2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC

Classes of recommendations

Table 2

Levels of evidence

The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. Their declarations of interest were reviewed according to the ESC declaration of interest rules and can be found on the ESC website (http://www.escardio.org/guidelines). This process ensures transparency and prevents potential biases in the development and review processes. Any changes in declarations of interest that arise during the writing period were notified to the ESC and updated. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry.

The ESC CPG supervises and coordinates the preparation of new Guidelines. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG for publication in the European Heart Journal. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.

The task of developing ESC Guidelines also includes the creation of educational tools and implementation programmes for the recommendations including condensed pocket guideline versions, summary slides, booklets with essential messages, summary cards for non-specialists, and an electronic version for digital applications (smartphones, etc.). These versions are abridged and thus, for more detailed information, the user should always access the full text version of the Guidelines, which is freely available via the ESC website and hosted on the EHJ website. The National Cardiac Societies of the ESC are encouraged to endorse, adopt, translate, and implement all ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.

Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies. However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient or the patient’s caregiver where appropriate and/or necessary. It is also the health professional’s responsibility to verify the rules and regulations applicable in each country to drugs and devices at the time of prescription.

2 Introduction

Atrial fibrillation (AF) poses significant burden to patients, physicians, and healthcare systems globally. Substantial research efforts and resources are being directed towards gaining detailed information about the mechanisms underlying AF, its natural course and effective treatments (see also the ESC Textbook of Cardiovascular Medicine: CardioMed) and new evidence is continuously generated and published.

The complexity of AF requires a multifaceted, holistic, and multidisciplinary approach to the management of AF patients, with their active involvement in partnership with clinicians. Streamlining the care of patients with AF in daily clinical practice is a challenging but essential requirement for effective management of AF. In recent years, substantial progress has been made in the detection of AF and its management, and new evidence is timely integrated in this third edition of the ESC guidelines on AF. The 2016 ESC AF Guidelines introduced the concept of the five domains to facilitate an integrated structured approach to AF care and promote consistent, guideline-adherent management for all patients. The Atrial Fibrillation Better Care (ABC) approach in the 2020 ESC AF Guidelines is a continuum of this approach, with the goal to further improve the structured management of AF patients, promote patient values, and finally improve patient outcomes.

Reflecting the multidisciplinary input into the management of patients with AF and interpretation of new evidence, the Task Force includes cardiologists with varying subspecialty expertise, cardiac surgeons, methodologists, and specialist nurses amongst its members.

Further to adhering to the standards for generating recommendations that are common to all ESC guidelines (see preamble), this Task Force discussed each draft recommendation during web-based conference calls dedicated to specific chapters, followed by consensus modifications and an online vote on each recommendation. Only recommendations that were supported by at least 75% of the Task Force members were included in the Guidelines.

2.1 What is new in the 2020 Guidelines?

New recommendations

AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; CCS = chronic coronary syndrome; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female); CrCl = creatinine clearance; ECG = electrocardiogram; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; HCM = hypertrophic cardiomyopathy; i.v. = intravenous; LA = left atrium/atrial; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; OSA = obstructive sleep apnoea; PCI = percutaneous coronary intervention; PRO = patient-reported outcome; PVI = pulmonary vein isolation; QTc = corrected QT interval; TOE = transoesophageal echocardiography; VKA = vitamin K antagonist therapy.

^aClass of recommendation.

Changes in the recommendations

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; CTI = cavotricuspid isthmus; HFrEF = heart failure with reduced ejection fraction; ICH = intracranial haemorrhage; INR = international normalized ratio; LV = left ventricular; LVEF = left ventricular ejection fraction; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant or oral anticoagulation; PVI = pulmonary vein isolation; TTR = time in therapeutic range; VKA = vitamin K antagonist.

^aClass of recommendation.

3 Definition and diagnosis of atrial fibrillation

3.1 Definition

Table 3

Definition of atrial fibrillation

	Definition
AF	A supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. Electrocardiographic characteristics of AF include: Irregularly irregular R-R intervals (when atrioventricular conduction is not impaired), Absence of distinct repeating P waves, and Irregular atrial activations.
	Currently used terms
Clinical AF	Symptomatic or asymptomatic AF that is documented by surface ECG. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 seconds, or entire 12-lead ECG.¹^,²
AHRE, subclinical AF	Refers to individuals without symptoms attributable to AF, in whom clinical AF is NOT previously detected (that is, there is no surface ECG tracing of AF), see also section 3.3. AHRE − events fulfilling programmed or specified criteria for AHRE that are detected by CIEDs with an atrial lead allowing automated continuous monitoring of atrial rhythm and tracings storage. CIED-recorded AHRE need to be visually inspected because some AHRE may be electrical artefacts/false positives. Subclinical AF includes AHRE confirmed to be AF, AFL, or an AT, or AF episodes detected by insertable cardiac monitor or wearable monitor and confirmed by visually reviewed intracardiac electrograms or ECG-recorded rhythm.
Device-programmed rate criterion for AHRE is ≥175 bpm, whereas there is no specific rate limit for subclinical AF. The criterion for AHRE duration is usually set at ≥5 min (mainly to reduce the inclusion of artefacts), whereas a wide range of subclinical AF duration cut-offs (from 10 − 20 seconds to >24 hours) is reported in studies of the association of subclinical AF with thromboembolism. The reported duration refers to either the longest single episode or, more commonly, total duration of AHRE/subclinical AF during the specified monitoring period. Although not completely identical, the terms AHRE and subclinical AF are often used interchangeably (in this document the amalgamated term AHRE/subclinical AF will be used for practicality).^3–5 Whereas a large body of high-quality evidence from RCTs informing the management of AF patients pertains exclusively to ‘clinical’ AF (that is, the ECG documentation of AF was a mandatory inclusion criterion in those RCTs), data on optimal management of AHRE and subclinical AF are lacking. For this reason, AF is currently described as either ‘clinical’ or ‘AHRE/subclinical’, until the results of several ongoing RCTs expected to inform the management of AHRE and ‘subclinical’ AF are available.

	Definition
AF	A supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. Electrocardiographic characteristics of AF include: Irregularly irregular R-R intervals (when atrioventricular conduction is not impaired), Absence of distinct repeating P waves, and Irregular atrial activations.
	Currently used terms
Clinical AF	Symptomatic or asymptomatic AF that is documented by surface ECG. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 seconds, or entire 12-lead ECG.¹^,²
AHRE, subclinical AF	Refers to individuals without symptoms attributable to AF, in whom clinical AF is NOT previously detected (that is, there is no surface ECG tracing of AF), see also section 3.3. AHRE − events fulfilling programmed or specified criteria for AHRE that are detected by CIEDs with an atrial lead allowing automated continuous monitoring of atrial rhythm and tracings storage. CIED-recorded AHRE need to be visually inspected because some AHRE may be electrical artefacts/false positives. Subclinical AF includes AHRE confirmed to be AF, AFL, or an AT, or AF episodes detected by insertable cardiac monitor or wearable monitor and confirmed by visually reviewed intracardiac electrograms or ECG-recorded rhythm.
Device-programmed rate criterion for AHRE is ≥175 bpm, whereas there is no specific rate limit for subclinical AF. The criterion for AHRE duration is usually set at ≥5 min (mainly to reduce the inclusion of artefacts), whereas a wide range of subclinical AF duration cut-offs (from 10 − 20 seconds to >24 hours) is reported in studies of the association of subclinical AF with thromboembolism. The reported duration refers to either the longest single episode or, more commonly, total duration of AHRE/subclinical AF during the specified monitoring period. Although not completely identical, the terms AHRE and subclinical AF are often used interchangeably (in this document the amalgamated term AHRE/subclinical AF will be used for practicality).^3–5 Whereas a large body of high-quality evidence from RCTs informing the management of AF patients pertains exclusively to ‘clinical’ AF (that is, the ECG documentation of AF was a mandatory inclusion criterion in those RCTs), data on optimal management of AHRE and subclinical AF are lacking. For this reason, AF is currently described as either ‘clinical’ or ‘AHRE/subclinical’, until the results of several ongoing RCTs expected to inform the management of AHRE and ‘subclinical’ AF are available.

AHRE = atrial high-rate episode; AF = atrial fibrillation; ECG = electrocardiogram; AFL = atrial flutter; AT = atrial tachycardia; bpm = beats per minute; CIED = cardiac implantable electronic device; ECG = electrocardiogram; RCT = randomized controlled trial.

Table 3

Definition of atrial fibrillation

	Definition
AF	A supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. Electrocardiographic characteristics of AF include: Irregularly irregular R-R intervals (when atrioventricular conduction is not impaired), Absence of distinct repeating P waves, and Irregular atrial activations.
	Currently used terms
Clinical AF	Symptomatic or asymptomatic AF that is documented by surface ECG. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 seconds, or entire 12-lead ECG.¹^,²
AHRE, subclinical AF	Refers to individuals without symptoms attributable to AF, in whom clinical AF is NOT previously detected (that is, there is no surface ECG tracing of AF), see also section 3.3. AHRE − events fulfilling programmed or specified criteria for AHRE that are detected by CIEDs with an atrial lead allowing automated continuous monitoring of atrial rhythm and tracings storage. CIED-recorded AHRE need to be visually inspected because some AHRE may be electrical artefacts/false positives. Subclinical AF includes AHRE confirmed to be AF, AFL, or an AT, or AF episodes detected by insertable cardiac monitor or wearable monitor and confirmed by visually reviewed intracardiac electrograms or ECG-recorded rhythm.
Device-programmed rate criterion for AHRE is ≥175 bpm, whereas there is no specific rate limit for subclinical AF. The criterion for AHRE duration is usually set at ≥5 min (mainly to reduce the inclusion of artefacts), whereas a wide range of subclinical AF duration cut-offs (from 10 − 20 seconds to >24 hours) is reported in studies of the association of subclinical AF with thromboembolism. The reported duration refers to either the longest single episode or, more commonly, total duration of AHRE/subclinical AF during the specified monitoring period. Although not completely identical, the terms AHRE and subclinical AF are often used interchangeably (in this document the amalgamated term AHRE/subclinical AF will be used for practicality).^3–5 Whereas a large body of high-quality evidence from RCTs informing the management of AF patients pertains exclusively to ‘clinical’ AF (that is, the ECG documentation of AF was a mandatory inclusion criterion in those RCTs), data on optimal management of AHRE and subclinical AF are lacking. For this reason, AF is currently described as either ‘clinical’ or ‘AHRE/subclinical’, until the results of several ongoing RCTs expected to inform the management of AHRE and ‘subclinical’ AF are available.

	Definition
AF	A supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. Electrocardiographic characteristics of AF include: Irregularly irregular R-R intervals (when atrioventricular conduction is not impaired), Absence of distinct repeating P waves, and Irregular atrial activations.
	Currently used terms
Clinical AF	Symptomatic or asymptomatic AF that is documented by surface ECG. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 seconds, or entire 12-lead ECG.¹^,²
AHRE, subclinical AF	Refers to individuals without symptoms attributable to AF, in whom clinical AF is NOT previously detected (that is, there is no surface ECG tracing of AF), see also section 3.3. AHRE − events fulfilling programmed or specified criteria for AHRE that are detected by CIEDs with an atrial lead allowing automated continuous monitoring of atrial rhythm and tracings storage. CIED-recorded AHRE need to be visually inspected because some AHRE may be electrical artefacts/false positives. Subclinical AF includes AHRE confirmed to be AF, AFL, or an AT, or AF episodes detected by insertable cardiac monitor or wearable monitor and confirmed by visually reviewed intracardiac electrograms or ECG-recorded rhythm.
Device-programmed rate criterion for AHRE is ≥175 bpm, whereas there is no specific rate limit for subclinical AF. The criterion for AHRE duration is usually set at ≥5 min (mainly to reduce the inclusion of artefacts), whereas a wide range of subclinical AF duration cut-offs (from 10 − 20 seconds to >24 hours) is reported in studies of the association of subclinical AF with thromboembolism. The reported duration refers to either the longest single episode or, more commonly, total duration of AHRE/subclinical AF during the specified monitoring period. Although not completely identical, the terms AHRE and subclinical AF are often used interchangeably (in this document the amalgamated term AHRE/subclinical AF will be used for practicality).^3–5 Whereas a large body of high-quality evidence from RCTs informing the management of AF patients pertains exclusively to ‘clinical’ AF (that is, the ECG documentation of AF was a mandatory inclusion criterion in those RCTs), data on optimal management of AHRE and subclinical AF are lacking. For this reason, AF is currently described as either ‘clinical’ or ‘AHRE/subclinical’, until the results of several ongoing RCTs expected to inform the management of AHRE and ‘subclinical’ AF are available.

AHRE = atrial high-rate episode; AF = atrial fibrillation; ECG = electrocardiogram; AFL = atrial flutter; AT = atrial tachycardia; bpm = beats per minute; CIED = cardiac implantable electronic device; ECG = electrocardiogram; RCT = randomized controlled trial.

3.2 Diagnostic criteria for atrial fibrillation

The diagnosis of AF requires rhythm documentation with an electrocardiogram (ECG) tracing showing AF. By convention, an episode lasting at least 30 s is diagnostic for clinical AF.⁶

Recommendations for diagnosis of AF

AF = atrial fibrillation; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

3.3 Diagnosis of atrial high-rate episodes/subclinical atrial fibrillation

Various implanted devices and wearable monitors allow detection of atrial high-rate episodes (AHRE) /subclinical AF (Figure 1).³ Owing to a short monitoring, detection of AHRE/subclinical AF via external ECG is less likely.⁷

Figure 1

Diagnosis of AHRE/subclinical AF. CIEDs with an atrial lead can monitor atrial rhythm and store the tracings. ICMs have no intracardiac leads but continuously monitor cardiac electrical activity by recording and analysing a single-lead bipolar surface ECG based on a specific algorithm. Left-bottom image: pacemaker with a right atrial lead, and a ventricular lead in the right ventricular apex. In addition to pacing at either site, these leads can sense activity in the respective cardiac chamber. The device can also detect pre-programmed events, such as AHRE. Right-bottom image: subcutaneous ICM: these devices have no intra-cardiac leads and essentially record a single, bipolar, surface ECG, with inbuilt algorithms for detection of AHRE or AF. AF = atrial fibrillation; AHRE = atrial high rate episode; CIED = cardiac implantable electronic device; ECG = electrocardiogram; ICM = insertable cardiac monitor; RCT = randomized clinical trial.

When AHRE/subclinical AF is detected by a device/wearable, inspection of the stored electrograms/ECG rhythm strips is recommended to exclude artefacts or other causes of inappropriate detection.⁸^,⁹

4 Epidemiology

Worldwide, AF is the most common sustained cardiac arrhythmia in adults¹⁰ (Figure 2, upper panel). AF is associated with substantial morbidity and mortality, thus portending significant burden to patients, societal health, and health economy (Figure 2, lower panel) (Supplementary section 1).

Figure 2

Epidemiology of AF: prevalence (upper panel)^10–20; and lifetime risk and projected rise in the incidence and prevalence (lower panel).¹⁹^,^21–34 AF = atrial fibrillation; AFL = atrial flutter; BP = blood pressure; CI = confidence interval; EU = European Union. ^aSmoking, alcohol consumption, body mass index, BP, diabetes mellitus (type 1 or 2), and history of myocardial infarction or heart failure. ^bRisk profile: optimal − all risk factors are negative or within the normal range; borderline − no elevated risk factors but >1 borderline risk factor; elevated − >1 elevated risk factor.

The currently estimated prevalence of AF in adults is between 2% and 4%,¹⁰ and a 2.3-fold rise¹¹ is expected,¹²^,¹³ owing to extended longevity in the general population and intensifying search for undiagnosed AF.¹⁵ Increasing age is a prominent AF risk factor, but increasing burden of other comorbidities including hypertension, diabetes mellitus, heart failure (HF), coronary artery disease (CAD), chronic kidney disease (CKD),²¹ obesity, and obstructive sleep apnoea (OSA) is also important;^22–26 modifiable risk factors are potent contributors to AF development and progression²⁷^,²⁸ (Figure 3). The age-adjusted incidence, prevalence, and lifetime risk of AF are lower in women vs. men and in non-Caucasian vs. Caucasian cohorts.¹⁰^,^14–20 A previous lifetime AF risk estimate of 1 in 4 individuals²⁹^,³⁰ was recently revised to 1 in 3 individuals of European ancestry at index age of 55 years.³¹^,³² The AF lifetime risk depends on age, genetic, and (sub)clinical factors.¹⁰^,³³^,³⁴ The observed impact of clinical risk factor burden/multiple comorbidity on AF risk (Figure 3, lower panel³¹) suggests that an early intervention and modifiable risk factor control could reduce incident AF.

Summary of risk factors for incident AF10,22,33,35–72 (Supplementary Table 1 for full list). AF = atrial fibrillation; COPD = chronic obstructive pulmonary disease.

Figure 3

Summary of risk factors for incident AF¹⁰^,²²^,³³^,^35–72 (Supplementary Table 1 for full list). AF = atrial fibrillation; COPD = chronic obstructive pulmonary disease.

4.1 Prediction of incident atrial fibrillation

Identifying individuals at higher risk of developing AF in the community could facilitate targeting of preventive interventions and screening programmes for early AF detection, for example in high-risk subgroups such as post-stroke patients.⁷³ Various predictive scores for new-onset AF have been proposed (Supplementary Table 2), but none has been widely used in clinical practice.

4.2 Pathophysiology of atrial fibrillation

A complex interplay of triggers, perpetuators, and substrate development eventually resulting in AF occurrence is shown in Supplementary Figure 1.

5 Clinical features of atrial fibrillation

Clinical presentation of AF and AF-related outcomes are shown in Figure 4 (see also Supplementary section 2 and Supplementary Box 1).

Clinical presentation of AF and AF-related outcomes.10,31,74–140 AF = atrial fibrillation; HF = heart failure; HR = Hazard Ratio; LV = left ventricle; MI = myocardial infarction; QoL = quality of life. Patients with AF may have various symptoms92,108,109,128,131 but 50 − 87% are initially asymptomatic,75,82,88,111,117,120,125,127 with possibly a less favourable prognosis.79,82,87,88,117,119,127,134,139 First-onset AF symptoms are less well studied,92,105,108,109,,127 may change with treatment119 and AF recurrences are commonly asymptomatic.113Stroke/systolic embolism: annual AF-related stroke risk in AF patients depends on comorbidities.78,84,85,91,106,112 Cardioembolic strokes associated with AF are usually severe, highly recurrent, often fatal, or with permanent disability.10,83,115 In a population-based registry, patients with new-onset AF also had increased rates of systemic embolism.89 Left ventricular (LV) dysfunction and HF: multiple AF-associated mechanisms/myocardial alterations may lead to LV dysfunction and HF,102,138 resulting in a high prevalence and incidence of HF among AF patients. Sharing common risk factors, AF and HF often coexist, or may precipitate/exacerbate each other, resulting in significantly greater mortality than either condition alone.140Hospitalization: approximately 30% of AF patients have at least one, and 10% have ≥2, hospital admissions annually,99,110,129 being twice as likely to be hospitalized as age- and sex-matched non-AF individuals (37.5% vs. 17.5%, respectively).98 In a nationwide cohort, AF was the main cause for admission in 14% of hospitalized patients but their in-hospital mortality was <1%.101 The most common reasons for hospitalization of AF patients were cardiovascular disorders (49%), non-cardiovascular causes (43%) and bleeding (8%).129Quality of life (QoL) and functional status: >60% of AF patients have significantly impaired QoL/exercise tolerance,81,88,136 but only 17% have disabling symptoms.88 QoL is significantly lower in women,81,107,114,124 young individuals, and those with comorbidities.118 AF burden100 may also affect QoL, but only psychological functioning consistently predicted symptoms and QoL.136 Patients with AF more often developed anxiety disorders,126 had a higher burden of depressive symptoms,123 and poorer QoL with a Distressed personality type (Type D).103 Key symptom and QoL drivers are important to identify optimal AF treatment. It is also important to confirm that symptoms are related to AF or, if absent, to exclude a subconscious adaptation to living with suboptimal physical capacity by asking for breathlessness or fatigue on exertion and recording possible improvements after cardioversion. Cognitive impairment/dementia: AF may lead to cognitive impairment ranging from mild dysfunction to dementia97,104,141 via clinically apparent or silent stroke or insufficiently understood stroke-independent pathways.94,96,97,122 Magnetic resonance imaging (MRI) studies have shown that AF is associated with a greater than twofold increase in the odds of having silent cerebral ischaemia.90,121,142 A recent expert consensus paper summarized the available data.86Mortality: AF is independently associated with a twofold increased risk of all-cause mortality in women and a 1.5-fold increase in men,77,80,130,137 with an overall 3.5-fold mortality risk increase.31 Whereas the mechanistic explanation for this association is multifaceted, associated comorbidities play an important role.95 In a recent study, the most common causes of death among AF patients were HF (14.5%), malignancy (23.1%), and infection/sepsis (17.3%), whereas stroke-related mortality was only 6.5%.76 These and other recent data indicate that, in addition to anticoagulation and HF treatment, comorbid conditions need to be actively treated in the endeavour to reduce AF-related mortality.77,93,116,133

Figure 4

Clinical presentation of AF and AF-related outcomes.¹⁰^,³¹^,^74–140 AF = atrial fibrillation; HF = heart failure; HR = Hazard Ratio; LV = left ventricle; MI = myocardial infarction; QoL = quality of life. Patients with AF may have various symptoms⁹²^,¹⁰⁸^,¹⁰⁹^,¹²⁸^,¹³¹ but 50 − 87% are initially asymptomatic,⁷⁵^,⁸²^,⁸⁸^,¹¹¹^,¹¹⁷^,¹²⁰^,¹²⁵^,¹²⁷ with possibly a less favourable prognosis.⁷⁹^,⁸²^,⁸⁷^,⁸⁸^,¹¹⁷^,¹¹⁹^,¹²⁷^,¹³⁴^,¹³⁹ First-onset AF symptoms are less well studied,⁹²^,¹⁰⁵^,¹⁰⁸^,¹⁰⁹^,,¹²⁷ may change with treatment¹¹⁹ and AF recurrences are commonly asymptomatic.¹¹³^,Stroke/systolic embolism: annual AF-related stroke risk in AF patients depends on comorbidities.⁷⁸^,⁸⁴^,⁸⁵^,⁹¹^,¹⁰⁶^,¹¹² Cardioembolic strokes associated with AF are usually severe, highly recurrent, often fatal, or with permanent disability.¹⁰^,⁸³^,¹¹⁵ In a population-based registry, patients with new-onset AF also had increased rates of systemic embolism.⁸⁹^, Left ventricular (LV) dysfunction and HF: multiple AF-associated mechanisms/myocardial alterations may lead to LV dysfunction and HF,¹⁰²^,¹³⁸ resulting in a high prevalence and incidence of HF among AF patients. Sharing common risk factors, AF and HF often coexist, or may precipitate/exacerbate each other, resulting in significantly greater mortality than either condition alone.¹⁴⁰^,Hospitalization: approximately 30% of AF patients have at least one, and 10% have ≥2, hospital admissions annually,⁹⁹^,¹¹⁰^,¹²⁹ being twice as likely to be hospitalized as age- and sex-matched non-AF individuals (37.5% vs. 17.5%, respectively).⁹⁸ In a nationwide cohort, AF was the main cause for admission in 14% of hospitalized patients but their in-hospital mortality was <1%.¹⁰¹ The most common reasons for hospitalization of AF patients were cardiovascular disorders (49%), non-cardiovascular causes (43%) and bleeding (8%).¹²⁹^,Quality of life (QoL) and functional status: >60% of AF patients have significantly impaired QoL/exercise tolerance,⁸¹^,⁸⁸^,¹³⁶ but only 17% have disabling symptoms.⁸⁸ QoL is significantly lower in women,⁸¹^,¹⁰⁷^,¹¹⁴^,¹²⁴ young individuals, and those with comorbidities.¹¹⁸ AF burden¹⁰⁰ may also affect QoL, but only psychological functioning consistently predicted symptoms and QoL.¹³⁶ Patients with AF more often developed anxiety disorders,¹²⁶ had a higher burden of depressive symptoms,¹²³ and poorer QoL with a Distressed personality type (Type D).¹⁰³ Key symptom and QoL drivers are important to identify optimal AF treatment. It is also important to confirm that symptoms are related to AF or, if absent, to exclude a subconscious adaptation to living with suboptimal physical capacity by asking for breathlessness or fatigue on exertion and recording possible improvements after cardioversion. Cognitive impairment/dementia: AF may lead to cognitive impairment ranging from mild dysfunction to dementia⁹⁷^,¹⁰⁴^,¹⁴¹ via clinically apparent or silent stroke or insufficiently understood stroke-independent pathways.⁹⁴^,⁹⁶^,⁹⁷^,¹²² Magnetic resonance imaging (MRI) studies have shown that AF is associated with a greater than twofold increase in the odds of having silent cerebral ischaemia.⁹⁰^,¹²¹^,¹⁴² A recent expert consensus paper summarized the available data.⁸⁶^,Mortality: AF is independently associated with a twofold increased risk of all-cause mortality in women and a 1.5-fold increase in men,⁷⁷^,⁸⁰^,¹³⁰^,¹³⁷ with an overall 3.5-fold mortality risk increase.³¹ Whereas the mechanistic explanation for this association is multifaceted, associated comorbidities play an important role.⁹⁵ In a recent study, the most common causes of death among AF patients were HF (14.5%), malignancy (23.1%), and infection/sepsis (17.3%), whereas stroke-related mortality was only 6.5%.⁷⁶ These and other recent data indicate that, in addition to anticoagulation and HF treatment, comorbid conditions need to be actively treated in the endeavour to reduce AF-related mortality.⁷⁷^,⁹³^,¹¹⁶^,¹³³

6 Atrial fibrillation subtypes, burden, and progression

6.1 Classification of atrial fibrillation

Different AF classifications have been proposed but, traditionally, five patterns of AF are distinguished, based on presentation, duration, and spontaneous termination of AF episodes (Table 4).¹⁴³

Table 4

Classification of AF

AF pattern

Definition

First diagnosed

AF not diagnosed before, irrespective of its duration or the presence/severity of AF-related symptoms.

Paroxysmal

AF that terminates spontaneously or with intervention within 7 days of onset.

Persistent

AF that is continuously sustained beyond 7 days, including episodes terminated by cardioversion (drugs or electrical cardioversion) after ≥7 days

Long-standing persistent

Continuous AF of >12 months’ duration when decided to adopt a rhythm control strategy.

Permanent

AF that is accepted by the patient and physician, and no further attempts to restore/maintain sinus rhythm will be undertaken. Permanent AF represents a therapeutic attitude of the patient and physician rather than an inherent pathophysiological attribute of AF, and the term should not be used in the context of a rhythm control strategy with antiarrhythmic drug therapy or AF ablation. Should a rhythm control strategy be adopted, the arrhythmia would be re-classified as ‘long-standing persistent AF’.

Terminology that should be abandoned

Lone AF

A historical descriptor. Increasing knowledge about the pathophysiology of AF shows that in every patient a cause is present. Hence, this term is potentially confusing and should be abandoned.¹⁴⁷

Valvular/non- valvular AF

Differentiates patients with moderate/severe mitral stenosis and those with mechanical prosthetic heart valve(s) from other patients with AF, but may be confusing¹⁴⁸ and should not be used.

Chronic AF

Has variable definitions and should not be used to describe populations of AF patients.

AF = atrial fibrillation.

Table 4

Classification of AF

AF pattern

Definition

First diagnosed

AF not diagnosed before, irrespective of its duration or the presence/severity of AF-related symptoms.

Paroxysmal

AF that terminates spontaneously or with intervention within 7 days of onset.

Persistent

AF that is continuously sustained beyond 7 days, including episodes terminated by cardioversion (drugs or electrical cardioversion) after ≥7 days

Long-standing persistent

Continuous AF of >12 months’ duration when decided to adopt a rhythm control strategy.

Permanent

AF that is accepted by the patient and physician, and no further attempts to restore/maintain sinus rhythm will be undertaken. Permanent AF represents a therapeutic attitude of the patient and physician rather than an inherent pathophysiological attribute of AF, and the term should not be used in the context of a rhythm control strategy with antiarrhythmic drug therapy or AF ablation. Should a rhythm control strategy be adopted, the arrhythmia would be re-classified as ‘long-standing persistent AF’.

Terminology that should be abandoned

Lone AF

A historical descriptor. Increasing knowledge about the pathophysiology of AF shows that in every patient a cause is present. Hence, this term is potentially confusing and should be abandoned.¹⁴⁷

Valvular/non- valvular AF

Differentiates patients with moderate/severe mitral stenosis and those with mechanical prosthetic heart valve(s) from other patients with AF, but may be confusing¹⁴⁸ and should not be used.

Chronic AF

Has variable definitions and should not be used to describe populations of AF patients.

AF = atrial fibrillation.

In patients experiencing both paroxysmal and persistent AF episodes, the more common type should be used for classification. However, clinically determined AF patterns do not correspond well to the AF burden measured by long-term ECG monitoring.^144–146

Other classifications of AF reflect the presence of symptoms (asymptomatic AF is diagnosed with an opportune 12-lead ECG or rhythm strip in asymptomatic patients) or underlying cause of AF (e.g. postoperative AF, see section 11.19). Classifying AF by underlying drivers could inform management, but the evidence in support of the clinical use of such classification is lacking (Supplementary Table 3). Terms that should no longer be used to describe AF are listed in Table 4.

Recommendations for AF management are not based on the temporal AF patterns, except for the restoration of sinus rhythm.¹⁴³^,¹⁴⁹^,¹⁵⁰ It is very unlikely that a simple but comprehensive AF classification will be proposed, given the multiplicity of factors relevant for its management, advances in AF monitoring, multiplicity of risk assessment tools, evolving treatments, and complexity of AF itself. Indeed, a paradigm shift from classification towards a structured characterization of AF, addressing specific domains with treatment and prognostic implications has been recently proposed.¹⁵¹ Such a scheme would streamline the assessment of AF patients at any healthcare level, thus facilitating communication among physicians, treatment decision making, and optimal management of AF patients, and should become a standard in clinical practice when reporting an AF case.

The proposed 4S-AF scheme (Stroke risk, Symptom severity, Severity of AF burden, Substrate severity) includes four AF-related domains (Figure 5).¹⁵¹ The currently used assessment tools/classifications pertinent to specific domains (e.g. stroke risk scores, symptom scores, clinical factors, imaging modalities, etc.) can be easily fitted in, but the 4S-AF has great potential for future refinements guided by advances in technology, and the most appropriate descriptors of AF domains are yet to be defined. Given the descriptors of AF included in the 4S-AF scheme, the structured characterization of AF patients using 4S-AF could also provide prognostic information, but the clinical utility and prognostic value of the 4S-AF scheme needs extensive validation in different AF cohorts and clinical settings.

4S-AF scheme as an example of structured characterization of AF.151 AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CT = computed tomography; EHRA = European Heart Rhythm Association; LA = left atrium; MRI = magnetic resonance imaging; QoL = quality of life; TOE = transoesophageal echocardiography; TTE = transthoracic echocardiography.

Figure 5

4S-AF scheme as an example of structured characterization of AF.¹⁵¹ AF = atrial fibrillation; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CT = computed tomography; EHRA = European Heart Rhythm Association; LA = left atrium; MRI = magnetic resonance imaging; QoL = quality of life; TOE = transoesophageal echocardiography; TTE = transthoracic echocardiography.

Recommendations for structured characterization of AF

AF = atrial fibrillation

a

Class of recommendation.

b

Level of evidence.

6.2 Definition and assessment of atrial fibrillation burden

The term ‘burden’ refers to various AF aspects (e.g. epidemiological, economic).¹⁴⁴ Regarding continuous device-based monitoring, ‘AF burden’ is currently defined as the overall time spent in AHRE/subclinical AF during a specified monitoring period (e.g. 1 day). Both the time in AF and the monitoring period should be acknowledged when reporting AF burden (most studies reported the maximum time spent in AF over a 24-h period), but optimal measures are yet to be determined.¹⁵² The term ‘AF burden’ is different from ‘burden of AF’, the latter referring to AF consequences.

Clinical AF burden is routinely determined by AF temporal pattern¹⁴⁶ (Table 4) and intermittent ECG monitoring,¹⁵³ neither corresponding well to the long-term ECG monitoring. The relationship of clinical AF burden with specific outcomes is not well characterized,¹⁵⁴ but may be associated with higher risk of incident HF¹⁵⁵ and all-cause mortality,¹⁵⁶ while the association with quality of life (QoL) is complex and data about cognitive impairment/dementia are lacking.⁸⁶ Recent randomized controlled trial (RCT) data consistently showed significantly lower residual thrombo-embolic risk among anticoagulated patients with paroxysmal vs. persistent AF,^156–159 whereas earlier trial-based¹⁶⁰ and observational data¹⁶¹^,¹⁶² are contradictory. Among non-anticoagulated patients, stroke risk was lower with paroxysmal than non-paroxysmal AF,¹⁵⁶ and a greater total AF burden (but not the longest AF episode) was independently associated with higher thrombo-embolic event rates.¹⁶³ Clinical AF burden may influence the response to rhythm control therapy.¹⁶⁴^,¹⁶⁵ The presence of >6 h of AF per week (especially when progressing to >24 h weekly) was associated with increased mortality, especially in women.¹⁶⁶

Available evidence on the association of AF burden with AF-related outcomes is insufficient to guide treatment and should not be a major factor in treatment decisions. Comprehensive management of modifiable cardiovascular risk factors/comorbidity reduces AF burden (section 10.3).

6.3 Atrial fibrillation progression

Transition from paroxysmal to non-paroxysmal AF (or from subclinical to clinical AF)¹⁵⁴^,^167–169 is often characterized by advancing atrial structural remodelling or worsening of atrial cardiomyopathy.¹⁷⁰^,¹⁷¹

Assessment of AF progression depends on duration of rhythm monitoring and underlying substrate.¹⁷²^,¹⁷³ Reported annual rates of paroxysmal AF progression range from <1% to 15% (up to 27 − 36% in studies with ≥10-year follow-up).¹⁶⁹^,¹⁷⁴ Risk factors for AF progression include age, HF, hypertension, CKD, chronic pulmonary diseases, diabetes mellitus, previous stroke, and left atrial (LA) size,¹⁶⁷ whereas the added predictive value of biomarkers is presently not well defined. Older age is associated with permanent AF,⁸²^,¹¹⁷^,¹⁵⁴ and various triggers may also play a role, with different progression patterns resulting from their interaction with substrate remodelling.¹⁷¹ Progression to persistent/permanent AF is associated with adverse cardiovascular events, hospitalizations, and death,¹⁶⁶ but it is unclear whether AF progression is a determinant of adverse prognosis or rather a marker of an underlying progressive disease/substrate.¹⁷⁵^,¹⁷⁶ The true impact of different therapeutic interventions at different disease stages on AF progression and associated outcomes is also less well defined.

6.4 Atrial cardiomyopathy: definition, classification, clinical implications, and diagnostic assessment

Important progress in understanding AF mechanisms and thrombogenicity reconsiders the role of atrial cardiomyopathy (i.e. atrial structural, architectural, contractile, or electrophysiological changes with potentially relevant clinical manifestations).¹⁷⁰

Clinical classification of atrial cardiomyopathy should be based on the atrial structure, morphology, electrical and mechanical function, and the diagnosis could be based on easily accessible parameters (e.g. aetiology, the prothrombotic state,¹⁷⁷ and abnormal LA volume/function).¹⁷⁸ Major clinical issues in AF (i.e. prevention of thrombo-embolic complications and AF progression) are influenced by atrial remodelling; and, importantly, AF is not only a risk factor for but also a marker of atrial cardiomyopathy, which could explain the lack of temporal relationship between detected AF and stroke.¹⁷⁹

The diagnostic algorithm for atrial cardiomyopathy should follow a stepwise approach, identifying risk factors for atrial cardiomyopathy,¹⁷⁰ atrial electrical and mechanical dysfunction,¹⁸⁰ and increased thrombotic risk.¹⁸¹ More data are needed to define prognostic and treatment implications of different atrial cardiomyopathy morphofunctional forms.

7 Screening for atrial fibrillation

Multiple factors (i.e. increasing AF prevalence, previously unknown AF detection in about 10% of all ischaemic strokes,⁴^,¹⁸² high prevalence of asymptomatic AF,¹¹⁷ potential to prevent AF-related strokes with appropriate treatment and increasing availability of AF detection tools) have fuelled international initiatives to implement screening for AF in clinical practice.¹⁷²

Asymptomatic clinical AF has been independently associated with increased risk of stroke and mortality compared with symptomatic AF.⁸²^,¹¹⁷^,¹²⁷^,¹⁸³ Data derived from studies of incidentally detected asymptomatic AF are the closest possible approximation of the risk of stroke and death in screen-detected AF subjects, because delaying treatment to discern a natural history would be unethical. Observational data suggest that screen-detected AF responds to treatment similarly to AF detected by routine care,¹⁸³ thus favouring AF screening.

