sleep apneas on stroke volume in patients with heart failure

.

Am J Respir Crit Care Med

2013

;

187

:

433

–

438

.

491

Bradley

TD

,

Logan

AG

,

Kimoff

RJ

,

Series

F

,

Morrison

D

,

Ferguson

K

,

Belenkie

I

,

Pfeifer

M

,

Fleetham

J

,

Hanly

P

,

Smilovitch

M

,

Tomlinson

G

,

Floras

JS

.

Continuous positive airway pressure for central sleep apnea and heart failure

.

N Engl J Med

2005

;

353

:

2025

–

2033

.

492

Costanzo

MR

,

Augostini

R

,

Goldberg

LR

,

Ponikowski

P

,

Stellbrink

C

,

Javaheri

S

.

Design of the remedē System Pivotal Trial: a prospective, randomized study in the use of respiratory rhythm management to treat central sleep apnea

.

J Card Fail

2015

;

21

:

892

–

902

.

493

Vahanian

A

,

Alfieri

O

,

Andreotti

F

,

Antunes

MJ

,

Baron-Esquivias

G

,

Baumgartner

H

,

Borger

MA

,

Carrel

TP

,

De Bonis

M

,

Evangelista

A

,

Falk

V

,

Iung

B

,

Lancellotti

P

,

Pierard

L

,

Price

S

,

Schafers

H-J

,

Schuler

G

,

Stepinska

J

,

Swedberg

K

,

Takkenberg

J

,

Von Oppell

UO

,

Windecker

S

,

Zamorano

JL

,

Zembala

M

,

Bax

JJ

,

Baumgartner

H

,

Ceconi

C

,

Dean

V

,

Deaton

C

,

Fagard

R

,

Funck-Brentano

C

,

Hasdai

D

,

Hoes

A

,

Kirchhof

P

,

Knuuti

J

,

Kolh

P

,

McDonagh

T

,

Moulin

C

,

Popescu

BA

,

Reiner

Z

,

Sechtem

U

,

Sirnes

PA

,

Tendera

M

,

Torbicki

A

,

Vahanian

A

,

Windecker

S

,

Popescu

BA

,

Von Segesser

L

,

Badano

LP

,

Bunc

M

,

Claeys

MJ

,

Drinkovic

N

,

Filippatos

G

,

Habib

G

,

Kappetein

AP

,

Kassab

R

,

Lip

GYH

,

Moat

N

,

Nickenig

G

,

Otto

CM

,

Pepper

J

,

Piazza

N

,

Pieper

PG

,

Rosenhek

R

,

Shuka

N

,

Schwammenthal

E

,

Schwitter

J

,

Mas

PT

,

Trindade

PT

,

Walther

T

.

Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)

.

Eur Heart J

2012

;

33

:

2451

–

2496

.

494

Nishimura

RA

,

Otto

CM

,

Bonow

RO

,

Carabello

BA

,

Erwin

JP

,

Guyton

RA

,

O'Gara

PT

,

Ruiz

CE

,

Skubas

NJ

,

Sorajja

P

,

Sundt

TM

,

Thomas

JD

,

American College of Cardiology/American Heart Association Task Force on Practice Guidelines

.

2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

.

J Am Coll Cardiol

2014

;

63

:

2438

–

2488

.

495

Smith

CR

,

Leon

MB

,

Mack

MJ

,

Miller

DC

,

Moses

JW

,

Svensson

LG

,

Tuzcu

EM

,

Webb

JG

,

Fontana

GP

,

Makkar

RR

,

Williams

M

,

Dewey

T

,

Kapadia

S

,

Babaliaros

V

,

Thourani

VH

,

Corso

P

,

Pichard

AD

,

Bavaria

JE

,

Herrmann

HC

,

Akin

JJ

,

Anderson

WN

,

Wang

D

,

Pocock

SJ

.

Transcatheter versus surgical aortic-valve replacement in high-risk patients

.

N Engl J Med

2011

;

364

:

2187

–

2198

.

496

Leon

MB

,

Smith

CR

,

Mack

M

,

Miller

DC

,

Moses

JW

,

Svensson

LG

,

Tuzcu

EM

,

Webb

JG

,

Fontana

GP

,

Makkar

RR

,

Brown

DL

,

Block

PC

,

Guyton

RA

,

Pichard

AD

,

Bavaria

JE

,

Herrmann

HC

,

Douglas

PS

,

Petersen

JL

,

Akin

JJ

,

Anderson

WN

,

Wang

D

,

Pocock

S

.

Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery

.

N Engl J Med

2010

;

363

:

1597

–

1607

.

497

Reardon

MJ

,

Adams

DH

,

Kleiman

NS

,

Yakubov

SJ

,

Coselli

JS

,

Deeb

GM

,

Gleason

TG

,

Lee

JS

,

Hermiller

JB

,

Chetcuti

S

,

Heiser

J

,

Merhi

W

,

Zorn

GL

,

Tadros

P

,

Robinson

N

,

Petrossian

G

,

Hughes

GC

,

Harrison

JK

,

Maini

B

,

Mumtaz

M

,

Conte

JV

,

Resar

JR

,

Aharonian

V

,

Pfeffer

T

,

Oh

JK

,

Qiao

H

,

Popma

JJ

.

2-Year outcomes in patients undergoing surgical or self-expanding transcatheter aortic valve replacement

.

J Am Coll Cardiol

2015

;

66

:

113

–

121

.

498

Adams

DH

,

Popma

JJ

,

Reardon

MJ

,

Yakubov

SJ

,

Coselli

JS

,

Deeb

GM

,

Gleason

TG

,

Buchbinder

M

,

Hermiller

J

,

Kleiman

NS

,

Chetcuti

S

,

Heiser

J

,

Merhi

W

,

Zorn

G

,

Tadros

P

,

Robinson

N

,

Petrossian

G

,

Hughes

GC

,

Harrison

JK

,

Conte

J

,

Maini

B

,

Mumtaz

M

,

Chenoweth

S

,

Oh

JK

.

Transcatheter aortic-valve replacement with a self-expanding prosthesis

.

N Engl J Med

2014

;

370

:

1790

–

1798

.

499

Lancellotti

P

,

Tribouilloy

C

,

Hagendorff

A

,

Popescu

BA

,

Edvardsen

T

,

Pierard

LA

,

Badano

L

,

Zamorano

JL

.

Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging

.

Eur Heart J Cardiovasc Imaging

2013

;

14

:

611

–

644

.

500

Chaliki

HP

,

Mohty

D

,

Avierinos

JF

,

Scott

CG

,

Schaff

H V

,

Tajik

AJ

,

Enriquez-Sarano

M

.

Outcomes after aortic valve replacement in patients with severe aortic regurgitation and markedly reduced left ventricular function

.

Circulation

2002

;

106

:

2687

–

2693

.

501

Smith

PK

,

Puskas

JD

,

Ascheim

DD

,

Voisine

P

,

Gelijns

AC

,

Moskowitz

AJ

,

Hung

JW

,

Parides

MK

,

Ailawadi

G

,

Perrault

LP

,

Acker

MA

,

Argenziano

M

,

Thourani

V

,

Gammie

JS

,

Miller

MA

,

Pagé

P

,

Overbey

JR

,

Bagiella

E

,

Dagenais

F

,

Blackstone

EH

,

Kron

IL

,

Goldstein

DJ

,

Rose

EA

,

Moquete

EG

,

Jeffries

N

,

Gardner

TJ

,

O'Gara

PT

,

Alexander

JH

,

Michler

RE

.

Surgical treatment of moderate ischemic mitral regurgitation

.

N Engl J Med

2014

;

371

:

2178

–

2188

.

502

Acker

MA

,

Parides

MK

,

Perrault

LP

,

Moskowitz

AJ

,

Gelijns

AC

,

Voisine

P

,

Smith

PK

,

Hung

JW

,

Blackstone

EH

,

Puskas

JD

,

Argenziano

M

,

Gammie

JS

,

Mack

M

,

Ascheim

DD

,

Bagiella

E

,

Moquete

EG

,

Ferguson

TB

,

Horvath

KA

,

Geller

NL

,

Miller

MA

,

Woo

YJ

,

D'Alessandro

DA

,

Ailawadi

G

,

Dagenais

F

,

Gardner

TJ

,

O'Gara

PT

,

Michler

RE

,

Kron

IL

.

Mitral-valve repair versus replacement for severe ischemic mitral regurgitation

.

N Engl J Med

2014

;

370

:

23

–

32

.

503

De Bonis

M

,

Al-Attar

N

,

Antunes

M

,

Borger

M

,

Casselman

F

,

Falk

V

,

Folliguet

T

,

Iung

B

,

Lancellotti

P

,

Lentini

S

,

Maisano

F

,

Messika-Zeitoun

D

,

Muneretto

C

,

Pibarot

P

,

Pierard

L

,

Punjabi

P

,

Rosenhek

R

,

Suwalski

P

,

Vahanian

A

.

Surgical and interventional management of mitral valve regurgitation: a position statement from the European Society of Cardiology Working Groups on Cardiovascular Surgery and Valvular Heart Disease

.

Eur Heart J

2016

;

37

:

133

–

139

.

504

D'ascenzo

F

,

Moretti

C

,

Marra

WG

,

Montefusco

A

,

Omede

P

,

Taha

S

,

Castagno

D

,

Gaemperli

O

,

Taramasso

M

,

Frea

S

,

Pidello

S

,

Rudolph

V

,

Franzen

O

,

Braun

D

,

Giannini

C

,

Ince

H

,

Perl

L

,

Zoccai

G

,

Marra

S

,

D'Amico

M

,

Maisano

F

,

Rinaldi

M

,

Gaita

F

.

Meta-analysis of the usefulness of mitraclip in patients with functional mitral regurgitation

.

Am J Cardiol

2015

;

116

:

325

–

331

.

505

Nickenig

G

,

Estevez-Loureiro

R

,

Franzen

O

,

Tamburino

C

,

Vanderheyden

M

,

Lüscher

TF

,

Moat

N

,

Price

S

,

Dall'Ara

G

,

Winter

R

,

Corti

R

,

Grasso

C

,

Snow

TM

,

Jeger

R

,

Blankenberg

S

,

Settergren

M

,

Tiroch

K

,

Balzer

J

,

Petronio

AS

,

Büttner

H-J

,

Ettori

F

,

Sievert

H

,

Fiorino

MG

,

Claeys

M

,

Ussia

GP

,

Baumgartner

H

,

Scandura

S

,

Alamgir

F

,

Keshavarzi

F

,

Colombo

A

,

Maisano

F

,

Ebelt

H

,

Aruta

P

,

Lubos

E

,

Plicht

B

,

Schueler

R

,

Pighi

M

,

Di Mario

C

,

Transcatheter Valve Treatment Sentinel Registry Investigators of the EURObservational Research Programme of the European Society of Cardiology

.

Percutaneous mitral valve edge-to-edge repair: in-hospital results and 1-year follow-up of 628 patients of the 2011–2012 pilot European Sentinel Registry

.

J Am Coll Cardiol

2014

;

64

:

875

–

884

.

506

Puls

M

,

Lubos

E

,

Boekstegers

P

,

von Bardeleben

RS

,

Ouarrak

T

,

Butter

C

,

Zuern

CS

,

Bekeredjian

R

,

Sievert

H

,

Nickenig

G

,

Eggebrecht

H

,

Senges

J

,

Schillinger

W

.

One-year outcomes and predictors of mortality after MitraClip therapy in contemporary clinical practice: results from the German transcatheter mitral valve interventions registry

.

Eur Heart J

2016

;

37

:

703

–

12

.

507

Perez-Ayuso

RM

,

Arroyo

V

,

Planas

R

,

Gaya

J

,

Bory

F

,

Rimola

A

,

Rivera

F

,

Rodes

J

.

Randomized comparative study of efficacy of furosemide versus spironolactone in nonazotemic cirrhosis with ascites. Relationship between the diuretic response and the activity of the renin-aldosterone system

.

Gastroenterology

1983

;

84

:

961

–

968

.

508

Schofer

J

,

Bijuklic

K

,

Tiburtius

C

,

Hansen

L

,

Groothuis

A

,

Hahn

RT

.

First-in-human transcatheter tricuspid valve repair in a patient with severely regurgitant tricuspid valve

.

J Am Coll Cardiol

2015

;

65

:

1190

–

1195

.

509

Herrmann

HC

,

Pibarot

P

,

Hueter

I

,

Gertz

ZM

,

Stewart

WJ

,

Kapadia

S

,

Tuzcu

EM

,

Babaliaros

V

,

Thourani

V

,

Szeto

WY

,

Bavaria

JE

,

Kodali

S

,

Hahn

RT

,

Williams

M

,

Miller

DC

,

Douglas

PS

,

Leon

MB

.

Predictors of mortality and outcomes of therapy in low-flow severe aortic stenosis: a Placement of Aortic Transcatheter Valves (PARTNER) trial analysis

.

Circulation

2013

;

127

:

2316

–

2326

.

510

Ponikowski

P

,

Jankowska

EA

.

Pathogenesis and clinical presentation of acute heart failure

.

Rev Esp Cardiol (Engl Ed)

2015

;

68

:

331

–337.

511

Metra

M

,

Felker

GM

,

Zacà

V

,

Bugatti

S

,

Lombardi

C

,

Bettari

L

,

Voors

AA

,

Gheorghiade

M

,

Dei Cas

L

.

Acute heart failure: multiple clinical profiles and mechanisms require tailored therapy

.

Int J Cardiol

2010

;

144

:

175

–

179

.

512

Filippatos

G

,

Zannad

F

.

An introduction to acute heart failure syndromes: definition and classification

.

Heart Fail Rev

2007

;

12

:

87

–

90

.

513

Alla

F

,

Zannad

F

,

Filippatos

G

.

Epidemiology of acute heart failure syndromes

.

Heart Fail Rev

2007

;

12

:

91

–

95

.

514

Nohria

A

,

Tsang

SW

,

Fang

JC

,

Lewis

EF

,

Jarcho

JA

,

Mudge

GH

,

Stevenson

LW

.

Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure

.

J Am Coll Cardiol

2003

;

41

:

1797

–

1804

.

515

Stevenson

LW

.

Design of therapy for advanced heart failure

.

Eur J Heart Fail

2005

;

7

:

323

–

331

.

516

Maisel

AS

,

Peacock

WF

,

McMullin

N

,

Jessie

R

,

Fonarow

GC

,

Wynne

J

,

Mills

RM

.

Timing of immunoreactive B-type natriuretic peptide levels and treatment delay in acute decompensated heart failure: an ADHERE (Acute Decompensated Heart Failure National Registry) analysis

.

J Am Coll Cardiol

2008

;

52

:

534

–

540

.

517

Peacock

WF

,

Emerman

C

,

Costanzo

MR

,

Diercks

DB

,

Lopatin

M

,

Fonarow

GC

.

Early vasoactive drugs improve heart failure outcomes

.

Congest Heart Fail

15

:

256

–

264

.