Although AF fulfils many of the criteria for disease screening¹⁸⁴ (Supplementary Figure 2), RCT data to confirm the health benefits from screening for AF and inform the choice of optimal screening programmes and strategies for its implementation are scarce.¹⁸⁵^,¹⁸⁶ Advances in wearable technology will likely yield inexpensive and practical options for AF detection and AF burden assessment in the near future.

7.1 Screening tools

The systems used for AF screening are shown in Table 5 and Figure 6.¹⁷³^,¹⁸⁷

Figure 6

Systems used for AF screening. Pulse palpation, automated BP monitors, single-lead ECG devices, PPG devices, other sensors (using seismocardiography, accelerometers, and gyroscopes, etc.) used in applications for smartphones, wrist bands, and watches. Intermittent smartwatch detection of AF is possible through PPG or ECG recordings. Smartwatches and other ‘wearables’ can passively measure pulse rate from the wrist using an optical sensor for PPG and alerting the consumer of a pulse irregularity (based on a specific algorithm for AF detection analysing pulse irregularity and variability).¹⁷²^,¹⁷³^,^188–196 AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram; PPG = photoplethysmography.

Table 5

Sensitivity and specificity of various AF screening tools considering the 12-lead ECG as the gold standard¹⁷³

	Sensitivity	Specificity
Pulse taking²⁰³	87 − 97%	70 − 81%
Automated BP monitors^204–207	93 − 100%	86 − 92%
Single lead ECG^208–211	94 − 98%	76 − 95%
Smartphone apps¹⁸⁸^,¹⁸⁹^,¹⁹¹^,¹⁹⁵^,²¹²^,²¹³	91.5 − 98.5%	91.4 − 100%
Watches¹⁹⁶^,¹⁹⁸^,²¹³^,²¹⁴	97 − 99%	83 − 94%

	Sensitivity	Specificity
Pulse taking²⁰³	87 − 97%	70 − 81%
Automated BP monitors^204–207	93 − 100%	86 − 92%
Single lead ECG^208–211	94 − 98%	76 − 95%
Smartphone apps¹⁸⁸^,¹⁸⁹^,¹⁹¹^,¹⁹⁵^,²¹²^,²¹³	91.5 − 98.5%	91.4 − 100%
Watches¹⁹⁶^,¹⁹⁸^,²¹³^,²¹⁴	97 − 99%	83 − 94%

AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram.

Table 5

Sensitivity and specificity of various AF screening tools considering the 12-lead ECG as the gold standard¹⁷³

	Sensitivity	Specificity
Pulse taking²⁰³	87 − 97%	70 − 81%
Automated BP monitors^204–207	93 − 100%	86 − 92%
Single lead ECG^208–211	94 − 98%	76 − 95%
Smartphone apps¹⁸⁸^,¹⁸⁹^,¹⁹¹^,¹⁹⁵^,²¹²^,²¹³	91.5 − 98.5%	91.4 − 100%
Watches¹⁹⁶^,¹⁹⁸^,²¹³^,²¹⁴	97 − 99%	83 − 94%

	Sensitivity	Specificity
Pulse taking²⁰³	87 − 97%	70 − 81%
Automated BP monitors^204–207	93 − 100%	86 − 92%
Single lead ECG^208–211	94 − 98%	76 − 95%
Smartphone apps¹⁸⁸^,¹⁸⁹^,¹⁹¹^,¹⁹⁵^,²¹²^,²¹³	91.5 − 98.5%	91.4 − 100%
Watches¹⁹⁶^,¹⁹⁸^,²¹³^,²¹⁴	97 − 99%	83 − 94%

AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram.

Mobile health technologies are rapidly developing for AF detection and other purposes (>100 000 mHealth apps and ≥400 wearable activity monitors are currently available).¹⁹⁷ Caution is needed in their clinical use, as many are not clinically validated. Several studies evaluated AF detection using smartwatches,¹⁹⁸^,¹⁹⁹ thus opening new perspectives for AF detection targeting specific populations at risk. Machine learning and artificial intelligence may be capable of identifying individuals with previous AF episodes from a sinus rhythm ECG recording,²⁰⁰ which would be a major technological breakthrough in AF detection.²⁰⁰

The Apple Heart study²⁰¹ included 419 297 self-enrolled smartwatch app users (mean age 40 years) in the United States of America (USA), of whom 0.5% received an irregular pulse notification (0.15% of those aged <40 years, 3.2% among those aged >65 years). Subsequent (notification-triggered) 1-week ECG patch monitoring revealed AF in 34% of monitored participants. The Huawei Heart study²⁰² included 187 912 individuals (mean age 35 years, 86.7% male), of whom 0.23% received a ‘suspected AF’ notification. Of those effectively followed up, 87.0% were confirmed as having AF, with the positive predictive value of photoplethysmography signals being 91.6% [95% confidence interval (CI) 91.5 − 91.8]. Of those with identified AF, 95.1% entered an integrated AF management programme using a mobile AF App (mAFA).

When AF is detected by a screening tool, including mobile or wearable devices, a single-lead ECG tracing of ≥30 s or 12-lead ECG showing AF analysed by a physician with expertise in ECG rhythm interpretation is necessary to establish a definitive diagnosis of AF (devices capable of ECG recording enable direct analysis of the device-provided tracings). When AF detection is not based on an ECG recording (e.g. with devices using photoplethysmography) or in case of uncertainty in the interpretation of device-provided ECG tracing, a confirmatory ECG diagnosis has to be obtained using additional ECG recording (e.g. 12-lead ECG, Holter monitoring, etc.)

The data reported in Table 5 should be interpreted with caution, as assessment of sensitivity and specificity in many studies was based on small observational cohorts, with a substantial risk of bias due to signal selection. Moreover, there is a continuous evolution of algorithms and technologies available in commercial devices.

Two recent meta-analyses reported that screening for AF using an ECG would not detect more cases than would screening with pulse palpation.²¹⁵

7.2 Screening types and strategies

Commonly used AF screening types and strategies¹⁷²^,¹⁷³^,²¹⁶ include opportunistic or systematic screening of individuals above a certain age (usually ≥65 years) or with other characteristics suggestive of increased stroke risk, using intermittent single-point or repeated 30-s ECG recording over 2 weeks. The appropriate frequency of monitoring using smartphones or watches is undefined. Primary care, pharmacies, or community screening during special events is a good setting for AF screening.¹⁷²^,¹⁷³ Overall, there was no significant difference between systematic vs. opportunistic or general practice vs. community screening in a meta-analysis, but repeated heart rhythm monitoring was associated with significantly better effectiveness compared with single assessment.²¹⁵ Importantly, a structured referral of screen-detected or suspected AF cases for further clinical evaluation should be organized, to provide an appropriate management.

7.3 Benefits from and risks of screening for atrial fibrillation

Potential advantages and disadvantages of detecting a previously undiagnosed AF through screening are shown in Figure 7.¹⁷³

Figure 7

Potential benefits from and risks of screening for AF. AF = atrial fibrillation; ECG = electrocardiogram; OAC = oral anticoagulant; SE =systemic embolism.

Screening can also highlight cases of known suboptimally managed AF.²¹⁷ Intermittent ECG recording increased new AF detection four-fold.²¹⁷ In the REHEARSE-AF (REmote HEArt Rhythm Sampling using the AliveCor heart monitor to scrEen for Atrial Fibrillation) controlled study using a smartphone/tablet-based single-lead ECG system twice weekly over 12 months vs. routine care resulted in a 3.9-fold increase in AF detection in patients aged ≥65 years.²¹⁸ Appropriate patient information and screening programme organization with rapid ECG clarification may reduce anxiety induced by suspicion of abnormality.

7.4 Cost-effectiveness of screening for atrial fibrillation

Higher AF-related medical costs justify strategies to identify and treat undiagnosed AF.²¹⁹ Opportunistic AF screening is associated with lower costs than systematic screening.¹⁷³ Appropriate choice of the screening tool and setting is important,²²⁰ and a favourable cost-effectiveness profile has been estimated for screening programmes based on pulse palpation, hand-held ECG devices, and smartphones with pulse photoplethysmography algorithms.¹⁷² Both systematic and opportunistic screening are more cost-effective than routine practice for patients ≥65 years, with opportunistic screening more likely to be cost-effective than systematic population screening.¹⁴⁹¹

7.5 Screening in high-risk populations

7.5.1 Elderly

The risk of AF (often asymptomatic) and stroke increase with age,⁸²^,¹²⁷^,²²¹ thus justifying AF screening in the elderly. Opportunistic AF screening seems to be cost-effective in elderly populations (≥65 years)²²² and among 75 − 76-year-old individuals undergoing a 2-week intermittent ECG screening.²²³

Pulse palpation and/or short-term ECG among the elderly (≥65 years) yielded an AF prevalence of 4.4%, with previously undiagnosed AF in 1.4%, suggesting a number needed to screen of 70.²²⁴ Repeated hand-held ECG recordings over 2 weeks in an unselected population aged 75 − 76 years increased the detection of asymptomatic AF up to 7.4% in subjects with ≥2 stroke risk factors.²²⁵

Recommendations for screening to detect AF

AF = atrial fibrillation; AHRE = atrial high-rate episode; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

c

See sections 3.2 and 3.3 for diagnostic criteria for AF and AHRE, and section 16 for the management of patients with AHRE.

8 Diagnostic assessment in atrial fibrillation

Often occurring in patients with cardiovascular risk factors/comorbidities, AF may sometimes be a marker of undiagnosed conditions. Hence, all AF patients will benefit from a comprehensive cardiovascular assessment (Figure 8).

Diagnostic work-up and follow-up in AF patients. AF = atrial fibrillation; BNP = B-type natriuretic peptide; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CAD = coronary artery disease; CRP = C-reactive protein; CT = computed tomography; CTA = computed tomography angiography; cTnT-hs = high-sensitivity cardiac troponin T; ECG = electrocardiogram; LAA = left atrial appendage; LGE-CMR = late gadolinium contrast-enhanced cardiac magnetic resonance; MRI = magnetic resonance imaging; NT-ProBNP = N-terminal (NT)-prohormone B-type natriuretic peptide.

Figure 8

Diagnostic work-up and follow-up in AF patients. AF = atrial fibrillation; BNP = B-type natriuretic peptide; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CAD = coronary artery disease; CRP = C-reactive protein; CT = computed tomography; CTA = computed tomography angiography; cTnT-hs = high-sensitivity cardiac troponin T; ECG = electrocardiogram; LAA = left atrial appendage; LGE-CMR = late gadolinium contrast-enhanced cardiac magnetic resonance; MRI = magnetic resonance imaging; NT-ProBNP = N-terminal (NT)-prohormone B-type natriuretic peptide.

The ‘standard package’ for diagnostic evaluation of AF patients should include complete medical history and assessment of concomitant conditions, AF pattern, stroke risk, AF-related symptoms, thrombo-embolism, and LV dysfunction.¹⁴³ A 12-lead ECG is recommended in all AF patients, to establish the diagnosis of AF, assess ventricular rate during AF, and check for the presence of conduction defects, ischaemia, or signs of structural heart disease. Laboratory tests (thyroid and kidney function, serum electrolytes, full blood count) and transthoracic echocardiography (LV size and function, LA size, valvular disease, and right heart size and systolic function) are needed to guide treatment. Based on the patient’s characteristics, specific additional information can be obtained. Most AF patients need regular follow-up (primary care) to ensure continued optimal management.

8.1 Symptoms and quality of life

As symptoms related to AF may range from none to disabling, and rhythm control treatment decisions (including catheter ablation) are influenced by symptom severity, symptom status should be characterized using the European Heart Rhythm Association (EHRA) symptom scale²²⁸ (Table 6), and the relation of symptoms (especially if non-specific, such as shortness of breath, fatigue, chest discomfort, etc.) to AF should be elucidated because symptoms may also result from undiagnosed or suboptimally managed concomitant cardiovascular risk factors or pathological conditions.²²⁹

Table 6

EHRA symptom scale

Score	Symptoms	Description
1	None	AF does not cause any symptoms
2a	Mild	Normal daily activity not affected by symptoms related to AF
2b	Moderate	Normal daily activity not affected by symptoms related to AF, but patient troubled by symptoms
3	Severe	Normal daily activity affected by symptoms related to AF
4	Disabling	Normal daily activity discontinued

Score	Symptoms	Description
1	None	AF does not cause any symptoms
2a	Mild	Normal daily activity not affected by symptoms related to AF
2b	Moderate	Normal daily activity not affected by symptoms related to AF, but patient troubled by symptoms
3	Severe	Normal daily activity affected by symptoms related to AF
4	Disabling	Normal daily activity discontinued

Six symptoms, including palpitations, fatigue, dizziness, dyspnoea, chest pain, and anxiety during AF, are evaluated with regard to how it affects the patient’s daily activity, ranging from none to symptom frequency or severity that leads to a discontinuation of daily activities.

To measure treatment effects, QoL and symptom questionnaires should be sensitive to changes in AF burden. The EHRA symptom scale is a physician-assessed tool for quantification of AF-related symptoms that is used to guide symptom-driven AF treatment decisions,²²⁸ and has been related to adverse outcomes in more symptomatic patients (score 3 − 4) versus those with a score of 1 − 2.²²⁸^,²³⁰ However, it does not consider the symptom dimensions such as anxiety, treatment concerns, and medication adverse effects that are captured by general QoL scales,²³⁰ or the patient-reported symptom-related outcomes. As discrepancies between patient-reported and physician-assessed outcomes are frequently observed,²³¹ the AF-related treatment decisions also need to be informed by a quantified patient perception of symptoms, but further research is needed to identify optimal tool(s) for capturing this information.

AF = atrial fibrillation; EHRA = European Heart Rhythm Association; QoL = quality of life.

Table 6

EHRA symptom scale

Score	Symptoms	Description
1	None	AF does not cause any symptoms
2a	Mild	Normal daily activity not affected by symptoms related to AF
2b	Moderate	Normal daily activity not affected by symptoms related to AF, but patient troubled by symptoms
3	Severe	Normal daily activity affected by symptoms related to AF
4	Disabling	Normal daily activity discontinued

Score	Symptoms	Description
1	None	AF does not cause any symptoms
2a	Mild	Normal daily activity not affected by symptoms related to AF
2b	Moderate	Normal daily activity not affected by symptoms related to AF, but patient troubled by symptoms
3	Severe	Normal daily activity affected by symptoms related to AF
4	Disabling	Normal daily activity discontinued

Six symptoms, including palpitations, fatigue, dizziness, dyspnoea, chest pain, and anxiety during AF, are evaluated with regard to how it affects the patient’s daily activity, ranging from none to symptom frequency or severity that leads to a discontinuation of daily activities.

To measure treatment effects, QoL and symptom questionnaires should be sensitive to changes in AF burden. The EHRA symptom scale is a physician-assessed tool for quantification of AF-related symptoms that is used to guide symptom-driven AF treatment decisions,²²⁸ and has been related to adverse outcomes in more symptomatic patients (score 3 − 4) versus those with a score of 1 − 2.²²⁸^,²³⁰ However, it does not consider the symptom dimensions such as anxiety, treatment concerns, and medication adverse effects that are captured by general QoL scales,²³⁰ or the patient-reported symptom-related outcomes. As discrepancies between patient-reported and physician-assessed outcomes are frequently observed,²³¹ the AF-related treatment decisions also need to be informed by a quantified patient perception of symptoms, but further research is needed to identify optimal tool(s) for capturing this information.

AF = atrial fibrillation; EHRA = European Heart Rhythm Association; QoL = quality of life.

In selected AF patients, long-term ECG monitoring is recommended to assess the adequacy of rate control or to relate symptoms with AF episodes. Sometimes the association of symptoms with AF can be established only retrospectively, after successful rhythm control intervention. In selected patients, a trial of sinus rhythm using cardioversion and a quantified patient perception of symptoms using a validated assessment tool (Supplementary Table 4) may inform the decision about subsequent AF catheter ablation (section 10.2).

Symptomatic and functional improvement with rhythm control therapies (cardioversion,^232–234 antiarrhythmic medications, and AF catheter-ablation procedures^235–242) largely depends on sinus rhythm maintenance²⁴³; however, QoL may improve despite AF recurrences, unless AF burden is high²⁴⁴ (e.g. >2 h daily¹⁰⁰) owing to optimized management of cardiovascular risk factors or comorbidities²⁴⁵ or a treatment expectancy effect. The effect of AF treatment²⁴⁶^,²⁴⁷ is supported by reports of persistently improved QoL 10 years after paroxysmal AF catheter ablation in patients with a low AF progression rate.²⁴⁸

8.2 Substrate

The substrate for AF relates to LA dilation and fibrosis with subsequent LA dysfunction and delay in electromechanical conduction. Non-invasive, multimodality imaging can provide all needed information (Figure 9).²⁴⁹^,²⁵⁰

Figure 9

Imaging in AF. Anatomical imaging provides the LA size, shape, and fibrosis. Most accurate assessment of LA dilation is obtained by CMR or CT. For routine assessment, two-dimensional (2D) or (preferably) three-dimensional (3D) transthoracic echocardiography is used. The 3D echocardiographic normal volume values are 15 − 42 mL/m² for men and 15 − 39 mL/m² for women.²⁵⁰ Assessment of LA fibrosis with LGE-CMR has been described but only rarely applied in clinical practice.²⁵¹ Functional imaging includes TDI and strain. TDI measures the velocities of the myocardium in diastole and systole, whereas LA strain reflects active LA contraction. The PA-TDI interval reflects the atrial electromechanical delay (total LA conduction time, the time interval between the P-wave on the ECG and the A’ [atrial peak velocity] on TDI) and reflects LA strain.²⁵² LA wall infiltration by epicardial fat is a potential early marker of inflammation and can be detected with CT or cardiac MRI.²⁵³ Before AF ablation, the pulmonary vein anatomy can be visualized with CT or CMR. AF = atrial fibrillation; CT = computed tomography; EP = electrophysiology; LA = left atrium; LAA = left atrial appendage; LV = left ventricular; LGE-CMR = late gadolinium contrast-enhanced cardiac magnetic resonance; MRI = magnetic resonance imaging; TDI = tissue doppler imaging; TOE = transoesophageal echocardiography; TTE = transthoracic echocardiography.

In selected patients, transoesophageal echocardiography (TOE) can be used to evaluate valvular heart disease (VHD) or left atrial appendage (LAA) thrombus; CT coronary angiography can be performed for assessment of CAD; CT/MRI of the brain can be performed when stroke is suspected. Specific predictors of stroke have been suggested: LA dilation, spontaneous LA contrast, reduced LA strain, LAA thrombus, low peak LAA velocity (<20 cm/s), and LAA non-chicken wing configuration (on CT).²⁵⁰

Recommendations for diagnostic evaluation of patients with AF

AF = atrial fibrillation; EHRA = European Heart Rhythm Association.

a

Class of recommendation.

b

Level of evidence.

9 Integrated management of patients with atrial fibrillation

9.1 Definitions and components of integrated management of atrial fibrillation patients

Integrated management of AF patients requires a coordinated and agreed patient-individualized care pathway to deliver optimized treatment (Figure 10) by an interdisciplinary team (Figure 11). Central to this approach is the patient; treatment options should be discussed, and the management plan agreed in discussion with healthcare professionals. Treatment is subject to change over time with the development of new risk factors, symptoms, disease progression, and the advent of new treatments.

Figure 10

Components of integrated AF management. AF = atrial fibrillation; HCP = healthcare professional; MDT = multidisciplinary team.

9.2 Multidisciplinary atrial fibrillation teams

Integrated AF management requires a coordinated multidisciplinary team (Figure 11) composed according to individual patient needs and local availability of services. Complex patients would benefit from a multidisciplinary team that includes relevant specialists, as well as their primary care physician (for post-discharge care) and their family/carer. Involvement of patient and family/carers is integral to the success of AF management.

Figure 11

Integrated AF management team (an example). The figure gives an example on the potential composition of AF teams showing a variety of different specialists supporting individual patients as needed. AF = atrial fibrillation. ^aAccording to local standards, this could be a general cardiologist with special interest in arrhythmias/AF or an electrophysiologist.

9.2.1 Role of healthcare systems and budget constraints

Optimized AF treatment requires a well-structured healthcare system and significant financial resources.²⁵⁴ Allocation of resources will vary due to differing healthcare system structures and budget constraints in diverse geographies. The significant inequalities in the access to AF management-related resources are documented in the recent ESC Atlas on Cardiovascular Disease.²⁵⁵ It is important to consider optimizing use of available resources to reduce stroke, improve symptoms, and treat comorbidities.

9.3 Patient involvement and shared decision making

9.3.1 Patient values and preferences

Exploring patient’s values, goals, and preferences should be the first step of shared decision making.²⁵⁶^,²⁵⁷ Qualitative research demonstrates recurring discordance between caregivers reporting shared decision making and patients experiencing a paternalistic model,¹⁰⁹^,^258–261 and a misperception that many prefer not to be involved in decision making, rather deferring to their physician.²⁵⁹^,^262–266 For shared decision making,²⁶¹ the importance attached by the patient to stroke prevention and rhythm control and the respective risk of death, stroke, and major bleeding, as well as the burden of treatment, should be thoroughly assessed and respected.²⁵⁷^,²⁶⁴^,^266–268

9.3.2 Patient education

Patient knowledge about AF and its management is often limited²⁵⁷^,^269–272 particularly when first diagnosed, when the majority of treatment decisions are discussed and made.

Information on useful resources to help educate AF patients²⁷³ can be found in the ESC Textbook of Cardiovascular Medicine, but education alone is often insufficient to produce and maintain medication adherence and lifestyle modifications.

9.4 Healthcare professional education

A mixed-methods approach has been used when targeting healthcare professionals including individual needs assessment followed by bespoke education and training, whether by smart technology, online resources, or upskilling face-to-face workshops or a combination.²⁷⁴ The mAFA, integrating clinical-decision support and education for healthcare professionals, has been successfully piloted and subsequently tested in an outcome RCT.²⁷⁵ Education alone is insufficient to change healthcare-professional behaviour.²⁷⁶ In the Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) trial,²⁷⁷ a multifaceted educational intervention including healthcare-professional education and feedback resulted in a significant increase in the proportion of patients treated with oral anticoagulant (OAC) therapy.

9.5 Adherence to treatment

Factors affecting adherence to treatment can be grouped into patient-related (e.g. demographics, comorbidities, cognitive impairment, polypharmacy, treatment side-effects, psychological health, patient understanding of the treatment regimen), physician-related (knowledge, awareness of guidelines, expertise, multidisciplinary team approach), and healthcare system-related (work-setting, access to treatments, cost) factors.²⁷⁸

Ensuring patients are appropriately informed about treatment options, how to adhere to treatment, potential consequences of non-adherence, in addition to managing patient’s expectations of treatment goals, are crucial to promote adherence. Regular review by any member of the multidisciplinary team is important to identify non-adherence and implement strategies to improve adherence where appropriate.

9.6 Technology tools supporting atrial fibrillation management

Clinical decision support systems are intelligent systems that digitize and provide evidence-based guidelines, clinical pathways, and algorithms facilitating personalized, timely, and evidence-based treatment.

The MobiGuide project²⁷⁹ and several applications^280–283 (Supplementary Tables 5 and 6) have been used to enhance patient education, improve communication between patients and healthcare professionals, and encourage active patient involvement. The ESC/CATCH-ME (Characterizing AF by Translating its Causes into Health Modifiers in the Elderly) consortium also has a smartphone/tablet app²⁸¹ for AF patients, but this is yet to be tested prospectively. A Cochrane review²⁸⁴ demonstrated that patient decision-support aids reduce decision conflict.^285–288 Nevertheless, contradictory results²⁷⁷^,²⁸⁹^,²⁹⁰ illustrate the need for more carefully designed studies, including assessment of the intervention’s effect on clinical events.

9.7 Advantages of integrated management of atrial fibrillation patients

Limited evidence exists on the effectiveness of integrated management of AF. Available intervention studies vary widely in number and content of ‘integrated care’ employed. Six studies—one cluster RCT,²⁹¹ four RCTs,²⁷⁷^,^292–295 and one before-and-after study²⁹⁴—of integrated AF management have demonstrated mixed findings (Supplementary Table 7). Two studies²⁹²^,²⁹⁴ and one meta-analysis²⁹⁶ report significantly lower rates of cardiovascular hospitalization and death with nurse-led, integrated care, whereas others reported no effect of integrated care on these outcomes. One multifaceted study²⁷⁷ demonstrated improved OAC rates in the intervention group at 12 months. The IMPACT-AF study²⁷⁷ found no significant difference in the composite efficacy outcome (unplanned emergency department visit or cardiovascular hospitalization) or the primary safety outcome of major bleeding between intervention and usual care.

9.8 Measures (or approaches) for implementation of integrated management

Integrated management of AF requires a change in the current approach to patient care, to focus on moving from a multidisciplinary team to interdisciplinary working, including behaviour change for all AF team members and key stakeholders including patients and their family²⁹⁷^,²⁹⁸ (Supplementary Figure 3).

To understand whether integrated AF management has been implemented into clinical practice and had an impact on important outcomes (mortality, stroke, hospitalization, QoL, symptom reduction, etc.), a specific international standard set of outcome measures should be collected (Supplementary Figure 4).²⁹⁹ This would also highlight areas requiring further development.

9.9 Treatment burden

Patient-perceived treatment burden³⁰⁰ is defined as the workload imposed by healthcare on patients and its effect on patient functioning and well-being apart from specific treatment side-effects.³⁰¹^,³⁰² It includes everything patients do for their health (drug management, self-monitoring, visits to the doctor, laboratory tests, lifestyle changes) and healthcare impact on their social relationships, potentially affecting adherence to treatment,³⁰³^,³⁰⁴ QoL, and outcomes (e.g. hospitalization and survival).³⁰⁵^,³⁰⁶ Patient-perceived treatment burden is influenced by their knowledge about disease.³⁰² Patients with similar treatment regimens may have very different treatment burden,³⁰⁷ with only a weak agreement between patient’s and physicians’ treatment burden evaluation, suggesting that the patient’s experience is not shared in depth during consultations.³⁰²^,³⁰⁸^,³⁰⁹

Treatment burden can be overwhelming for patients with multiple chronic conditions³⁰¹ (e.g. those with three chronic conditions would have to take 6 − 12 medications daily, visit a healthcare giver 1.2 − 5.9 times per month, and spend 49.6 − 71.0 h monthly in healthcare-related activities³¹⁰). Treatment burden in AF patients is largely unknown. In a single-centre prospective study, AF patient-perceived total treatment burden was higher than in patients with other chronic conditions (27.6% vs. 24.3%, P =0.011), and 1 in 5 AF patients reported a high treatment burden that could question the sustainability of their treatment. Notably, AF patients attributed the highest proportion of treatment burden to healthcare system-related aspects (e.g. attending appointments etc.) and lifestyle modification requirements. Female sex and younger age were independently significantly associated with a higher treatment burden, whereas non-vitamin K antagonist oral anticoagulants (NOACs) and rhythm control reduced the odds for high treatment burden by >50%.³¹¹

The discussion of treatment burden should be an integral part of shared, informed treatment decision making, and treatment burden can be assessed using a validated questionnaire.³¹²

9.10 Patient-reported outcomes

There is increasing advocacy for including patient-reported outcomes (PROs) as endpoints in clinical trials³¹³ and their routine collection^314–316 to improve care and assess treatment success from the patient’s perspective. Patients’ experience of AF and its management is highly subjective; AF management has become increasingly complex, potentially resulting in significant treatment burden and poorer health-related QoL.

Measuring outcomes that are important to patients, in addition to ‘hard’ clinical endpoints (death, stroke, major bleeding, etc.), can inform AF management. An international consortium of AF patients and healthcare professionals has identified the following PROs as important to measure for AF: health-related QoL, physical and emotional functioning, cognitive function, symptom severity, exercise tolerance, and ability to work (Supplementary Figure 4)²⁹⁹; PRO measures can be used to assess these factors and the international standard set of AF outcome measures proposes some tools for assessing PROs.²⁹⁹ Health informatics systems could help capture PRO data. Despite increasing support for the role of PRO measures in healthcare management, few studies and registries report collecting PRO data using validated tools.³¹³ Implementation of PRO measures in the management of AF patients is addressed in a dedicated expert consensus paper developed in collaboration with patient representatives by the EHRA.³¹⁷

Recommendations about integrated AF management

AF = atrial fibrillation; PRO = patient-reported outcome.

a

Class of recommendation.

b

Level of evidence.

10 Patient management: the integrated ABC pathway

The simple Atrial fibrillation Better Care (ABC) holistic pathway ('A' Anticoagulation/Avoid stroke; ‘B’ Better symptom management; ‘C’ Cardiovascular and Comorbidity optimization³¹⁸) streamlines integrated care of AF patients across all healthcare levels and among different specialties. Compared with usual care, implementation of the ABC pathway has been significantly associated with lower risk of all-cause death, composite outcome of stroke/major bleeding/cardiovascular death and first hospitalization,³¹⁹ lower rates of cardiovascular events,³²⁰^,³²¹ and lower health-related costs.³²² In the prospective, randomized mAFA-II trial, the composite outcome was significantly lowered with ABC pathway management intervention compared with usual care [1.9% vs. 6.0%; hazard ratio (HR) 0.39; 95% CI 0.22 − 0.67; P <0.001].³²³

10. 1 ‘A’ – Anticoagulation/Avoid stroke

This section refers to AF in the absence of severe mitral stenosis or prosthetic heart valves (for AF with concomitant VHD see section 11.7).¹⁴⁸

10.1.1 Stroke risk assessment

Overall, AF increases the risk of stroke five-fold, but this risk is not homogeneous, depending on the presence of specific stroke risk factors/modifiers. Main clinical stroke risk factors have been identified from non-anticoagulated arms of the historical RCTs conducted >20 years ago, notwithstanding that these trials only randomized <10% of patients screened, whereas many common risk factors were not recorded or consistently defined.³²⁴ These data have been supplemented by evidence from large observational cohorts also studying patients who would not have been included in the RCTs. Subsequently, various imaging, blood, and urine biological markers (biomarkers) have been associated with stroke risk (Table 7).³²⁴^,³²⁵ In addition, non-paroxysmal AF is associated with an increase in thrombo-embolism (multivariable adjusted HR 1.38; 95% CI 1.19 − 1.61; P <0.001) compared with paroxysmal AF.¹⁵⁶ Notably, many of the risk factors for AF-related complications are also risk factors for incident AF.³³

Table 7

Stroke risk factors in patients with AF

Most commonly studied clinical risk factors (a systematic review)³²⁴	Positive studies/All studies	Other clinical risk factors³²⁵	Imaging biomarkers²⁹¹^,^326–328	Blood/urine biomarkers^329–332
Stroke/TIA/systemic embolism	15/16	Impaired renal function/CKD	Echocardiography	Cardiac troponin T and I Natriuretic peptides Cystatin C Proteinuria CrCl/eGFR CRP IL-6 GDF-15 von Willebrand factor D-dimer
Hypertension	11/20	OSA	LA dilatation Spontaneous contrast or thrombus in LA Low LAA velocities Complex aortic plaque
Ageing (per decade)	9/13	HCM
Structural heart disease	9/13	Amyloidosis in degenerative cerebral and heart diseases
Diabetes mellitus	9/14	Hyperlipidaemia
Vascular disease	6/17	Smoking	Cerebral imaging
CHF/LV dysfunction	7/18	Metabolic syndrome³³³	Small-vessel disease
Sex category (female)	8/22	Malignancy

Most commonly studied clinical risk factors (a systematic review)³²⁴	Positive studies/All studies	Other clinical risk factors³²⁵	Imaging biomarkers²⁹¹^,^326–328	Blood/urine biomarkers^329–332
Stroke/TIA/systemic embolism	15/16	Impaired renal function/CKD	Echocardiography	Cardiac troponin T and I Natriuretic peptides Cystatin C Proteinuria CrCl/eGFR CRP IL-6 GDF-15 von Willebrand factor D-dimer
Hypertension	11/20	OSA	LA dilatation Spontaneous contrast or thrombus in LA Low LAA velocities Complex aortic plaque
Ageing (per decade)	9/13	HCM
Structural heart disease	9/13	Amyloidosis in degenerative cerebral and heart diseases
Diabetes mellitus	9/14	Hyperlipidaemia
Vascular disease	6/17	Smoking	Cerebral imaging
CHF/LV dysfunction	7/18	Metabolic syndrome³³³	Small-vessel disease
Sex category (female)	8/22	Malignancy

CHF = congestive heart failure; CKD = chronic kidney disease; CrCl = creatinine clearance; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; GDF-15 = growth differentiation factor-15; IL-6 = interleukin 6; LA = left atrium; LAA = left atrial appendage; LV = left ventricular; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

Table 7

Stroke risk factors in patients with AF

Most commonly studied clinical risk factors (a systematic review)³²⁴	Positive studies/All studies	Other clinical risk factors³²⁵	Imaging biomarkers²⁹¹^,^326–328	Blood/urine biomarkers^329–332
Stroke/TIA/systemic embolism	15/16	Impaired renal function/CKD	Echocardiography	Cardiac troponin T and I Natriuretic peptides Cystatin C Proteinuria CrCl/eGFR CRP IL-6 GDF-15 von Willebrand factor D-dimer
Hypertension	11/20	OSA	LA dilatation Spontaneous contrast or thrombus in LA Low LAA velocities Complex aortic plaque
Ageing (per decade)	9/13	HCM
Structural heart disease	9/13	Amyloidosis in degenerative cerebral and heart diseases
Diabetes mellitus	9/14	Hyperlipidaemia
Vascular disease	6/17	Smoking	Cerebral imaging
CHF/LV dysfunction	7/18	Metabolic syndrome³³³	Small-vessel disease
Sex category (female)	8/22	Malignancy

Most commonly studied clinical risk factors (a systematic review)³²⁴	Positive studies/All studies	Other clinical risk factors³²⁵	Imaging biomarkers²⁹¹^,^326–328	Blood/urine biomarkers^329–332
Stroke/TIA/systemic embolism	15/16	Impaired renal function/CKD	Echocardiography	Cardiac troponin T and I Natriuretic peptides Cystatin C Proteinuria CrCl/eGFR CRP IL-6 GDF-15 von Willebrand factor D-dimer
Hypertension	11/20	OSA	LA dilatation Spontaneous contrast or thrombus in LA Low LAA velocities Complex aortic plaque
Ageing (per decade)	9/13	HCM
Structural heart disease	9/13	Amyloidosis in degenerative cerebral and heart diseases
Diabetes mellitus	9/14	Hyperlipidaemia
Vascular disease	6/17	Smoking	Cerebral imaging
CHF/LV dysfunction	7/18	Metabolic syndrome³³³	Small-vessel disease
Sex category (female)	8/22	Malignancy

CHF = congestive heart failure; CKD = chronic kidney disease; CrCl = creatinine clearance; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; GDF-15 = growth differentiation factor-15; IL-6 = interleukin 6; LA = left atrium; LAA = left atrial appendage; LV = left ventricular; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

Table 8

CHA₂DS₂-VASc score³³⁴

CHA₂DS₂-VASc score
Risk factors and definitions		Points awarded	Comment
C	Congestive heart failure Clinical HF, or objective evidence of moderate to severe LV dysfunction, or HCM	1	Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even if asymptomatic) of moderate-severe LV systolic impairment on cardiac imaging³³⁵; HCM confers a high stroke risk³³⁶ and OAC is beneficial for stroke reduction.³³⁷
H	Hypertension or on antihypertensive therapy	1	History of hypertension may result in vascular changes that predispose to stroke, and a well-controlled BP today may not be well-controlled over time.³²⁴ Uncontrolled BP − the optimal BP target associated with the lowest risk of ischaemic stroke, death, and other cardiovascular outcomes is 120 − 129/<80 mmHg.³³⁸
A	Age 75 years or older	2	Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years upwards.³³⁹ Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 65 − 74 years and 2 points for age ≥75 years.
D	Diabetes mellitus Treatment with oral hypoglycaemic drugs and/or insulin or fasting blood glucose >125 mg/dL (7 mmol/L)	1	Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thromboembolism³⁴⁰) and presence of diabetic target organ damage, e.g. retinopathy.³⁴¹ Both type 1 and type 2 diabetes mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients aged <65 years with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus.³⁴²
S	StrokePrevious stroke, TIA, or thromboembolism	2	Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischaemic stroke, hence weighted 2 points. Although excluded from RCTs, AF patients with ICH (including haemorrhagic stroke) are at very high risk of subsequent ischaemic stroke, and recent observational studies suggest that such patients would benefit from oral anticoagulation.^343–345
V	Vascular disease Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque	1	Vascular disease (PAD or myocardial infarction) confers a 17 − 22% excess risk, particularly in Asian patients.^346–348 Angiographically significant CAD is also an independent risk factor for ischaemic stroke among AF patients (adjusted incidence rate ratio 1.29, 95% CI 1.08 − 1.53).³⁴⁹ Complex aortic plaque on the descending aorta, as an indicator of significant vascular disease, is also a strong predictor of ischaemic stroke.³⁵⁰
A	Age 65 − 74 years	1	See above. Recent data from Asia suggest that the risk of stroke may rise from age 50 − 55 years upwards and that a modified CHA₂DS₂-VASc score may be used in Asian patients.³⁵¹^,³⁵²
Sc	Sex category (female)	1	A stroke risk modifier rather than a risk factor.³⁵³
Maximum score		9

CHA₂DS₂-VASc score
Risk factors and definitions		Points awarded	Comment
C	Congestive heart failure Clinical HF, or objective evidence of moderate to severe LV dysfunction, or HCM	1	Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even if asymptomatic) of moderate-severe LV systolic impairment on cardiac imaging³³⁵; HCM confers a high stroke risk³³⁶ and OAC is beneficial for stroke reduction.³³⁷
H	Hypertension or on antihypertensive therapy	1	History of hypertension may result in vascular changes that predispose to stroke, and a well-controlled BP today may not be well-controlled over time.³²⁴ Uncontrolled BP − the optimal BP target associated with the lowest risk of ischaemic stroke, death, and other cardiovascular outcomes is 120 − 129/<80 mmHg.³³⁸
A	Age 75 years or older	2	Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years upwards.³³⁹ Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 65 − 74 years and 2 points for age ≥75 years.
D	Diabetes mellitus Treatment with oral hypoglycaemic drugs and/or insulin or fasting blood glucose >125 mg/dL (7 mmol/L)	1	Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thromboembolism³⁴⁰) and presence of diabetic target organ damage, e.g. retinopathy.³⁴¹ Both type 1 and type 2 diabetes mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients aged <65 years with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus.³⁴²
S	StrokePrevious stroke, TIA, or thromboembolism	2	Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischaemic stroke, hence weighted 2 points. Although excluded from RCTs, AF patients with ICH (including haemorrhagic stroke) are at very high risk of subsequent ischaemic stroke, and recent observational studies suggest that such patients would benefit from oral anticoagulation.^343–345
V	Vascular disease Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque	1	Vascular disease (PAD or myocardial infarction) confers a 17 − 22% excess risk, particularly in Asian patients.^346–348 Angiographically significant CAD is also an independent risk factor for ischaemic stroke among AF patients (adjusted incidence rate ratio 1.29, 95% CI 1.08 − 1.53).³⁴⁹ Complex aortic plaque on the descending aorta, as an indicator of significant vascular disease, is also a strong predictor of ischaemic stroke.³⁵⁰
A	Age 65 − 74 years	1	See above. Recent data from Asia suggest that the risk of stroke may rise from age 50 − 55 years upwards and that a modified CHA₂DS₂-VASc score may be used in Asian patients.³⁵¹^,³⁵²
Sc	Sex category (female)	1	A stroke risk modifier rather than a risk factor.³⁵³
Maximum score		9

AF = atrial fibrillation; BP = blood pressure; CAD = coronary artery disease; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (female); CI = confidence interval; EF = ejection fraction; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ICH = intracranial haemorrhage; LV = left ventricular; LVEF = left ventricular ejection fraction; OAC = oral anticoagulant; PAD = peripheral artery disease; RCT = randomized controlled trial; TIA = transient ischaemic attack.

Table 8

CHA₂DS₂-VASc score³³⁴

CHA₂DS₂-VASc score
Risk factors and definitions		Points awarded	Comment
C	Congestive heart failure Clinical HF, or objective evidence of moderate to severe LV dysfunction, or HCM	1	Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even if asymptomatic) of moderate-severe LV systolic impairment on cardiac imaging³³⁵; HCM confers a high stroke risk³³⁶ and OAC is beneficial for stroke reduction.³³⁷
H	Hypertension or on antihypertensive therapy	1	History of hypertension may result in vascular changes that predispose to stroke, and a well-controlled BP today may not be well-controlled over time.³²⁴ Uncontrolled BP − the optimal BP target associated with the lowest risk of ischaemic stroke, death, and other cardiovascular outcomes is 120 − 129/<80 mmHg.³³⁸
A	Age 75 years or older	2	Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years upwards.³³⁹ Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 65 − 74 years and 2 points for age ≥75 years.
D	Diabetes mellitus Treatment with oral hypoglycaemic drugs and/or insulin or fasting blood glucose >125 mg/dL (7 mmol/L)	1	Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thromboembolism³⁴⁰) and presence of diabetic target organ damage, e.g. retinopathy.³⁴¹ Both type 1 and type 2 diabetes mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients aged <65 years with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus.³⁴²
S	StrokePrevious stroke, TIA, or thromboembolism	2	Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischaemic stroke, hence weighted 2 points. Although excluded from RCTs, AF patients with ICH (including haemorrhagic stroke) are at very high risk of subsequent ischaemic stroke, and recent observational studies suggest that such patients would benefit from oral anticoagulation.^343–345
V	Vascular disease Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque	1	Vascular disease (PAD or myocardial infarction) confers a 17 − 22% excess risk, particularly in Asian patients.^346–348 Angiographically significant CAD is also an independent risk factor for ischaemic stroke among AF patients (adjusted incidence rate ratio 1.29, 95% CI 1.08 − 1.53).³⁴⁹ Complex aortic plaque on the descending aorta, as an indicator of significant vascular disease, is also a strong predictor of ischaemic stroke.³⁵⁰
A	Age 65 − 74 years	1	See above. Recent data from Asia suggest that the risk of stroke may rise from age 50 − 55 years upwards and that a modified CHA₂DS₂-VASc score may be used in Asian patients.³⁵¹^,³⁵²
Sc	Sex category (female)	1	A stroke risk modifier rather than a risk factor.³⁵³
Maximum score		9

CHA₂DS₂-VASc score
Risk factors and definitions		Points awarded	Comment
C	Congestive heart failure Clinical HF, or objective evidence of moderate to severe LV dysfunction, or HCM	1	Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even if asymptomatic) of moderate-severe LV systolic impairment on cardiac imaging³³⁵; HCM confers a high stroke risk³³⁶ and OAC is beneficial for stroke reduction.³³⁷
H	Hypertension or on antihypertensive therapy	1	History of hypertension may result in vascular changes that predispose to stroke, and a well-controlled BP today may not be well-controlled over time.³²⁴ Uncontrolled BP − the optimal BP target associated with the lowest risk of ischaemic stroke, death, and other cardiovascular outcomes is 120 − 129/<80 mmHg.³³⁸
A	Age 75 years or older	2	Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years upwards.³³⁹ Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 65 − 74 years and 2 points for age ≥75 years.
D	Diabetes mellitus Treatment with oral hypoglycaemic drugs and/or insulin or fasting blood glucose >125 mg/dL (7 mmol/L)	1	Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thromboembolism³⁴⁰) and presence of diabetic target organ damage, e.g. retinopathy.³⁴¹ Both type 1 and type 2 diabetes mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients aged <65 years with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus.³⁴²
S	StrokePrevious stroke, TIA, or thromboembolism	2	Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischaemic stroke, hence weighted 2 points. Although excluded from RCTs, AF patients with ICH (including haemorrhagic stroke) are at very high risk of subsequent ischaemic stroke, and recent observational studies suggest that such patients would benefit from oral anticoagulation.^343–345
V	Vascular disease Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque	1	Vascular disease (PAD or myocardial infarction) confers a 17 − 22% excess risk, particularly in Asian patients.^346–348 Angiographically significant CAD is also an independent risk factor for ischaemic stroke among AF patients (adjusted incidence rate ratio 1.29, 95% CI 1.08 − 1.53).³⁴⁹ Complex aortic plaque on the descending aorta, as an indicator of significant vascular disease, is also a strong predictor of ischaemic stroke.³⁵⁰
A	Age 65 − 74 years	1	See above. Recent data from Asia suggest that the risk of stroke may rise from age 50 − 55 years upwards and that a modified CHA₂DS₂-VASc score may be used in Asian patients.³⁵¹^,³⁵²
Sc	Sex category (female)	1	A stroke risk modifier rather than a risk factor.³⁵³
Maximum score		9

AF = atrial fibrillation; BP = blood pressure; CAD = coronary artery disease; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (female); CI = confidence interval; EF = ejection fraction; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ICH = intracranial haemorrhage; LV = left ventricular; LVEF = left ventricular ejection fraction; OAC = oral anticoagulant; PAD = peripheral artery disease; RCT = randomized controlled trial; TIA = transient ischaemic attack.

Common stroke risk factors are summarized in the clinical risk-factor−based CHA₂DS₂-VASc [Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female)] score (Table 8).³³⁴

Stroke risk scores have to balance simplicity and practicality against precision.^354–356 As any clinical risk-factor−based score, CHA₂DS₂-VASc performs only modestly in predicting high-risk patients who will sustain thrombo-embolic events, but those identified as low-risk [CHA₂DS₂-VASc 0 (males), or score of 1 (females)] consistently have low ischaemic stroke or mortality rates (<1%/year) and do not need any stroke prevention treatment.

Female sex is an age-dependent stroke risk modifier rather than a risk factor per se.³⁵⁷^,³⁵⁸ Observational studies showed that women with no other risk factors (CHA₂DS₂-VASc score of 1) have a low stroke risk, similar to men with a CHA₂DS₂-VASc score of 0.³⁵⁹ The simplified CHA₂DS₂-VA score could guide the initial decision about OAC in AF patients, but not considering the sex component would underestimate stroke risk in women with AF.³⁶⁰^,³⁶¹ In the presence of >1 non-sex stroke risk factor, women with AF consistently have significantly higher stroke risk than men.³⁵³^,³⁶²

Many clinical stroke risk factors (e.g. renal impairment, OSA, LA dilatation²⁹¹^,³²⁶^,^363–365) are closely related to the CHA₂DS₂-VASc components, and their consideration does not improve its predictive value (the relationship of smoking or obesity to stroke risk in AF is also contentious).³⁶⁶ Various biomarkers [e.g. troponin, natriuretic peptides, growth differentiation factor (GDF)-15, von Willebrand factor] have shown improved performance of biomarker-based over clinical scores in the assessment of residual stroke risk among anticoagulated AF patients³²⁹^,³⁶⁷; notwithstanding, many of these biomarkers (as well as some clinical risk factors) are predictive of both stroke and bleeding³²⁹ or non-AF and non-cardiovascular conditions, often (non-specifically) reflecting simply a sick heart or patient.

More complex clinical scores [e.g. Global Anticoagulant Registry in the FIELD − Atrial Fibrillation (GARFIELD-AF)]³⁶⁸ and those inclusive of biomarkers [e.g. Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA),³⁶⁹^,³⁷⁰ Intermountain Risk Score,³⁷¹ABC-stroke (Age, Biomarkers, Clinical history)]³⁷² improve stroke risk prediction modestly but statistically significantly. The ABC-stroke risk score that considers age, previous stroke/transient ischaemic attack (TIA), high-sensitivity troponin T (cTnT-hs) and N-terminal (NT)-prohormone B-type natriuretic peptide has been validated in the cohorts of landmark NOAC trials.^373–375 A biomarker score-guided treatment strategy to reduce stroke and mortality in AF patients is being evaluated in an ongoing RCT (the ABC-AF Study, NCT03753490).

Whereas the routine use of biomarker-based risk scores currently would not substantially add to initial stroke prevention treatment decisions in patients already qualifying for treatment based on the CHA₂DS₂-VASc score (and a limited practicality would be accompanied by increased healthcare costs),³⁵⁵^,³⁷⁶^,³⁷⁷ biomarkers could further refine stroke risk differentiation among patients initially classified as low risk and those with a single non-sex CHA₂DS₂-VASc risk factor.³⁷⁸

Studies of the CHA₂DS₂-VASc score report a broad range of stroke rates depending on study setting (community vs. hospital), methodology (e.g. excluding patients subsequently treated with OAC would bias stroke rates towards lower levels), ethnicity, and prevalence of specific stroke risk factors in the study population (different risk factors carry different weight, and age thresholds for initiating NOACs may even differ for patients with a different single non-sex stroke risk factor, as follows: age 35 years for HF, 50 years for hypertension or diabetes, and 55 years for vascular disease).³⁷⁹^,³⁸⁰ No RCT has specifically addressed the need for OAC in patients with a single non-sex CHA₂DS₂-VASc risk factor (to obtain high event rates and timely complete the study, anticoagulation trials have preferentially included high-risk patients), but an overview of subgroup analyses and observational data suggests that OAC use in such patients confers a positive net clinical benefit when balancing the reduction in stroke against the potential for harm with serious bleeding.³³⁹^,³⁸¹

For many risk factors (e.g. age), stroke risk is a continuum rather than an artificial low-, moderate-, or high-risk category. Risk factors are dynamic and, given the elderly AF population with multiple (often changing) comorbidities, stroke risk needs to be re-evaluated at each clinical review. Recent studies have shown that patients with a change in their risk profile are more likely to sustain strokes.³⁸²^,³⁸³ Many initially low-risk patients (>15%) would have ≥1 non-sex CHA₂DS₂-VASc risk factor at 1 year after incident AF,^384–386 and 90% of new comorbidities were evident at 4.4 months after AF was diagnosed.³⁸⁷

A Patient-Centred Outcomes Research Institute (PCORI)-commissioned systematic review of 61 studies compared diagnostic accuracy and impact on clinical decision making of available clinical and imaging tools and associated risk factors for predicting thrombo-embolic and bleeding risk in AF patients.³⁸⁸ The authors concluded that the CHADS₂ (CHF history, Hypertension history, Age ≥75 y, Diabetes mellitus history, Stroke or TIA symptoms previously), CHA₂DS₂-VASc, and ABC risk scores have the best evidence for predicting thrombo-embolic risk (moderate strength of evidence for limited prediction ability of each score).

10.1.2 Bleeding risk assessment

When initiating antithrombotic therapy, potential risk for bleeding also needs to be assessed. Non-modifiable and partially modifiable bleeding risks (Table 9) are important drivers of bleeding events in synergy with modifiable factors.³⁸⁹ Notably, a history of falls is not an independent predictor of bleeding on OAC (a modelling study estimated that a patient would need to fall 295 times per year for the benefits of ischaemic stroke reduction with OAC to be outweighed by the potential for serious bleeding).³⁹⁰

Table 9

Risk factors for bleeding with OAC and antiplatelet therapy

Non-modifiable	Potentially modifiable	Modifiable	Biomarkers
Age >65 years Previous major bleeding Severe renal impairment (on dialysis or renal transplant) Severe hepatic dysfunction (cirrhosis) Malignancy Genetic factors (e.g. CYP 2C9 polymorphisms) Previous stroke, small-vessel disease, etc. Diabetes mellitus Cognitive impairment/dementia	Extreme frailty ± excessive risk of falls^a Anaemia Reduced platelet count or function Renal impairment with CrCl <60 mL/min VKA management strategy^b	Hypertension/elevated SBP Concomitant antiplatelet/NSAID Excessive alcohol intake Non-adherence to OAC Hazardous hobbies/occupations Bridging therapy with heparin INR control (target 2.0 − 3.0), target TTR >70%^c Appropriate choice of OAC and correct dosing^d	GDF-15 Cystatin C/CKD-EPI cTnT-hs von Willebrand factor (+ other coagulation markers)

Non-modifiable

Potentially modifiable

Modifiable

Biomarkers

Age >65 years

Previous major bleeding

Severe renal impairment (on dialysis or renal transplant)

Severe hepatic dysfunction (cirrhosis)

Malignancy

Genetic factors (e.g. CYP 2C9 polymorphisms)

Previous stroke, small-vessel disease, etc.

Diabetes mellitus

Cognitive impairment/dementia

Extreme frailty ± excessive risk of falls^a

Anaemia

Reduced platelet count or function

Renal impairment with CrCl <60 mL/min

VKA management strategy^b

Hypertension/elevated SBP

Concomitant antiplatelet/NSAID

Excessive alcohol intake

Non-adherence to OAC

Hazardous hobbies/occupations

Bridging therapy with heparin

INR control (target 2.0 − 3.0), target TTR >70%^c

Appropriate choice of OAC and correct dosing^d

GDF-15

Cystatin C/CKD-EPI

cTnT-hs

von Willebrand factor (+ other coagulation markers)

CKD-EPI= Chronic Kidney Disease Epidemiology Collaboration; CrCl = creatinine clearance; cTnT-hs = high-sensitivity troponin T; CYP = cytochrome P; GDF-15 = growth differentiation factor-15; INR = international normalized ratio; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; SBP = systolic blood pressure; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Walking aids; appropriate footwear; home review to remove trip hazards; neurological assessment where appropriate.

b

Increased INR monitoring, dedicated OAC clinicals, self-monitoring/self-management, educational/behavioural interventions.

c

For patients receiving VKA treatment.

d

Dose adaptation based on patient’s age, body weight, and serum creatinine level.

Table 9

Risk factors for bleeding with OAC and antiplatelet therapy

Non-modifiable	Potentially modifiable	Modifiable	Biomarkers
Age >65 years Previous major bleeding Severe renal impairment (on dialysis or renal transplant) Severe hepatic dysfunction (cirrhosis) Malignancy Genetic factors (e.g. CYP 2C9 polymorphisms) Previous stroke, small-vessel disease, etc. Diabetes mellitus Cognitive impairment/dementia	Extreme frailty ± excessive risk of falls^a Anaemia Reduced platelet count or function Renal impairment with CrCl <60 mL/min VKA management strategy^b	Hypertension/elevated SBP Concomitant antiplatelet/NSAID Excessive alcohol intake Non-adherence to OAC Hazardous hobbies/occupations Bridging therapy with heparin INR control (target 2.0 − 3.0), target TTR >70%^c Appropriate choice of OAC and correct dosing^d	GDF-15 Cystatin C/CKD-EPI cTnT-hs von Willebrand factor (+ other coagulation markers)

Non-modifiable

Potentially modifiable

Modifiable

Biomarkers

Age >65 years

Previous major bleeding

Severe renal impairment (on dialysis or renal transplant)

Severe hepatic dysfunction (cirrhosis)

Malignancy

Genetic factors (e.g. CYP 2C9 polymorphisms)

Previous stroke, small-vessel disease, etc.

Diabetes mellitus

Cognitive impairment/dementia

Extreme frailty ± excessive risk of falls^a

Anaemia

Reduced platelet count or function

Renal impairment with CrCl <60 mL/min

VKA management strategy^b

Hypertension/elevated SBP

Concomitant antiplatelet/NSAID

Excessive alcohol intake

Non-adherence to OAC

Hazardous hobbies/occupations

Bridging therapy with heparin

INR control (target 2.0 − 3.0), target TTR >70%^c

Appropriate choice of OAC and correct dosing^d

GDF-15

Cystatin C/CKD-EPI

cTnT-hs

von Willebrand factor (+ other coagulation markers)

CKD-EPI= Chronic Kidney Disease Epidemiology Collaboration; CrCl = creatinine clearance; cTnT-hs = high-sensitivity troponin T; CYP = cytochrome P; GDF-15 = growth differentiation factor-15; INR = international normalized ratio; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; SBP = systolic blood pressure; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Walking aids; appropriate footwear; home review to remove trip hazards; neurological assessment where appropriate.

b

Increased INR monitoring, dedicated OAC clinicals, self-monitoring/self-management, educational/behavioural interventions.

c

For patients receiving VKA treatment.

d

Dose adaptation based on patient’s age, body weight, and serum creatinine level.

Modifiable and non-modifiable bleeding risk factors have been used to formulate various bleeding risk scores,³⁶⁸^,^391–395 generally with a modest predictive ability for bleeding events.³⁹⁶^,³⁹⁷ Studies comparing specific bleeding risk scores provided conflicting findings.³⁹³^,³⁹⁴^,³⁹⁸ Various biomarkers have been proposed as bleeding risk predictors, but many have been studied in anticoagulated trial cohorts (while bleeding risk assessment is needed at all parts of the patient pathway—when initially not using OAC, if taking aspirin, and, subsequently, on OAC). Additionally, biomarkers are non-specifically predictive of stroke, death, HF, etc.³⁹⁹^,⁴⁰⁰ or even non-cardiovascular conditions (e.g. glaucoma),⁴⁰¹ and the availability of some biomarkers is limited in routine clinical practice.

The biomarker-based ABC-bleeding risk score [Age, Biomarkers (GDF-15, cTnT-hs, haemoglobin) and Clinical history (prior bleeding)]³⁷⁵^,⁴⁰² reportedly outperformed clinical scores, but in another study there was no long-term advantage of ABC-bleeding over HAS-BLED score (Table 10), whereas HAS-BLED was better in identifying patients at low risk of bleeding (HAS-BLED 0 − 2).⁴⁰³ In the PCORI-commissioned systematic review,³⁸⁸ encompassing 38 studies of bleeding risk prediction, the HAS-BLED score had the best evidence for predicting bleeding risk (moderate strength of evidence), consistent with other systematic reviews and meta-analyses comparing bleeding risk prediction approaches.^404–406

Table 10

Clinical risk factors in the HAS-BLED score³⁹⁵

Risk factors and definitions		Points awarded
H	Uncontrolled hypertension SBP >160 mmHg	1
A	Abnormal renal and/or hepatic function Dialysis, transplant, serum creatinine >200 µmol/L, cirrhosis, bilirubin > × 2 upper limit of normal, AST/ALT/ALP >3 × upper limit of normal	1 point for each
S	Stroke Previous ischaemic or haemorrhagic^a stroke	1
B	Bleeding history or predisposition Previous major haemorrhage or anaemia or severe thrombocytopenia	1
L	Labile INR^b TTR <60% in patient receiving VKA	1
E	Elderly Aged >65 years or extreme frailty	1
D	Drugs or excessive alcohol drinking Concomitant use of antiplatelet or NSAID; and/or excessive^c alcohol per week	1 point for each
Maximum score		9

Risk factors and definitions		Points awarded
H	Uncontrolled hypertension SBP >160 mmHg	1
A	Abnormal renal and/or hepatic function Dialysis, transplant, serum creatinine >200 µmol/L, cirrhosis, bilirubin > × 2 upper limit of normal, AST/ALT/ALP >3 × upper limit of normal	1 point for each
S	Stroke Previous ischaemic or haemorrhagic^a stroke	1
B	Bleeding history or predisposition Previous major haemorrhage or anaemia or severe thrombocytopenia	1
L	Labile INR^b TTR <60% in patient receiving VKA	1
E	Elderly Aged >65 years or extreme frailty	1
D	Drugs or excessive alcohol drinking Concomitant use of antiplatelet or NSAID; and/or excessive^c alcohol per week	1 point for each
Maximum score		9

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; SBP = systolic blood pressure; INR = international normalized ratio; NSAID = Non-steroidal anti-inflammatory drug; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Haemorrhagic stroke would also score 1 point under the ‘B’ criterion.

b

Only relevant if patient receiving a VKA.

c

Alcohol excess or abuse refers to a high intake (e.g. >14 units per week), where the clinician assesses there would be an impact on health or bleeding risk.

Table 10

Clinical risk factors in the HAS-BLED score³⁹⁵

Risk factors and definitions		Points awarded
H	Uncontrolled hypertension SBP >160 mmHg	1
A	Abnormal renal and/or hepatic function Dialysis, transplant, serum creatinine >200 µmol/L, cirrhosis, bilirubin > × 2 upper limit of normal, AST/ALT/ALP >3 × upper limit of normal	1 point for each
S	Stroke Previous ischaemic or haemorrhagic^a stroke	1
B	Bleeding history or predisposition Previous major haemorrhage or anaemia or severe thrombocytopenia	1
L	Labile INR^b TTR <60% in patient receiving VKA	1
E	Elderly Aged >65 years or extreme frailty	1
D	Drugs or excessive alcohol drinking Concomitant use of antiplatelet or NSAID; and/or excessive^c alcohol per week	1 point for each
Maximum score		9

Risk factors and definitions		Points awarded
H	Uncontrolled hypertension SBP >160 mmHg	1
A	Abnormal renal and/or hepatic function Dialysis, transplant, serum creatinine >200 µmol/L, cirrhosis, bilirubin > × 2 upper limit of normal, AST/ALT/ALP >3 × upper limit of normal	1 point for each
S	Stroke Previous ischaemic or haemorrhagic^a stroke	1
B	Bleeding history or predisposition Previous major haemorrhage or anaemia or severe thrombocytopenia	1
L	Labile INR^b TTR <60% in patient receiving VKA	1
E	Elderly Aged >65 years or extreme frailty	1
D	Drugs or excessive alcohol drinking Concomitant use of antiplatelet or NSAID; and/or excessive^c alcohol per week	1 point for each
Maximum score		9

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; SBP = systolic blood pressure; INR = international normalized ratio; NSAID = Non-steroidal anti-inflammatory drug; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Haemorrhagic stroke would also score 1 point under the ‘B’ criterion.

b

Only relevant if patient receiving a VKA.

c

Alcohol excess or abuse refers to a high intake (e.g. >14 units per week), where the clinician assesses there would be an impact on health or bleeding risk.

A high bleeding risk score should not lead to withholding OAC, as the net clinical benefit of OAC is even greater amongst such patients. However, the formal assessment of bleeding risk informs management of patients taking OAC, focusing attention on modifiable bleeding risk factors that should be managed and (re)assessed at every patient contact, and identifying high-risk patients with non-modifiable bleeding risk factors who should be reviewed earlier (for instance in 4 weeks rather than 4 − 6 months) and more frequently.³⁸⁹^,⁴⁰⁷ Identification of ‘high bleeding risk’ patients is also needed when determining the antithrombotic strategy in specific AF patient groups, such as those undergoing percutaneous coronary intervention (PCI).

Overall, bleeding risk assessment based solely on modifiable bleeding risk factors is an inferior strategy compared with formal bleeding risk assessment using a bleeding risk score,^408–410 thus also considering the interaction between modifiable and non-modifiable bleeding risk factors. Bleeding risk is dynamic, and attention to the change in bleeding risk profile is a stronger predictor of major bleeding events compared with simply relying on baseline bleeding risk. In a recent study, there was a 3.5-fold higher risk of major bleeding in the first 3 months amongst patients who had a change in their bleeding risk profile.³⁸⁹

In the mAFA-II trial, prospective dynamic monitoring and reassessment using the HAS-BLED score (together with holistic App-based management) was associated with fewer major bleeding events, mitigated modifiable bleeding risk factors, and increased OAC uptake; in contrast, bleeding rates were higher and OAC use overall decreased by 25% in the ‘usual care’ arm when comparing baseline with 12 months.⁴¹¹

10.1.3 Absolute contraindications to oral anticoagulants

The few absolute contraindications to OAC include active serious bleeding (where the source should be identified and treated), associated comorbidities (e.g. severe thrombocytopenia <50 platelets/μL, severe anaemia under investigation, etc.), or a recent high-risk bleeding event such as intracranial haemorrhage (ICH). Non-drug options may be considered in such cases (section 11.4.3).

10.1.4 Stroke prevention therapies

10.1.4.1 Vitamin K antagonists

Compared with control or placebo, vitamin K antagonist (VKA) therapy (mostly warfarin) reduces stroke risk by 64% and mortality by 26%,⁴¹² and is still used in many AF patients worldwide. VKAs are currently the only treatment with established safety in AF patients with rheumatic mitral valve disease and/or an artificial heart valve.

The use of VKAs is limited by the narrow therapeutic interval, necessitating frequent international normalized ratio (INR) monitoring and dose adjustments.⁴¹³ At adequate time in therapeutic range [(TTR) >70%], VKAs are effective and relatively safe drugs. Quality of VKA management (quantified using the TTR based on the Rosendaal method, or the percentage of INRs in range) correlates with haemorrhagic and thrombo-embolic rates.⁴¹⁴ At high TTR values, the efficacy of VKAs in stroke prevention may be similar to NOACs, whereas the relative safety benefit with NOACs is less affected by TTR, with consistently lower serious bleeding rates (e.g. ICH) seen with NOACs compared with warfarin, notwithstanding that the absolute difference is small.⁴¹⁵^,⁴¹⁶

Numerous factors (including genetics, concomitant drugs, etc.) influence the intensity of VKA anticoagulant effect; the more common ones have been used to derive and validate the SAMe-TT₂R₂ {Sex [female], Age [<60 years], Medical history of ≥2 comorbidities [hypertension, diabetes mellitus, CAD/myocardial infarction, peripheral artery disease (PAD), HF, previous stroke, pulmonary disease, and hepatic or renal disease], Treatment [interacting drugs, e.g. amiodarone], Tobacco use, Race [non-Caucasian]} score,⁴¹⁷ which can help to identify patients who are less likely to achieve a good TTR on VKA therapy (score >2) and would do better with a NOAC. If such patients with SAMe-TT₂R₂>2 are prescribed a VKA, greater efforts to improve TTR, such as more intense regular reviews, education/counselling, and frequent INR monitoring are needed or, more conveniently, the use of a NOAC should be reconsidered.⁴¹⁸

10.1.4.2 Non-vitamin K antagonist oral anticoagulants

In four pivotal RCTs, apixaban, dabigatran, edoxaban, and rivaroxaban have shown non-inferiority to warfarin in the prevention of stroke/systemic embolism.^419–422 In a meta-analysis of these RCTs, NOACs were associated with a 19% significant stroke/systemic embolism risk reduction, a 51% reduction in haemorrhagic stroke,⁴²³ and similar ischaemic stroke risk reduction compared with VKAs, but NOACs were associated with a significant 10% reduction in all-cause mortality (Supplementary Table 8). There was a non-significant 14% reduction in major bleeding risk, significant 52% reduction in ICH, and 25% increase in gastrointestinal bleeding with NOACs vs. warfarin.⁴²³

The major bleeding relative risk reduction with NOACs was significantly greater when INR control was poor (i.e. centre-based TTR<66%). A meta-analysis of the five NOAC trials [RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy), ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), J-ROCKET AF, ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), and ENGAGE AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48)] showed that, compared with warfarin, standard-dose NOACs were more effective and safer in Asians than in non-Asians.⁴²⁴ In the AVERROES [Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment] trial of AF patients who refused or were deemed ineligible for VKA therapy, apixaban 5 mg b.i.d. (twice a day) significantly reduced the risk of stroke/systemic embolism with no significant difference in major bleeding or ICH compared with aspirin.⁴²⁵

Post-marketing observational data on the effectiveness and safety of dabigatran,⁴²⁶^,⁴²⁷ rivaroxaban,⁴²⁸^,⁴²⁹ apixaban,⁴³⁰ and edoxaban⁴³¹ vs. warfarin show general consistency with the respective RCT. Given the compelling evidence about NOACs, AF patients should be informed of this treatment option.

Persistence to NOAC therapy is generally higher than to VKAs, being facilitated by a better pharmacokinetic profile of NOACs⁴³² (Supplementary Table 9) and favourable safety and efficacy, especially amongst vulnerable patients including the elderly, those with renal dysfunction or previous stroke, and so on.⁴³³ Whereas patients with end-stage renal dysfunction were excluded from the pivotal RCTs, reduced dose regimens of rivaroxaban, edoxaban, and apixaban are feasible options for severe CKD [creatinine clearance (CrCl) 15 − 30 mL/min using the Cockcroft-Gault equation].⁴³⁴^,⁴³⁵ Considering that inappropriate dose reductions are frequent in clinical practice,⁴³⁶ thus increasing the risks of stroke/systemic embolism, hospitalization, and death, but without decreasing bleeding risk,⁴³⁷ NOAC therapy should be optimized based on the efficacy and safety profile of each NOAC in different patient subgroups (Table 11).

Table 11

Dose selection criteria for NOACs

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Standard dose	150 mg b.i.d.	20 mg o.d.	5 mg b.i.d.	60 mg o.d.
Lower dose	110 mg b.i.d.
Reduced dose		15 mg o.d.	2.5 mg b.i.d.	30 mg o.d.
Dose-reduction criteria	Dabigatran 110 mg b.i.d. in patients with: Age ≥80 years Concomitant use of verapamil, or Increased bleeding risk	CrCl 15 − 49 mL/min	At least 2 of 3 criteria: Age ≥80 years, Body weight ≤60 kg, or Serum creatinine ≥1.5 mg/dL (133 μmol/L)	If any of the following: CrCl 15 − 50 mL/min, Body weight ≤60 kg, Concomitant use of dronedarone, ciclosporine, erythromycin, or ketoconazole

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Standard dose	150 mg b.i.d.	20 mg o.d.	5 mg b.i.d.	60 mg o.d.
Lower dose	110 mg b.i.d.
Reduced dose		15 mg o.d.	2.5 mg b.i.d.	30 mg o.d.
Dose-reduction criteria	Dabigatran 110 mg b.i.d. in patients with: Age ≥80 years Concomitant use of verapamil, or Increased bleeding risk	CrCl 15 − 49 mL/min	At least 2 of 3 criteria: Age ≥80 years, Body weight ≤60 kg, or Serum creatinine ≥1.5 mg/dL (133 μmol/L)	If any of the following: CrCl 15 − 50 mL/min, Body weight ≤60 kg, Concomitant use of dronedarone, ciclosporine, erythromycin, or ketoconazole

b.i.d. = bis in die (twice a day); CrCl = creatinine clearance; o.d. = omni die (once daily).

Table 11

Dose selection criteria for NOACs

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Standard dose	150 mg b.i.d.	20 mg o.d.	5 mg b.i.d.	60 mg o.d.
Lower dose	110 mg b.i.d.
Reduced dose		15 mg o.d.	2.5 mg b.i.d.	30 mg o.d.
Dose-reduction criteria	Dabigatran 110 mg b.i.d. in patients with: Age ≥80 years Concomitant use of verapamil, or Increased bleeding risk	CrCl 15 − 49 mL/min	At least 2 of 3 criteria: Age ≥80 years, Body weight ≤60 kg, or Serum creatinine ≥1.5 mg/dL (133 μmol/L)	If any of the following: CrCl 15 − 50 mL/min, Body weight ≤60 kg, Concomitant use of dronedarone, ciclosporine, erythromycin, or ketoconazole

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Standard dose	150 mg b.i.d.	20 mg o.d.	5 mg b.i.d.	60 mg o.d.
Lower dose	110 mg b.i.d.
Reduced dose		15 mg o.d.	2.5 mg b.i.d.	30 mg o.d.
Dose-reduction criteria	Dabigatran 110 mg b.i.d. in patients with: Age ≥80 years Concomitant use of verapamil, or Increased bleeding risk	CrCl 15 − 49 mL/min	At least 2 of 3 criteria: Age ≥80 years, Body weight ≤60 kg, or Serum creatinine ≥1.5 mg/dL (133 μmol/L)	If any of the following: CrCl 15 − 50 mL/min, Body weight ≤60 kg, Concomitant use of dronedarone, ciclosporine, erythromycin, or ketoconazole

b.i.d. = bis in die (twice a day); CrCl = creatinine clearance; o.d. = omni die (once daily).

10.1.4.3 Other antithrombotic drugs

In the ACTIVE W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) trial, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was less effective than warfarin for prevention of stroke, systemic embolism, myocardial infarction, and vascular death (the annual risk of events was 5.6% vs. 3.9%, P =0.0003), with a similar rate of major bleeding.⁴³⁸ In the ACTIVE-A trial, patients unsuitable for anticoagulation had a lower rate of thrombo-embolic complications when clopidogrel was added to aspirin compared with aspirin alone, but with a significant increase in major bleeding.⁴³⁹ Aspirin monotherapy was ineffective for stroke prevention compared with no antithrombotic treatment and was associated with a higher risk of ischaemic stroke in elderly patients.⁴⁴⁰

Overall, antiplatelet monotherapy is ineffective for stroke prevention and is potentially harmful, (especially amongst elderly AF patients),⁴⁴¹^,⁴⁴² whereas DAPT is associated with a bleeding risk similar to OAC therapy. Hence, antiplatelet therapy should not be used for stroke prevention in AF patients.

10.1.4.4 Combination therapy with oral anticoagulant and antiplatelet drugs

The use of antiplatelet therapy remains common in clinical practice, often in patients without an indication (e.g. PAD, CAD, or cerebrovascular disease) beyond AF.⁴⁴³ There is limited evidence to support the combination therapy solely for stroke prevention in AF, with no effect on reductions in stroke, myocardial infarction, or death, but with a substantial increase in the risk of major bleeding and ICH.⁴⁴¹^,⁴⁴²

10.1.4.5 Left atrial appendage occlusion and exclusion

Left atrial appendage occlusion devices

Only the Watchman device has been compared with VKA therapy in RCTs [the PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) and PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy)],^444–446 where LAA occlusion was non-inferior to VKA stroke prevention treatment in AF patients with moderate stroke risk, with a possibility of lower bleeding rates on longer follow-up.⁴⁴⁷ The LAA occlusion may also reduce stroke risk in patients with contraindications to OAC.⁴⁴⁸^,⁴⁴⁹

A large European registry reported a high implantation success rate (98%), with an acceptable procedure-related complication rate of 4% at 30 days.⁴⁵⁰ Nevertheless, the implantation procedure can cause serious complications (higher event rates have been reported in real-world analyses compared with industry-sponsored studies, possibly identifying some reporting bias) and device-related thrombosis may not be a benign finding.^451–454 Antithrombotic management after LAA occlusion has never been evaluated in a randomized manner and is based on historical studies, at least including aspirin (Table 12). For patients who do not tolerate any antiplatelet therapy, either an epicardial catheter approach (e.g. Lariat system) or thoracoscopic clipping of the LAA may be an option.⁴⁵⁵^,⁴⁵⁶

Table 12

Antithrombotic therapy after left atrial appendage occlusion

Device/patient	Aspirin	OAC	Clopidogrel	Comments
Watchman/low bleeding risk	75 − 325 mg/day indefinitely	Start warfarin after procedure (target INR 2 − 3) until 45 days or continue until adequate LAA sealing is confirmed^a by TOE. NOAC is a possible alternative	Start 75 mg/day when OAC stopped, continue until 6 months after the procedure	Some centres do not withhold OAC at the time of procedure (no data to support/deny this approach)
Watchman/high bleeding risk	75 − 325 mg/day indefinitely	None	75 mg/day for 1 − 6 months while ensuring adequate LAA sealing^a	Clopidogrel often given for shorter time in very high-risk situations
ACP/Amulet	75 − 325 mg/day indefinitely	None	75 mg/day for 1 − 6 months while ensuring adequate LAA sealing^a	Clopidogrel may replace long-term aspirin if better tolerated

Device/patient	Aspirin	OAC	Clopidogrel	Comments
Watchman/low bleeding risk	75 − 325 mg/day indefinitely	Start warfarin after procedure (target INR 2 − 3) until 45 days or continue until adequate LAA sealing is confirmed^a by TOE. NOAC is a possible alternative	Start 75 mg/day when OAC stopped, continue until 6 months after the procedure	Some centres do not withhold OAC at the time of procedure (no data to support/deny this approach)
Watchman/high bleeding risk	75 − 325 mg/day indefinitely	None	75 mg/day for 1 − 6 months while ensuring adequate LAA sealing^a	Clopidogrel often given for shorter time in very high-risk situations
ACP/Amulet	75 − 325 mg/day indefinitely	None	75 mg/day for 1 − 6 months while ensuring adequate LAA sealing^a	Clopidogrel may replace long-term aspirin if better tolerated

ACP = Amplatzer^TM Cardiac Plug; INR = international normalized ratio; LAA = left atrial appendage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant ; TOE = transoesophageal echocardiography.