518

Wuerz

RC

,

Meador

SA

.

Effects of prehospital medications on mortality and length of stay in congestive heart failure

.

Ann Emerg Med

1992

;

21

:

669

–

674

.

519

Chakko

S

,

Woska

D

,

Martinez

H

,

de Marchena

E

,

Futterman

L

,

Kessler

KM

,

Myerberg

RJ

.

Clinical, radiographic, and hemodynamic correlations in chronic congestive heart failure: conflicting results may lead to inappropriate care

.

Am J Med

1991

;

90

:

353

–

359

.

520

Wang

CS

,

FitzGerald

JM

,

Schulzer

M

,

Mak

E

,

Ayas

NT

.

Does this dyspneic patient in the emergency department have congestive heart failure?

JAMA

2005

;

294

:

1944

–

1956

.

521

Kelder

JC

,

Cowie

MR

,

McDonagh

TA

,

Hardman

SM

,

Grobbee

DE

,

Cost

B

,

Hoes

AW

.

Quantifying the added value of BNP in suspected heart failure in general practice: an individual patient data meta-analysis

.

Heart

2011

;

97

:

959

–

963

.

522

Gupta

DK

,

Wang

TJ

.

Natriuretic peptides and cardiometabolic health

.

Circ J

2015

;

79

:

1647

–

1655

.

523

Zois

NE

,

Bartels

ED

,

Hunter

I

,

Kousholt

BS

,

Olsen

LH

,

Goetze

JP

.

Natriuretic peptides in cardiometabolic regulation and disease

.

Nat Rev Cardiol

2014

;

11

:

403

–

412

.

524

Nishikimi

T

,

Kuwahara

K

.

Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides

.

J Cardiol

2011

;

57

:

131

–

140

.

525

Felker

GM

,

Mentz

RJ

,

Teerlink

JR

,

Voors

AA

,

Pang

PS

,

Ponikowski

P

,

Greenberg

BH

,

Filippatos

G

,

Davison

BA

,

Cotter

G

,

Prescott

MF

,

Hua

TA

,

Lopez-Pintado

S

,

Severin

T

,

Metra

M

.

Serial high sensitivity cardiac troponin T measurement in acute heart failure: insights from the RELAX-AHF study

.

Eur J Heart Fail

2015

;

17

:

1262

–

70

.

526

Konstantinides

S V

,

Torbicki

A

,

Agnelli

G

,

Danchin

N

,

Fitzmaurice

D

,

Galiè

N

,

Gibbs

JSR

,

Huisman

MV

,

Humbert

M

,

Kucher

N

,

Lang

I

,

Lankeit

M

,

Lekakis

J

,

Maack

C

,

Mayer

E

,

Meneveau

N

,

Perrier

A

,

Pruszczyk

P

,

Rasmussen

LH

,

Schindler

TH

,

Svitil

P

,

Vonk Noordegraaf

A

,

Zamorano

JL

,

Zompatori

M

,

Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)

.

2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism

.

Eur Heart J

2014

;

35

:

3033

–

3073

.

527

Maisel

A

,

Neath

SX

,

Landsberg

J

,

Mueller

C

,

Nowak

RM

,

Peacock

WF

,

Ponikowski

P

,

Möckel

M

,

Hogan

C

,

Wu

AHB

,

Richards

M

,

Clopton

P

,

Filippatos

GS

,

Di Somma

S

,

Anand

I

,

Ng

LL

,

Daniels

LB

,

Christenson

RH

,

Potocki

M

,

McCord

J

,

Terracciano

G

,

Hartmann

O

,

Bergmann

A

,

Morgenthaler

NG

,

Anker

SD

.

Use of procalcitonin for the diagnosis of pneumonia in patients presenting with a chief complaint of dyspnoea: results from the BACH (Biomarkers in Acute Heart Failure) trial

.

Eur J Heart Fail

2012

;

14

:

278

–

286

.

528

van Deursen

VM

,

Damman

K

,

Hillege

HL

,

van Beek

AP

,

van Veldhuisen

DJ

,

Voors

AA

.

Abnormal liver function in relation to hemodynamic profile in heart failure patients

.

J Card Fail

2010

;

16

:

84

–

90

.

529

Biegus

J

,

Zymliński

R

,

Sokolski

M

,

Nawrocka

S

,

Siwołowski

P

,

Szachniewicz

J

,

Jankowska

EA

,

Banasiak

W

,

Ponikowski

P

.

Liver function tests in patients with acute heart failure

.

Pol Arch Med Wewnętrznej

2012

;

122

:

471

–

479

.

530

Nikolaou

M

,

Parissis

J

,

Yilmaz

MB

,

Seronde

M-F

,

Kivikko

M

,

Laribi

S

,

Paugam-Burtz

C

,

Cai

D

,

Pohjanjousi

P

,

Laterre

P-F

,

Deye

N

,

Poder

P

,

Cohen-Solal

A

,

Mebazaa

A

.

Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure

.

Eur Heart J

2013

;

34

:

742

–

749

.

531

Moe

GW

,

Howlett

J

,

Januzzi

JL

,

Zowall

H

.

N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study

.

Circulation

2007

;

115

:

3103

–

3110

.

532

Maisel

A

,

Mueller

C

,

Nowak

R

,

Peacock

WF

,

Landsberg

JW

,

Ponikowski

P

,

Mockel

M

,

Hogan

C

,

Wu

AHB

,

Richards

M

,

Clopton

P

,

Filippatos

GS

,

Di_Somma

S

,

Anand

I

,

Ng

L

,

Daniels

LB

,

Neath

S-X

,

Christenson

R

,

Potocki

M

,

McCord

J

,

Terracciano

G

,

Kremastinos

D

,

Hartmann

O

,

von Haehling

S

,

Bergmann

A

,

Morgenthaler

NG

,

Anker

SD

,

Di Somma

S

,

Anand

I

,

Ng

L

,

Daniels

LB

,

Neath

S-X

,

Christenson

R

,

Potocki

M

,

McCord

J

,

Terracciano

G

,

Kremastinos

D

,

Hartmann

O

,

von Haehling

S

,

Bergmann

A

,

Morgenthaler

NG

,

Anker

SD

.

Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea

.

J Am Coll Cardiol

2010

;

55

:

2062

–

2076

.

533

Mueller

C

,

Scholer

A

,

Laule-Kilian

K

,

Martina

B

,

Schindler

C

,

Buser

P

,

Pfisterer

M

,

Perruchoud

AP

.

Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea

.

N Engl J Med

2004

;

350

:

647

–

654

.

534

Krishnaswamy

P

,

Nowak

RM

,

McCord

J

,

Hollander

JE

,

Duc

P

,

Omland

T

,

Storrow

AB

,

Abraham

WT

,

Wu

AHB

,

Clopton

P

,

Steg

PG

,

Westheim

A

,

Knudsen

CW

,

Perez

A

,

Kazanegra

R

,

Herrmann

HC

,

McCullough

PA

.

Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure

.

N Engl J Med

2002

;

347

:

161

–

167

.

535

Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC)

Steg

PG

,

James

SK

,

Atar

D

,

Badano

LP

,

Blömstrom-Lundqvist

C

,

Borger

MA

,

Di Mario

C

,

Dickstein

K

,

Ducrocq

G

,

Fernandez-Aviles

F

,

Gershlick

AH

,

Giannuzzi

P

,

Halvorsen

S

,

Huber

K

,

Juni

P

,

Kastrati

A

,

Knuuti

J

,

Lenzen

MJ

,

Mahaffey

KW

,

Valgimigli

M

,

van 't Hof

A

,

Widimsky

P

,

Zahger

D

.

ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation

.

Eur Heart J

2012

;

33

:

2569

–

2619

.

536

Levy

P

,

Compton

S

,

Welch

R

,

Delgado

G

,

Jennett

A

,

Penugonda

N

,

Dunne

R

,

Zalenski

R

.

Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis

.

Ann Emerg Med

2007

;

50

:

144

–

152

.

537

Cotter

G

,

Metzkor

E

,

Kaluski

E

,

Faigenberg

Z

,

Miller

R

,

Simovitz

A

,

Shaham

O

,

Marghitay

D

,

Koren

M

,

Blatt

A

,

Moshkovitz

Y

,

Zaidenstein

R

,

Golik

A

.

Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema

.

Lancet

1998

;

351

:

389

–

393

.

538

Peterson

PN

,

Rumsfeld

JS

,

Liang

L

,

Albert

NM

,

Hernandez

AF

,

Peterson

ED

,

Fonarow

GC

,

Masoudi

FA

.

A validated risk score for in-hospital mortality in patients with heart failure from the American Heart Association get with the guidelines program

.

Circ Cardiovasc Qual Outcomes

2010

;

3

:

25

–

32

.

539

Adams

KF

,

Abraham

WT

,

Yancy

CW

,

Boscardin

WJ

.

Risk stratification for in-hospital mortality in acutely decompensated heart failure classification and regression tree analysis

.

JAMA

2015

;

293

:

572

–

580

.

540

Mebazaa

A

,

Yilmaz

MB

,

Levy

P

,

Ponikowski

P

,

Peacock

WF

,

Laribi

S

,

Ristic

AD

,

Lambrinou

E

,

Masip

J

,

Riley

JP

,

McDonagh

T

,

Mueller

C

,

DeFilippi

C

,

Harjola

V-P

,

Thiele

H

,

Piepoli

MF

,

Metra

M

,

Maggioni

A

,

McMurray

J

,

Dickstein

K

,

Damman

K

,

Seferovic

PM

,

Ruschitzka

F

,

Leite-Moreira

AF

,

Bellou

A

,

Anker

SD

,

Filippatos

G

.

Recommendations on pre-hospital and early hospital management of acute heart failure: a consensus paper from the HFA of the ESC, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine

.

Eur J Heart Fail

2015

;

17

:

544

–

558

.

541

Weng

C-L

,

Zhao

Y-T

,

Liu

Q-H

,

Fu

C-J

,

Sun

F

,

Ma

Y-L

,

Chen

Y-W

,

He

Q-Y

.

Meta-analysis: noninvasive ventilation in acute cardiogenic pulmonary edema

.

Ann Intern Med

2010

;

152

:

590

–

600

.

542

Gray

AJ

,

Goodacre

S

,

Newby

DE

,

Masson

MA

,

Sampson

F

,

Dixon

S

,

Crane

S

,

Elliott

M

,

Nicholl

J

.

A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO Trial

.

Health Technol Assess

2009

;

13

:

1

–

106

.

543

Vital

FMR

,

Ladeira

MT

,

Atallah

AN

.

Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema

.

Cochrane Database Syst Rev

2013

;

5

:

CD005351

.

544

Park

M

,

Sangean

MC

,

Volpe

MDS

,

Feltrim

MIZ

,

Nozawa

E

,

Leite

PF

,

Passos Amato

MB

,

Lorenzi-Filho

G

.

Randomized, prospective trial of oxygen, continuous positive airway pressure, and bilevel positive airway pressure by face mask in acute cardiogenic pulmonary edema

.

Crit Care Med

2004

;

32

:

2407

–

2415

.

545

Gray

A

,

Goodacre

S

,

Newby

DE

,

Masson

M

,

Sampson

F

,

Nicholl

J

,

3CPO Trialists

.

Noninvasive ventilation in acute cardiogenic pulmonary edema

.

N Engl J Med

2008

;

359

:

142

–

151

.

546

Rawles

JM

,

Kenmure

AC

.

Controlled trial of oxygen in uncomplicated myocardial infarction

.

Br Med J

1976

;

1

:

1121

–

1123

.

547

Park

JH

,

Balmain

S

,

Berry

C

,

Morton

JJ

,

McMurray

JJV

.

Potentially detrimental cardiovascular effects of oxygen in patients with chronic left ventricular systolic dysfunction

.

Heart

2010

;

96

:

533

–

538

.

548

Felker

GM

,

Lee

KL

,

Bull

DA

,

Redfield

MM

,

Stevenson

LW

,

Goldsmith

SR

,

LeWinter

MM

,

Deswal

A

,

Rouleau

JL

,

Ofili

EO

,

Anstrom

KJ

,

Hernandez

AF

,

McNulty

SE

,

Velazquez

EJ

,

Kfoury

AG

,

Chen

HH

,

Givertz

MM

,

Semigran

MJ

,

Bart

BA

,

Mascette

AM

,

Braunwald

E

,

O'Connor

CM

.

Diuretic strategies in patients with acute decompensated heart failure

.

N Engl J Med

2011

;

364

:

797

–

805

.

549

Jentzer

JC

,

DeWald

TA

,

Hernandez

AF

.

Combination of loop diuretics with thiazide-type diuretics in heart failure

.

J Am Coll Cardiol

2010

;

56

:

1527

–

1534

.

550

O'Connor

CM

,

Starling

RC

,

Hernandez

AF

,

Armstrong

PW

,

Dickstein

K

,

Hasselblad

V

,

Heizer

GM

,

Komajda

M

,

Massie

BM

,

McMurray

JJ V

,

Nieminen

MS

,

Reist

CJ

,

Rouleau

JL

,

Swedberg

K

,

Adams

KF

,

Anker

SD

,

Atar

D

,

Battler

A

,

Botero

R

,

Bohidar

NR

,

Butler

J

,

Clausell

N

,

Corbalán

R

,

Costanzo

MR

,

Dahlstrom

U

,

Deckelbaum

LI

,

Diaz

R

,

Dunlap

ME

,

Ezekowitz

JA

,

Feldman

D

,

Felker

GM

,

Fonarow

GC

,

Gennevois

D

,

Gottlieb

SS

,

Hill

JA

,

Hollander

JE

,

Howlett

JG

,

Hudson

MP

,

Kociol

RD

,

Krum

H

,

Laucevicius

A

,

Levy

WC

,

Méndez

GF

,

Metra

M

,

Mittal

S

,

Oh

B-H

,

Pereira

NL

,

Ponikowski

P

,

Tang

WHW

,

Wilson

WH

,

Tanomsup

S

,

Teerlink

JR

,

Triposkiadis

F

,

Troughton

RW

,

Voors

AA

,

Whellan

DJ

,

Zannad

F

,

Califf

RM

.

Effect of nesiritide in patients with acute decompensated heart failure

.

N Engl J Med

2011

;

365

:

32

–

43

.

551

Wakai

A

,

McCabe

A

,

Kidney

R

,

Brooks

SC

,

Seupaul

RA

,

Diercks

DB

,

Salter

N

,

Fermann

GJ

,

Pospisil

C

.

Nitrates for acute heart failure syndromes

.

Cochrane Database Syst Rev

2013

;

8

:

CD005151

.

552

Mebazaa

A

,

Parissis

J

,

Porcher

R

,

Gayat

E

,

Nikolaou

M

,

Boas

FV

,

Delgado

JF

,

Follath

F

.

Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods

.

Intensive Care Med

2011

;

37

:

290

–

301

.