Note: Load aspirin or clopidogrel before procedure if untreated. Heparin with activated clotting time >250 seconds before or immediately after trans-septal punctures for all patients, followed by LMWH when warfarin needed.

a

Less than 5 mm leak.

Table 12

Antithrombotic therapy after left atrial appendage occlusion

Device/patient	Aspirin	OAC	Clopidogrel	Comments
Watchman/low bleeding risk	75 − 325 mg/day indefinitely	Start warfarin after procedure (target INR 2 − 3) until 45 days or continue until adequate LAA sealing is confirmed^a by TOE. NOAC is a possible alternative	Start 75 mg/day when OAC stopped, continue until 6 months after the procedure	Some centres do not withhold OAC at the time of procedure (no data to support/deny this approach)
Watchman/high bleeding risk	75 − 325 mg/day indefinitely	None	75 mg/day for 1 − 6 months while ensuring adequate LAA sealing^a	Clopidogrel often given for shorter time in very high-risk situations
ACP/Amulet	75 − 325 mg/day indefinitely	None	75 mg/day for 1 − 6 months while ensuring adequate LAA sealing^a	Clopidogrel may replace long-term aspirin if better tolerated

Device/patient	Aspirin	OAC	Clopidogrel	Comments
Watchman/low bleeding risk	75 − 325 mg/day indefinitely	Start warfarin after procedure (target INR 2 − 3) until 45 days or continue until adequate LAA sealing is confirmed^a by TOE. NOAC is a possible alternative	Start 75 mg/day when OAC stopped, continue until 6 months after the procedure	Some centres do not withhold OAC at the time of procedure (no data to support/deny this approach)
Watchman/high bleeding risk	75 − 325 mg/day indefinitely	None	75 mg/day for 1 − 6 months while ensuring adequate LAA sealing^a	Clopidogrel often given for shorter time in very high-risk situations
ACP/Amulet	75 − 325 mg/day indefinitely	None	75 mg/day for 1 − 6 months while ensuring adequate LAA sealing^a	Clopidogrel may replace long-term aspirin if better tolerated

ACP = Amplatzer^TM Cardiac Plug; INR = international normalized ratio; LAA = left atrial appendage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant ; TOE = transoesophageal echocardiography.

Note: Load aspirin or clopidogrel before procedure if untreated. Heparin with activated clotting time >250 seconds before or immediately after trans-septal punctures for all patients, followed by LMWH when warfarin needed.

a

Less than 5 mm leak.

Notably, the non-inferiority of LAA occlusion to VKA treatment was mostly driven by the prevention of haemorrhagic stroke, with a trend for more ischaemic strokes. The limitations of LAA occlusion as a strategy to reduce the risk of stroke associated with AF also include the consideration that AF acts as a risk marker of stroke. Withholding OAC after LAA occlusion is likely to result in undertreating the overall risk of stroke related to atrial cardiomyopathy.

Surgical left atrial appendage occlusion or exclusion

Multiple observational studies indicate the feasibility and safety of surgical LAA occlusion/exclusion, but only limited controlled trial data are available.^457–459 Residual LAA flow or incomplete LAA occlusion may be associated with an increased risk of stroke.⁴⁶⁰ In most studies, LAA occlusion/exclusion was performed during other open heart surgery, and in more recent years in combination with surgical ablation of AF⁴⁵⁹^,⁴⁶¹ or as an isolated thoracoscopic procedure. A large RCT in patients with an associated cardiac surgical procedure is ongoing.⁴⁶²

The most common justification for LAA occlusion/exclusion in clinical practice is a perceived high bleeding risk or, less often, contraindications for OAC.⁴⁵⁰ However, LAA occluders have not been randomly tested in such populations. Most patients who some years ago would be considered unsuitable for OAC therapy with VKA now seem to do relatively well on NOAC,⁴³³^,⁴⁶³^,⁴⁶⁴ and LAA occluders have not been compared with NOAC therapy in patients at risk for bleeding, or with surgical LAA occlusion/exclusion. Long-term aspirin is a common strategy in these patients,⁴⁶⁵ and one may question whether a NOAC would not be a better strategy if aspirin is tolerated. There is the need for adequately powered trials to define the best indications of LAA occlusion/exclusion compared with NOAC therapy in patients with relative or absolute contraindications for anticoagulation, in those suffering from an ischaemic stroke on anticoagulant therapy, and for assessment of the appropriate antithrombotic therapy after LAA occlusion.

10.1.4.6 Long-term oral anticoagulation per atrial fibrillation burden

Although the risk of ischaemic stroke/systemic embolism is higher with non-paroxysmal vs. paroxysmal AF, and AF progression is associated with an excess of adverse outcomes,¹⁶⁹^,⁴⁶⁶ the clinically determined temporal pattern of AF should not affect the decision regarding long-term OAC, which is driven by the presence of stroke risk factors.¹⁵⁶ Management of patients with AHRE/subclinical AF is reviewed in section 16. Stroke risk in AHRE patients may be lower than in patients with diagnosed AF,⁴⁶⁷ and strokes often occur without a clear temporal relationship with AHRE/subclinical AF,¹⁷⁹^,²²⁶ underscoring its role as a risk marker rather than a stroke risk factor.⁴^,¹⁷² Whether AHRE and subclinical AF have the same therapeutic requirements as clinical AF⁷ is presently unclear, and the net clinical benefit of OAC for AHRE/subclinical AF>24 h is currently being studied in several RCTs.⁴

Notably, patients with subclinical AF/AHRE may develop atrial tachyarrhythmias lasting more than 24 h⁴⁶⁸ or clinical AF; hence careful monitoring of these patients is recommended, even considering remote monitoring, especially with longer AHRE and higher risk profile.⁴⁶⁹ Given the dynamic nature of AF as well as stroke risk, a recorded duration in one monitoring period would not necessarily be the same in the next.

10.1.4.7 Long-term oral anticoagulation per symptom control strategy

Symptom control focuses on patient-centred and symptom-directed approaches to rate or rhythm control. Again, symptom control strategy should not affect the decision regarding long-term OAC, which is driven by the presence of stroke risk factors, and not the estimated success in maintaining sinus rhythm.

10.1.5 Management of anticoagulation-related bleeding risk

10.1.5.1 Strategies to minimize the risk of bleeding

Ensuring good quality of VKA treatment (TTR>70%) and selecting the appropriate dose of a NOAC (as per the dose reduction criteria specified on the respective drug label) are important considerations to minimize bleeding risk. As discussed in section 10.1.2, attention to modifiable bleeding risk factors should be made at every patient contact, and formal bleeding risk assessment is needed to help identify high-risk patients who should be followed up or reviewed earlier (e.g. 4 weeks rather than 4 − 6 months).⁴⁰⁷ Concomitant regular administration of antiplatelet drugs or non-steroidal anti-inflammatory drug (NSAID) should be avoided in anticoagulated patients. Bleeding risk is dynamic, and attention to the change in bleeding risk profile is a stronger predictor of major bleeding events, especially in the first 3 months.³⁸⁹

10.1.5.2 High-risk groups

Certain high-risk AF populations have been under-represented in RCTs, including the extreme elderly (≥90 years), those with cognitive impairment/dementia, recent bleeding or previous ICH, end-stage renal failure, liver impairment, cancer, and so on. Observational data suggest that such patients are at high risk for ischaemic stroke and death, and many would benefit from OAC.

Patients with liver function abnormalities may be at higher risk of bleeding on VKA, possibly less so on NOACs. Observational data in cirrhotic patients suggest that ischaemic stroke reduction may outweigh bleeding risk.^470–472

In patients with a recent bleeding event, attention should be directed towards addressing the predisposing pathology (e.g. bleeding ulcer or polyp in a patient with gastrointestinal bleeding), and the reintroduction of OAC as soon as feasible, as part of a multidisciplinary team decision. Consideration should be made for drugs such as apixaban or dabigatran 110 mg b.i.d., which are not associated with an excess of gastrointestinal bleeding compared with warfarin. Where OAC is not reintroduced, there is a higher risk of stroke and death compared with restarting OAC, although the risk of re-bleeding may be higher.⁴⁷³ Similarly, thromboprophylaxis in cancer may require a multidisciplinary team decision balancing stroke reduction against serious bleeding, which may be dependent on cancer type, site(s), staging, anti-cancer therapy and so on.

Thromboprophylaxis in specific high-risk groups is discussed in detail throughout section 11.

10.1.6 Decision making to avoid stroke

In observational population cohorts, both stroke and death are relevant endpoints, as some deaths could be due to fatal strokes (given that endpoints are not adjudicated in population cohorts, and cerebral imaging or post-mortems are not mandated). As OAC significantly reduces stroke (by 64%) and all-cause mortality (by 26%) compared with control or placebo,⁴¹² the endpoints of stroke and/or mortality are relevant in relation to decision making for thromboprophylaxis.

The threshold for initiating OAC for stroke prevention, balancing ischaemic stroke reduction against the risk of ICH and associated QoL, has been estimated to be 1.7%/year for warfarin and 0.9%/year for a NOAC (dabigatran data were used for the modelling analysis).⁴⁷⁴ The threshold for warfarin may be even lower, if good-quality anticoagulation control is achieved, with average TTR>70%.⁴⁷⁵

Given the limitations of clinical risk scores, the dynamic nature of stroke risk, the greater risk of stroke and death among AF patients with ≥1 non-sex stroke risk factor, and the positive net clinical benefit of OAC among such patients, we recommend a risk-factor–based approach to stroke prevention rather than undue focus on (artificially defined) ‘high-risk’ patients. As the default is to offer stroke prevention unless the patient is low risk, the CHA₂DS₂-VASc score should be applied in a reductionist manner, to decide on OAC or not.⁴⁷⁶

Thus, the first step in decision making (‘A’ Anticoagulation/Avoid stroke) is to identify low-risk patients who do not need antithrombotic therapy. Step 2 is to offer stroke prevention (i.e. OAC) to those with ≥1 non-sex stroke risk factors (the strength of evidence differs, with multiple clinical trials for patients with ≥2 stroke risk factors, and subgroups from trials/observational data on patients with 1 non-sex stroke risk factor). Step 3 is the choice of OAC—a NOAC (given their relative effectiveness, safety and convenience, these drugs are generally first choice as OAC for stroke prevention in AF) or VKA (with good TTR at >70%). This ‘AF 3-step’ patient pathway¹⁸²^,⁴⁷⁷ for stroke risk stratification and treatment decision making is shown in Figure 12.

‘A’ - Anticoagulation/Avoid stroke: The ‘AF 3-step’ pathway. AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; SAMe-TT2R2 = Sex (female), Age (<60 years), Medical history, Treatment (interacting drug(s)), Tobacco use, Race (non-Caucasian) (score); TTR = time in therapeutic range; VKA = vitamin K antagonist. aIf a VKA being considered, calculate SAMe-TT2R2 score: if score 0–2, may consider VKA treatment (e.g. warfarin) or NOAC; if score >2, should arrange regular review/frequent INR checks/ counselling for VKA users to help good anticoagulation control, or reconsider the use of NOAC instead; TTR ideally >70%.

Figure 12

‘A’ - Anticoagulation/Avoid stroke: The ‘AF 3-step’ pathway. AF = atrial fibrillation; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; SAMe-TT₂R₂ = Sex (female), Age (<60 years), Medical history, Treatment (interacting drug(s)), Tobacco use, Race (non-Caucasian) (score); TTR = time in therapeutic range; VKA = vitamin K antagonist. ^aIf a VKA being considered, calculate SAMe-TT₂R₂ score: if score 0–2, may consider VKA treatment (e.g. warfarin) or NOAC; if score >2, should arrange regular review/frequent INR checks/ counselling for VKA users to help good anticoagulation control, or reconsider the use of NOAC instead; TTR ideally >70%.

Recommendations for the prevention of thrombo-embolic events in AF

AF = atrial fibrillation; BP = blood pressure; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; LAA = left atrial appendage; NOAC = non-vitamin K antagonist oral anticoagulant; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant ; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

Including uncontrolled BP; labile INRs (in a patient taking VKA); alcohol excess; concomitant use of NSAIDs or aspirin in an anticoagulated patient; bleeding tendency or predisposition (e.g. treat gastric ulcer, optimize renal or liver function, etc.).

10.2 ‘B’ – Better symptom control

10.2.1 Rate control

Rate control is an integral part of AF management, and is often sufficient to improve AF-related symptoms. Very little robust evidence exists to inform the best type and intensity of rate control treatment.^484–486

10.2.1.1 Target/optimal ventricular rate range

The optimal heart-rate target in AF patients is unclear. In the RACE (Race Control Efficacy in Permanent Atrial Fibrillation) II RCT of permanent AF patients, there was no difference in a composite of clinical events, New York Heart Association (NYHA) class, or hospitalizations between the strict [target heart rate <80 beats per minute (bpm) at rest and <110 bpm during moderate exercise] and lenient (heart-rate target <110 bpm) arm,⁴⁸⁷^,⁴⁸⁸ similar to an analysis from the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) and RACE trials.⁴⁸⁹ Therefore, lenient rate control is an acceptable initial approach, regardless of HF status (with the exception of tachycardia-induced cardiomyopathy), unless symptoms call for stricter rate control (Figure 13).

Outline of rate control therapy.490 AF = atrial fibrillation; AVN = atrioventricular node; bpm = beats per minute; BV = biventricular; CRT = cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; ECG = electrocardiogram; LV = left ventricular; SR = sinus rhythm.

Figure 13

Outline of rate control therapy.⁴⁹⁰ AF = atrial fibrillation; AVN = atrioventricular node; bpm = beats per minute; BV = biventricular; CRT = cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; ECG = electrocardiogram; LV = left ventricular; SR = sinus rhythm.

10.2.1.2 Drugs

Pharmacological rate control can be achieved with beta-blockers, digoxin, diltiazem, and verapamil, or combination therapy (Table 13). Some antiarrhythmic drugs (AADs) also have rate-limiting properties (e.g. amiodarone, dronedarone, sotalol) but generally they should be used only for rhythm control. The choice of rate control drugs depends on symptoms, comorbidities, and potential side-effects (Table 13).

Beta-blockers are often first-line rate-controlling agents, largely based on better acute rate control. Interestingly, the prognostic benefit of beta-blockers seen in HF with reduced ejection fraction (HFrEF) patients with sinus rhythm has been questioned in patients with AF.⁴⁹¹

Non-dihydropyridine calcium channel blockers (NDCC) verapamil and diltiazem provide reasonable rate control⁴⁹² and can improve AF-related symptoms⁴⁸⁶ compared with beta-blockers. In one small trial of patients with preserved LVEF, NDCC preserved exercise capacity and reduced B-type natriuretic peptide.⁴⁹³^,⁴⁹⁴

Digoxin and digitoxin are not effective in patients with increased sympathetic drive. Observational studies have associated digoxin use with excess mortality in AF patients.^495–497 This finding was likely due to selection and prescription biases rather than harm caused by digoxin,^498–501 particularly as digoxin is commonly prescribed to sicker patients.⁵⁰² Lower doses of digoxin may be associated with better prognosis.⁵⁰² An ongoing RCT is addressing digitoxin use in patients with HFrEF.⁵⁰³

Amiodarone can be useful as a last resort when heart rate cannot be controlled with combination therapy in patients who do not qualify for non-pharmacological rate control, i.e. atrioventricular node ablation and pacing, notwithstanding the extracardiac adverse effects of the drug⁵⁰⁴ (Table 13).

Table 13

Drugs for rate control in AF^a

	Intravenous administration	Usual oral maintenance dose	Contraindicated
Beta-blockers^b
Metoprolol tartrate	2.5 − 5 mg i.v. bolus; up to 4 doses	25 − 100 mg b.i.d.	In case of asthma use beta-1-blockers Contraindicated in acute HF and history of severe bronchospasm
Metoprolol XL (succinate)	N/A	50 − 400 mg o.d.
Bisoprolol	N/A	1.25 − 20 mg o.d.
Atenolol^c	N/A	25 − 100 mg o.d.
Esmolol	500 µg/kg i.v. bolus over 1 min; followed by 50 − 300 µg/kg/min	N/A
Landiolol	100 µg/kg i.v. bolus over 1 min, followed by 10 - 40 µg/kg/min; in patients with cardiac dysfunction: 1 - 10 µg/kg/min	N/A
Nebivolol	N/A	2.5 − 10 mg o.d.
Carvedilol	N/A	3.125 − 50 mg b.i.d.
Non-dihydropyridine calcium channel antagonists
Verapamil	2.5 − 10 mg i.v. bolus over 5 min	40 mg b.i.d. to 480 mg (extended release) o.d.	Contraindicated in HFrEF Adapt doses in hepatic and renal impairment
Diltiazem	0.25 mg/kg i.v. bolus over 5 min, then 5 − 15 mg/h	60 mg t.i.d. to 360 mg (extended release) o.d.
Digitalis glycosides
Digoxin	0.5 mg i.v. bolus (0.75 − 1.5 mg over 24 hours in divided doses)	0.0625 − 0.25 mg o.d.	High plasma levels associated with increased mortality Check renal function before starting and adapt dose in CKD patients
Digitoxin	0.4 − 0.6 mg	0.05 − 0.1 mg o.d.	High plasma levels associated with increased mortality
Other
Amiodarone	300 mg i.v. diluted in 250 mL 5% dextrose over 30 − 60 min (preferably via central venous cannula), followed by 900 − 1200 mg i.v. over 24 hours diluted in 500 − 1000 mL via a central venous cannula	200 mg o.d. after loading 3 × 200 mg daily over 4 weeks, then 200 mg daily⁵³⁶^d(reduce other rate controlling drugs according to heart rate)	In case of thyroid disease, only if no other options

	Intravenous administration	Usual oral maintenance dose	Contraindicated
Beta-blockers^b
Metoprolol tartrate	2.5 − 5 mg i.v. bolus; up to 4 doses	25 − 100 mg b.i.d.	In case of asthma use beta-1-blockers Contraindicated in acute HF and history of severe bronchospasm
Metoprolol XL (succinate)	N/A	50 − 400 mg o.d.
Bisoprolol	N/A	1.25 − 20 mg o.d.
Atenolol^c	N/A	25 − 100 mg o.d.
Esmolol	500 µg/kg i.v. bolus over 1 min; followed by 50 − 300 µg/kg/min	N/A
Landiolol	100 µg/kg i.v. bolus over 1 min, followed by 10 - 40 µg/kg/min; in patients with cardiac dysfunction: 1 - 10 µg/kg/min	N/A
Nebivolol	N/A	2.5 − 10 mg o.d.
Carvedilol	N/A	3.125 − 50 mg b.i.d.
Non-dihydropyridine calcium channel antagonists
Verapamil	2.5 − 10 mg i.v. bolus over 5 min	40 mg b.i.d. to 480 mg (extended release) o.d.	Contraindicated in HFrEF Adapt doses in hepatic and renal impairment
Diltiazem	0.25 mg/kg i.v. bolus over 5 min, then 5 − 15 mg/h	60 mg t.i.d. to 360 mg (extended release) o.d.
Digitalis glycosides
Digoxin	0.5 mg i.v. bolus (0.75 − 1.5 mg over 24 hours in divided doses)	0.0625 − 0.25 mg o.d.	High plasma levels associated with increased mortality Check renal function before starting and adapt dose in CKD patients
Digitoxin	0.4 − 0.6 mg	0.05 − 0.1 mg o.d.	High plasma levels associated with increased mortality
Other
Amiodarone	300 mg i.v. diluted in 250 mL 5% dextrose over 30 − 60 min (preferably via central venous cannula), followed by 900 − 1200 mg i.v. over 24 hours diluted in 500 − 1000 mL via a central venous cannula	200 mg o.d. after loading 3 × 200 mg daily over 4 weeks, then 200 mg daily⁵³⁶^d(reduce other rate controlling drugs according to heart rate)	In case of thyroid disease, only if no other options

AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CKD = chronic kidney disease; HF = heart failure; HFrEF = HF with reduced ejection fraction; i.v. = intravenous; min = minutes; N/A = not available or not widely available; o.d. = omni die (once daily); t.i.d. = ter in die (three times a day).

a

All rate control drugs are contraindicated in Wolff−Parkinson−White syndrome, also i.v. amiodarone.

b

Other beta-blockers are available but not recommended as specific rate control therapy in AF and therefore not mentioned here (e.g. propranolol and labetalol).

c

No data on atenolol; should not be used in HFrEF.

d

Loading regimen may vary; i.v. dosage should be considered when calculating total load.

Table 13

Drugs for rate control in AF^a

	Intravenous administration	Usual oral maintenance dose	Contraindicated
Beta-blockers^b
Metoprolol tartrate	2.5 − 5 mg i.v. bolus; up to 4 doses	25 − 100 mg b.i.d.	In case of asthma use beta-1-blockers Contraindicated in acute HF and history of severe bronchospasm
Metoprolol XL (succinate)	N/A	50 − 400 mg o.d.
Bisoprolol	N/A	1.25 − 20 mg o.d.
Atenolol^c	N/A	25 − 100 mg o.d.
Esmolol	500 µg/kg i.v. bolus over 1 min; followed by 50 − 300 µg/kg/min	N/A
Landiolol	100 µg/kg i.v. bolus over 1 min, followed by 10 - 40 µg/kg/min; in patients with cardiac dysfunction: 1 - 10 µg/kg/min	N/A
Nebivolol	N/A	2.5 − 10 mg o.d.
Carvedilol	N/A	3.125 − 50 mg b.i.d.
Non-dihydropyridine calcium channel antagonists
Verapamil	2.5 − 10 mg i.v. bolus over 5 min	40 mg b.i.d. to 480 mg (extended release) o.d.	Contraindicated in HFrEF Adapt doses in hepatic and renal impairment
Diltiazem	0.25 mg/kg i.v. bolus over 5 min, then 5 − 15 mg/h	60 mg t.i.d. to 360 mg (extended release) o.d.
Digitalis glycosides
Digoxin	0.5 mg i.v. bolus (0.75 − 1.5 mg over 24 hours in divided doses)	0.0625 − 0.25 mg o.d.	High plasma levels associated with increased mortality Check renal function before starting and adapt dose in CKD patients
Digitoxin	0.4 − 0.6 mg	0.05 − 0.1 mg o.d.	High plasma levels associated with increased mortality
Other
Amiodarone	300 mg i.v. diluted in 250 mL 5% dextrose over 30 − 60 min (preferably via central venous cannula), followed by 900 − 1200 mg i.v. over 24 hours diluted in 500 − 1000 mL via a central venous cannula	200 mg o.d. after loading 3 × 200 mg daily over 4 weeks, then 200 mg daily⁵³⁶^d(reduce other rate controlling drugs according to heart rate)	In case of thyroid disease, only if no other options

	Intravenous administration	Usual oral maintenance dose	Contraindicated
Beta-blockers^b
Metoprolol tartrate	2.5 − 5 mg i.v. bolus; up to 4 doses	25 − 100 mg b.i.d.	In case of asthma use beta-1-blockers Contraindicated in acute HF and history of severe bronchospasm
Metoprolol XL (succinate)	N/A	50 − 400 mg o.d.
Bisoprolol	N/A	1.25 − 20 mg o.d.
Atenolol^c	N/A	25 − 100 mg o.d.
Esmolol	500 µg/kg i.v. bolus over 1 min; followed by 50 − 300 µg/kg/min	N/A
Landiolol	100 µg/kg i.v. bolus over 1 min, followed by 10 - 40 µg/kg/min; in patients with cardiac dysfunction: 1 - 10 µg/kg/min	N/A
Nebivolol	N/A	2.5 − 10 mg o.d.
Carvedilol	N/A	3.125 − 50 mg b.i.d.
Non-dihydropyridine calcium channel antagonists
Verapamil	2.5 − 10 mg i.v. bolus over 5 min	40 mg b.i.d. to 480 mg (extended release) o.d.	Contraindicated in HFrEF Adapt doses in hepatic and renal impairment
Diltiazem	0.25 mg/kg i.v. bolus over 5 min, then 5 − 15 mg/h	60 mg t.i.d. to 360 mg (extended release) o.d.
Digitalis glycosides
Digoxin	0.5 mg i.v. bolus (0.75 − 1.5 mg over 24 hours in divided doses)	0.0625 − 0.25 mg o.d.	High plasma levels associated with increased mortality Check renal function before starting and adapt dose in CKD patients
Digitoxin	0.4 − 0.6 mg	0.05 − 0.1 mg o.d.	High plasma levels associated with increased mortality
Other
Amiodarone	300 mg i.v. diluted in 250 mL 5% dextrose over 30 − 60 min (preferably via central venous cannula), followed by 900 − 1200 mg i.v. over 24 hours diluted in 500 − 1000 mL via a central venous cannula	200 mg o.d. after loading 3 × 200 mg daily over 4 weeks, then 200 mg daily⁵³⁶^d(reduce other rate controlling drugs according to heart rate)	In case of thyroid disease, only if no other options

AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CKD = chronic kidney disease; HF = heart failure; HFrEF = HF with reduced ejection fraction; i.v. = intravenous; min = minutes; N/A = not available or not widely available; o.d. = omni die (once daily); t.i.d. = ter in die (three times a day).

a

All rate control drugs are contraindicated in Wolff−Parkinson−White syndrome, also i.v. amiodarone.

b

Other beta-blockers are available but not recommended as specific rate control therapy in AF and therefore not mentioned here (e.g. propranolol and labetalol).

c

No data on atenolol; should not be used in HFrEF.

d

Loading regimen may vary; i.v. dosage should be considered when calculating total load.

10.2.1.3 Acute rate control

In acute settings, physicians should always evaluate underlying causes, such as infection or anaemia. Beta-blockers and diltiazem/verapamil are preferred over digoxin because of their rapid onset of action and effectiveness at high sympathetic tone.^507–511 The choice of drug (Table 13 and Figure 14) and target heart rate will depend on the patient characteristics, symptoms, LVEF value, and haemodynamics, but a lenient initial rate control approach seems acceptable (Figure 13). Combination therapy may be required. In patients with HFrEF, beta-blockers, digitalis, or their combination should be used.⁵¹²^,⁵¹³ In critically ill patients and those with severely impaired LV systolic function, i.v. amiodarone can be used.⁵⁰⁴^,⁵¹⁴^,⁵¹⁵ In unstable patients, urgent cardioversion should be considered (section 11.1).

$Choice of rate control drugs.490 AF = atrial fibrillation; AFL = atrial flutter; COPD = chronic obstructive pulmonary disease; CRT-D = cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; NDCC = Non-dihydropyridine calcium channel blocker. aClinical reassessment should be focused on evaluation of resting heart rate, AF/AFL-related symptoms and quality of life. In case suboptimal rate control (resting heart rate >110 bpm), worsening of symptoms or quality of life consider 2nd line and, if necessary, 3rd line treatment options. bCareful institution of beta-blocker and NDCC, 24-hour Holter to check for bradycardia.$

Figure 14

Choice of rate control drugs.⁴⁹⁰ AF = atrial fibrillation; AFL = atrial flutter; COPD = chronic obstructive pulmonary disease; CRT-D = cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; NDCC = Non-dihydropyridine calcium channel blocker. ^aClinical reassessment should be focused on evaluation of resting heart rate, AF/AFL-related symptoms and quality of life. In case suboptimal rate control (resting heart rate >110 bpm), worsening of symptoms or quality of life consider 2nd line and, if necessary, 3rd line treatment options. ^bCareful institution of beta-blocker and NDCC, 24-hour Holter to check for bradycardia.

10.2.1.4 Atrioventricular node ablation and pacing

Ablation of the atrioventricular node and pacemaker implantation can control ventricular rate when medication fails. The procedure is relatively simple and has a low complication rate and low long-term mortality risk,⁵¹⁶^,⁵¹⁷ especially when the pacemaker is implanted a few weeks before the atrioventricular node ablation and the initial pacing rate after ablation is set at 70–90 bpm.⁵¹⁸^,⁵¹⁹ The procedure does not worsen LV function⁵²⁰ and may even improve LVEF in selected patients.^521–523 Most studies have included older patients with limited life expectancy. For younger patients, ablation of the atrioventricular node should only be considered if there is urgent need for rate control and all other pharmacological and non-pharmacological treatment options have been carefully considered. The choice of pacing therapy (right ventricular or biventricular pacing) will depend on patient characteristics.⁵²⁴^,⁵²⁵ His-bundle pacing after atrioventricular node ablation may evolve as an attractive alternative pacing mode,⁵²⁶ as currently tested in ongoing clinical trials (NCT02805465, NCT02700425).

In severely symptomatic patients with permanent AF and at least one hospitalization for HF, atrioventricular node ablation combined with cardiac resynchronization therapy (CRT) may be preferred. In a small RCT, the primary composite outcome (death or hospitalization for HF, or worsening HF) was significantly less common in the ablation + CRT group vs. the drug arm (P =0.013), and ablation + CRT patients showed a 36% decrease in symptoms and physical limitations at 1-year follow-up (P =0.004).⁵²⁷ Emerging evidence suggest that His-bundle pacing could be an alternative in these patients.⁵²⁸

Recommendations for ventricular rate control in patients with AF^a

AF = atrial fibrillation; bpm = beats per minute; ECG = electrocardiogram; LA = left atrial; LVEF = left ventricular ejection fraction.

a

See section 11 for ventricular rate control in various concomitant conditions and AF populations

b

Class of recommendation.

c

Level of evidence.

d

Combining beta-blocker with verapamil or diltiazem should be performed with careful monitoring of heart rate by 24-h ECG to check for bradycardia.⁴⁸⁸

10.2.2 Rhythm control

The ‘rhythm control strategy’ refers to attempts to restore and maintain sinus rhythm, and may engage a combination of treatment approaches, including cardioversion,¹⁶⁴^,²³⁴ antiarrhythmic medication,²³³^,⁵³⁷^,⁵³⁸ and catheter ablation,^539–541 along with an adequate rate control, anticoagulation therapy (section 10.2.2.6) and comprehensive cardiovascular prophylactic therapy (upstream therapy, including lifestyle and sleep apnoea management) (Figure 15).

Figure 15

Rhythm control strategy. AAD = antiarrhythmic drug; AF = atrial fibrillation; CMP = cardiomyopathy; CV = cardioversion; LAVI = left atrial volume index; PAF = paroxysmal atrial fibrillation; PVI = pulmonary vein isolation; QoL = quality of life; SR = sinus rhythm. ^aConsider cardioversion to confirm that the absence of symptoms is not due to unconscious adaptation to reduced physical and/or mental capacity.

10.2.2.1 Indications for rhythm control

Based on the currently available evidence from RCTs, the primary indication for rhythm control is to reduce AF-related symptoms and improve QoL (Figure 15). In case of uncertainty, an attempt to restore sinus rhythm in order to evaluate the response to therapy may be a rational first step. Factors that may favour an attempt at rhythm control should be considered⁵⁴²^,⁵⁴³ (Figure 15).

As AF progression is associated with a decrease in QoL⁵⁴⁴ and, with time, becomes irreversible or less amenable to treatment,¹⁷⁶ rhythm control may be a relevant choice, although currently there is no substantial evidence that this may result in a different outcome. Reportedly, rates of AF progression were significantly lower with rhythm control than rate control.⁵⁴⁵ Older age, persistent AF, and previous stroke/TIA independently predicted AF progression,⁵⁴⁵ which may be considered when deciding the treatment strategy. For many patients, an early intervention to prevent AF progression may be worth considering,⁵⁴⁶ including optimal risk-factor management.²⁴⁵ Ongoing trials in patients with newly diagnosed symptomatic AF will assess whether early rhythm control interventions such as AF catheter ablation offer an opportunity to halt the progressive patho-anatomical changes associated with AF.⁵⁴⁷ However, there is evidence that, at least in some patients, a successful rhythm control strategy with AF catheter ablation may not affect atrial substrate development.⁵⁴⁸ Important evidence regarding the effect of early rhythm control therapy on clinical outcomes are expected in 2020 from the ongoing EAST (Early treatment of Atrial fibrillation for Stoke prevention Trial) trial.⁵⁴⁹

General recommendations regarding active informed patient involvement in shared decision making (section 9) also apply for rhythm control strategies. The same principles should be applied in female and male AF patients when considering rhythm control therapy.⁵⁵⁰

Recommendations for rhythm control

AF = atrial fibrillation; QoL = quality of life.

a

Class of recommendation.

b

Level of evidence.

10.2.2.2 Cardioversion

Immediate cardioversion/elective cardioversion

Acute rhythm control can be performed as an emergency cardioversion in a haemodynamically unstable AF patient or in a non-emergency situation. Synchronized direct current electrical cardioversion is the preferred choice in haemodynamically compromised AF patients as it is more effective than pharmacological cardioversion and results in immediate restoration of sinus rhythm.⁵⁵⁴^,⁵⁵⁵ In stable patients, either pharmacological cardioversion or electrical cardioversion can be attempted; pharmacological cardioversion is less effective but does not require sedation. Of note, pre-treatment with AADs can improve the efficacy of elective electrical cardioversion.⁵⁵⁶ A RCT showed maximum fixed-energy electrical cardioversion was more effective than an energy-escalation strategy.⁵⁵⁷

In a RCT, a wait-and-watch approach with rate control medication only and cardioversion when needed within 48 h of symptom onset was as safe as and non-inferior to immediate cardioversion of paroxysmal AF, which often resolves spontaneously within 24 h.⁵⁵⁸

Elective cardioversion refers to the situation when cardioversion can be planned beyond the nearest hours. Observational data²⁴³ showed that cardioversion did not result in improved AF-related QoL or halted AF progression, but many of these patients did not receive adjunctive rhythm control therapies.²⁴³ Other studies reported significant QoL improvement in patients who maintain sinus rhythm after electrical cardioversion and the only variable independently associated with a moderate to large effect size was sinus rhythm at 3 months.²³²

Factors associated with an increased risk for AF recurrence after elective cardioversion include older age, female sex, previous cardioversion, chronic obstructive pulmonary disease (COPD), renal impairment, structural heart disease, larger LA volume index, and HF.¹⁶⁴^,⁵⁵⁹^,⁵⁶⁰ Treatment of potentially modifiable conditions should be considered before cardioversion to facilitate maintenance of sinus rhythm (Figure 15).²⁴⁵ In case of AF recurrence after cardioversion in patients with persistent AF, an early re-cardioversion may prolong subsequent duration of sinus rhythm.⁵⁶¹

Non-emergency cardioversion is contraindicated in the presence of known LA thrombus. Peri-procedural thrombo-embolic risk should be evaluated and peri-procedural and long-term OAC use considered irrespective of cardioversion mode (i.e. pharmacological cardioversion or electrical cardioversion) (section 10.2.2.6). A flowchart for decision making on cardioversion is shown in Figure 16.

$Flowchart for decision making on cardioversion of AF depending on clinical presentation, AF onset, oral anticoagulation intake, and risk factors for stroke. AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); cardioversion = cardioversion; ECV = electrical cardioversion; h = hour; LA = left atrium; LAA = left atrial appendage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TE = thromboembolism; TOE = transoesophageal echocardiography; UFH = unfractionated heparin; VKA = vitamin K antagonist.$

Figure 16

Flowchart for decision making on cardioversion of AF depending on clinical presentation, AF onset, oral anticoagulation intake, and risk factors for stroke. AF = atrial fibrillation; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); cardioversion = cardioversion; ECV = electrical cardioversion; h = hour; LA = left atrium; LAA = left atrial appendage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TE = thromboembolism; TOE = transoesophageal echocardiography; UFH = unfractionated heparin; VKA = vitamin K antagonist.

Electrical cardioversion

Electrical cardioversion can be performed safely in sedated patients treated with i.v. midazolam and/or propofol or etomidate.⁵⁶² BP monitoring and oximetry during the procedure should be used routinely. Skin burns may occasionally be observed. Intravenous atropine or isoproterenol, or temporary transcutaneous pacing, should be available in case of post-cardioversion bradycardia. Biphasic defibrillators are standard because of their superior efficacy compared with monophasic defibrillators.⁵⁶³^,⁵⁶⁴ Anterior–posterior electrode positions restore sinus rhythm more effectively,⁵⁵⁴^,⁵⁵⁵ while other reports suggest that specific electrical pad positioning is not critically important for successful cardioversion.⁵⁶⁵

Pharmacological cardioversion (including ‘pill in the pocket’)

Pharmacological cardioversion to sinus rhythm is an elective procedure indicated in haemodynamically stable patients. Its true efficacy is biased by the spontaneous restoration of sinus rhythm within 48 h of hospitalization in 76 − 83% of patients with recent onset AF (10 − 18% within first 3 h, 55 − 66% within 24 h, and 69% within 48 h).^566–568 Therefore, a ‘wait-and-watch’ strategy (usually for <24 h) may be considered in patients with recent-onset AF as a non-inferior alternative to early cardioversion.⁵⁵⁸

Table 14

Antiarrhythmic drugs used for restoration of sinus rhythm

Antiarrhythmic drugs for restoration of sinus rhythm (pharmacological cardioversion)
Drug	Administration route	Initial dose for cardioversion	Further dosing for cardioversion	Acute success rate and expected time to sinus rhythm	Contraindications/precautions/comments
Flecainide^a	Oral^b i.v.	200–300 mg 2 mg/kg over 10 min	−	Overall: 59–78% (51% at 3 h, 72% at 8 h)	Should not be used in ischaemic heart disease and/or significant structural heart disease May induce hypotension, AFL with 1:1 conduction (in 3.5 − 5.0% of patients) Flecainide may induce mild QRS complex widening Do NOT use for pharmacological cardioversion of AFL
Propafenone^a	Oral^b i.v.	450–600 mg 1.5 − 2 mg/kg over 10 min	−	Oral: 45–55% at 3 h, 69–78% at 8 h; i.v.: 43–89% Up to 6 h
Vernakalant^c	i.v.	3 mg/kg over 10 min	2 mg/kg over 10 min (10 − 15 min after the initial dose)	<1 h (50% conversion within 10 min)	Should not be used in patients with arterial hypotension (SBP <100 mmHg), recent ACS (within 1 month), NYHA III or IV HF, prolonged QT, or severe aortic stenosis May cause arterial hypotension, QT prolongation, QRS widening, or non-sustained ventricular tachycardia
Amiodarone^a	i.v.	5 − 7 mg/kg over 1 − 2 h	50 mg/h (maximum 1.2 g for 24 h)	44% (8–12 h to several days)	May cause phlebitis (use a large peripheral vein, avoid i.v. administration >24 hours and use preferably volumetric pump) May cause hypotension, bradycardia/atrioventricular block, QT prolongation Only if no other options in patients with hyperthyroidism (risk of thyrotoxicosis)
Ibutilide^c	i.v.	1 mg over 10 min 0.01 mg/kg if body weight <60 kg	1 mg over 10 min (10 − 20 min after the initial dose)	31–51% (AF) 63–73% (AFL) ≈1 h	Effective for conversion of AFL Should not be used in patients with prolonged QT, severe LVH, or low LVEF Should be used in the setting of a cardiac care unit as it may cause QT prolongation, polymorphic ventricular tachycardia (torsades de pointes) ECG monitoring for at least 4 hours after administration to detect a proarrhythmic event

Antiarrhythmic drugs for restoration of sinus rhythm (pharmacological cardioversion)
Drug	Administration route	Initial dose for cardioversion	Further dosing for cardioversion	Acute success rate and expected time to sinus rhythm	Contraindications/precautions/comments
Flecainide^a	Oral^b i.v.	200–300 mg 2 mg/kg over 10 min	−	Overall: 59–78% (51% at 3 h, 72% at 8 h)	Should not be used in ischaemic heart disease and/or significant structural heart disease May induce hypotension, AFL with 1:1 conduction (in 3.5 − 5.0% of patients) Flecainide may induce mild QRS complex widening Do NOT use for pharmacological cardioversion of AFL
Propafenone^a	Oral^b i.v.	450–600 mg 1.5 − 2 mg/kg over 10 min	−	Oral: 45–55% at 3 h, 69–78% at 8 h; i.v.: 43–89% Up to 6 h
Vernakalant^c	i.v.	3 mg/kg over 10 min	2 mg/kg over 10 min (10 − 15 min after the initial dose)	<1 h (50% conversion within 10 min)	Should not be used in patients with arterial hypotension (SBP <100 mmHg), recent ACS (within 1 month), NYHA III or IV HF, prolonged QT, or severe aortic stenosis May cause arterial hypotension, QT prolongation, QRS widening, or non-sustained ventricular tachycardia
Amiodarone^a	i.v.	5 − 7 mg/kg over 1 − 2 h	50 mg/h (maximum 1.2 g for 24 h)	44% (8–12 h to several days)	May cause phlebitis (use a large peripheral vein, avoid i.v. administration >24 hours and use preferably volumetric pump) May cause hypotension, bradycardia/atrioventricular block, QT prolongation Only if no other options in patients with hyperthyroidism (risk of thyrotoxicosis)
Ibutilide^c	i.v.	1 mg over 10 min 0.01 mg/kg if body weight <60 kg	1 mg over 10 min (10 − 20 min after the initial dose)	31–51% (AF) 63–73% (AFL) ≈1 h	Effective for conversion of AFL Should not be used in patients with prolonged QT, severe LVH, or low LVEF Should be used in the setting of a cardiac care unit as it may cause QT prolongation, polymorphic ventricular tachycardia (torsades de pointes) ECG monitoring for at least 4 hours after administration to detect a proarrhythmic event

AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; AFL = atrial flutter; b.i.d. = bis in die (twice a day); CrCl = creatinine clearance; CYP2D6 = cytochrome P450 2D6; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; HCM = hypertrophic cardiomyopathy; HF = heart failure; i.v. = intravenous; LV = left ventricular; LVEF = left ventricular ejection fraction; LVH = LV hypertrophy; NYHA = New York Heart Association; QRS = QRS interval; QT = QT interval; SA = sinoatrial; SBP = systolic blood pressure; VKA = vitamin K antagonist.

a

Most frequently used for cardioversion of AF, available in most countries.

b

May be self-administered by selected outpatients as a ‘pill-in-the-pocket’ treatment strategy.

c

Not available in some countries.

For more details regarding pharmacokinetic or pharmacodynamic properties refer to EHRA AADs–clinical use and clinical decision making: a consensus document.⁵⁶⁸

Table 14

Antiarrhythmic drugs used for restoration of sinus rhythm

Antiarrhythmic drugs for restoration of sinus rhythm (pharmacological cardioversion)
Drug	Administration route	Initial dose for cardioversion	Further dosing for cardioversion	Acute success rate and expected time to sinus rhythm	Contraindications/precautions/comments
Flecainide^a	Oral^b i.v.	200–300 mg 2 mg/kg over 10 min	−	Overall: 59–78% (51% at 3 h, 72% at 8 h)	Should not be used in ischaemic heart disease and/or significant structural heart disease May induce hypotension, AFL with 1:1 conduction (in 3.5 − 5.0% of patients) Flecainide may induce mild QRS complex widening Do NOT use for pharmacological cardioversion of AFL
Propafenone^a	Oral^b i.v.	450–600 mg 1.5 − 2 mg/kg over 10 min	−	Oral: 45–55% at 3 h, 69–78% at 8 h; i.v.: 43–89% Up to 6 h
Vernakalant^c	i.v.	3 mg/kg over 10 min	2 mg/kg over 10 min (10 − 15 min after the initial dose)	<1 h (50% conversion within 10 min)	Should not be used in patients with arterial hypotension (SBP <100 mmHg), recent ACS (within 1 month), NYHA III or IV HF, prolonged QT, or severe aortic stenosis May cause arterial hypotension, QT prolongation, QRS widening, or non-sustained ventricular tachycardia
Amiodarone^a	i.v.	5 − 7 mg/kg over 1 − 2 h	50 mg/h (maximum 1.2 g for 24 h)	44% (8–12 h to several days)	May cause phlebitis (use a large peripheral vein, avoid i.v. administration >24 hours and use preferably volumetric pump) May cause hypotension, bradycardia/atrioventricular block, QT prolongation Only if no other options in patients with hyperthyroidism (risk of thyrotoxicosis)
Ibutilide^c	i.v.	1 mg over 10 min 0.01 mg/kg if body weight <60 kg	1 mg over 10 min (10 − 20 min after the initial dose)	31–51% (AF) 63–73% (AFL) ≈1 h	Effective for conversion of AFL Should not be used in patients with prolonged QT, severe LVH, or low LVEF Should be used in the setting of a cardiac care unit as it may cause QT prolongation, polymorphic ventricular tachycardia (torsades de pointes) ECG monitoring for at least 4 hours after administration to detect a proarrhythmic event

Antiarrhythmic drugs for restoration of sinus rhythm (pharmacological cardioversion)
Drug	Administration route	Initial dose for cardioversion	Further dosing for cardioversion	Acute success rate and expected time to sinus rhythm	Contraindications/precautions/comments
Flecainide^a	Oral^b i.v.	200–300 mg 2 mg/kg over 10 min	−	Overall: 59–78% (51% at 3 h, 72% at 8 h)	Should not be used in ischaemic heart disease and/or significant structural heart disease May induce hypotension, AFL with 1:1 conduction (in 3.5 − 5.0% of patients) Flecainide may induce mild QRS complex widening Do NOT use for pharmacological cardioversion of AFL
Propafenone^a	Oral^b i.v.	450–600 mg 1.5 − 2 mg/kg over 10 min	−	Oral: 45–55% at 3 h, 69–78% at 8 h; i.v.: 43–89% Up to 6 h
Vernakalant^c	i.v.	3 mg/kg over 10 min	2 mg/kg over 10 min (10 − 15 min after the initial dose)	<1 h (50% conversion within 10 min)	Should not be used in patients with arterial hypotension (SBP <100 mmHg), recent ACS (within 1 month), NYHA III or IV HF, prolonged QT, or severe aortic stenosis May cause arterial hypotension, QT prolongation, QRS widening, or non-sustained ventricular tachycardia
Amiodarone^a	i.v.	5 − 7 mg/kg over 1 − 2 h	50 mg/h (maximum 1.2 g for 24 h)	44% (8–12 h to several days)	May cause phlebitis (use a large peripheral vein, avoid i.v. administration >24 hours and use preferably volumetric pump) May cause hypotension, bradycardia/atrioventricular block, QT prolongation Only if no other options in patients with hyperthyroidism (risk of thyrotoxicosis)
Ibutilide^c	i.v.	1 mg over 10 min 0.01 mg/kg if body weight <60 kg	1 mg over 10 min (10 − 20 min after the initial dose)	31–51% (AF) 63–73% (AFL) ≈1 h	Effective for conversion of AFL Should not be used in patients with prolonged QT, severe LVH, or low LVEF Should be used in the setting of a cardiac care unit as it may cause QT prolongation, polymorphic ventricular tachycardia (torsades de pointes) ECG monitoring for at least 4 hours after administration to detect a proarrhythmic event

AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; AFL = atrial flutter; b.i.d. = bis in die (twice a day); CrCl = creatinine clearance; CYP2D6 = cytochrome P450 2D6; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; HCM = hypertrophic cardiomyopathy; HF = heart failure; i.v. = intravenous; LV = left ventricular; LVEF = left ventricular ejection fraction; LVH = LV hypertrophy; NYHA = New York Heart Association; QRS = QRS interval; QT = QT interval; SA = sinoatrial; SBP = systolic blood pressure; VKA = vitamin K antagonist.

a

Most frequently used for cardioversion of AF, available in most countries.

b

May be self-administered by selected outpatients as a ‘pill-in-the-pocket’ treatment strategy.

c

Not available in some countries.

For more details regarding pharmacokinetic or pharmacodynamic properties refer to EHRA AADs–clinical use and clinical decision making: a consensus document.⁵⁶⁸

The choice of a specific drug is based on the type and severity of associated heart disease (Table 14), and pharmacological cardioversion is more effective in recent onset AF. Flecainide (and other class Ic agents), indicated in patients without significant LV hypertrophy (LVH), LV systolic dysfunction, or ischaemic heart disease, results in prompt (3 − 5 h) and safe⁵⁶⁹ restoration of sinus rhythm in >50% of patients,^570–574 while i.v. amiodarone, mainly indicated in HF patients, has a limited and delayed effect but can slow heart rate within 12 h.⁵⁷⁰, 575–577 Intravenous vernakalant is the most rapidly cardioverting drug, including patients with mild HF and ischaemic heart disease, and is more effective than amiodarone^578–583 or flecainide.⁵⁸⁴ Dofetilide is not used in Europe and is rarely used outside Europe. Ibutilide is effective to convert atrial flutter (AFL) to sinus rhythm.⁵⁸⁵

In selected outpatients with rare paroxysmal AF episodes, a self-administered oral dose of flecainide or propafenone is slightly less effective than in-hospital pharmacological cardioversion but may be preferred (permitting an earlier conversion), provided that the drug safety and efficacy has previously been established in the hospital setting.⁵⁸⁶ An atrioventricular node-blocking drug should be instituted in patients treated with class Ic AADs (especially flecainide) to avoid transformation to AFL with 1:1 conduction.⁵⁸⁷

Follow-up after cardioversion

The goals of follow-up after cardioversion are shown in Table 15. When assessing the efficacy of a rhythm control strategy, it is important to balance symptoms and AAD side-effects. Patients should be reviewed after cardioversion to detect whether an alternative rhythm control strategy including AF catheter ablation, or a rate control approach is needed instead of current treatment.

Table 15

Goals of follow-up after cardioversion of AF

Goals
Early recognition of AF recurrence by ECG recording after cardioversion
Evaluation of the efficacy of rhythm control by symptom assessment
Monitoring of risk for proarrhythmia by regular control of PR, QRS, and QTc intervals in patients on Class I or III AADs
Evaluation of balance between symptoms and side-effects of therapy considering QoL and symptoms
Evaluation of AF-related morbidities and AAD-related side-effects on concomitant cardiovascular conditions and LV function
Optimization of conditions for maintenance of sinus rhythm including cardiovascular risk management (BP control, HF treatment, increasing cardiorespiratory fitness, and other measures, see section 11).

Goals
Early recognition of AF recurrence by ECG recording after cardioversion
Evaluation of the efficacy of rhythm control by symptom assessment
Monitoring of risk for proarrhythmia by regular control of PR, QRS, and QTc intervals in patients on Class I or III AADs
Evaluation of balance between symptoms and side-effects of therapy considering QoL and symptoms
Evaluation of AF-related morbidities and AAD-related side-effects on concomitant cardiovascular conditions and LV function
Optimization of conditions for maintenance of sinus rhythm including cardiovascular risk management (BP control, HF treatment, increasing cardiorespiratory fitness, and other measures, see section 11).

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram; HF = heart failure; LV = left ventricular; PR = PR interval; QoL = quality of life; QRS = QRS interval; QTc = corrected QT interval.

Table 15

Goals of follow-up after cardioversion of AF

Goals
Early recognition of AF recurrence by ECG recording after cardioversion
Evaluation of the efficacy of rhythm control by symptom assessment
Monitoring of risk for proarrhythmia by regular control of PR, QRS, and QTc intervals in patients on Class I or III AADs
Evaluation of balance between symptoms and side-effects of therapy considering QoL and symptoms
Evaluation of AF-related morbidities and AAD-related side-effects on concomitant cardiovascular conditions and LV function
Optimization of conditions for maintenance of sinus rhythm including cardiovascular risk management (BP control, HF treatment, increasing cardiorespiratory fitness, and other measures, see section 11).

Goals
Early recognition of AF recurrence by ECG recording after cardioversion
Evaluation of the efficacy of rhythm control by symptom assessment
Monitoring of risk for proarrhythmia by regular control of PR, QRS, and QTc intervals in patients on Class I or III AADs
Evaluation of balance between symptoms and side-effects of therapy considering QoL and symptoms
Evaluation of AF-related morbidities and AAD-related side-effects on concomitant cardiovascular conditions and LV function
Optimization of conditions for maintenance of sinus rhythm including cardiovascular risk management (BP control, HF treatment, increasing cardiorespiratory fitness, and other measures, see section 11).

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram; HF = heart failure; LV = left ventricular; PR = PR interval; QoL = quality of life; QRS = QRS interval; QTc = corrected QT interval.

Recommendations for cardioversion

ACS = acute coronary syndrome; AF = atrial fibrillation; HF = heart failure; ms = milliseconds; i.v. = intravenous; QTc = corrected QT interval. Note: For cardioversion in various specific conditions and AF populations see section 11.

a

Class of recommendation.

b

Level of evidence.

10.2.2.3 Atrial fibrillation catheter ablation

AF catheter ablation is a well-established treatment for the prevention of AF recurrences.¹^,^602–604 When performed by appropriately trained operators, AF catheter ablation is a safe and superior alternative to AADs for maintenance of sinus rhythm and symptom improvement.¹⁶⁵^,235–242^,²⁴⁶^,²⁴⁷^,^605–618 It is advised to discuss the efficacy and complication rates of AF catheter ablation and AADs with the patient once rhythm control as long-term management has been selected.

Indications

In the following section, indications for AF catheter ablation are presented for paroxysmal and persistent AF in patients with and without risk factors for post-ablation AF recurrence. Differentiation of persistent and long-standing persistent AF was omitted because the latter only expresses the duration of persistent AF above an arbitrary and artificial cut-off at 12 months’ duration. The significance of such a cut-off as a single measure has never been substantially proven.

A number of risk factors for AF recurrence after AF ablation have been identified, including LA size, AF duration, patient age, renal dysfunction, and substrate visualization by means of MRI.^619–625 Recent systematic reviews on prediction models for AF recurrence after catheter ablation showed the potential benefits of risk predictions, but a more robust evaluation of such models is desirable.¹⁶⁷^,⁶²⁶ The model variables can be measured before ablation; therefore models could be used pre-procedurally to predict the likelihood of recurrence.^627–635 However, no single score has been presently identified as consistently superior to others. Thus, at present, for an improved and more balanced indication for ablation in patients with persistent AF and risk factors for recurrence, the most intensely evaluated risk predictors (including duration of AF) should be considered, and adjusted to the individual patient’s situation including their preferences. Notably, patients must also be explicitly informed about the importance of treating modifiable risk factors to reduce risk of recurrent AF.^{621,636–652}

The indications for AF catheter ablation are summarized in Figure 17. AF catheter ablation is effective in maintaining sinus rhythm in patients with paroxysmal and persistent AF.¹⁶⁵^,^235–242^,^605–616 The main clinical benefit of AF catheter ablation is the reduction of arrhythmia-related symptoms.²⁴⁶^,²⁴⁷^,⁶⁰³^,⁶⁰⁴^,⁶⁰⁷^,⁶¹⁷^,⁶⁵³^,⁶⁵⁴ This has been confirmed in a recent RCT showing that the improvement in QoL was significantly higher in the ablation vs. medical therapy group, as was the associated reduction in AF burden.²⁴⁶ Symptom improvement has also been confirmed in the recent large CABANA (Catheter ABlation vs. ANtiarrhythmic Drug Therapy for Atrial Fibrillation) RCT,⁶⁵⁵ but the trial showed that the strategy of AF catheter ablation did not significantly reduce the primary composite outcome of death, disabling stroke, serious bleeding, or cardiac arrest compared with medical therapy.⁶¹⁷ As no RCT has yet demonstrated a significant reduction in all-cause mortality, stroke, or major bleeding with AF catheter ablation in the 'general' AF population, the indications for the procedure have not been broadened beyond symptom relief,⁶¹⁷ and AF catheter ablation is generally not indicated in asymptomatic patients. Further important evidence regarding the impact of ablation on major cardiovascular events is expected from the EAST trial.⁶⁵⁶

$Indications for catheter ablation of symptomatic AF. The arrows from AAD to ablation indicate failed drug therapy. AAD = antiarrhythmic drug; AF = atrial fibrillation; EF = ejection fraction; LA = left atrial. aSignificantly enlarged LA volume, advanced age, long AF duration, renal dysfunction, and other cardiovascular risk factors. bIn rare individual circumstances, catheter ablation may be carefully considered as first-line therapy. cRecommended to reverse LV dysfunction when tachycardiomyopathy is highly probable. dTo improve survival and reduce hospitalization.$

Figure 17

Indications for catheter ablation of symptomatic AF. The arrows from AAD to ablation indicate failed drug therapy. AAD = antiarrhythmic drug; AF = atrial fibrillation; EF = ejection fraction; LA = left atrial. ^aSignificantly enlarged LA volume, advanced age, long AF duration, renal dysfunction, and other cardiovascular risk factors. ^bIn rare individual circumstances, catheter ablation may be carefully considered as first-line therapy. ^cRecommended to reverse LV dysfunction when tachycardiomyopathy is highly probable. ^dTo improve survival and reduce hospitalization.

In selected patients with HF and reduced LVEF, two RCTs have shown a reduction in all-cause mortality and hospitalizations with AF catheter ablation,⁶¹¹^,⁶⁵⁷ although combined mortality and HF hospitalization was a primary endpoint only in the CASTLE-AF (Catheter Ablation vs. Standard conventional Treatment in patients with LEft ventricular dysfunction and Atrial Fibrillation) trial.⁶⁵⁷ The generalizability of the trial has recently been evaluated in a large HF patient population.⁶⁵⁸ This analysis showed that only a small number of patients met the trial inclusion criteria (<10%) and patients who met the CASTLE-AF inclusion criteria had a significant benefit from treatment as demonstrated in the trial.⁶⁵⁸ The smaller AMICA (Atrial Fibrillation Management in Congestive Heart Failure With Ablation) RCT, which included patients with more advanced HFrEF, did not show benefits gained by AF catheter ablation at 1-year follow-up,⁶⁵⁹ whereas a recent CABANA subgroup analysis supported the benefits of AF catheter ablation in patients with HFrEF, showing a significant reduction in the study primary endpoint (death, stroke, bleeding, cardiac arrest) and reduced mortality in the ablation group.⁶¹⁷^,⁶⁶⁰ Overall, AF catheter ablation in patients with HFrEF results in higher rates of preserved sinus rhythm and greater improvement in LVEF, exercise performance, and QoL compared with AAD and rate control.^{611,657,661–671} Accordingly, ablation should be considered in patients with HFrEF who have been selected for rhythm control treatment to improve QoL and LV function, and to reduce HF hospitalization and, potentially, mortality.

When AF-mediated tachycardia-induced cardiomyopathy (i.e. ventricular dysfunction secondary to rapid and/or asynchronous/irregular myocardial contraction, partially or completely reversed after treatment of the causative arrhythmia) is highly suspected, AF catheter ablation is recommended to restore LV function.^672–676

Ablation is recommended, in general, as a second-line therapy after failure (or intolerance) of class I or class III AADs. This recommendation is based on the results of multiple RCTs showing superiority of AF catheter ablation vs. AADs regarding freedom from recurrent arrhythmia or improvement in symptoms, exercise capacity, and QoL after medication failure.^235–239^,²⁴⁶^,²⁴⁷^,^605–607^,⁶⁰⁹^,⁶¹¹^,^613–617

Clinical trials considering AF catheter ablation before any AAD suggest that AF catheter ablation is more effective in maintaining sinus rhythm, with comparable complication rates in experienced centres.^240–242^,⁶¹⁴ The 5-year follow-up in the MANTRA-PAF (Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) trial showed a significantly lower AF burden in the ablation arm that did not, however, translate into improved QoL compared with AAD treatment,⁶¹⁵ whereas the CAPTAF (Catheter Ablation compared with Pharmacological Therapy for Atrial Fibrillation) study showed that, in AF patients mostly naive to class I and III AADs, the greater improvement in QoL in the ablation arm was directly associated with greater reduction in AF burden compared with the AAD arm.²⁴⁶ Based on these studies and patient preferences, AF catheter ablation should be considered before a trial of AAD in patients with paroxysmal AF episodes (class IIa), or may be considered in patients with persistent AF without risk factors for recurrence (class IIb).

Techniques and technologies

The cornerstone of AF catheter ablation is the complete isolation of pulmonary veins by linear lesions around their antrum, either using point-by-point radiofrequency ablation or single-shot ablation devices.²³⁵^,²³⁷^,²³⁹^,^607–609^,⁶¹²^,⁶¹³^,⁶⁵⁴^,^677–686 Unfortunately, persistent pulmonary vein electrical isolation is difficult to achieve (pulmonary vein reconnection rates of >70% are reported⁶⁸³^,^687–697, but could be significantly lower with the newer generation of catheters^698–700).

Particularly in persistent and long-standing persistent AF, more extensive ablation has been advocated. This may include linear lesions in the atria, isolation of the LAA or of the superior vena cava, ablation of complex fractionated electrograms, rotors, non-pulmonary foci, or ganglionated plexi, fibrosis-guided voltage and/or MRI-mapping, or ablation of high dominant frequency sites.^701–710 However, additional benefit vs. pulmonary vein isolation (PVI) alone, justifying its use during the first procedure, is yet to be confirmed.⁶⁷⁷^,⁶⁸⁰^,^711–730 A RCT-based data suggest improved outcome with targeting extrapulmonary (particularly the LAA) foci and selective ablation of low-voltage areas as adjunct to PVI.⁷⁰⁸^,⁷²⁵ In patients with documented cavotricuspid isthmus (CTI)-dependent flutter undergoing AF catheter ablation, right isthmus ablation may be considered.^731–734 In case of non−CTI-dependent atrial tachycardia, the ablation technique depends on the underlying mechanism and tachycardia focus or circuit.¹^,⁶¹⁴

Several RCTs and observational studies have compared point-by-point radiofrequency and cryoballoon ablation, mostly in the first procedure for paroxysmal AF.⁶¹²^,⁶⁸¹^,^735–755 They reported broadly similar arrhythmia-free survival and overall complications with either technique, with slightly shorter procedure duration but longer fluoroscopy time with cryoballoon ablation.⁶¹²^,⁶⁸¹^,^735–755 However, some studies showed reduced hospitalization and lower complication rates with cryoballoon ablation.⁷⁴⁶^,⁷⁵⁶^,⁷⁵⁷ The choice of energy source may depend on centre availability, operator preference/experience, and patient preference. Alternative catheter designs and energy sources have been developed in an attempt to simplify the ablation procedure and improve outcomes,⁶¹³^,⁷⁵⁵^,^758–761 but further evidence is required before changing current recommendations.

Complications

Prospective, registry-based data show that approximately 4 − 14% of patients undergoing AF catheter ablation experience complications, 2 − 3% of which are potentially life-threatening.^602–604^,^762–765 In the recent CABANA trial, mostly including experienced high-volume centres, complications occurred in the lower range of these rates.⁶¹⁷ Complications occur mostly within the first 24 h after the procedure, but some may appear 1 − 2 months after ablation¹^,^602–604 (Table 16 and Supplementary Table 10). Peri-procedural death is rare (<0.2%) and usually related to cardiac tamponade.⁶⁰³^,⁶⁰⁴^,^766–770

Table 16

Procedure-related complications in catheter ablation and thoracoscopic ablation of AF⁷⁷¹

Complication severity	Complication type	Complication rate
Complication severity	Complication type	Catheter ablation	Thoracoscopic ablation
Life-threatening complications	Periprocedural death	<0.1%	<0.1%
	Oesophageal perforation/fistula	<0.5%	N/A
	Periprocedural thromboembolic event	<1.0%	<1.5%
	Cardiac tamponade	≈1%	<1.0%
Severe complications	Pulmonary vein stenosis	<1.0%	N/A
	Persistent phrenic nerve palsy	<1.0%	N/A
	Vascular complications	2-4%	N/A
	Conversion to sternotomy	N/A	<1.7%
	Pneumothorax	N/A	<6.5%
Moderate or minor complications	Various	1 − 2%	1 − 3%
Complications of unknown significance	Asymptomatic cerebral embolism	5 − 15%	N/A

Complication severity	Complication type	Complication rate
Complication severity	Complication type	Catheter ablation	Thoracoscopic ablation
Life-threatening complications	Periprocedural death	<0.1%	<0.1%
	Oesophageal perforation/fistula	<0.5%	N/A
	Periprocedural thromboembolic event	<1.0%	<1.5%
	Cardiac tamponade	≈1%	<1.0%
Severe complications	Pulmonary vein stenosis	<1.0%	N/A
	Persistent phrenic nerve palsy	<1.0%	N/A
	Vascular complications	2-4%	N/A
	Conversion to sternotomy	N/A	<1.7%
	Pneumothorax	N/A	<6.5%
Moderate or minor complications	Various	1 − 2%	1 − 3%
Complications of unknown significance	Asymptomatic cerebral embolism	5 − 15%	N/A

NA = not available.

Table 16

Procedure-related complications in catheter ablation and thoracoscopic ablation of AF⁷⁷¹

Complication severity	Complication type	Complication rate
Complication severity	Complication type	Catheter ablation	Thoracoscopic ablation
Life-threatening complications	Periprocedural death	<0.1%	<0.1%
	Oesophageal perforation/fistula	<0.5%	N/A
	Periprocedural thromboembolic event	<1.0%	<1.5%
	Cardiac tamponade	≈1%	<1.0%
Severe complications	Pulmonary vein stenosis	<1.0%	N/A
	Persistent phrenic nerve palsy	<1.0%	N/A
	Vascular complications	2-4%	N/A
	Conversion to sternotomy	N/A	<1.7%
	Pneumothorax	N/A	<6.5%
Moderate or minor complications	Various	1 − 2%	1 − 3%
Complications of unknown significance	Asymptomatic cerebral embolism	5 − 15%	N/A

Complication severity	Complication type	Complication rate
Complication severity	Complication type	Catheter ablation	Thoracoscopic ablation
Life-threatening complications	Periprocedural death	<0.1%	<0.1%
	Oesophageal perforation/fistula	<0.5%	N/A
	Periprocedural thromboembolic event	<1.0%	<1.5%
	Cardiac tamponade	≈1%	<1.0%
Severe complications	Pulmonary vein stenosis	<1.0%	N/A
	Persistent phrenic nerve palsy	<1.0%	N/A
	Vascular complications	2-4%	N/A
	Conversion to sternotomy	N/A	<1.7%
	Pneumothorax	N/A	<6.5%
Moderate or minor complications	Various	1 − 2%	1 − 3%
Complications of unknown significance	Asymptomatic cerebral embolism	5 − 15%	N/A

NA = not available.

AF catheter ablation outcome and impact of modifiable risk factors

Multiple RCTs have compared AADs with AF catheter ablation using different technologies/energy sources, either as ‘first-line’ therapy or after AAD failure, showing superiority of AF catheter ablation in arrhythmia-free survival.¹⁶⁵^,^235–242^,^605–616 However, many patients require several procedures and late recurrences are not infrequent.²⁴⁸^,⁶³⁹^,^772–780

Key outcomes include QoL, HF, stroke, and mortality.^539–541^,⁶⁰⁸^,⁷⁸¹^,⁷⁸² Compared with AADs, AF catheter ablation was associated with significant and sustained improvement in QoL scores in several RCTs and meta-analyses.¹^,²³⁵^,^239–242^,²⁴⁶^,²⁴⁷^,^539–541^,⁷⁸³^,⁷⁸⁴ To date, there is no RCT sufficiently large to properly evaluate a reduction in stroke by catheter ablation.

Several factors, including AF type and duration,^235–237^,²³⁹^,⁶⁰⁷^,⁶⁰⁹^,⁶¹²^,⁶¹³^,⁶⁵⁴^,⁶⁸⁰^,⁶⁸²^,⁷⁸⁵ and the presence of comorbidities such as hypertension,⁶²¹^,^639–641 obesity,⁶³⁸^,⁶³⁹^,⁶⁴³^,⁶⁴⁶^,⁷⁷²^,^786–791 metabolic syndrome,^792–794 and sleep apnoea^643–645^,^647–652 may influence the outcome of catheter ablation (Figure 18 and Supplementary Box 2). Prospective cohort studies suggest that aggressive control of modifiable risk factors may improve arrhythmia-free survival after catheter ablation.⁶³⁶

Figure 18

Risk factors for AF contributing to the development of an abnormal substrate translating into poorer outcomes with rhythm control strategies. AF = atrial fibrillation; BMI = body mass index; CPAP = continuous positive airway pressure; HbA_1C = haemoglobin A1c; OSA = obstructive sleep apnoea. Several AF risk factors may contribute to the development of LA substrates and thus affect the outcome of AF catheter ablation, predisposing to a higher recurrence rate. Aggressive control of modifiable risk factors may reduce recurrence rate.

Follow-up after atrial fibrillation ablation

AF catheter ablation is a complex procedure that may be associated with a range of specific post-procedural complications (section 10.2.2.3.3)⁶⁰³^,⁶⁰⁴^,^766–770. Although mostly rare, potentially catastrophic complications may initially present with non-specific symptoms and signs to which managing physicians should be attuned. Key issues in follow-up are shown in Table 17.

Table 17

Key issues in follow-up after AF catheter ablation

Key issues
Recognition and management of complications Patients must be fully informed about the clinical signs and symptoms of rare but potentially dangerous ablation-related complications that may occur after hospital discharge (e.g. atrio-oesophageal fistula, pulmonary vein stenosis).
Follow-up monitoring: Useful to assess procedural success and correlate symptom status with rhythm.⁷⁹⁵^,⁷⁹⁶ Recurrences beyond the first month post-ablation are generally predictive of late recurrences,⁷⁹⁷^,⁷⁹⁸ but recurrent symptoms may be due to ectopic beats or other non-sustained arrhythmia⁶⁴⁰^,⁷⁹⁹^,⁸⁰⁰; conversely the presence of asymptomatic AF after ablation is well described.^801–803 Monitoring may be performed with intermittent ECG, Holter, Patch recordings, external or implanted loop recorder, or smart phone monitor (although the latter has not been validated for such use). Patients should be first reviewed at a minimum of 3 months and annually thereafter.¹
Management of antiarrhythmic medication and treatment of AF recurrences a. Continuing AAD treatment for 6 weeks to 3 months may reduce early AF recurrences, rehospitalizations and cardioversions during this period.⁷⁹⁷^,⁸⁰⁴ Clinical practice regarding routine AAD treatment after ablation varies and there is no convincing evidence that such treatment is routinely needed. b. Subsequently, AADs may be weaned, ceased, or continued according to symptoms and rhythm status. Recent findings suggest that in AAD-treated patients remaining free of AF at the end of the blanking period, AAD continuation beyond the blanking period reduces arrhythmia recurrences.⁸⁰⁵
Management of anticoagulation therapy a. In general, OAC therapy is continued for 2 months following ablation in all patients.¹^,⁸⁰⁶ Beyond this time, a decision to continue OAC is determined primarily by the presence of CHA₂DS₂-VASc stroke risk factors rather than the rhythm status (section 10.2.2.6).

Key issues
Recognition and management of complications Patients must be fully informed about the clinical signs and symptoms of rare but potentially dangerous ablation-related complications that may occur after hospital discharge (e.g. atrio-oesophageal fistula, pulmonary vein stenosis).
Follow-up monitoring: Useful to assess procedural success and correlate symptom status with rhythm.⁷⁹⁵^,⁷⁹⁶ Recurrences beyond the first month post-ablation are generally predictive of late recurrences,⁷⁹⁷^,⁷⁹⁸ but recurrent symptoms may be due to ectopic beats or other non-sustained arrhythmia⁶⁴⁰^,⁷⁹⁹^,⁸⁰⁰; conversely the presence of asymptomatic AF after ablation is well described.^801–803 Monitoring may be performed with intermittent ECG, Holter, Patch recordings, external or implanted loop recorder, or smart phone monitor (although the latter has not been validated for such use). Patients should be first reviewed at a minimum of 3 months and annually thereafter.¹
Management of antiarrhythmic medication and treatment of AF recurrences a. Continuing AAD treatment for 6 weeks to 3 months may reduce early AF recurrences, rehospitalizations and cardioversions during this period.⁷⁹⁷^,⁸⁰⁴ Clinical practice regarding routine AAD treatment after ablation varies and there is no convincing evidence that such treatment is routinely needed. b. Subsequently, AADs may be weaned, ceased, or continued according to symptoms and rhythm status. Recent findings suggest that in AAD-treated patients remaining free of AF at the end of the blanking period, AAD continuation beyond the blanking period reduces arrhythmia recurrences.⁸⁰⁵
Management of anticoagulation therapy a. In general, OAC therapy is continued for 2 months following ablation in all patients.¹^,⁸⁰⁶ Beyond this time, a decision to continue OAC is determined primarily by the presence of CHA₂DS₂-VASc stroke risk factors rather than the rhythm status (section 10.2.2.6).

AAD = antiarrhythmic drug; AF = atrial fibrillation; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); ECG=electrocardiogram; OAC = oral anticoagulant.