553

Sharon

A

,

Shpirer

I

,

Kaluski

E

,

Moshkovitz

Y

,

Milovanov

O

,

Polak

R

,

Blatt

A

,

Simovitz

A

,

Shaham

O

,

Faigenberg

Z

,

Metzger

M

,

Stav

D

,

Yogev

R

,

Golik

A

,

Krakover

R

,

Vered

Z

,

Cotter

G

.

High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema

.

J Am Coll Cardiol

2000

;

36

:

832

–

837

.

554

Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF)

.

Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial

.

JAMA

2002

;

287

:

1531

–

1540

.

555

Cohn

JN

,

Franciosa

JA

,

Francis

GS

,

Archibald

D

,

Tristani

F

,

Fletcher

R

,

Montero

A

,

Cintron

G

,

Clarke

J

,

Hager

D

,

Saunders

R

,

Cobb

F

,

Smith

R

,

Loeb

H

,

Settle

H

.

Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: results of a Veterans Administration cooperative study

.

N Engl J Med

1982

;

306

:

1129

–

1135

.

556

Elkayam

U

,

Tasissa

G

,

Binanay

C

,

Stevenson

LW

,

Gheorghiade

M

,

Warnica

JW

,

Young

JB

,

Rayburn

BK

,

Rogers

JG

,

DeMarco

T

,

Leier

C V

.

Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure

.

Am Heart J

2007

;

153

:

98

–

104

.

557

Belletti

A

,

Castro

ML

,

Silvetti

S

,

Greco

T

,

Biondi-Zoccai

G

,

Pasin

L

,

Zangrillo

A

,

Landoni

G

.

The effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials

.

Br J Anaesth

2015

;

115

:

656

–

675

.

558

De Backer

D

,

Biston

P

,

Devriendt

J

,

Madl

C

,

Chochrad

D

,

Aldecoa

C

,

Brasseur

A

,

Defrance

P

,

Gottignies

P

,

Vincent

J-L

.

Comparison of dopamine and norepinephrine in the treatment of shock

.

N Engl J Med

2010

;

362

:

779

–

789

.

559

Gong

B

,

Li

Z

,

Yat Wong

PC

.

Levosimendan treatment for heart failure: a systematic review and meta-analysis

.

J Cardiothorac Vasc Anesth

2015

;

29

:

1415

–

25

.

560

Tang

X

,

Liu

P

,

Li

R

,

Jing

Q

,

Lv

J

,

Liu

L

,

Liu

Y

.

Milrinone for the treatment of acute heart failure after acute myocardial infarction: a systematic review and meta-analysis

.

Basic Clin Pharmacol Toxicol

2015

;

117

:

186

–

194

.

561

Cuffe

MS

,

Califf

RM

,

Adams

KF

,

Benza

R

,

Bourge

R

,

Colucci

WS

,

Massie

BM

,

O'Connor

CM

,

Pina

I

,

Quigg

R

,

Silver

MA

,

Gheorghiade

M

,

Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators

.

Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial

.

JAMA

2002

;

287

:

1541

–

1547

.

562

O'Connor

CM

,

Gattis

WA

,

Uretsky

BF

,

Adams

KF

,

McNulty

SE

,

Grossman

SH

,

McKenna

WJ

,

Zannad

F

,

Swedberg

K

,

Gheorghiade

M

,

Califf

RM

.

Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST)

.

Am Heart J

1999

;

138

:

78

–

86

.

563

Wang

X-C

,

Zhu

D-M

,

Shan

Y-X

.

Dobutamine therapy is associated with worse clinical outcomes compared with nesiritide therapy for acute decompensated heart failure: a systematic review and meta-analysis

.

Am J Cardiovasc Drugs

2015

;

15

:

429

–

37

.

564

Dentali

F

,

Douketis

JD

,

Gianni

M

,

Lim

W

,

Crowther

M a

.

Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients

.

Ann Intern Med

2007

;

146

:

278

–

288

.

565

Clemo

H

,

Wood

M

,

Gilligan

D

,

Ellenbogen

K

.

Intravenous amiodarone for acute heart rate control in the critically ill patient with atrial tachyarrhythmias

.

Am J Cardiol

1998

;

81

:

594

–

598

.

566

Hou

ZY

,

Chang

MS

,

Chen

CY

,

Tu

MS

,

Lin

SL

,

Chiang

HT

,

Woosley

RL

.

Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone

.

A randomized, digoxin-controlled study. Eur Heart J

1995

;

16

:

521

–

528

.

567

Delle Karth

G

,

Geppert

A

,

Neunteufl

T

,

Priglinger

U

,

Haumer

M

,

Gschwandtner

M

,

Siostrzonek

P

,

Heinz

G

.

Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias

.

Crit Care Med

2001

;

29

:

1149

–

1153

.

568

Iakobishvili

Z

,

Cohen

E

,

Garty

M

,

Behar

S

,

Shotan

A

,

Sandach

A

,

Gottlieb

S

,

Mager

A

,

Battler

A

,

Hasdai

D

.

Use of intravenous morphine for acute decompensated heart failure in patients with and without acute coronary syndromes

.

Acute Card Care

2011

;

13

:

76

–

80

.

569

Peacock

WF

,

Hollander

JE

,

Diercks

DB

,

Lopatin

M

,

Fonarow

G

,

Emerman

CL

.

Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis

.

Emerg Med J

2008

;

25

:

205

–

209

.

570

Cox

ZL

,

Lenihan

DJ

.

Loop diuretic resistance in heart failure: resistance etiology-based strategies to restoring diuretic efficacy

.

J Card Fail

2014

;

20

:

611

–

622

.

571

Mentz

RJ

,

Kjeldsen

K

,

Rossi

GP

,

Voors

AA

,

Cleland

JGF

,

Anker

SD

,

Gheorghiade

M

,

Fiuzat

M

,

Rossignol

P

,

Zannad

F

,

Pitt

B

,

O'Connor

C

,

Felker

GM

.

Decongestion in acute heart failure

.

Eur J Heart Fail

2014

;

16

:

471

–

482

.

572

Mebazaa

A

,

Nieminen

MS

,

Filippatos

GS

,

Cleland

JG

,

Salon

JE

,

Thakkar

R

,

Padley

RJ

,

Huang

B

,

Cohen-Solal

A

.

Levosimendan vs. dobutamine: outcomes for acute heart failure patients on β-blockers in SURVIVE

.

Eur J Heart Fail

2009

;

11

:

304

–

311

.

573

Pathak

A

,

Lebrin

M

,

Vaccaro

A

,

Senard

JM

,

Despas

F

.

Pharmacology of levosimendan: inotropic, vasodilatory and cardioprotective effects

.

J Clin Pharm Ther

2013

;

38

:

341

–

349

.

574

Papp

Z

,

Edes

I

,

Fruhwald

S

,

De Hert

SG

,

Salmenpera

M

,

Leppikangas

H

,

Mebazaa

A

,

Landoni

G

,

Grossini

E

,

Caimmi

P

,

Morelli

A

,

Guarracino

F

,

Schwinger

RH

,

Meyer

S

,

Algotsson

L

,

Wikstrom

BG

,

Jorgensen

K

,

Filippatos

G

,

Parissis

JT

,

Gonzalez

MJ

,

Parkhomenko

A

,

Yilmaz

MB

,

Kivikko

M

,

Pollesello

P

,

Follath

F

.

Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan

.

Int J Cardiol

2012

;

159

:

82

–

87

.

575

Delaney

A

,

Bradford

C

,

McCaffrey

J

,

Bagshaw

SM

,

Lee

R

.

Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials

.

Int J Cardiol

2010

;

138

:

281

–

289

.