Table 17

Key issues in follow-up after AF catheter ablation

Key issues
Recognition and management of complications Patients must be fully informed about the clinical signs and symptoms of rare but potentially dangerous ablation-related complications that may occur after hospital discharge (e.g. atrio-oesophageal fistula, pulmonary vein stenosis).
Follow-up monitoring: Useful to assess procedural success and correlate symptom status with rhythm.⁷⁹⁵^,⁷⁹⁶ Recurrences beyond the first month post-ablation are generally predictive of late recurrences,⁷⁹⁷^,⁷⁹⁸ but recurrent symptoms may be due to ectopic beats or other non-sustained arrhythmia⁶⁴⁰^,⁷⁹⁹^,⁸⁰⁰; conversely the presence of asymptomatic AF after ablation is well described.^801–803 Monitoring may be performed with intermittent ECG, Holter, Patch recordings, external or implanted loop recorder, or smart phone monitor (although the latter has not been validated for such use). Patients should be first reviewed at a minimum of 3 months and annually thereafter.¹
Management of antiarrhythmic medication and treatment of AF recurrences a. Continuing AAD treatment for 6 weeks to 3 months may reduce early AF recurrences, rehospitalizations and cardioversions during this period.⁷⁹⁷^,⁸⁰⁴ Clinical practice regarding routine AAD treatment after ablation varies and there is no convincing evidence that such treatment is routinely needed. b. Subsequently, AADs may be weaned, ceased, or continued according to symptoms and rhythm status. Recent findings suggest that in AAD-treated patients remaining free of AF at the end of the blanking period, AAD continuation beyond the blanking period reduces arrhythmia recurrences.⁸⁰⁵
Management of anticoagulation therapy a. In general, OAC therapy is continued for 2 months following ablation in all patients.¹^,⁸⁰⁶ Beyond this time, a decision to continue OAC is determined primarily by the presence of CHA₂DS₂-VASc stroke risk factors rather than the rhythm status (section 10.2.2.6).

Key issues
Recognition and management of complications Patients must be fully informed about the clinical signs and symptoms of rare but potentially dangerous ablation-related complications that may occur after hospital discharge (e.g. atrio-oesophageal fistula, pulmonary vein stenosis).
Follow-up monitoring: Useful to assess procedural success and correlate symptom status with rhythm.⁷⁹⁵^,⁷⁹⁶ Recurrences beyond the first month post-ablation are generally predictive of late recurrences,⁷⁹⁷^,⁷⁹⁸ but recurrent symptoms may be due to ectopic beats or other non-sustained arrhythmia⁶⁴⁰^,⁷⁹⁹^,⁸⁰⁰; conversely the presence of asymptomatic AF after ablation is well described.^801–803 Monitoring may be performed with intermittent ECG, Holter, Patch recordings, external or implanted loop recorder, or smart phone monitor (although the latter has not been validated for such use). Patients should be first reviewed at a minimum of 3 months and annually thereafter.¹
Management of antiarrhythmic medication and treatment of AF recurrences a. Continuing AAD treatment for 6 weeks to 3 months may reduce early AF recurrences, rehospitalizations and cardioversions during this period.⁷⁹⁷^,⁸⁰⁴ Clinical practice regarding routine AAD treatment after ablation varies and there is no convincing evidence that such treatment is routinely needed. b. Subsequently, AADs may be weaned, ceased, or continued according to symptoms and rhythm status. Recent findings suggest that in AAD-treated patients remaining free of AF at the end of the blanking period, AAD continuation beyond the blanking period reduces arrhythmia recurrences.⁸⁰⁵
Management of anticoagulation therapy a. In general, OAC therapy is continued for 2 months following ablation in all patients.¹^,⁸⁰⁶ Beyond this time, a decision to continue OAC is determined primarily by the presence of CHA₂DS₂-VASc stroke risk factors rather than the rhythm status (section 10.2.2.6).

AAD = antiarrhythmic drug; AF = atrial fibrillation; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); ECG=electrocardiogram; OAC = oral anticoagulant.

Risk assessment for recurrence of atrial fibrillation post catheter ablation

Recurrence of AF after catheter ablation is driven by the complex interaction of various factors. These include increasing AF duration, age, and LA size,^619–624 and structural factors such as the abundance of epicardial fat tissue^807–810 and the presence of atrial substrate as evident from electrical or morphological markers.⁸¹¹ A number of risk-prediction scores have been evaluated (for detailed description see Supplementary Table 11 and Supplementary Box 2). Whereas these scores only moderately predict AF recurrence, one of the strongest predictors is early recurrent AF, indicating the need for further refinement of these scoring systems.⁶²⁹

Recommendations for rhythm control/catheter ablation of AF

AAD = antiarrhythmic drug; AF = atrial fibrillation; AFL = atrial flutter; CTI = cavotricuspid isthmus; HF = heart failure; LV = left ventricular; LVEF = left ventricular ejection fraction; PVI = pulmonary vein isolation.

a

Class of recommendation.

b

Level of evidence.

10.2.2.4 Surgery for atrial fibrillation

With development of the maze procedure for surgical cure from AF, Cox et al. opened up a new window of therapeutic opportunities for AF patients.⁸²² The classical cut-and-sew maze procedure underwent several modifications and various device-based surgical ablation procedures have been developed.⁸²³^,⁸²⁴ More than 200 publications documented the application of these techniques and technologies in various clinical scenarios.⁸²⁵ Most studies are retrospective and/or observational, but some RCTs and meta-analyses have also been published.⁷⁷¹^,^826–828 While the effects of surgical ablation on rhythm outcome (i.e. restoration of sinus rhythm/freedom from AF) have been clearly demonstrated, the effects on endpoints such as QoL, hospitalization, stroke, and mortality are not well established.⁴⁶¹^,⁸²⁷^,⁸²⁹^,⁸³⁰ The only RCT with longer follow-up has shown a significant reduction in stroke risk at 5 years and a greater likelihood of maintaining sinus rhythm although the trial was underpowered for stroke risk assessment.⁸²⁸ The largest registry published, from the Polish National Health Service, describes better survival when ablation is performed concomitant to mitral or coronary surgery.⁸³¹^,⁸³² Close cooperation between cardiac surgeons and electrophysiologists (heart team) for proper patient selection and postoperative management, especially for handling of arrhythmia recurrences, seems advisable for high-standard quality care.

Concomitant surgery for atrial fibrillation: indications, outcome, complications

Most trials of concomitant AF ablation have been based mainly on patients undergoing mitral valve repair or replacement. While surgical PVI has been shown to be effective for maintaining sinus rhythm,⁸³³ the most effective ablation treatment for AF isolates the pulmonary veins and the LA posterior wall, creates ablation lines that impede electrical impulses around the most important structures (mitral and tricuspid annuli, venae cavae and appendages), and excludes the LAA. Most evidence supports bipolar radiofrequency clamps and cryothermy to perform a maze.⁸³⁴ For non-paroxysmal AF, a biatrial lesion pattern is more effective than left-sided only, performed by sternotomy or minimally invasive techniques.⁸²⁶

In general, the same preoperative risk factors for AF recurrence after concomitant AF surgery as for AF catheter ablation have been identified. These include LA size, patient age, AF duration, HF/reduced LVEF, and renal dysfunction.³⁷⁹^,⁶³⁶^,^835–841 The significant positive effects of concomitant surgical ablation on freedom from atrial arrhythmias is clearly documented. Most RCTs with 1-year follow-up show no effect on QoL, stroke, and mortality,^842–845 but some reported reduced event rates.⁸²⁸^,⁸³⁰^,⁸⁴⁶

Surgical AF ablation concomitant to other cardiac surgery significantly increases the need for pacemaker implantation with biatrial (but not left-sided) lesions,⁸²⁷ being reported from 6.8% to 21.5%, while other complications are not increased.^827–830^,⁸⁴⁶^,⁸⁴⁷

Stand-alone surgery for atrial fibrillation: indications, outcome, complications

Thoracoscopic radiofrequency ablation targets the pulmonary veins, LA posterior wall, and LAA closure in AF patients with no structural heart disease. Freedom from AF after the procedure is well documented, but only a few studies have reported improved QoL.⁸⁴⁴^,⁸⁴⁵^,^848–850 A recent meta-analysis of three RCTs showed a significantly higher freedom from atrial tachyarrhythmia and less need for repeat ablations after thoracoscopic ablation compared with AF catheter ablation for paroxysmal or persistent AF.⁸⁵¹ The FAST trial randomized patients who were prone to AF catheter-ablation failure (i.e. failed previous ablation or LA dilatation and hypertension) and reported common but substantially lower recurrence after thoracoscopic compared with AF catheter ablation (56% vs. 87%) at long-term follow-up (mean 7 years).⁸⁴⁹ Hospitalization was longer and complication rates of surgical ablation were higher compared with catheter ablation⁷⁷¹ (Table 16). A systematic safety analysis of thoracoscopic ablation showed a 30-day complication rate of 11.3%, mainly self-limiting, whereas it was significantly lower (3.6%) in a multicentre registry.⁴⁵⁶ In RCTs, thoracoscopic ablation proved more effective in rhythm control than catheter ablation; however, surgical ablation is more invasive, with higher complication rates and longer hospitalization.⁴⁶¹^,⁸⁵² Because of this risk−benefit ratio of surgical vs. catheter ablation, it seems reasonable to consider thoracoscopic surgery preferentially in patients with previous failed catheter ablation or with a high risk of catheter-ablation failure. There are no convincing data on the effects on stroke of surgical ablation as a stand-alone procedure or in combination with LAA occlusion or exclusion. Hence, OAC therapy should be continued after the procedure regardless of rhythm outcome in AF patients with stroke risk factors.

10.2.2.5 Hybrid surgical/catheter ablation procedures

Hybrid AF procedures combine a minimally invasive epicardial non-sternotomy ablation not using cardiopulmonary bypass with a percutaneous endocardial approach. They can be performed as a single intervention or sequentially, when the endocardial catheter mapping and, if needed, additional ablations are done within 6 months after the epicardial procedure.⁸⁵³ There are no studies comparing these two hybrid strategies.

A systematic review on rhythm outcome and complications with a hybrid procedure or AF catheter ablation in patients with persistent or long-standing persistent AF showed that at 12 months or longer, a hybrid procedure achieved a significantly higher rate of freedom from atrial arrhythmias with and without the use of AAD compared with AF catheter ablation. Although the overall complication rate was low for both strategies, hybrid ablations had more complications (13.8% vs. 5.9%).⁸⁵⁴ The difference in outcome could be explained by a long-lasting isolation of the pulmonary veins after bipolar radiofrequency clamping of the pulmonary veins, epicardial clipping of the LAA, and the add-on possibility of an endocardial touch-up.⁸⁵⁵^,⁸⁵⁶

Recommendations for surgical ablation of AF

AAD = antiarrhythmic drug; AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

10.2.2.6 Peri-procedural stroke risk management in patients undergoing rhythm control interventions

10.2.2.6.1 Management of stroke risk and oral anticoagulant therapy in atrial fibrillation patients undergoing cardioversion. Patients undergoing cardioversion of AF are at increased risk of stroke and thrombo-embolism, especially in the absence of OAC and if AF has been present for ≥12 h.^860–862 The exact duration of an AF episode before cardioversion may be difficult to ascertain, as many patients develop AF asymptomatically, seeking help only when symptoms or complications occur. If there is uncertainty over the exact onset of AF (i.e. unknown duration of AF), peri-cardioversion anticoagulation is managed as for AF of >12 h to 24 h. Mechanisms of the increased propensity to peri-cardioversion thrombo-embolism include the presence of pre-existing thrombus (especially if not anticoagulated), change in the atrial mechanical function with restoration of sinus rhythm, atrial stunning post-cardioversion, and a transient prothrombotic state.⁸⁶³

No RCT has evaluated anticoagulation vs. no anticoagulation in AF patients undergoing cardioversion with a definite duration of AF<48 h. Observational data suggest that the risk of stroke/thrombo-embolism is very low (0 − 0.2%) in patients with a definite AF duration of <12 h and a very low stroke risk (CHA₂DS₂-VASc 0 in men, 1 in women),⁸⁶⁰^,⁸⁶⁴^,⁸⁶⁵ in whom the benefit of 4-week anticoagulation after cardioversion is undefined and the prescription of anticoagulants can be optional, based on an individualized approach.

Peri-cardioversion anticoagulation with a VKA results in a significant decrease of stroke and thrombo-embolism,⁸⁶³ but achieving the necessary therapeutic anticoagulation (INR 2.0 − 3.0) for a minimum of 3 weeks before cardioversion may be difficult. This 3-week period is arbitrary, based on the time presumably needed for endothelialization or resolution of pre-existing AF thrombus. To shorten this time, TOE-guided cardioversion was introduced. If there is no atrial thrombus on TOE, cardioversion is performed after administration of heparin, and OAC is continued post-cardioversion.⁸⁶⁶^,⁸⁶⁷

As NOACs act rapidly, cardioversion can be scheduled 3 weeks after NOAC initiation, provided that patients are counselled about the need for compliance to NOAC therapy^868–870; NOACs have at least comparable efficacy and safety to warfarin in AF patients undergoing cardioversion.^871–874 A review of the three largest prospective trials (n =5203 patients) showed that the composite primary outcome (stroke/systemic embolism, myocardial infarction, or cardiovascular death) was significantly reduced with NOACs compared with VKA.⁸⁷³

Long-term OAC therapy after cardioversion should not be based on successful restoration of sinus rhythm, but on the stroke risk profile (using the CHA₂DS₂-VASc score), balanced against bleeding risk (e.g. HAS-BLED score).

For patients in whom a thrombus is identified on TOE, effective anticoagulation for at least 3 weeks before reassessment for cardioversion is recommended. A repeat TOE to ensure thrombus resolution should be considered before cardioversion.⁸⁷⁵ Antithrombotic management for these patients is challenging and decided on an individual basis based on the efficacy (or inefficacy) of previous treatments.

Recommendations for stroke risk management peri-cardioversion

AF = atrial fibrillation; AFL = atrial flutter; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TOE = transoesophageal echocardiography.

a

Class of recommendation.

b

Level of evidence.

Management of stroke risk and oral anticoagulant therapy in atrial fibrillation patients undergoing atrial fibrillation catheter ablation

Although there is some variability in the peri-procedural OAC management in patients undergoing AF ablation, more recently operators have moved towards a strategy of performing the ablation under uninterrupted VKA or NOAC treatment, provided the INR is within therapeutic range. In non-anticoagulated patients, initiating therapeutic anticoagulation 3 − 4 weeks before ablation may be considered.¹

In a meta-analysis of 12 studies,⁸⁷⁷ uninterrupted anticoagulation using NOACs vs. VKAs for AF catheter ablation was associated with low rates of stroke/TIA (NOACs, 0.08%; VKA, 0.16%) and similar rates of silent cerebral embolic events (8.0% vs 9.6%). However, major bleeding was significantly reduced with uninterrupted NOACs (0.9%) compared with VKAs (2%).

In the largest RCT comparing peri-procedural NOAC vs. warfarin [the RE-CIRCUIT trial (Randomized Evaluation of dabigatran etexilate Compared to warfarIn in pulmonaRy vein ablation: assessment of different peri-proCedUral antIcoagulation sTrategies)],⁸⁷⁸ the incidence of major bleeding events during and up to 8 weeks after ablation was significantly lower with dabigatran vs. warfarin (1.6% vs. 6.9%). Other RCTs (VENTURE-AF with rivaroxaban,⁸⁷⁹ AXAFA-AF NET 5 with apixaban,⁸⁸⁰ and ELIMINATE-AF with edoxaban⁸⁸¹) also showed similar event rates under uninterrupted NOACs vs. VKAs. Overall, uninterrupted peri-procedural NOACs were associated with a low incidence of stroke/TIA and a significant reduction in major bleeding compared with uninterrupted VKAs in patients undergoing AF catheter ablation. In contrast, heparin bridging increases the bleeding risk and should be avoided.

Frequently, the term ‘uninterrupted’ is used in clinical practice for the description of regimens where one or two NOAC doses are omitted before ablation, whereas in the RCTs comparing uninterrupted NOACs vs. warfarin, NOAC administration before ablation was truly uninterrupted.⁸⁶⁹^,⁸⁷⁸ Hence, there is no reason to recommend omitting one or two NOAC doses before ablation. After the procedure, administration of the first dose the evening after ablation or the next morning (if this corresponds to the timing of the next dose according to the patient’s previous OAC regimen) appears to be safe.⁸⁷⁸^,⁸⁸¹.

Recommendations for stroke risk management peri-catheter ablation

AF = atrial fibrillation; LA = left atrial; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant therapy; TOE=transoesophageal echocardiography.

a

Class of recommendation

b

Level of evidence

Postoperative anticoagulation after surgery for atrial fibrillation

Owing to endothelial damage during ablation, OAC is advisable in all patients after AF surgery, starting as soon as possible (balancing the risk of postoperative bleeding). There are no RCT data regarding interruption of OAC over the long term. Non-randomized studies with longer follow-up have shown better long-term freedom from stroke in patients with persistent sinus rhythm, but not in those with AF despite LAA exclusion.⁸²⁴ Therefore, long-term OAC is recommended in all patients at risk of stroke despite a successful maze surgery and appendage closure.

Recommendations for postoperative anticoagulation after AF surgery

AF = atrial fibrillation; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); OAC = oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

10.2.2.7 Long-term antiarrhythmic drug therapy for rhythm control

Antiarrhythmic drugs

The aim of AAD therapy is to improve AF-related symptoms.⁴⁸⁴^,⁸⁸²^,⁸⁸³ Hence, the decision to initiate long-term AAD therapy needs to balance symptom burden, possible adverse drug reactions, and patient preferences. The principles of AAD therapy are shown in Tables 18 and19.

Table 18

Principles of antiarrhythmic drug therapy¹⁴³

Principles
AAD therapy aims to reduce AF-related symptoms
Efficacy of AADs to maintain sinus rhythm is modest
Clinically successful AAD therapy may reduce rather than eliminate AF recurrences
If one AAD ‘fails’, a clinically acceptable response may be achieved by another drug
Drug-induced proarrhythmia or extracardiac side-effects are frequent
Safety rather than efficacy considerations should primarily guide the choice of AAD

Principles
AAD therapy aims to reduce AF-related symptoms
Efficacy of AADs to maintain sinus rhythm is modest
Clinically successful AAD therapy may reduce rather than eliminate AF recurrences
If one AAD ‘fails’, a clinically acceptable response may be achieved by another drug
Drug-induced proarrhythmia or extracardiac side-effects are frequent
Safety rather than efficacy considerations should primarily guide the choice of AAD

AAD = antiarrhythmic drug; AF = atrial fibrillation.

Table 18

Principles of antiarrhythmic drug therapy¹⁴³

Principles
AAD therapy aims to reduce AF-related symptoms
Efficacy of AADs to maintain sinus rhythm is modest
Clinically successful AAD therapy may reduce rather than eliminate AF recurrences
If one AAD ‘fails’, a clinically acceptable response may be achieved by another drug
Drug-induced proarrhythmia or extracardiac side-effects are frequent
Safety rather than efficacy considerations should primarily guide the choice of AAD

Principles
AAD therapy aims to reduce AF-related symptoms
Efficacy of AADs to maintain sinus rhythm is modest
Clinically successful AAD therapy may reduce rather than eliminate AF recurrences
If one AAD ‘fails’, a clinically acceptable response may be achieved by another drug
Drug-induced proarrhythmia or extracardiac side-effects are frequent
Safety rather than efficacy considerations should primarily guide the choice of AAD

AAD = antiarrhythmic drug; AF = atrial fibrillation.

Table 19

Rules to initiate antiarrhythmic drugs for long-term rhythm control in AF

Consideration	Criteria
Indication for AAD	Is the patient symptomatic? Are AF symptoms severe enough (EHRA class) to justify AAD use? Are there associated conditions predicting poor tolerance of AF episodes?
When to start AAD	Usually not for the first episode, but it may enhance efficacy of cardioversion
How to choose among AADs	Minimize proarrhythmic risk and organ toxicity Evaluate for: basal ECG abnormalities (QRS duration, PR, QTc) and possible interference with AAD impact on LV function important pharmacokinetic and pharmacodynamic interactions (i.e. antithrombotic drugs) Risk factors for proarrhythmia may be dynamic and change over time
How to minimize proarrhythmic risk	Evaluate ECG after the treatment, as indicated in these Guidelines Evaluate periodically for organ toxicity (amiodarone) Long-term Holter monitoring and exercise test in selected cases Avoid AAD combinations
How to verify efficacy	Estimate AF burden under therapy (ask patient for noting episodes) If the patient is already on AAD and it was effective but was stopped because of intolerance, choose preferably from the same class
Adjuvant interventions and hybrid therapy	In patients with atrioventricular conduction abnormalities and/or sinus node dysfunction, pacemaker implantation should be considered if AAD therapy is deemed necessary Short-term AAD therapy could prevent early recurrences after AF ablation

Consideration	Criteria
Indication for AAD	Is the patient symptomatic? Are AF symptoms severe enough (EHRA class) to justify AAD use? Are there associated conditions predicting poor tolerance of AF episodes?
When to start AAD	Usually not for the first episode, but it may enhance efficacy of cardioversion
How to choose among AADs	Minimize proarrhythmic risk and organ toxicity Evaluate for: basal ECG abnormalities (QRS duration, PR, QTc) and possible interference with AAD impact on LV function important pharmacokinetic and pharmacodynamic interactions (i.e. antithrombotic drugs) Risk factors for proarrhythmia may be dynamic and change over time
How to minimize proarrhythmic risk	Evaluate ECG after the treatment, as indicated in these Guidelines Evaluate periodically for organ toxicity (amiodarone) Long-term Holter monitoring and exercise test in selected cases Avoid AAD combinations
How to verify efficacy	Estimate AF burden under therapy (ask patient for noting episodes) If the patient is already on AAD and it was effective but was stopped because of intolerance, choose preferably from the same class
Adjuvant interventions and hybrid therapy	In patients with atrioventricular conduction abnormalities and/or sinus node dysfunction, pacemaker implantation should be considered if AAD therapy is deemed necessary Short-term AAD therapy could prevent early recurrences after AF ablation

AAD = antiarrhythmic drug; AF = atrial fibrillation; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; LV = left ventricular; PR = PR interval; QRS = QRS interval; QTc = corrected QT interval.

Table 19

Rules to initiate antiarrhythmic drugs for long-term rhythm control in AF

Consideration	Criteria
Indication for AAD	Is the patient symptomatic? Are AF symptoms severe enough (EHRA class) to justify AAD use? Are there associated conditions predicting poor tolerance of AF episodes?
When to start AAD	Usually not for the first episode, but it may enhance efficacy of cardioversion
How to choose among AADs	Minimize proarrhythmic risk and organ toxicity Evaluate for: basal ECG abnormalities (QRS duration, PR, QTc) and possible interference with AAD impact on LV function important pharmacokinetic and pharmacodynamic interactions (i.e. antithrombotic drugs) Risk factors for proarrhythmia may be dynamic and change over time
How to minimize proarrhythmic risk	Evaluate ECG after the treatment, as indicated in these Guidelines Evaluate periodically for organ toxicity (amiodarone) Long-term Holter monitoring and exercise test in selected cases Avoid AAD combinations
How to verify efficacy	Estimate AF burden under therapy (ask patient for noting episodes) If the patient is already on AAD and it was effective but was stopped because of intolerance, choose preferably from the same class
Adjuvant interventions and hybrid therapy	In patients with atrioventricular conduction abnormalities and/or sinus node dysfunction, pacemaker implantation should be considered if AAD therapy is deemed necessary Short-term AAD therapy could prevent early recurrences after AF ablation

Consideration	Criteria
Indication for AAD	Is the patient symptomatic? Are AF symptoms severe enough (EHRA class) to justify AAD use? Are there associated conditions predicting poor tolerance of AF episodes?
When to start AAD	Usually not for the first episode, but it may enhance efficacy of cardioversion
How to choose among AADs	Minimize proarrhythmic risk and organ toxicity Evaluate for: basal ECG abnormalities (QRS duration, PR, QTc) and possible interference with AAD impact on LV function important pharmacokinetic and pharmacodynamic interactions (i.e. antithrombotic drugs) Risk factors for proarrhythmia may be dynamic and change over time
How to minimize proarrhythmic risk	Evaluate ECG after the treatment, as indicated in these Guidelines Evaluate periodically for organ toxicity (amiodarone) Long-term Holter monitoring and exercise test in selected cases Avoid AAD combinations
How to verify efficacy	Estimate AF burden under therapy (ask patient for noting episodes) If the patient is already on AAD and it was effective but was stopped because of intolerance, choose preferably from the same class
Adjuvant interventions and hybrid therapy	In patients with atrioventricular conduction abnormalities and/or sinus node dysfunction, pacemaker implantation should be considered if AAD therapy is deemed necessary Short-term AAD therapy could prevent early recurrences after AF ablation

AAD = antiarrhythmic drug; AF = atrial fibrillation; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; LV = left ventricular; PR = PR interval; QRS = QRS interval; QTc = corrected QT interval.

Compared with no therapy, AAD therapy approximately doubles sinus rhythm maintenance,⁸⁸³ but it is difficult to draw firm conclusions from existing trials on their comparative efficacy.⁸⁸⁴ In general, AAD therapy is less effective than AF catheter ablation,¹¹⁴^,⁶¹¹^,⁶¹⁵ but previously ineffective AADs can be continued after PVI, to reduce recurrent AF.⁸⁰⁵ A shorter duration of AAD therapy would likely reduce the risk of side-effects⁸⁸³^,⁸⁸⁵ but late recurrences may occur.⁵⁹⁵ Short-term AAD therapy is also used to prevent early AF recurrences after catheter ablation,⁸⁸⁶ although the benefit is still debated⁷⁹⁷^,⁸⁸⁷; this strategy may be reasonable in patients deemed at increased risk of AAD side-effects or in those with a low perceived risk of recurrent AF. Concomitant management of underlying cardiovascular conditions is pivotal to reduce AF symptom burden and facilitate the maintenance of sinus rhythm.²⁴⁵^,⁶³⁶^,⁸⁸⁸^,⁸⁸⁹

Available antiarrhythmic drugs

Several AADs have been shown to reduce AF recurrences (Table 20).⁸⁹⁰ Class Ia (quinidine and disopyramide) and sotalol have been associated with increased overall mortality.⁸⁸⁴ Again, safety should dictate both the initiation and continuation of AADs.

Table 20

Antiarrhythmic drugs used for long-term maintenance of sinus rhythm in AF patients⁸⁹⁰

Drug	Administration route	Dose	Contraindications/precautions/comments
Amiodarone²³³^,⁵⁰⁶^,^891–896	Oral	3 × 200 mg daily over 4 weeks, then 200 mg daily⁵⁰⁶	The most effective AAD⁸⁹⁰^,⁸⁹⁷ RCTs showed lower AF recurrence compared with sotalol and dronedarone⁸⁸⁴ Also reduces ventricular rate (for 10 − 12 bpm), safe in patients with HF^898–900 Concomitant use with other QT-prolonging drugs with caution Concomitant use with VKAs or digitalis (their dose should be reduced) Increased risk of myopathy when used with statins Requires regular surveillance for liver, lung, and thyroid toxicity Has atrioventricular nodal-slowing properties, but should not be used as first intention for rate control QT prolongation is common but rarely associated with torsades de pointes (<0.5%)⁹⁰¹ Torsades de pointes occurs infrequently during treatment with amiodarone (the proarrhythmia caution requires QT-interval and TU-wave monitoring)⁹⁰² Should be discontinued in case of excessive QT prolongation (>500 ms) ECG at baseline, after 4 weeks Contraindicated in manifest hyperthyroidism Numerous and frequent extracardiac side-effects may warrant discontinuation of amiodarone, thus making it a second-line treatment when other choices are possible^903–907
Flecainide Flecainide slow release⁸⁹⁶^,⁹⁰⁸^,⁹⁰⁹	Oral	100 − 200 mg b.i.d., or 200 mg once daily (flecainide slow release)	Effective in preventing recurrence of AF⁸⁹¹^,⁹⁰⁸^,⁹¹⁰ Should not be used in patients with CrCl <35 mL/min/1.73 m² and significant liver disease Both are contraindicated in patients with ischaemic heart disease or reduced LVEF^911–913 Should be discontinued in case of QRS widening >25% above baseline and patients with left bundle-branch block or any other conduction block >120 ms Caution when sinoatrial/atrioventricular conduction disturbances present^a CYP2D6 inhibitors increase concentration May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate.⁹¹⁴ This risk can be reduced by concomitant administration of an atrioventricular nodal-blocking drug such as a beta-blocker or NDCC In patients properly screened for propensity to proarrhythmias, both flecainide and propafenone are associated with a low proarrhythmic risk⁹¹⁵ ECG at baseline, after 1 − 2 weeks
Propafenone Propafenone slow release⁸⁹⁵^,⁸⁹⁶^,^916–922	Oral	150 − 300 mg three times daily, or 225 − 425 mg b.i.d. (propafenone slow release)	Should not be used in patients with significant renal or liver disease, ischaemic heart disease, reduced LV systolic function, or asthma Should be discontinued in case of QRS widening >25% above baseline and in patients left bundle-branch block and any other conduction block >120 ms Caution when sinoatrial/atrioventricular conduction disturbances present^a Increases concentration of warfarin/acenocoumarin and digoxin when used in combination May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate ECG at baseline and after 1 − 2 weeks
Dronedarone^923–927	Oral	400 mg b.i.d.	Less effective than amiodarone in rhythm control but has very few extracardiac side-effects⁹²⁵^,^928–930 Reduces cardiovascular hospitalizations and death in patients with paroxysmal or persistent AF or AFL and cardiovascular comorbidity⁹²³^,⁹³¹ Associated with increased mortality in patients with recent decompensated HF⁹²⁷ or permanent AF⁹³² Dronedarone has the most solid safety data and may thus be a preferable first choice,⁹³³^,⁹³⁴ however not indicated in patients with HF and permanent AF⁹³⁵^,⁹³⁶ Should not be used in NYHA class III or IV or unstable HF, in combination with QT-prolonging drugs or with strong CYP3A4 inhibitors (e.g. verapamil, diltiazem) and in patients with CrCl <30 mL/min Concomitant use with dabigatran is contraindicated Combination with digoxin may significantly increase digoxin serum concentration When used with digitalis or beta-blockers their doses should be reduced Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase) A modest increase in serum creatinine is common and reflects drug-induced reduction in CrCl rather than a decline in renal function⁹³⁷ Has atrioventricular nodal-slowing properties ECG at baseline and after 4 weeks
Sotalol (d,l racemic mixture)²³³^,⁸⁹¹^,⁸⁹⁴^,⁸⁹⁵^,⁹²⁰^,^938–940	Oral	80 − 160 mg b.i.d.	Only class III effects if dosing >160 mg daily Considering its safety and efficacy and potential drug alternatives, sotalol should be used with a caution Should not be used in patients with HFrEF, significant LVH, prolonged QT, asthma, hypokalaemia, or CrCl <30 mL/min Dose-related torsades de pointes may occur in >2% of patients⁹⁴¹ Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase) The potassium channel-blocking effect increases with increasing dose and, consequently, the risk of ventricular proarrhythmia (torsades de pointes) increases Observational data and a recent meta-analysis revealed a correlation with an increased all-cause mortality⁸⁹⁰^,⁸⁹⁷^,⁹³⁴ , whereas a nationwide registry analysis and two RCTs found no evidence for increased safety concerns with sotalol²³³^,⁹³³^,⁹⁴²^,⁹⁴³ ECG at baseline, after 1 day and after 1 − 2 weeks
Disopyramide^944–946	Oral	100 − 400 mg two or t.i.d. (maximum 800 mg/24 h)	Associated with significantly increased mortality⁸⁹⁰^,⁹⁴⁷, and rarely used for rhythm control in AF.⁹⁴⁸^,⁹⁴⁹ Should not be used in patients with a structural heart disease. Rarely used for rhythm control in AF patients, due to increased mortality and frequent intolerance to side-effects May be useful in ‘vagal’ AF occurring in athletes or during sleep⁹⁰¹ Reduces LV outflow obstruction and symptoms in patients with HCM⁹⁵⁰

Drug	Administration route	Dose	Contraindications/precautions/comments
Amiodarone²³³^,⁵⁰⁶^,^891–896	Oral	3 × 200 mg daily over 4 weeks, then 200 mg daily⁵⁰⁶	The most effective AAD⁸⁹⁰^,⁸⁹⁷ RCTs showed lower AF recurrence compared with sotalol and dronedarone⁸⁸⁴ Also reduces ventricular rate (for 10 − 12 bpm), safe in patients with HF^898–900 Concomitant use with other QT-prolonging drugs with caution Concomitant use with VKAs or digitalis (their dose should be reduced) Increased risk of myopathy when used with statins Requires regular surveillance for liver, lung, and thyroid toxicity Has atrioventricular nodal-slowing properties, but should not be used as first intention for rate control QT prolongation is common but rarely associated with torsades de pointes (<0.5%)⁹⁰¹ Torsades de pointes occurs infrequently during treatment with amiodarone (the proarrhythmia caution requires QT-interval and TU-wave monitoring)⁹⁰² Should be discontinued in case of excessive QT prolongation (>500 ms) ECG at baseline, after 4 weeks Contraindicated in manifest hyperthyroidism Numerous and frequent extracardiac side-effects may warrant discontinuation of amiodarone, thus making it a second-line treatment when other choices are possible^903–907
Flecainide Flecainide slow release⁸⁹⁶^,⁹⁰⁸^,⁹⁰⁹	Oral	100 − 200 mg b.i.d., or 200 mg once daily (flecainide slow release)	Effective in preventing recurrence of AF⁸⁹¹^,⁹⁰⁸^,⁹¹⁰ Should not be used in patients with CrCl <35 mL/min/1.73 m² and significant liver disease Both are contraindicated in patients with ischaemic heart disease or reduced LVEF^911–913 Should be discontinued in case of QRS widening >25% above baseline and patients with left bundle-branch block or any other conduction block >120 ms Caution when sinoatrial/atrioventricular conduction disturbances present^a CYP2D6 inhibitors increase concentration May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate.⁹¹⁴ This risk can be reduced by concomitant administration of an atrioventricular nodal-blocking drug such as a beta-blocker or NDCC In patients properly screened for propensity to proarrhythmias, both flecainide and propafenone are associated with a low proarrhythmic risk⁹¹⁵ ECG at baseline, after 1 − 2 weeks
Propafenone Propafenone slow release⁸⁹⁵^,⁸⁹⁶^,^916–922	Oral	150 − 300 mg three times daily, or 225 − 425 mg b.i.d. (propafenone slow release)	Should not be used in patients with significant renal or liver disease, ischaemic heart disease, reduced LV systolic function, or asthma Should be discontinued in case of QRS widening >25% above baseline and in patients left bundle-branch block and any other conduction block >120 ms Caution when sinoatrial/atrioventricular conduction disturbances present^a Increases concentration of warfarin/acenocoumarin and digoxin when used in combination May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate ECG at baseline and after 1 − 2 weeks
Dronedarone^923–927	Oral	400 mg b.i.d.	Less effective than amiodarone in rhythm control but has very few extracardiac side-effects⁹²⁵^,^928–930 Reduces cardiovascular hospitalizations and death in patients with paroxysmal or persistent AF or AFL and cardiovascular comorbidity⁹²³^,⁹³¹ Associated with increased mortality in patients with recent decompensated HF⁹²⁷ or permanent AF⁹³² Dronedarone has the most solid safety data and may thus be a preferable first choice,⁹³³^,⁹³⁴ however not indicated in patients with HF and permanent AF⁹³⁵^,⁹³⁶ Should not be used in NYHA class III or IV or unstable HF, in combination with QT-prolonging drugs or with strong CYP3A4 inhibitors (e.g. verapamil, diltiazem) and in patients with CrCl <30 mL/min Concomitant use with dabigatran is contraindicated Combination with digoxin may significantly increase digoxin serum concentration When used with digitalis or beta-blockers their doses should be reduced Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase) A modest increase in serum creatinine is common and reflects drug-induced reduction in CrCl rather than a decline in renal function⁹³⁷ Has atrioventricular nodal-slowing properties ECG at baseline and after 4 weeks
Sotalol (d,l racemic mixture)²³³^,⁸⁹¹^,⁸⁹⁴^,⁸⁹⁵^,⁹²⁰^,^938–940	Oral	80 − 160 mg b.i.d.	Only class III effects if dosing >160 mg daily Considering its safety and efficacy and potential drug alternatives, sotalol should be used with a caution Should not be used in patients with HFrEF, significant LVH, prolonged QT, asthma, hypokalaemia, or CrCl <30 mL/min Dose-related torsades de pointes may occur in >2% of patients⁹⁴¹ Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase) The potassium channel-blocking effect increases with increasing dose and, consequently, the risk of ventricular proarrhythmia (torsades de pointes) increases Observational data and a recent meta-analysis revealed a correlation with an increased all-cause mortality⁸⁹⁰^,⁸⁹⁷^,⁹³⁴ , whereas a nationwide registry analysis and two RCTs found no evidence for increased safety concerns with sotalol²³³^,⁹³³^,⁹⁴²^,⁹⁴³ ECG at baseline, after 1 day and after 1 − 2 weeks
Disopyramide^944–946	Oral	100 − 400 mg two or t.i.d. (maximum 800 mg/24 h)	Associated with significantly increased mortality⁸⁹⁰^,⁹⁴⁷, and rarely used for rhythm control in AF.⁹⁴⁸^,⁹⁴⁹ Should not be used in patients with a structural heart disease. Rarely used for rhythm control in AF patients, due to increased mortality and frequent intolerance to side-effects May be useful in ‘vagal’ AF occurring in athletes or during sleep⁹⁰¹ Reduces LV outflow obstruction and symptoms in patients with HCM⁹⁵⁰

AAD = antiarrhythmic drug; AF = atrial fibrillation; AFL = atrial flutter; b.i.d. = bis in die (twice a day); bpm = beats per minute; CrCl = creatinine clearance; CYP2D6 = cytochrome P450 2D6; CYP34A = cytochrome 34A; ECG=electrocardiogram; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFrEF = HF with reduced ejection fraction; LV = left ventricular; LVEF = LV ejection fraction; LVH = LV hypertrophy; NDCC = non-dihydropyridinecalcium-channel blocker; NYHA = New York Heart Association; QRS = QRS interval; QT = QT interval; RCT=randomized controlled trial; SBP = systolic blood pressure; t.i.d. = ter in die (three times a day); VKA = vitamin K antagonist.

a

Caution is needed when using any AAD in patients with conduction-system disease (e.g. sinoatrial or atrioventricular node disease).

Table 20

Antiarrhythmic drugs used for long-term maintenance of sinus rhythm in AF patients⁸⁹⁰

Drug	Administration route	Dose	Contraindications/precautions/comments
Amiodarone²³³^,⁵⁰⁶^,^891–896	Oral	3 × 200 mg daily over 4 weeks, then 200 mg daily⁵⁰⁶	The most effective AAD⁸⁹⁰^,⁸⁹⁷ RCTs showed lower AF recurrence compared with sotalol and dronedarone⁸⁸⁴ Also reduces ventricular rate (for 10 − 12 bpm), safe in patients with HF^898–900 Concomitant use with other QT-prolonging drugs with caution Concomitant use with VKAs or digitalis (their dose should be reduced) Increased risk of myopathy when used with statins Requires regular surveillance for liver, lung, and thyroid toxicity Has atrioventricular nodal-slowing properties, but should not be used as first intention for rate control QT prolongation is common but rarely associated with torsades de pointes (<0.5%)⁹⁰¹ Torsades de pointes occurs infrequently during treatment with amiodarone (the proarrhythmia caution requires QT-interval and TU-wave monitoring)⁹⁰² Should be discontinued in case of excessive QT prolongation (>500 ms) ECG at baseline, after 4 weeks Contraindicated in manifest hyperthyroidism Numerous and frequent extracardiac side-effects may warrant discontinuation of amiodarone, thus making it a second-line treatment when other choices are possible^903–907
Flecainide Flecainide slow release⁸⁹⁶^,⁹⁰⁸^,⁹⁰⁹	Oral	100 − 200 mg b.i.d., or 200 mg once daily (flecainide slow release)	Effective in preventing recurrence of AF⁸⁹¹^,⁹⁰⁸^,⁹¹⁰ Should not be used in patients with CrCl <35 mL/min/1.73 m² and significant liver disease Both are contraindicated in patients with ischaemic heart disease or reduced LVEF^911–913 Should be discontinued in case of QRS widening >25% above baseline and patients with left bundle-branch block or any other conduction block >120 ms Caution when sinoatrial/atrioventricular conduction disturbances present^a CYP2D6 inhibitors increase concentration May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate.⁹¹⁴ This risk can be reduced by concomitant administration of an atrioventricular nodal-blocking drug such as a beta-blocker or NDCC In patients properly screened for propensity to proarrhythmias, both flecainide and propafenone are associated with a low proarrhythmic risk⁹¹⁵ ECG at baseline, after 1 − 2 weeks
Propafenone Propafenone slow release⁸⁹⁵^,⁸⁹⁶^,^916–922	Oral	150 − 300 mg three times daily, or 225 − 425 mg b.i.d. (propafenone slow release)	Should not be used in patients with significant renal or liver disease, ischaemic heart disease, reduced LV systolic function, or asthma Should be discontinued in case of QRS widening >25% above baseline and in patients left bundle-branch block and any other conduction block >120 ms Caution when sinoatrial/atrioventricular conduction disturbances present^a Increases concentration of warfarin/acenocoumarin and digoxin when used in combination May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate ECG at baseline and after 1 − 2 weeks
Dronedarone^923–927	Oral	400 mg b.i.d.	Less effective than amiodarone in rhythm control but has very few extracardiac side-effects⁹²⁵^,^928–930 Reduces cardiovascular hospitalizations and death in patients with paroxysmal or persistent AF or AFL and cardiovascular comorbidity⁹²³^,⁹³¹ Associated with increased mortality in patients with recent decompensated HF⁹²⁷ or permanent AF⁹³² Dronedarone has the most solid safety data and may thus be a preferable first choice,⁹³³^,⁹³⁴ however not indicated in patients with HF and permanent AF⁹³⁵^,⁹³⁶ Should not be used in NYHA class III or IV or unstable HF, in combination with QT-prolonging drugs or with strong CYP3A4 inhibitors (e.g. verapamil, diltiazem) and in patients with CrCl <30 mL/min Concomitant use with dabigatran is contraindicated Combination with digoxin may significantly increase digoxin serum concentration When used with digitalis or beta-blockers their doses should be reduced Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase) A modest increase in serum creatinine is common and reflects drug-induced reduction in CrCl rather than a decline in renal function⁹³⁷ Has atrioventricular nodal-slowing properties ECG at baseline and after 4 weeks
Sotalol (d,l racemic mixture)²³³^,⁸⁹¹^,⁸⁹⁴^,⁸⁹⁵^,⁹²⁰^,^938–940	Oral	80 − 160 mg b.i.d.	Only class III effects if dosing >160 mg daily Considering its safety and efficacy and potential drug alternatives, sotalol should be used with a caution Should not be used in patients with HFrEF, significant LVH, prolonged QT, asthma, hypokalaemia, or CrCl <30 mL/min Dose-related torsades de pointes may occur in >2% of patients⁹⁴¹ Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase) The potassium channel-blocking effect increases with increasing dose and, consequently, the risk of ventricular proarrhythmia (torsades de pointes) increases Observational data and a recent meta-analysis revealed a correlation with an increased all-cause mortality⁸⁹⁰^,⁸⁹⁷^,⁹³⁴ , whereas a nationwide registry analysis and two RCTs found no evidence for increased safety concerns with sotalol²³³^,⁹³³^,⁹⁴²^,⁹⁴³ ECG at baseline, after 1 day and after 1 − 2 weeks
Disopyramide^944–946	Oral	100 − 400 mg two or t.i.d. (maximum 800 mg/24 h)	Associated with significantly increased mortality⁸⁹⁰^,⁹⁴⁷, and rarely used for rhythm control in AF.⁹⁴⁸^,⁹⁴⁹ Should not be used in patients with a structural heart disease. Rarely used for rhythm control in AF patients, due to increased mortality and frequent intolerance to side-effects May be useful in ‘vagal’ AF occurring in athletes or during sleep⁹⁰¹ Reduces LV outflow obstruction and symptoms in patients with HCM⁹⁵⁰

Drug	Administration route	Dose	Contraindications/precautions/comments
Amiodarone²³³^,⁵⁰⁶^,^891–896	Oral	3 × 200 mg daily over 4 weeks, then 200 mg daily⁵⁰⁶	The most effective AAD⁸⁹⁰^,⁸⁹⁷ RCTs showed lower AF recurrence compared with sotalol and dronedarone⁸⁸⁴ Also reduces ventricular rate (for 10 − 12 bpm), safe in patients with HF^898–900 Concomitant use with other QT-prolonging drugs with caution Concomitant use with VKAs or digitalis (their dose should be reduced) Increased risk of myopathy when used with statins Requires regular surveillance for liver, lung, and thyroid toxicity Has atrioventricular nodal-slowing properties, but should not be used as first intention for rate control QT prolongation is common but rarely associated with torsades de pointes (<0.5%)⁹⁰¹ Torsades de pointes occurs infrequently during treatment with amiodarone (the proarrhythmia caution requires QT-interval and TU-wave monitoring)⁹⁰² Should be discontinued in case of excessive QT prolongation (>500 ms) ECG at baseline, after 4 weeks Contraindicated in manifest hyperthyroidism Numerous and frequent extracardiac side-effects may warrant discontinuation of amiodarone, thus making it a second-line treatment when other choices are possible^903–907
Flecainide Flecainide slow release⁸⁹⁶^,⁹⁰⁸^,⁹⁰⁹	Oral	100 − 200 mg b.i.d., or 200 mg once daily (flecainide slow release)	Effective in preventing recurrence of AF⁸⁹¹^,⁹⁰⁸^,⁹¹⁰ Should not be used in patients with CrCl <35 mL/min/1.73 m² and significant liver disease Both are contraindicated in patients with ischaemic heart disease or reduced LVEF^911–913 Should be discontinued in case of QRS widening >25% above baseline and patients with left bundle-branch block or any other conduction block >120 ms Caution when sinoatrial/atrioventricular conduction disturbances present^a CYP2D6 inhibitors increase concentration May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate.⁹¹⁴ This risk can be reduced by concomitant administration of an atrioventricular nodal-blocking drug such as a beta-blocker or NDCC In patients properly screened for propensity to proarrhythmias, both flecainide and propafenone are associated with a low proarrhythmic risk⁹¹⁵ ECG at baseline, after 1 − 2 weeks
Propafenone Propafenone slow release⁸⁹⁵^,⁸⁹⁶^,^916–922	Oral	150 − 300 mg three times daily, or 225 − 425 mg b.i.d. (propafenone slow release)	Should not be used in patients with significant renal or liver disease, ischaemic heart disease, reduced LV systolic function, or asthma Should be discontinued in case of QRS widening >25% above baseline and in patients left bundle-branch block and any other conduction block >120 ms Caution when sinoatrial/atrioventricular conduction disturbances present^a Increases concentration of warfarin/acenocoumarin and digoxin when used in combination May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate ECG at baseline and after 1 − 2 weeks
Dronedarone^923–927	Oral	400 mg b.i.d.	Less effective than amiodarone in rhythm control but has very few extracardiac side-effects⁹²⁵^,^928–930 Reduces cardiovascular hospitalizations and death in patients with paroxysmal or persistent AF or AFL and cardiovascular comorbidity⁹²³^,⁹³¹ Associated with increased mortality in patients with recent decompensated HF⁹²⁷ or permanent AF⁹³² Dronedarone has the most solid safety data and may thus be a preferable first choice,⁹³³^,⁹³⁴ however not indicated in patients with HF and permanent AF⁹³⁵^,⁹³⁶ Should not be used in NYHA class III or IV or unstable HF, in combination with QT-prolonging drugs or with strong CYP3A4 inhibitors (e.g. verapamil, diltiazem) and in patients with CrCl <30 mL/min Concomitant use with dabigatran is contraindicated Combination with digoxin may significantly increase digoxin serum concentration When used with digitalis or beta-blockers their doses should be reduced Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase) A modest increase in serum creatinine is common and reflects drug-induced reduction in CrCl rather than a decline in renal function⁹³⁷ Has atrioventricular nodal-slowing properties ECG at baseline and after 4 weeks
Sotalol (d,l racemic mixture)²³³^,⁸⁹¹^,⁸⁹⁴^,⁸⁹⁵^,⁹²⁰^,^938–940	Oral	80 − 160 mg b.i.d.	Only class III effects if dosing >160 mg daily Considering its safety and efficacy and potential drug alternatives, sotalol should be used with a caution Should not be used in patients with HFrEF, significant LVH, prolonged QT, asthma, hypokalaemia, or CrCl <30 mL/min Dose-related torsades de pointes may occur in >2% of patients⁹⁴¹ Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase) The potassium channel-blocking effect increases with increasing dose and, consequently, the risk of ventricular proarrhythmia (torsades de pointes) increases Observational data and a recent meta-analysis revealed a correlation with an increased all-cause mortality⁸⁹⁰^,⁸⁹⁷^,⁹³⁴ , whereas a nationwide registry analysis and two RCTs found no evidence for increased safety concerns with sotalol²³³^,⁹³³^,⁹⁴²^,⁹⁴³ ECG at baseline, after 1 day and after 1 − 2 weeks
Disopyramide^944–946	Oral	100 − 400 mg two or t.i.d. (maximum 800 mg/24 h)	Associated with significantly increased mortality⁸⁹⁰^,⁹⁴⁷, and rarely used for rhythm control in AF.⁹⁴⁸^,⁹⁴⁹ Should not be used in patients with a structural heart disease. Rarely used for rhythm control in AF patients, due to increased mortality and frequent intolerance to side-effects May be useful in ‘vagal’ AF occurring in athletes or during sleep⁹⁰¹ Reduces LV outflow obstruction and symptoms in patients with HCM⁹⁵⁰

AAD = antiarrhythmic drug; AF = atrial fibrillation; AFL = atrial flutter; b.i.d. = bis in die (twice a day); bpm = beats per minute; CrCl = creatinine clearance; CYP2D6 = cytochrome P450 2D6; CYP34A = cytochrome 34A; ECG=electrocardiogram; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFrEF = HF with reduced ejection fraction; LV = left ventricular; LVEF = LV ejection fraction; LVH = LV hypertrophy; NDCC = non-dihydropyridinecalcium-channel blocker; NYHA = New York Heart Association; QRS = QRS interval; QT = QT interval; RCT=randomized controlled trial; SBP = systolic blood pressure; t.i.d. = ter in die (three times a day); VKA = vitamin K antagonist.

a

Caution is needed when using any AAD in patients with conduction-system disease (e.g. sinoatrial or atrioventricular node disease).

A flow chart for use of AADs for long-term rhythm control, depending on the underlying disease, is given in Figure 19.

$Long-term rhythm control therapy. ACEi = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CAD=coronary artery disease; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; LVH = left ventricular hypertrophy; MRA=mineralocorticoid receptor antagonist.$

Figure 19

Long-term rhythm control therapy. ACEi = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CAD=coronary artery disease; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; LVH = left ventricular hypertrophy; MRA=mineralocorticoid receptor antagonist.

$Post-procedural management of patients with AF and ACS/PCI (full-outlined arrows represent a default strategy; graded/dashed arrows show treatment modifications depending on individual patient’s ischaemic and bleeding risks). Pretreatment with a P2Y12 inhibitor is recommended in STEMI patients or when coronary anatomy is known; it should be withheld in non-STEMI ACS until the time of coronary angiography in case of an early invasive strategy within 24 hours. Observational studies indicate that PCI on uninterrupted VKAs is generally safe compared with OAC interruption and heparin-bridging therapy,1073 particularly with radial artery access; in contrast, studies on NOACs are conflicting, predominantly discouraging a PCI on fully uninterrupted NOAC therapy.1074,1075 If urgent PCI is needed, administration of a parenteral anticoagulant (UFH, LMWH, or bivalirudin) is suggested, with temporary withdrawal of NOAC at least for the initial post-procedural period (e.g. 24 h) depending on the patient’s thrombotic and bleeding risk profile. Where thrombolysis is being considered in a patient with STEMI, the initial step should be to assess the anticoagulation status (e.g. INR in a patient taking VKA; with a NOAC, assessing, for example, activated partial thromboplastin time on dabigatran or anti-factor Xa activity on factor Xa inhibitors). Thrombolytic therapy may be associated with an increased risk of bleeding in systemically anticoagulated patients, especially if parenteral heparin and antiplatelet drugs are coadministered. A balance between the potential benefit (e.g. large anterior myocardial infarction) and harm (e.g. ICH) is needed, as well as the reassessment of urgent transfer to a PCI centre. If the supposedly anticoagulated patient does not have evidence of a therapeutic anticoagulation effect (e.g. INR <2.0 on warfarin; or no NOAC anticoagulant effect detected), systemic thrombolysis may be considered if no access to primary PCI is possible. ACS = acute coronary syndromes; ASA = acetylsalicylic acid; CAD = coronary artery disease; CCS = chronic coronary syndromes; CKD = chronic kidney disease; DAPT = dual antithrombotic therapy; eGFR = estimated glomerular filtration rate; ICH = intracranial haemorrhage; INR = international normalized ratio; LMWH = low-molecular-weight heparin; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; PPI = proton-pump inhibitor; STEMI = ST-segment elevation myocardial infarction; UFH = unfractionated heparin; VKA = vitamin K antagonist.$

Figure 20

Post-procedural management of patients with AF and ACS/PCI (full-outlined arrows represent a default strategy; graded/dashed arrows show treatment modifications depending on individual patient’s ischaemic and bleeding risks). Pretreatment with a P2Y₁₂ inhibitor is recommended in STEMI patients or when coronary anatomy is known; it should be withheld in non-STEMI ACS until the time of coronary angiography in case of an early invasive strategy within 24 hours. Observational studies indicate that PCI on uninterrupted VKAs is generally safe compared with OAC interruption and heparin-bridging therapy,¹⁰⁷³ particularly with radial artery access; in contrast, studies on NOACs are conflicting, predominantly discouraging a PCI on fully uninterrupted NOAC therapy.¹⁰⁷⁴^,¹⁰⁷⁵ If urgent PCI is needed, administration of a parenteral anticoagulant (UFH, LMWH, or bivalirudin) is suggested, with temporary withdrawal of NOAC at least for the initial post-procedural period (e.g. 24 h) depending on the patient’s thrombotic and bleeding risk profile. Where thrombolysis is being considered in a patient with STEMI, the initial step should be to assess the anticoagulation status (e.g. INR in a patient taking VKA; with a NOAC, assessing, for example, activated partial thromboplastin time on dabigatran or anti-factor Xa activity on factor Xa inhibitors). Thrombolytic therapy may be associated with an increased risk of bleeding in systemically anticoagulated patients, especially if parenteral heparin and antiplatelet drugs are coadministered. A balance between the potential benefit (e.g. large anterior myocardial infarction) and harm (e.g. ICH) is needed, as well as the reassessment of urgent transfer to a PCI centre. If the supposedly anticoagulated patient does not have evidence of a therapeutic anticoagulation effect (e.g. INR <2.0 on warfarin; or no NOAC anticoagulant effect detected), systemic thrombolysis may be considered if no access to primary PCI is possible. ACS = acute coronary syndromes; ASA = acetylsalicylic acid; CAD = coronary artery disease; CCS = chronic coronary syndromes; CKD = chronic kidney disease; DAPT = dual antithrombotic therapy; eGFR = estimated glomerular filtration rate; ICH = intracranial haemorrhage; INR = international normalized ratio; LMWH = low-molecular-weight heparin; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; PPI = proton-pump inhibitor; STEMI = ST-segment elevation myocardial infarction; UFH = unfractionated heparin; VKA = vitamin K antagonist.

Non-antiarrhythmic drugs with antiarrhythmic properties (upstream therapy)

Either resulting from, or being a marker of structural atrial remodelling, AF is closely related to atrial cardiomyopathy. Drugs that affect the atrial-remodelling process could prevent new-onset AF acting as non-conventional AADs (i.e. upstream therapy) (Table 21).

Table 21

Non-antiarrhythmic drugs with antiarrhythmic properties (upstream therapy)

Drugs	Comment
ACEi, ARBs	Activated renin-angiotensin-aldosterone system is up-regulated in AF.⁹⁵¹^,⁹⁵² ACEi and ARBs showed encouraging results in preventing AF in preclinical studies.⁹⁵³
	As suggested by retrospective analyses and studies where AF was a prespecified secondary endpoint, ACEi/ARBs could prevent new-onset AF in patients with LV dysfunction, LVH, or hypertension.^954–961
	As initial treatment, ACEi and ARBs seem to be superior to other antihypertensive regimens,⁹⁶² but ARBs did not reduce AF burden in patients without structural heart disease.⁹⁶³ Despite several positive small-scale prospective studies and retrospective analyses, larger RCTs have shown controversial results and failed to confirm the role of ACEi or ARBs in secondary (post-cardioversion) prevention of AF.⁹⁶⁴ The multifactorial pathways for AF promotion and study design could explain these negative results and should not discourage the use of ACEi or ARB to AAD in patients with structural heart disease.
MRAs	Aldosterone is implicated in inducibility and perpetuation of AF.^965–967 Evidence from RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF in parallel with improvement of other cardiovascular outcomes.⁹⁶⁸^,⁹⁶⁹
MRAs	Recently, the positive impact of MRAs was also shown in patients with HFpEF⁹⁷⁰ irrespective of baseline AF status. Regarding other renin-angiotensin-aldosterone system inhibitors, the role of MRAs as upstream therapy in rhythm control strategy for patients with HF and AF has not been clarified. As AF is a marker of HF severity, the beneficial antiarrhythmic effect could be driven indirectly, through improvement of HF. A recent meta-analysis showed that MRAs significantly reduced new-onset AF and recurrent AF, but not postoperative AF.⁹⁷¹
Beta-blockers	Several small studies suggested a lower AF recurrence rate with beta-blockers, with a comparable efficacy with sotalol.⁹³⁹^,⁹⁷²^,⁹⁷³ However, most evidence pleads against a significant role of beta-blockers in preventing AF.⁸⁹⁰ The observed beneficial effect could also result from transformation of clinically manifested AF to silent AF, because of the rate control with beta-blockers.
Statins	Statins are attractive candidates for upstream therapy, as the role of inflammation in AF is well established. However, in an adequately designed RCT,⁹⁷⁴ statins failed to show a beneficial effect, and their preventive effect was not confirmed in other settings.⁹⁷⁵^,⁹⁷⁶ Specific patient groups in whom statins could induce reverse remodelling are not identified yet, but findings from the CARAF registry suggested that AF patients already on beta-blockers could benefit from statin therapy.⁹⁷⁷ Polyunsaturated fatty acids also failed to show convincing benefit in preventing AF.^978–982

Drugs	Comment
ACEi, ARBs	Activated renin-angiotensin-aldosterone system is up-regulated in AF.⁹⁵¹^,⁹⁵² ACEi and ARBs showed encouraging results in preventing AF in preclinical studies.⁹⁵³
	As suggested by retrospective analyses and studies where AF was a prespecified secondary endpoint, ACEi/ARBs could prevent new-onset AF in patients with LV dysfunction, LVH, or hypertension.^954–961
	As initial treatment, ACEi and ARBs seem to be superior to other antihypertensive regimens,⁹⁶² but ARBs did not reduce AF burden in patients without structural heart disease.⁹⁶³ Despite several positive small-scale prospective studies and retrospective analyses, larger RCTs have shown controversial results and failed to confirm the role of ACEi or ARBs in secondary (post-cardioversion) prevention of AF.⁹⁶⁴ The multifactorial pathways for AF promotion and study design could explain these negative results and should not discourage the use of ACEi or ARB to AAD in patients with structural heart disease.
MRAs	Aldosterone is implicated in inducibility and perpetuation of AF.^965–967 Evidence from RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF in parallel with improvement of other cardiovascular outcomes.⁹⁶⁸^,⁹⁶⁹
MRAs	Recently, the positive impact of MRAs was also shown in patients with HFpEF⁹⁷⁰ irrespective of baseline AF status. Regarding other renin-angiotensin-aldosterone system inhibitors, the role of MRAs as upstream therapy in rhythm control strategy for patients with HF and AF has not been clarified. As AF is a marker of HF severity, the beneficial antiarrhythmic effect could be driven indirectly, through improvement of HF. A recent meta-analysis showed that MRAs significantly reduced new-onset AF and recurrent AF, but not postoperative AF.⁹⁷¹
Beta-blockers	Several small studies suggested a lower AF recurrence rate with beta-blockers, with a comparable efficacy with sotalol.⁹³⁹^,⁹⁷²^,⁹⁷³ However, most evidence pleads against a significant role of beta-blockers in preventing AF.⁸⁹⁰ The observed beneficial effect could also result from transformation of clinically manifested AF to silent AF, because of the rate control with beta-blockers.
Statins	Statins are attractive candidates for upstream therapy, as the role of inflammation in AF is well established. However, in an adequately designed RCT,⁹⁷⁴ statins failed to show a beneficial effect, and their preventive effect was not confirmed in other settings.⁹⁷⁵^,⁹⁷⁶ Specific patient groups in whom statins could induce reverse remodelling are not identified yet, but findings from the CARAF registry suggested that AF patients already on beta-blockers could benefit from statin therapy.⁹⁷⁷ Polyunsaturated fatty acids also failed to show convincing benefit in preventing AF.^978–982

AAD = antiarrhythmic drug; ACEi = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB=angiotensin receptor blocker; CARAF = Canadian Registry of Atrial Fibrillation; HF = heart failure; HFrEF = HF with reduced ejection fraction; HFpEF = HF with preserved ejection fraction; LV = left ventricular; LVH = LV hypertrophy; MRA = mineralocorticoid receptor antagonist; RCT = randomized controlled trial.

Table 21

Non-antiarrhythmic drugs with antiarrhythmic properties (upstream therapy)

Drugs	Comment
ACEi, ARBs	Activated renin-angiotensin-aldosterone system is up-regulated in AF.⁹⁵¹^,⁹⁵² ACEi and ARBs showed encouraging results in preventing AF in preclinical studies.⁹⁵³
	As suggested by retrospective analyses and studies where AF was a prespecified secondary endpoint, ACEi/ARBs could prevent new-onset AF in patients with LV dysfunction, LVH, or hypertension.^954–961
	As initial treatment, ACEi and ARBs seem to be superior to other antihypertensive regimens,⁹⁶² but ARBs did not reduce AF burden in patients without structural heart disease.⁹⁶³ Despite several positive small-scale prospective studies and retrospective analyses, larger RCTs have shown controversial results and failed to confirm the role of ACEi or ARBs in secondary (post-cardioversion) prevention of AF.⁹⁶⁴ The multifactorial pathways for AF promotion and study design could explain these negative results and should not discourage the use of ACEi or ARB to AAD in patients with structural heart disease.
MRAs	Aldosterone is implicated in inducibility and perpetuation of AF.^965–967 Evidence from RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF in parallel with improvement of other cardiovascular outcomes.⁹⁶⁸^,⁹⁶⁹
MRAs	Recently, the positive impact of MRAs was also shown in patients with HFpEF⁹⁷⁰ irrespective of baseline AF status. Regarding other renin-angiotensin-aldosterone system inhibitors, the role of MRAs as upstream therapy in rhythm control strategy for patients with HF and AF has not been clarified. As AF is a marker of HF severity, the beneficial antiarrhythmic effect could be driven indirectly, through improvement of HF. A recent meta-analysis showed that MRAs significantly reduced new-onset AF and recurrent AF, but not postoperative AF.⁹⁷¹
Beta-blockers	Several small studies suggested a lower AF recurrence rate with beta-blockers, with a comparable efficacy with sotalol.⁹³⁹^,⁹⁷²^,⁹⁷³ However, most evidence pleads against a significant role of beta-blockers in preventing AF.⁸⁹⁰ The observed beneficial effect could also result from transformation of clinically manifested AF to silent AF, because of the rate control with beta-blockers.
Statins	Statins are attractive candidates for upstream therapy, as the role of inflammation in AF is well established. However, in an adequately designed RCT,⁹⁷⁴ statins failed to show a beneficial effect, and their preventive effect was not confirmed in other settings.⁹⁷⁵^,⁹⁷⁶ Specific patient groups in whom statins could induce reverse remodelling are not identified yet, but findings from the CARAF registry suggested that AF patients already on beta-blockers could benefit from statin therapy.⁹⁷⁷ Polyunsaturated fatty acids also failed to show convincing benefit in preventing AF.^978–982

Drugs	Comment
ACEi, ARBs	Activated renin-angiotensin-aldosterone system is up-regulated in AF.⁹⁵¹^,⁹⁵² ACEi and ARBs showed encouraging results in preventing AF in preclinical studies.⁹⁵³
	As suggested by retrospective analyses and studies where AF was a prespecified secondary endpoint, ACEi/ARBs could prevent new-onset AF in patients with LV dysfunction, LVH, or hypertension.^954–961
	As initial treatment, ACEi and ARBs seem to be superior to other antihypertensive regimens,⁹⁶² but ARBs did not reduce AF burden in patients without structural heart disease.⁹⁶³ Despite several positive small-scale prospective studies and retrospective analyses, larger RCTs have shown controversial results and failed to confirm the role of ACEi or ARBs in secondary (post-cardioversion) prevention of AF.⁹⁶⁴ The multifactorial pathways for AF promotion and study design could explain these negative results and should not discourage the use of ACEi or ARB to AAD in patients with structural heart disease.
MRAs	Aldosterone is implicated in inducibility and perpetuation of AF.^965–967 Evidence from RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF in parallel with improvement of other cardiovascular outcomes.⁹⁶⁸^,⁹⁶⁹
MRAs	Recently, the positive impact of MRAs was also shown in patients with HFpEF⁹⁷⁰ irrespective of baseline AF status. Regarding other renin-angiotensin-aldosterone system inhibitors, the role of MRAs as upstream therapy in rhythm control strategy for patients with HF and AF has not been clarified. As AF is a marker of HF severity, the beneficial antiarrhythmic effect could be driven indirectly, through improvement of HF. A recent meta-analysis showed that MRAs significantly reduced new-onset AF and recurrent AF, but not postoperative AF.⁹⁷¹
Beta-blockers	Several small studies suggested a lower AF recurrence rate with beta-blockers, with a comparable efficacy with sotalol.⁹³⁹^,⁹⁷²^,⁹⁷³ However, most evidence pleads against a significant role of beta-blockers in preventing AF.⁸⁹⁰ The observed beneficial effect could also result from transformation of clinically manifested AF to silent AF, because of the rate control with beta-blockers.
Statins	Statins are attractive candidates for upstream therapy, as the role of inflammation in AF is well established. However, in an adequately designed RCT,⁹⁷⁴ statins failed to show a beneficial effect, and their preventive effect was not confirmed in other settings.⁹⁷⁵^,⁹⁷⁶ Specific patient groups in whom statins could induce reverse remodelling are not identified yet, but findings from the CARAF registry suggested that AF patients already on beta-blockers could benefit from statin therapy.⁹⁷⁷ Polyunsaturated fatty acids also failed to show convincing benefit in preventing AF.^978–982

AAD = antiarrhythmic drug; ACEi = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB=angiotensin receptor blocker; CARAF = Canadian Registry of Atrial Fibrillation; HF = heart failure; HFrEF = HF with reduced ejection fraction; HFpEF = HF with preserved ejection fraction; LV = left ventricular; LVH = LV hypertrophy; MRA = mineralocorticoid receptor antagonist; RCT = randomized controlled trial.

Recently, the RACE 3 study²⁴⁵ confirmed the importance of assessing underlying conditions and targeted upstream therapy for intense risk-factor control in AF patients with mild or moderate HF in optimizing rhythm control. The results showed that targeted therapy of underlying conditions improves maintenance of sinus rhythm in patients with persistent AF.

A list of new investigational antiarrhythmic drugs is provided in Supplementary Box 3.

Recommendations for long-term antiarrhythmic drugs

AAD = antiarrhythmic drug; AF = atrial fibrillation; CrCl = Creatinine clearance; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; LVH = LV hypertrophy; VHD = valvular heart disease.

a

Class of recommendation.

b

Level of evidence.

Assessment and long-term monitoring of the risk of proarrhythmia with antiarrhythmic drugs

A variety of clinical, echocardiographic, and ECG criteria have been associated with a higher risk of proarrhythmia.^986–989 Increasing age, female sex, impaired renal and/or liver function, and known CAD have been variously identified as associated with higher risk.⁸⁹⁰^,^990–992 Concomitant AAD use, hypokalaemia, or family history of sudden death have also been implicated.⁹⁹⁰ Proarrhythmic events tend to cluster shortly after drug initiation, especially if a loading dose or a change in usual dosage is prescribed.⁵⁶⁸ For quinidine, the risk is idiosyncratic independent of dosage. Impaired LV function and LVH are echocardiographic markers of increased proarrhythmic risk. Sotalol has a proarrhythmic risk even in the absence of structural heart disease. On the 12-lead ECG, prolonged corrected QT interval (QTc), widened QRS, and prolonged PR interval have all been associated with proarrhythmia.^993–995 Significant ion-channel mutations have been detected in only a minority of cases of drug-induced torsade.⁹⁹⁶ Periodic ECG analysis for proarrhythmia signs has been used successfully in recent AAD trials⁵⁹⁴^,.⁹⁹⁷ Specifically, ECG monitoring was used systematically on days 1–3 in patients receiving flecainide, propafenone, or sotalol to identify those at risk of proarrhythmia²³³^,⁵⁹⁴^,.⁹⁹⁸ The role of routine use of exercise stress testing in patients commencing 1C drugs who had no evidence of structural heart disease is still debatable⁹¹⁵^,.⁹⁹⁹

10.3 ‘C’ – Cardiovascular risk factors and concomitant diseases: detection and management

Cardiovascular risk-factor burden and comorbidities, including lifestyle factors and borderline conditions, significantly affect the lifetime risk for AF development (Supplementary Figure 5). The continuum of unhealthy lifestyle, risk factor(s), and cardiovascular disease can contribute to atrial remodelling/cardiomyopathy and development of AF that commonly results from a combined effect of multiple interacting factors (often without specific threshold values).

The ‘C’ component of the ABC pathway includes identification and management of concomitant diseases, cardiometabolic risk factors, and unhealthy lifestyle factors. Management of risk factors and cardiovascular disease complements stroke prevention and reduces AF burden and symptom severity. In a recent RCT, for example, targeted therapy of underlying conditions significantly improved maintenance of sinus rhythm in patients with persistent AF and HF.²⁴⁵

Whereas strategies on comprehensive risk-factor modification and interventions targeting underlying conditions have shown reduction of AF burden and recurrence, studies addressing isolated management of specific conditions alone (e.g. hypertension) yielded inconsistent findings,¹⁰⁰⁰ likely because the condition was not a sole contributor to AF.

10.3.1 Lifestyle interventions

10.3.1.1 Obesity and weight loss

Obesity increases the risk for AF progressively according to body mass index.³⁶⁶^,^1001–1005 It may also increase the risk for ischaemic stroke, thrombo-embolism, and death in AF patients,³⁶⁶ notwithstanding an obesity paradox in AF patients, especially regarding all-cause and cardiovascular death, with an inverse relationship between overweight/obesity and better cardiovascular prognosis in long-term follow-up.¹⁰⁰⁶

Intense weight reduction with comprehensive management of concomitant cardiovascular risk factors resulted in fewer AF recurrences and symptoms than general advice in obese patients with AF⁶³⁶^,⁸⁸⁸^,.⁸⁸⁹ Achieving a healthy weight may reduce blood pressure (BP), dyslipidaemia, and risk of developing type 2 diabetes mellitus, thus improving the cardiovascular risk profile.¹⁰⁰⁷ Obesity may increase AF recurrence rates after AF catheter ablation (with OSA as a potential confounder).⁶³⁸^,⁶⁴³^,⁷⁸⁹^,¹⁰⁰⁸ It has also been linked to a higher radiation dose and complication rate during AF ablation,¹⁰⁰⁹^,¹⁰¹⁰ whereas symptom improvement after AF catheter ablation seems comparable in obese and normal-weight patients.¹⁰⁰⁸ Given the potential to reduce AF episodes by weight reduction, AF catheter ablation should be offered to obese patients in conjunction with lifestyle modifications for weight reduction (Figure 18).

10.3.1.2 Alcohol and caffeine use

Alcohol excess is a risk factor for incident AF^1011–1014 and bleeding³⁹⁵ in anticoagulated patients (mediated by poor adherence, liver disease, variceal bleeding, and risk of major trauma), and high alcohol intake may be associated with thrombo-embolism or death.¹⁰¹⁵ In a recent RCT, alcohol abstinence reduced arrhythmia recurrence in regular drinkers with AF.¹⁰¹⁶

By contrast, it is unlikely that caffeine consumption causes or contributes to AF.⁴⁷ Habitual caffeine consumption might be associated with lower risk of AF, but caffeine intake may increase symptoms of palpitations unrelated to AF.

10.3.1.3 Physical activity

Many studies have demonstrated beneficial effects of moderate exercise/physical activity on cardiovascular health.^1017–1019 Nevertheless, the incidence of AF appears to be increased among elite athletes, and multiple small studies reported a relationship between AF and vigorous physical activity, mainly related to long-term or endurance sport participation.^1020–1023 A non-linear relationship between physical activity and AF seems likely. Based on these data, patients should be encouraged to undertake moderate-intensity exercise and remain physically active to prevent AF incidence or recurrence, but maybe avoid chronic excessive endurance exercise (such as marathons and long-distance triathlons, etc.), especially if aged >50 years. Owing to few randomized patients and outcomes, the effect of exercise-based cardiac rehabilitation on mortality or serious adverse events is uncertain.¹⁰²⁴

10.3.2 Specific cardiovascular risk factors/comorbidities

10.3.2.1 Hypertension

Hypertension is the most common aetiological factor associated with the development of AF, and patients with hypertension have a 1.7-fold higher risk of developing AF compared with normotensives.²⁶^,¹⁰²⁵

Hypertension also adds to the complications of AF, particularly stroke, HF, and bleeding risk. AF patients with a longer hypertension duration or uncontrolled systolic BP (SBP) levels should be categorized as ‘high-risk’, and strict BP control in addition to OAC is important to reduce the risk of ischaemic stroke and ICH.