576

Monsieurs

KG

,

Nolan

JP

,

Bossaert

LL

,

Greif

R

,

Maconochie

IK

,

Nikolaou

NI

,

Perkins

GD

,

Soar

J

,

Truhlář

A

,

Wyllie

J

,

Zideman

DA

.

European Resuscitation Council Guidelines for Resuscitation 2015: Section 1

.

Executive summary. Resuscitation

2015

;

95

:

1

–

80

.

577

Gheorghiade

M

,

Konstam

MA

,

Burnett

JC

,

Grinfeld

L

,

Maggioni

AP

,

Swedberg

K

,

Udelson

JE

,

Zannad

F

,

Cook

T

,

Ouyang

J

,

Zimmer

C

,

Orlandi

C

,

Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators

.

Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials

.

JAMA

2007

;

297

:

1332

–

1343

.

578

Bart

BA

,

Goldsmith

SR

,

Lee

KL

,

Givertz

MM

,

O'Connor

CM

,

Bull

DA

,

Redfield

MM

,

Deswal

A

,

Rouleau

JL

,

LeWinter

MM

,

Ofili

EO

,

Stevenson

LW

,

Semigran

MJ

,

Felker

GM

,

Chen

HH

,

Hernandez

AF

,

Anstrom

KJ

,

McNulty

SE

,

Velazquez

EJ

,

Ibarra

JC

,

Mascette

AM

,

Braunwald

E

.

Ultrafiltration in decompensated heart failure with cardiorenal syndrome

.

N Engl J Med

2012

;

367

:

2296

–

2304

.

579

Costanzo

MR

,

Guglin

ME

,

Saltzberg

MT

,

Jessup

ML

,

Bart

BA

,

Teerlink

JR

,

Jaski

BE

,

Fang

JC

,

Feller

ED

,

Haas

GJ

,

Anderson

AS

,

Schollmeyer

MP

,

Sobotka

PA

.

Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure

.

J Am Coll Cardiol

2007

;

49

:

675

–

683

.

580

Costanzo

MR

,

Saltzberg

MT

,

Jessup

M

,

Teerlink

JR

,

Sobotka

PA

.

Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in patients with decompensated heart failure: results from UNLOAD

.

J Card Fail

2010

;

16

:

277

–

284

.

581

Mullens

W

,

Abrahams

Z

,

Francis

GS

,

Taylor

DO

,

Starling

RC

,

Tang

WHW

.

Prompt reduction in intra-abdominal pressure following large-volume mechanical fluid removal improves renal insufficiency in refractory decompensated heart failure

.

J Card Fail

2008

;

14

:

508

–

514

.

582

Fuhrmann

JT

,

Schmeisser

A

,

Schulze

MR

,

Wunderlich

C

,

Schoen

SP

,

Rauwolf

T

,

Weinbrenner

C

,

Strasser

RH

.

Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction

.

Crit Care Med

2008

;

36

:

2257

–

2266

.

583

Russ

MA

,

Prondzinsky

R

,

Christoph

A

,

Schlitt

A

,

Buerke

U

,

Söffker

G

,

Lemm

H

,

Swyter

M

,

Wegener

N

,

Winkler

M

,

Carter

JM

,

Reith

S

,

Werdan

K

,

Buerke

M

.

Hemodynamic improvement following levosimendan treatment in patients with acute myocardial infarction and cardiogenic shock

.

Crit Care Med

2007

;

35

:

2732

–

2739

.

584

Felker

GM

,

Benza

RL

,

Chandler

AB

,

Leimberger

JD

,

Cuffe

MS

,

Califf

RM

,

Gheorghiade

M

,

O'Connor

CM

.

Heart failure etiology and response tomilrinone in decompensated heart failure

.

J Am Coll Cardiol

2003

;

41

:

997

–

1003

.

585

Thiele

H

,

Zeymer

U

,

Neumann

F-J

,

Ferenc

M

,

Olbrich

H-G

,

Hausleiter

J

,

Richardt

G

,

Hennersdorf

M

,

Empen

K

,

Fuernau

G

,

Desch

S

,

Eitel

I

,

Hambrecht

R

,

Fuhrmann

J

,

Böhm

M

,

Ebelt

H

,

Schneider

S

,

Schuler

G

,

Werdan

K

.

Intraaortic balloon support for myocardial infarction with cardiogenic shock

.

N Engl J Med

2012

;

367

:

1287

–

1296

.

586

Thiele

H

,

Zeymer

U

,

Neumann

F-J

,

Ferenc

M

,

Olbrich

H-GG

,

Hausleiter

J

,

de Waha

A

,

Richardt

G

,

Hennersdorf

M

,

Empen

K

,

Fuernau

G

,

Desch

S

,

Eitel

I

,

Hambrecht

R

,

Lauer

B

,

Böhm

M

,

Ebelt

H

,

Schneider

S

,

Werdan

K

,

Schuler

G

,

De Waha

A

,

Richardt

G

,

Hennersdorf

M

,

Empen

K

,

Fuernau

G

,

Desch

S

,

Eitel

I

,

Hambrecht

R

,

Lauer

B

,

Böhm

M

,

Ebelt

H

,

Schneider

S

,

Werdan

K

,

Schuler

G

.

Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial

.

Lancet

2013

;

382

:

1638

–

1645

.

587

Prins

KW

,

Neill

JM

,

Tyler

JO

,

Eckman

PM

,

Duval

S

.

Effects of beta-blocker withdrawal in acute decompensated heart failure: a systematic review and meta-analysis

.

JACC Heart Fail

2015

;

3

:

647

–

653

.

588

Santaguida

PL

,

Don-Wauchope

AC

,

Oremus

M

,

McKelvie

R

,

Ali

U

,

Hill

SA

,

Balion

C

,

Booth

RA

,

Brown

JA

,

Bustamam

A

,

Sohel

N

,

Raina

P

.

BNP and NT-proBNP as prognostic markers in persons with acute decompensated heart failure: a systematic review

.

Heart Fail Rev

2014

;

19

:

453

–

470

.

589

Savarese

G

,

Musella

F

,

D'Amore

C

,

Vassallo

E

,

Losco

T

,

Gambardella

F

,

Cecere

M

,

Petraglia

L

,

Pagano

G

,

Fimiani

L

,

Rengo

G

,

Leosco

D

,

Trimarco

B

,

Perrone-Filardi

P

.

Changes of natriuretic peptides predict hospital admissions in patients with chronic heart failure: a meta-analysis

.

JACC Heart Fail

2014

;

2

:

148

–

158

.

590

Volpe

M

,

Rubattu

S

,

Burnett

J

.

Natriuretic peptides in cardiovascular diseases: current use and perspectives

.

Eur Heart J

2014

;

35

:

419

–

425

.

591

Lainscak

M

,

Blue

L

,

Clark

AL

,

Dahlström

U

,

Dickstein

K

,

Ekman

I

,

McDonagh

T

,

McMurray

JJ

,

Ryder

M

,

Stewart

S

,

Strömberg

A

,

Jaarsma

T

.

Self-care management of heart failure: practical recommendations from the Patient Care Committee of the Heart Failure Association of the European Society of Cardiology

.

Eur J Heart Fail

2011

;

13

:

115

–

126

.

592

McDonagh

TA

,

Blue

L

,

Clark

AL

,

Dahlström

U

,

Ekman

I

,

Lainscak

M

,

McDonald

K

,

Ryder

M

,

Strömberg

A

,

Jaarsma

T

.

European Society of Cardiology Heart Failure Association Standards for delivering heart failure care

.

Eur J Heart Fail

2011

;

13

:

235

–

241

.

593

Stewart

GC

,

Givertz

MM

.

Mechanical circulatory support for advanced heart failure: patients and technology in evolution

.

Circulation

2012

;

125

:

1304

–

1315

.

594

Schmidt

M

,

Burrell

A

,

Roberts

L

,

Bailey

M

,

Sheldrake

J

,

Rycus

PT

,

Hodgson

C

,

Scheinkestel

C

,

Cooper

DJ

,

Thiagarajan

RR

,

Brodie

D

,

Pellegrino

V

,

Pilcher

D

.

Predicting survival after ECMO for refractory cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score

.

Eur Heart J

2015

;

36

:

1

–

11

.

595

Riebandt

J

,

Haberl

T

,

Mahr

S

,

Laufer

G

,

Rajek

A

,

Steinlechner

B

,

Schima

H

,

Zimpfer

D

.

Preoperative patient optimization using extracorporeal life support improves outcomes of INTERMACS level I patients receiving a permanent ventricular assist device

.

Eur J Cardiothorac Surg

2014

;

46

:

486

–

492

.

596

Cheng

JM

,

den Uil

CA

,

Hoeks

SE

,

van der Ent

M

,

Jewbali

LSD

,

van Domburg

RT

,

Serruys

PW

.

Percutaneous left ventricular assist devices vs. intra-aortic balloon pump counterpulsation for treatment of cardiogenic shock: a meta-analysis of controlled trials

.

Eur Heart J

2009

;

30

:

2102

–

2108

.

597

O'Neill

WW

,

Kleiman

NS

,

Moses

J

,

Henriques

JPS

,

Dixon

S

,

Massaro

J

,

Palacios

I

,

Maini

B

,

Mulukutla

S

,

Džavík

V

,

Popma

J

,

Douglas

PS

,

Ohman

M

.

A prospective, randomized clinical trial of hemodynamic support with impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the PROTECT II study

.

Circulation

2012

;

126

:

1717

–

1727

.

598

Rahmel

A

, ed.

Eurotransplant International Foundation Annual Report 2013

.

Leiden, The Netherlands

:

CIP-Gegevens Koninklijke Bibliotheek

,

2013

.

599

Trivedi

JR

,

Cheng

A

,

Singh

R

,

Williams

ML

,

Slaughter

MS

.

Survival on the heart transplant waiting list: impact of continuous flow left ventricular assist device as bridge to transplant

.

Ann Thorac Surg

2014

;

98

:

830

–

834

.

600

Miller

LW

,

Pagani

FD

,

Russell

SD

,

John

R

,

Boyle

AJ

,

Aaronson

KD

,

Conte

J V

,

Naka

Y

,

Mancini

D

,

Delgado

RM

,

MacGillivray

TE

,

Farrar

DJ

,

Frazier

OH

.

Use of a continuous-flow device in patients awaiting heart transplantation

.

N Engl J Med

2007

;

357

:

885

–

896

.

601

Kirklin

JK

,

Naftel

DC

,

Pagani

FD

,

Kormos

RL

,

Stevenson

LW

,

Blume

ED

,

Miller

MA

,

Baldwin

J

,

Young

JB

.

Sixth INTERMACS annual report: a 10,000-patient database

.

J Heart Lung Transplant

2014

;

33

:

555

–

564

.

602

Westaby

S

.

Cardiac transplant or rotary blood pump: contemporary evidence

.

J Thorac Cardiovasc Surg

2013

;

145

:

24

–

31

.

603

Teuteberg

JJ

,

Slaughter

MS

,

Rogers

JG

,

McGee

EC

,

Pagani

FD

,

Gordon

R

,

Rame

E

,

Acker

M

,

Kormos

RL

,

Salerno

C

,

Schleeter

TP

,

Goldstein

DJ

,

Shin

J

,

Starling

RC

,

Wozniak

T

,

Malik

AS

,

Silvestry

S

,

Ewald

GA

,

Jorde

UP

,

Naka

Y

,

Birks

E

,

Najarian

KB

,

Hathaway

DR

,

Aaronson

KD

.

The HVAD left ventricular assist device: risk factors for neurological events and risk mitigation strategies

.

JACC Heart Fail

2015

;

3

:

818

–

828

.

604

Kirklin

JK

,

Naftel

DC

,

Pagani

FD

,

Kormos

RL

,

Stevenson

LW

,

Blume

ED

,

Myers

SL

,

Miller

MA

,

Baldwin

JT

,

Young

JB

.

Seventh INTERMACS annual report: 15,000 patients and counting

.

J Heart Lung Transplant

2015

;

34

:

1495

–

1504

.

605

Estep

JD

,

Starling

RC

,

Horstmanshof

DA

,

Milano

CA

,

Selzman

CH

,

Shah

KB

,

Loebe

M

,

Moazami

N

,

Long

JW

,

Stehlik

J

,

Kasirajan

V

,

Haas

DC

,

O'Connell

JB

,

Boyle

AJ

,

Farrar

DJ

,

Rogers

JG

.

Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study

.

J Am Coll Cardiol

2015

;

66

:

1747

–

1761

.

606

Thompson

JS

,

Matlock

DD

,

McIlvennan

CK

,

Jenkins

AR

,

Allen

LA

.

Development of a decision aid for patients with advanced heart failure considering a destination therapy left ventricular assist device

.

JACC Heart Fail

2015

;

3

:

965

–

976

.

607

Lambrinou

E

,

Kalogirou

F

,

Lamnisos

D

,

Sourtzi

P

.

Effectiveness of heart failure management programmes with nurse-led discharge planning in reducing re-admissions: a systematic review and meta-analysis

.

Int J Nurs Stud

2012

;

49

:

610

–

624

.

608

Birks

EJ

,

Tansley

PD

,

Hardy

J

,

George

RS

,

Bowles

CT

,

Burke

M

,

Banner

NR

,

Khaghani

A

,

Yacoub

MH

.

Left ventricular assist device and drug therapy for the reversal of heart failure

.

N Engl J Med

2006

;

355

:

1873

–

1884

.

609

Dandel

M

,

Knosalla

C

,

Hetzer

R

.

Contribution of ventricular assist devices to the recovery of failing hearts: a review and the Berlin Heart Center Experience

.

Eur J Heart Fail

2014

;

16

:

248

–

263

.

610

Jorde

UP

,

Kushwaha

SS

,

Tatooles

AJ

,

Naka

Y

,

Bhat

G

,

Long

JW

,

Horstmanshof

DA

,

Kormos

RL

,

Teuteberg

JJ

,

Slaughter

MS

,

Birks

EJ

,

Farrar

DJ

,

Park

SJ

.

Results of the destination therapy post-food and drug administration approval study with a continuous flow left ventricular assist device: a prospective study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support)

.

J Am Coll Cardiol

2014

;

63

:

1751

–

1757

.

611

Khazanie

P

,

Rogers

JG

.

Patient selection for left ventricular assist devices

.

Congest Heart Fail

2011

;

17

:

227

–

234

.

612

Rose

EA

,

Gelijns

AC

,

Moskowitz

AJ

,

Heitjan

DF

,

Stevenson

LW

,

Dembitsky

W

,

Long

JW

,

Ascheim

DD

,

Tierney

AR

,

Levitan

RG

,

Watson

JT

,

Meier

P

,

Ronan

NS

,

Shapiro

PA

,

Lazar

RM

,

Miller

LW

,

Gupta

L

,

Frazier

OH

,

Desvigne-Nickens

P

,

Oz

MC

,

Poirier

VL

.

Long-term use of a left ventricular assist device for end-stage heart failure

.

N Engl J Med

2001

;

345

:

1435

–

1443

.

613

Slaughter

MS

,

Rogers

JG

,

Milano

C a

,

Russell

SD

,

Conte

J V

,

Feldman

D

,

Sun

B

,

Tatooles

AJ

,

Delgado

RM

,

Long

JW

,

Wozniak

TC

,

Ghumman

W

,

Farrar

DJ

,

Frazier

OH

.

Advanced heart failure treated with continuous-flow left ventricular assist device

.

N Engl J Med

2009

;

361

:

2241

–

2251

.

614

Banner

NR

,

Bonser

RS

,

Clark

AL

,

Clark

S

,

Cowburn

PJ

,

Gardner

RS

,

Kalra

PR

,

McDonagh

T

,

Rogers

CA

,

Swan

L

,

Parameshwar

J

,

Thomas

HL

,

Williams

SG

.

UK guidelines for referral and assessment of adults for heart transplantation

.

Heart

2011

;

97

:

1520

–

1527

.

615

Mehra

M

,

Kobashigawa

J

,

Starling

R

,

Russell

S

,

Uber

P

,

Parameshwar

J

,

Mohacsi

P

,

Augustine

S

,

Aaronson

K

,

Barr

M

.

Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006

.

J Heart Lung Transplant

2006

;

25

:

1024

–

1042

.

616

Mehra

MR

,

Canter

CE

,

Hannan

MM

,

Semigran

MJ

,

Uber

PA

,

Baran

DA

,

Danziger-Isakov

L

,

Kirklin

JK

,

Kirk

R

,

Kushwaha

SS

,

Lund

LH

,

Potena

L

,

Ross

HJ

,

Taylor

DO

,

Verschuuren

EAM

,

Zuckermann

A

.

The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update

.

J Heart Lung Transplant

2016

;

35

:

1

–

23

.

617

McDonagh

TA

,

Gardner

RS

,

Lainscak

M

,

Nielsen

OW

,

Parissis

J

,

Filippatos

G

,

Anker

SD

.

Heart failure association of the European Society of Cardiology specialist heart failure curriculum

.

Eur J Heart Fail

2014

;

16

:

151

–

162

.

618

O'Connor

CM

,

Whellan

DJ

,

Lee

KL

,

Keteyian

SJ

,

Cooper

LS

,

Ellis

SJ

,

Leifer

ES

,

Kraus

WE

,

Kitzman

DW

,

Blumenthal

JA

,

Rendall

DS

,

Miller

NH

,

Fleg

JL

,

Schulman

KA

,

McKelvie

RS

,

Zannad

F

,

Piña

IL

,

HF-ACTION Investigators

.

Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial

.

JAMA

2009

;

301

:

1439

–

1450

.

619

Taylor

RS

,

Sagar

VA

,

Davies

EJ

,

Briscoe

S

,

Coats

AJ

,

Dalal

H

,

Lough

F

,

Rees

K

,

Singh

S

.

Exercise-based rehabilitation for heart failure

.

Cochrane Database Syst Rev

2014

;

4

:

CD003331

.

620

Nolte

K

,

Herrmann-Lingen

C

,

Wachter

R

,

Gelbrich

G

,

Dungen

H-D

,

Duvinage

A

,

Hoischen

N

,

Von Oehsen

K

,

Schwarz

S

,

Hasenfuss

G

,

Halle

M

,

Pieske

B

,

Edelmann

F

.

Effects of exercise training on different quality of life dimensions in heart failure with preserved ejection fraction: the Ex-DHF-P trial

.

Eur J Prev Cardiol

2015

;

22

:

582

–

593

.

621

Ismail

H

,

McFarlane

JR

,

Nojoumian

AH

,

Dieberg

G

,

Smart

NA

.

Clinical outcomes and cardiovascular responses to different exercise training intensities in patients with heart failure: a systematic review and meta-analysis

.

JACC Heart Fail

2013

;

1

:

514

–

522

.

622

Phillips

CO

,

Wright

SM

,

Kern

DE

,

Singa

RM

,

Shepperd

S

,

Rubin

HR

.

Comprehensive discharge planning with postdischarge support for older patients with congestive heart failure: a meta-analysis

.

JAMA

2004

;

291

:

1358

–

1367

.

623

Stewart

S

,

Vandenbroek

AJ

,

Pearson

S

,

Horowitz

JD

.

Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure

.

Arch Intern Med

1999

;

159

:

257

–

261

.

624

McAlister

FA

,

Stewart

S

,

Ferrua

S

,

McMurray

JJ

.

Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials

.

J Am Coll Cardiol

2004

;

44

:

810

–

819

.

625

Feltner

C

,

Jones

CD

,

Cené

CW

,

Zheng

Z-J

,

Sueta

CA

,

Coker-Schwimmer

EJLL

,

Arvanitis

M

,

Lohr

KN

,

Middleton

JC

,

Jonas

DE

.

Transitional care interventions to prevent readmissions for persons with heart failure: a systematic review and meta-analysis

.

Ann Intern Med

2014

;

160

:

774

–

784

.

626

Schou

M

,

Gustafsson

F

,

Videbaek

L

,

Tuxen

C

,

Keller

N

,

Handberg

J

,

Sejr Knudsen

A

,

Espersen

G

,

Markenvard

J

,

Egstrup

K

,

Ulriksen

H

,

Hildebrandt

PR

.

Extended heart failure clinic follow-up in low-risk patients: a randomized clinical trial (NorthStar)

.

Eur Heart J

2013

;

34

:

432

–

442

.

627

Luttik

MLA

,

Jaarsma

T

,

van Geel

PP

,

Brons

M

,

Hillege

HL

,

Hoes

AW

,

de Jong

R

,

Linssen

G

,

Lok

DJA

,

Berge

M

,

van Veldhuisen

DJ

.

Long-term follow-up in optimally treated and stable heart failure patients: primary care vs. heart failure clinic. Results of the COACH-2 study

.

Eur J Heart Fail

2014

;

16

:

1241

–

1248

.

628

Abraham

WT

,

Adamson

PB

,

Bourge

RC

,

Aaron

MF

,

Costanzo

MR

,

Stevenson

LW

,

Strickland

W

,

Neelagaru

S

,

Raval

N

,

Krueger

S

,

Weiner

S

,

Shavelle

D

,

Jeffries

B

,

Yadav

JS

.

Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial

.

Lancet

2011

;

377

:

658

–

666

.

629

Abraham

WT

,

Stevenson

LW

,

Bourge

RC

,

Lindenfeld

JA

,

Bauman

JG

,

Adamson

PB

.

Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial

.

Lancet

2016

;

387

:

453

–

461

.

630

Hindricks

G

,

Taborsky

M

,

Glikson

M

,

Heinrich

U

,

Schumacher

B

,

Katz

A

,

Brachmann

J

,

Lewalter

T

,

Goette

A

,

Block

M

,

Kautzner

J

,

Sack

S

,

Husser

D

,

Piorkowski

C

,

Søgaard

P

.

Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial

.

Lancet

2014

;

384

:

583

–

590

.

631

Mueller

C

,

Christ

M

,

Cowie

M

,

Cullen

L

,

Maisel

AS

,

Masip

J

,

Miro

O

,

McMurray

J

,

Peacock

FW

,

Price

S

,

DiSomma

S

,

Bueno

H

,

Zeymer

U

,

Mebazaa

A

.

European Society of Cardiology-Acute Cardiovascular Care Association position paper on acute heart failure: a call for interdisciplinary care

.

Eur Heart J Acute Cardiovasc Care

2015 Jun 29. pii: 2048872615593279 [Epub ahead of print]

.