Given the importance of hypertension as a precipitating factor for AF, which should be regarded as a manifestation of hypertension target-organ damage, treatment of hypertension consistent with current BP guidelines¹⁰²⁶ is mandatory in AF patients, aiming to achieve BP≤130/80 mmHg to reduce adverse outcomes.³³⁸^,¹⁰²⁷^,¹⁰²⁸ A recent randomized trial in patients with paroxysmal AF and hypertension reported fewer recurrences in patients undergoing renal denervation in addition to PVI compared with patients undergoing PVI only.¹⁰²⁹ Sotalol should not be used in the presence of hypertensive LVH or renal impairment, owing to the risk of proarrhythmia. There is some evidence of angiotensin converting enzyme or angiotensin receptor blocker use to improve outcomes in AF or reduce progression of the arrhythmia²⁶^,.¹⁰²⁵ Other lifestyle changes, including obesity management, alcohol reduction, and attention to OSA, may also help in patients with AF and hypertension.

10.3.2.2 Heart failure

The interactions between AF and HF and the optimal management of patients with both AF and HF are discussed in section 11.6.

10.3.2.3 Coronary artery disease

The interactions between AF and CAD and the optimal management of patients with both AF and CAD are discussed in section 11.3.

10.3.2.4 Diabetes mellitus

In addition to shared risk factors (e.g. hypertension and obesity),¹⁰⁰⁴^,¹⁰³⁰ diabetes is an independent risk factor for AF, especially in young patients.¹⁰³¹ Silent AF episodes are favoured by concurrent autonomic dysfunction,¹⁰³² thus suggesting an opportunity for routine screening for AF in diabetes mellitus patients. The prevalence of AF is at least two-fold higher in patients with diabetes compared with people without diabetes,¹⁰³³ and AF incidence rises with increasing severity of microvascular complications (retinopathy, renal disease).¹⁰³⁴ Both type 1 and type 2 diabetes mellitus are the risk factors for stroke.³⁴²^,¹⁰³⁵

Intensive glycaemic control does not affect the rate of new-onset AF,¹⁰³⁶ but metformin and pioglitazone could be associated with lower long-term risk of AF in patients with diabetes,¹⁰³⁷ while this was not confirmed for rosiglitazone.¹⁰³⁸ Currently there is no evidence that glucagon-like peptide-1 agonists, sodium glucose co-transporter-2 inhibitors, and dipeptidyl peptidase-4 inhibitors affect the development of AF.¹⁰³⁹

Previous meta-analyses showed no significant interaction between diabetes mellitus and NOAC effects in AF patients,⁴²³^,¹⁰⁴⁰ but vascular mortality was lower in patients with diabetes treated with NOACs than in those on warfarin.¹⁰⁴⁰ Bleeding risk reduction with NOACs was similar in diabetic and non-diabetic patients except for apixaban, where a lower reduction in haemorrhagic complications was reported in the AF patients with diabetes compared with AF patients without diabetes.¹⁰⁴¹ Regarding potential side-effects of OAC, there is no evidence that bleeding risk is increased in patients with diabetes and retinopathy.³⁴¹

Optimal glycaemic control in 12 months before AF catheter ablation was associated with significant reduction in recurrent AF after ablation.¹⁰⁴²

10.3.2.5 Sleep apnoea

The most common form of sleep-disordered breathing, OSA, is highly prevalent in patients with AF, HF, and hypertension, and is associated with increased risk of mortality or major cardiovascular events.¹⁰⁴³ In a prospective analysis, approximately 50% of AF patients had OSA compared with 32% of controls.¹⁰⁴⁴ The mechanisms facilitating AF include intermittent nocturnal hypoxemia/hypercapnia, intrathoracic pressure shifts, sympathovagal imbalance, oxidative stress, inflammation, and neurohumoral activation.¹⁰⁴⁵ OSA has been shown to reduce success rates of AADs, electrical cardioversion, and catheter ablation in AF.¹⁰⁴⁵

Continuous positive airway pressure (CPAP) is the therapy of choice for OSA, and may ameliorate OSA effects on AF recurrences.¹⁰⁴⁶^,¹⁰⁴⁷ Observational studies and meta-analyses showed that appropriate CPAP treatment of OSA may improve rhythm control in AF patients.⁶⁴⁸^,⁶⁴⁹^,^1047–1051

It seems reasonable to test for OSA before the initiation of rhythm control therapy in symptomatic AF patients, with the aim to reduce symptomatic AF recurrences (Figure 18). In the ARREST-AF (Aggressive Risk Factor Reduction Study – Implication for AF) and LEGACY (Long-term Effect of Goal-directed weight management on an Atrial fibrillation Cohort: a 5-Year follow-up study) studies, an aggressive risk-factor reduction programme focusing on weight management, hyperlipidaemia, OSA, hypertension, diabetes, smoking cessation, and alcohol-intake reduction significantly reduced AF burden after PVI.⁶³⁶^,¹⁰⁵² However, it remains unclear how and when to test for OSA and implement OSA management in the standard work-up of AF patients.

Recommendations for lifestyle interventions and management of risk factors and concomitant diseases in patients with AF

AF = atrial fibrillation; BP = blood pressure; OAC = oral anticoagulant; OSA = obstructive sleep apnoea.

a

Class of recommendation.

b

Level of evidence.

11 The ABC pathway in specific clinical settings/conditions/patient populations

In this section, the management of AF in patient populations with specific conditions is described. The principles of the ABC pathway apply in these settings as well. Additionally, specific considerations are given for each of these special conditions and populations.

11.1 Atrial fibrillation with haemodynamic instability

Acute haemodynamic instability (i.e. syncope, acute pulmonary oedema, ongoing myocardial ischaemia, symptomatic hypotension, or cardiogenic shock) in AF patients presenting with a rapid ventricular rate requires prompt intervention. In severely compromised patients, emergency electrical cardioversion should be attempted without delay, and anticoagulation should be started as soon as possible.

In critically ill patients and those with severely impaired LV systolic function, AF is often precipitated/exacerbated by increased sympathetic tone, inotropes, and vasopressors, and rhythm control is often unsuccessful. It is important to identify and correct precipitating factors and secondary causes and optimize background treatment. Owing to their rate-controlling effect during exertion and increased sympathetic tone, rather than only at rest, beta-blockers are preferred over digitalis glycosides for ventricular rate control in AF.⁴⁹⁰ Beta-blockers and NDCC antagonists may exert a negative inotropic effect (the latter are contraindicated in HFrEF). Digoxin is often unsuccessful due to the increased sympathetic tone in these patients.

As conventional therapy is often ineffective or not well-tolerated,⁴⁹⁰ electrical cardioversion should always be considered, even as initial therapy, whereas intravenous amiodarone may be instituted for rate control (or potential cardioversion to sinus rhythm), with or without electrical cardioversion.⁵⁰⁴^,⁵¹⁴^,⁵¹⁵ Intravenous administration of amiodarone may lead to a further decrease in BP.

Recommendations for management of AF with haemodynamic instability

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

11.2 First-diagnosed (new-onset) atrial fibrillation

First-diagnosed or new-onset AF is a working diagnosis in a patient without a history of AF, until the pattern of AF can be defined more precisely. Although the clinical profile and outcome of patients with first-diagnosed AF in AF registries were less favourable than those with paroxysmal AF, rather resembling permanent AF,¹⁰⁵⁵^,¹⁰⁵⁶ OAC prescription rates were the lowest in patients with first-diagnosed AF.¹⁰⁵⁷ In patients with first-diagnosed AF, the ABC pathway should resemble all steps outlined in the Central Illustration.

11.3 Acute coronary syndromes, percutaneous coronary intervention, and chronic coronary syndromes in patients with atrial fibrillation

The incidence of AF in acute coronary syndromes (ACS) ranges from 2 − 23%,¹⁰⁵⁸ the risk of new-onset AF is increased by 60 − 77%¹⁰⁵⁹ in myocardial infarction patients, and AF per se may be associated with an increased risk of ST-segment elevation myocardial infarction (STEMI) or non−STEMI ACS.³⁸¹^,^1060–1063 Overall, 10 − 15% of AF patients undergo PCI for CAD.¹⁰⁶⁴ In observational studies, patients with AF and ACS were less likely to receive appropriate antithrombotic therapy¹⁰⁶⁵ and more likely to experience adverse outcomes¹⁰⁶⁶ than ACS patients without AF.

Peri-procedural management of patients with an ACS or undergoing PCI is detailed in the respective ESC Guidelines on myocardial revascularization¹⁰⁶⁷ and chronic coronary syndromes (CCS).¹⁰⁶⁸

Post-procedural management of atrial fibrillation patients with acute coronary syndrome and/or percutaneous coronary intervention

In AF patients having an ACS or undergoing PCI, concomitant risks of ischaemic stroke/systemic embolism, coronary ischaemic events, and antithrombotic treatment-related bleeding need to be carefully balanced when considering the use and duration of combined antithrombotic therapy.¹⁰⁶⁹ Overall, dual antithrombotic therapy including OAC (preferably NOAC) and a P2Y₁₂ inhibitor (preferably clopidogrel) is associated with significantly less major bleeding (and ICH) than triple therapy. However, available evidence suggests that at least a short course of triple therapy (e.g. ≤1 week) would be desirable in some AF patients after a recent ACS or undergoing PCI, especially in those at increased risk of ischaemic events¹⁰⁷⁰^,¹⁰⁷¹ (Figure 20).

Box 1 About post-procedural management of patients with AF and ACS and/or PCI

Shorter courses of triple therapy (OAC + DAPT) may be safe in post-ACS/PCI patients requiring OAC.¹⁰⁷⁶ Observational data¹⁰⁷⁷ and the WOEST trial with warfarin (a safety RCT, underpowered for ischaemic outcomes)¹⁰⁷⁸ suggested better safety and similar efficacy with dual (OAC + clopidogrel) vs. triple therapy.

RCTs of NOACs in AF patients after a recent ACS/PCI

Four RCTs compared dual therapy with a P2Y₁₂ inhibitor (mostly clopidogrel) plus a NOAC—dabigatran 110 mg or 150 mg b.i.d. (RE-DUAL PCI),¹⁰⁷⁹ rivaroxaban 15 mg o.d. (PIONEER AF-PCI),¹⁰⁸⁰ apixaban 5 mg b.i.d. (AUGUSTUS),¹⁰⁸¹ or edoxaban 60 mg o.d. (ENTRUST-AF PCI)¹⁰⁸² —vs. triple therapy with a VKA in AF patients with a recent ACS or undergoing PCI. The two-by-two factorial AUGUSTUS trial design enabled the comparison of aspirin vs. placebo (see Supplementary Table 12 for detailed information about these studies). All four trials had a primary safety endpoint (i.e. bleeding) and were underpowered to assess ischaemic outcomes.

Despite some heterogeneity among these trials, all have consistently:

Included a proportion of patients with an ACS/PCI (37 − 52%); nevertheless, the highest risk patients (e.g. previous stent thrombosis or a complex PCI with stent-in-stent placement) were largely under-represented;
Used triple therapy during PCI and until randomization (1 − 14 days post PCI);
Most commonly used the P2Y₁₂ inhibitor clopidogrel (overall, >90%); and
Reported a significant reduction of major/clinically significant bleeding, comparable rates of ischaemic stroke, similar or non-significantly higher rates of myocardial infarction and stent thrombosis, and a neutral effect on trial-defined major adverse cardiovascular events and all-cause mortality with dual (NOAC + P2Y₁₂) vs. triple (VKA + P2Y₁₂ + aspirin) therapy.

In AUGUSTUS,¹⁰⁸¹ both placebo (vs. aspirin) and apixaban (vs. VKA) regimens were associated with significant reduction in bleeding, and apixaban (vs. VKA) was associated with significantly lower rates of stroke, death, or hospitalization.

Meta-analyses of RCTs

Bleeding outcomes: Meta-analyses¹⁰⁷⁰^,¹⁰⁷¹^,¹⁰⁸³^,¹⁰⁸⁴ consistently showed a significant reduction in major bleeding with dual vs. triple and NOAC- vs. VKA-based therapies (NOAC-based treatments were also associated with a significant reduction in ICH).
Ischaemic events: Stroke rates were similar across all treatment arms, but the rates of myocardial infarction and stent thrombosis were numerically higher with dual vs. triple therapy. In two meta-analyses¹⁰⁷⁰^,,¹⁰⁷¹ stent thrombosis was statistically significantly increased on dual (i.e. no aspirin) vs. triple therapy. Also, the risk of myocardial infarction or stent thrombosis was slightly higher with dabigatran 110 mg but not dabigatran 150 mg.
The trial-defined major adverse cardiovascular events and mortality rates were similar in all treatment arms, suggesting that the benefit from major bleeding and ICH reduction is counterbalanced by a higher risk for coronary (mainly stent-related) ischaemic events with dual therapy.

ACS = acute coronary syndromes; AF = atrial fibrillation; b.i.d. = bis in die (twice a day); DAPT = dual antiplatelet therapy; ENTRUST-AF PCI = Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; ICH = intracranial haemorrhage; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once daily); PCI = percutaneous coronary intervention; PIONEER AF-PCI = (OPen-Label, Randomized, Controlled, Multicenter Study ExplorIng TwO TreatmeNt StratEgiEs of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention; RCT = randomized controlled trial; RE-DUAL PCI = Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; VKA = vitamin K antagonist; WOEST = What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing.

Whichever initial treatment plan was chosen, dual therapy with OAC and an antiplatelet drug (preferably clopidogrel) is recommended for the first 12 months after PCI for ACS, or 6 months after PCI in patients with CCS.¹⁰⁶⁷ Thereafter, OAC monotherapy is to be continued (irrespective of the stent type) provided that there were no recurrent ischaemic events in the interim. In 1-year event-free (i.e. ‘stable’) AF patients with CAD and no PCI, OAC monotherapy is also recommended.¹⁰⁷²

Use of prasugrel or ticagrelor has been associated with a greater risk of major bleeding compared with clopidogrel^1085–1089 and should be avoided in ACS patients with AF. In the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, 12% of patients received ticagrelor with dabigatran, but experience with ticagrelor or prasugrel was minimal in PIONEER-AF (OPen-Label, Randomized, Controlled, Multicenter Study ExplorIng TwO TreatmeNt StratEgiEs of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention), AUGUSTUS, and ENTRUST-AF PCI (Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention). In patients at potential risk of gastrointestinal bleeding, concomitant use of proton-pump inhibitors is reasonable.¹⁰⁸⁴

In AF patients treated with surgical coronary revascularization, OAC should be resumed as soon as bleeding is controlled, possibly in combination with clopidogrel, and triple therapy should be avoided.

Poor ventricular rate control during AF may exacerbate symptoms of myocardial ischaemia and precipitate or worsen HF. Appropriate treatment may include a beta-blocker or rate-limiting calcium antagonist. In haemodynamic instability, acute cardioversion may be indicated. Vernakalant, flecainide, and propafenone should not be used for rhythm control in patients with known CAD (section 10.2.2.2).

In all AF patients with an ACS/CCS, optimized management of risk factors is needed, and cardiovascular prevention strategies such as good BP control,³³⁸ lipid management, and other cardiovascular prevention interventions¹⁰⁰⁷ should be implemented as needed, once the acute presentation is stabilized.

Recommendations for patients with AF and an ACS, PCI, or CCS¹⁰⁶⁸

ACS = acute coronary syndrome; AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CCS = chronic coronary syndrome; CKD = chronic kidney disease; DAPT = Dual antiplatelet therapy; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; NOAC = non-vitamin K antagonist oral anticoagulant; o.d. = omni die (once daily); OAC = oral anticoagulant; PCI=percutaneous coronary intervention; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

See summary of product characteristics for reduced doses or contraindications for each NOAC in patients with CKD, body weight <60 kg, age >75 − 80 years, and/or drug interactions.

d

Risk of stent thrombosis encompasses: (i) risk of thrombosis occurring, and (ii) risk of death should stent thrombosis occur, both of which relate to anatomical, procedural, and clinical characteristics. Risk factors for CCS patients include: stenting of left main stem or last remaining patent artery; suboptimal stent deployment; stent length >60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antithrombotic therapy.

e

Bleeding risk in AF patients may be assessed using the HAS-BLED score (section 10.1.2), which draws attention to modifiable bleeding risk factors; those at high risk (score ≥3) can have more frequent or early review and follow-up. Bleeding risk is highly dynamic and does not remain static, and relying on modifiable bleeding risk factors alone is an inferior strategy to evaluate bleeding risk.³⁸⁹

f

When dabigatran is used in triple therapy, dabigatran 110 mg b.i.d may be used instead of 150 mg b.i.d, but the evidence is insufficient.

11.4 Acute stroke or intracranial haemorrhage in patients with atrial fibrillation

11.4.1 Patients with atrial fibrillation and acute ischaemic stroke or transient ischaemic attack

Management of acute stroke in AF patients is beyond the scope of this document. In AF patients presenting with acute ischaemic stroke while taking OAC, acute therapy depends on the treatment regimen and intensity of anticoagulation. Patients on VKA with an INR<1.7 are eligible for thrombolysis according to the neurological indication (if presenting with a clinically relevant neurological deficit within the appropriate time window and ICH is excluded with cerebral imaging). In patients taking NOACs, measurement of activated partial thromboplastin time or thrombin time (for dabigatran), or antifactor Xa levels (for factor Xa inhibitors) will provide information on whether the patient is systemically anticoagulated. Whenever possible, the time when the last NOAC dose was taken should be elucidated (generally, thrombolysis is considered to be safe in patients with last NOAC intake being ≥48 h, assuming normal renal function).¹⁰⁹⁰

If the patient is systemically anticoagulated, thrombolysis should not be performed due to the risk of haemorrhage, and endovascular treatment should be considered. In patients taking dabigatran, systemic thrombolysis may be performed after reversal of the dabigatran action by idarucizumab.¹⁰⁹¹

Secondary prevention of stroke/systemic embolism in patients after acute AF-related ischaemic stroke or TIA includes early prevention of recurrent ischaemic stroke in the 2 weeks after the index event and long-term prevention thereafter.

Box 2 About acute ischaemic stroke in patients with AF

AF-related ischaemic strokes are often fatal or disabling ¹⁰⁶ , with increased risk of early recurrence within 48 h ¹⁰⁹² to 2 weeks,^1092–1095 or haemorrhagic transformation,¹⁰⁹⁶ especially in the first days after large cardio-embolic lesions and acute recanalization therapy.¹⁰⁹⁷^,¹⁰⁹⁸ Notably, ICH is generally associated with higher mortality and morbidity than recurrent ischaemic stroke.

Timing of OAC (re)initiation after acute ischaemic stroke

Early anticoagulation after acute ischaemic stroke might cause parenchymal haemorrhage, with potentially serious clinical consequences¹⁰⁹⁷^,.¹⁰⁹⁹ Using UFH, LMWH, heparinoids, or VKAs <48 h after acute ischaemic stroke was associated with an increased risk of symptomatic ICH, without significant reduction in recurrent ischaemic stroke.¹⁰⁹⁵
Reportedly, the 90-day risk of recurrent ischaemic stroke outweighs the risk of symptomatic ICH in AF patients receiving a NOAC 4 − 14 days after the acute event^1100–1102 (ischaemic stroke recurrence rates after mild/moderate ischaemic stroke significantly increased with a later NOAC administration,¹¹⁰¹ e.g. >14 days).¹¹⁰⁰ In a small RCT, rivaroxaban use within 5 days after mild ischaemic stroke in AF patients was associated with similar event rates compared with VKA.¹¹⁰³

As high-quality RCT-derived evidence to inform optimal timing of anticoagulation after acute ischaemic stroke is lacking, OAC use in the early post-stroke period is currently based on expert consensus.⁵⁰⁵ Several ongoing RCTs [ELAN (NCT03148457), OPTIMAS (EudraCT, 2018-003859-3), TIMING (NCT02961348), and START (NCT03021928)] are investigating early (<1 week) vs. late NOAC initiation in patients with AF-related ischaemic stroke (first results are not expected before 2021).

Long-term secondary stroke prevention

There is no evidence that the addition of aspirin to OAC or supratherapeutic INRs would improve outcomes in secondary stroke prevention.
Compared with VKAs, NOACs were associated with better efficacy in secondary stroke prevention and better safety regarding ICH in a meta-analysis of landmark NOAC AF trial.¹¹⁰⁴
Good adherence to OAC treatment is essential for effective secondary stroke prevention.

There is some evidence to support that strokes can induce AF through neurogenic mechanisms¹¹⁰⁵^,.¹¹⁰⁶ The first study showed that damage to the insula increases the odds of AF detection after ischaemic stroke and is more prevalent in patients with AF diagnosed after stroke than among those without AF.¹¹⁰⁵ The second study explained the reason why AFDAS detected soon after ischaemic stroke is associated with a low risk of ischaemic stroke recurrence.¹¹⁰⁶

AF = atrial fibrillation; ELAN = Early versus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic Stroke Patients With AF; ICH = intracranial haemorrhage; INR = international normalized ratio; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; OPTIMAS = OPtimal TIMing of Anticoagulation after Stroke; RCT = randomized controlled trial; START = Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in AF; TIMING = TIMING of Oral Anticoagulant Therapy in Acute Ischemic Stroke With AF; UFH = unfractionated heparin; VKA = vitamin K antagonist.

Whereas infarct size/stroke severity is used clinically to guide timing of OAC initiation,¹⁰⁹⁰ the usefulness of such an approach in estimating the net benefit of early treatment may be limited. Robust data to inform optimal timing for (re)initiation of OAC after acute stroke are lacking. From the cardiological perspective, OAC should be (re)initiated as soon as considered possible from the neurological perspective (in most cases within the first 2 weeks). A multidisciplinary approach with involvement of stroke specialists, cardiologists, and patients is considered appropriate.

In AF patients who presented with acute ischaemic stroke despite taking OAC, optimization of OAC therapy is of key importance—if on VKA, optimize TTR (ideally >70%) or switch to a NOAC; if on NOAC, ensure appropriate dosing and good adherence to treatment. Inappropriate NOAC under-dosing using lower or reduced doses of specific NOACs has been associated with increased risk of stroke/systemic embolism, hospitalization, and deaths without appreciable reduction in major bleeding.¹¹⁰⁷

11.4.2 Cryptogenic stroke/embolic stroke with undetermined source

Currently available evidence including two recently completed RCTs¹¹⁰⁸^,¹¹⁰⁹ does not support routine OAC use in patients with acute ischaemic stroke of uncertain aetiology (cryptogenic stroke) or acute embolic stroke of undetermined source in patients without documented AF (Supplementary Box 4). Of note, subgroup analyses of those two RCTs suggested that certain subgroups (i.e. age ≥75 years, impaired renal function,¹¹⁰⁹ or enlarged LA¹¹¹⁰) could benefit from OAC, but more data are needed to inform optimal use of NOACs among patients with a cryptogenic stroke. Two ongoing trials will study the use of apixaban in this setting [ATTICUS (Apixaban for treatment of embolic stroke of undetermined source)]¹¹¹¹ and ARCADIA [(AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke) (NCT03192215)].

Efforts to improve detection of AF are needed in such patients (see also section 8). Clinical risk scores {e.g. C₂HEST [CAD/COPD (1 point each), Hypertension (1 point), Elderly ( ≥75 years, 2 points), Systolic heart failure (2 points), and Thyroid disease (hyperthyroidism, 1 point) (score)]} have been proposed for identification of ‘high-risk’ patients for AF diagnosis¹¹¹² and facilitation of prolonged monitoring.

Recommendations for the search for AF in patients with cryptogenic stroke

AF = atrial fibrillation; C₂HEST = CAD/COPD (1 point each), Hypertension (1 point), Elderly ( ≥75 years, 2 points), Systolic heart failure (2 points), and Thyroid disease (hyperthyroidism, 1 point) (score); ECG=electrocardiogram; LA = left atrial; TIA=transient ischaemic attack.

a

Class of recommendation.

b

Level of evidence.

c

Not all stroke patients would benefit from prolonged ECG monitoring; those deemed at risk of developing AF (e.g. elderly, with cardiovascular risk factors or comorbidities, indices of LA remodelling, high C₂HEST score, etc.) or those with cryptogenic stroke and stroke characteristics suggestive of an embolic stroke should be scheduled for prolonged ECG monitoring.

11.4.3 Post-stroke patients without known atrial fibrillation

Detection of previously unknown AF after stroke has important implications for secondary prevention. Several RCTs have established the effectiveness of ECG monitoring for post-stroke AF detection, with numbers needed to screen of 8–14.¹¹¹⁷^,¹¹¹⁸

Looking harder and longer and using more sophisticated monitoring may generally improve AF detection. In a meta-analysis¹¹¹⁸ of 50 post-stroke studies, the proportion of patients with post-stroke AF was 7.7% in the emergency room using admission ECG; 5.1% in the wards using serial ECG, continuous inpatient ECG monitoring/cardiac telemetry, and in-hospital Holter monitoring; 10.7% in the first ambulatory period using ambulatory Holter; and, after discharge, 16.9% using mobile cardiac outpatient telemetry and external or implantable loop recording. The overall post-stroke AF detection after all phases of cardiac monitoring reached 23.7%.¹¹¹⁸

In patients with ischaemic stroke/TIA, monitoring for AF is recommended by short-term ECG recording followed by continuous ECG monitoring for at least 72 h, also considering a tiered longer ECG monitoring approach¹¹¹³ and insertion of an intracardiac monitor in case of cryptogenic stroke.¹¹¹⁴^,¹¹¹⁹ Post-stroke ECG monitoring is likely cost-effective¹¹²⁰^,¹¹²¹; however, RCTs have not been powered to assess the effect of prolonged ECG monitoring and subsequent prescription of OAC on stroke or mortality in patients with detected AF.

11.4.4 Management of patients with atrial fibrillation post-intracranial haemorrhage

As ICH is the most feared, often lethal, complication of anticoagulant and antiplatelet therapy, there is a considerable reluctance to (re)initiate OAC in AF patients who survived an ICH, despite their high estimated risk of AF-related ischaemic stroke.

Patients with a history of recent ICH were excluded from RCTs of stroke prevention in AF, but available observational data suggest than many AF patients would benefit from (re)institution of OAC, depending on the cause(s) of ICH and findings on brain CT and MRI (Supplementary Box 5).

Treatment decision to (re)start OAC in AF patients after an ICH requires multidisciplinary-team input from cardiologists, stroke specialists, neurosurgeons, patients, and their family/carers. After acute spontaneous ICH (which includes epidural, subdural, subarachnoid, or intracerebral haemorrhage), OAC may be considered after careful assessment of risks and benefits, and cerebral imaging may help. The risk of recurrent ICH may be increased in the presence of specific risk factors, shown in Figure 21. Of note, the risk of OAC-related ICH is increased especially in Asian patients.¹¹²²

Figure 21

(Re-) initiation of anticoagulation post-intracranial bleeding. A pooled analysis of individual patient data from cohort studies (n=20 322 patients; 38 cohorts; >35 225 patient-years) showed that although cerebral microbleeds can inform regarding the risk for ICH in patients with recent ischaemic stroke/TIA treated with antithrombotic therapy, the absolute risk of ischaemic stroke is substantially higher than that of ICH, regardless of the presence, burden, or location of cerebral microbleeds.⁵⁰⁵^,¹¹²³ IS = ischaemic stroke;ACS = acute coronary syndrome; CMB = cerebral microbleeds; ICH = intracranial haemorrhage; LAA = left atrial appendage; LDL = low-density lipoprotein; LoE = level of evidence; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; RCT = randomized controlled trial; TIA = transient ischaemic attack.

Compared with VKAs, the use of NOACs in patients without previous ICH is associated with an approximately 50% lower risk of ICH,⁴²³ whereas the size and outcome of OAC-related ICH is similar with NOACs and VKAs.¹¹²⁴ Hence, NOACs should be preferred in NOAC-eligible ICH survivors with AF although there is no RCT to prove this.

The optimal timing of anticoagulation after ICH is unknown, but should be delayed beyond the acute phase, probably for at least 4 weeks; in AF patients at very high risk of recurrent ICH, LAA occlusion may be considered. Ongoing RCTs of NOACs and LAA occlusion may inform decision making in the future.

AF = atrial fibrillation; ICH = intracranial haemorrhage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TIA = transient ischaemic attack; UFH = unfractionated heparin; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

A more favourable net benefit is likely with deep ICH or without neuroimaging evidence of cerebral amyloid angiopathy or microbleeds.

11.5 Active bleeding on anticoagulant therapy: management and reversal drugs

Management of patients with active bleeding while on OAC is shown in Figure 22. General assessment should include detection of the bleeding site, assessment of bleeding severity, and evaluation of the time-point of last OAC intake. Concomitant antithrombotic drugs and other factors influencing bleeding risk (alcohol abuse, renal function) should be explored. Laboratory tests, such as INR, are useful in case of VKA therapy. More specific coagulation tests for NOACs include diluted thrombin time, ecarin clotting time, or ecarin chromogenic assay for dabigatran, and chromogenic anti-factor Xa assay for rivaroxaban, apixaban, and edoxaban.¹¹³¹ However, these tests or measurement of NOAC plasma levels are not always readily available in practice and are often unnecessary for bleeding management.¹¹³² An overview of reversal drugs for NOACs is given in Supplementary Table 13 and Supplementary Figure 6.

Management of active bleeding in patients receiving anticoagulation (institutions should have an agreed procedure in place).143 FFP = fresh frozen plasma; INR = international normalized ratio; i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation therapy; PCC = prothrombin complex concentrates; VKA = vitamin K antagonist.

Figure 22

Management of active bleeding in patients receiving anticoagulation (institutions should have an agreed procedure in place).¹⁴³ FFP = fresh frozen plasma; INR = international normalized ratio; i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation therapy; PCC = prothrombin complex concentrates; VKA = vitamin K antagonist.

Notably, the time of last drug ingestion combined with assessment of renal function, haemoglobin, haematocrit, and platelet count enable appropriate clinical decision making in most of the cases.

Minor bleeding events should be treated with supportive measures such as mechanical compression or minor surgery to achieve haemostasis. Withdrawal of VKAs is not associated with a prompt reduction of anticoagulant effect, while NOACs have a short plasma half-life and haemostasis can be expected within 12 − 24 h after an omitted dose.

Treatment of moderate bleeding events may require blood transfusions and fluid replacement. If the last intake of NOACs was less than 2 − 4 h before bleeding assessment, charcoal administration and/or gastric lavage will reduce further exposure. Specific diagnostic and treatment interventions to identify and manage the cause of bleeding (e.g. gastroscopy) should be performed promptly. Dialysis is effective in reducing dabigatran concentration and has been associated with reduction in the duration and/or severity of associated bleeding.¹¹³³

Severe or life-threatening bleeding requires immediate reversal of the antithrombotic effect of OACs. For VKAs, administration of fresh frozen plasma restores coagulation more rapidly than vitamin K, but prothrombin complex concentrates achieve even faster blood coagulation¹¹³⁴ and are first-line therapy for VKA reversal.¹¹³⁵ Specific reversal drugs are available for NOACs: idarucizumab (for dabigatran) and andexanet alfa (for factor Xa inhibitors) effectively reverse the anticoagulation action of NOACs and restore physiological haemostasis.¹¹³⁶^,¹¹³⁷ However, their use is often associated with subsequent non-reinitiation of OAC and increased rates of thrombotic events. These drugs can be effectively applied in case of severe life-threatening bleeding or urgent surgery, but their use is only very rarely necessary in daily clinical practice. Ciraparantag is an investigational synthetic drug that binds and inhibits direct factor Xa inhibitors, dabigatran, and heparin. The use of four-factor prothrombin complex concentrates may be considered as an alternative treatment for reversing the anticoagulant effect of rivaroxaban, apixaban, and edoxaban, although scientific evidence is very limited in this context and is frequently from healthy volunteers.^1138–1140

Recommendations for the management of active bleeding on OAC

AF = atrial fibrillation; OAC = oral anticoagulant; VKA=vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

11.6 Atrial fibrillation and heart failure

Both AF and HF facilitate the occurrence and aggravate the prognosis of each other, and often coexist (see also sections 4.2 and 5.3); HF is also a thrombo-embolic risk factor in AF. The efficacy and safety of NOACs do not seem to differ in AF patients with and without HF.¹¹⁴¹^,¹¹⁴²

The management of patients with AF and HF is often challenging (section 10.2). The optimal heart-rate target in AF patients with HF remains unclear, but a rate of <100 − 110 bpm is usually recommended.^1143–1145 Pharmacological rate control strategies are different for patients with heart failure with preserved ejection fraction (HFpEF) and HFrEF. Beta-blockers, diltiazem, verapamil, and digoxin are all viable options in HFpEF, while beta-blockers and digoxin can be used in those with HFrEF. Amiodarone may be considered for rate control in both forms of HF, but only in the acute setting. Atrioventricular-node ablation and pacing can control ventricular rate when medication fails (section 10.2.1.). However, in an observation study, rhythm control strategies showed a lower 1-year all-cause death over rate control in older patients (≥65 years) with HFpEF.¹¹⁴⁶

Haemodynamic instability or worsening of HF may require emergency or immediate electrical cardioversion of AF, whereas pharmacological cardioversion using i.v. amiodarone may be attempted if a delayed cardioversion is consistent with the clinical situation (section 10.2.2.2.2). AF catheter ablation has been shown to improve symptoms, exercise capacity, QoL, and LVEF in AF patients with HF,⁶⁶¹ whereas the recent CASTLE-AF RCT showed a reduction in all-cause mortality and hospitalization for worsening HF after AF catheter ablation in patients with HFrEF⁶⁵⁷ (section 10.2.2.3).

All patients with HF and AF should receive guideline-adherent HF therapy.¹¹⁴⁵ The benefit of beta-blocker therapy in reducing mortality in AF patients with HFrEF has been questioned by some meta-analyses,⁴⁹¹ although this is not a universal finding, especially with some real-world studies supporting an improved prognosis.¹¹⁴⁷^,¹¹⁴⁸

11.7 Atrial fibrillation and valvular heart disease

VHD is independently associated with AF¹¹⁴⁹ and more than one-third of patients with AF have some form of VHD.⁵¹²

Among patients with severe VHD, including those undergoing surgical and transcatheter aortic or mitral valve intervention, AF is associated with less favourable clinical outcomes.^1150–1155 Compared to AF patients without VHD, the risk of thrombo-embolism and stroke is increased among AF patients with VHD other than mitral stenosis and mechanical heart prostheses, mostly owing to older age and more frequent comorbidities.¹¹⁵⁶^,¹¹⁵⁷ While patients with moderate-to-severe mitral stenosis and mechanical prosthetic heart valves require anticoagulation with VKAs,¹¹⁵⁸ there is no evidence that the presence of other VHDs including aortic stenosis/regurgitation, mitral regurgitation, bioprostheses, or valve repair should modify the choice of OAC.¹¹⁵⁶^,¹¹⁵⁹ In a meta-analysis of the four pivotal RCTs comparing NOACs with VKAs, the effects of NOACs vs. VKAs in terms of stroke/systemic embolism and bleeding risk in patients with VHD other than mitral stenosis and mechanical prosthetic heart valves were consistent with those in the main RCTs.¹¹⁶⁰ In an observational study, NOACs were associated with better outcomes, with reduced rates of ischaemic stroke and major bleeding compared to warfarin in AF patients with mitral stenosis.¹¹⁶¹

Recently, a functional categorization of VHD in relation to OAC use was introduced, categorizing patients with moderate-severe or rheumatic mitral stenosis as type 1 and all other VHD as type 2.¹⁴⁸^,¹¹⁵⁷^,¹¹⁶² There are gaps in evidence on NOAC use in AF patients with rheumatic mitral valve disease, and during the first 3 months after surgical or transcatheter implantation of a bioprosthesis, and observational data regarding NOACs use after transcatheter aortic valve implantation are conflicting.¹¹⁶³ An RCT in non-AF patients comparing rivaroxaban 10 mg daily with aspirin after transcatheter aortic valve implantation was stopped early due to higher risks of death or thrombo-embolic complications and bleeding in the rivaroxaban arm.¹¹⁶⁴

Recommendations for patients with valvular heart disease and AF

AF = atrial fibrillation; NOAC = non-vitamin K antagonist oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

11.8 Atrial fibrillation and chronic kidney disease

Independently of AF, CKD is a prothrombotic and prohaemorrhagic condition (Supplementary Figure 7),¹¹⁶⁶^,¹¹⁶⁷^,¹¹⁶⁸ and AF may accelerate CKD progression. Coexisting in 15–20% of CKD patients,¹¹⁶⁹ AF is associated with increased mortality,¹¹⁷⁰ whereas CKD may be present in 40 − 50% of AF patients.¹¹⁷¹ In AF patients, renal function can deteriorate over time,¹¹⁷² and worsening CrCl is a better independent predictor of ischaemic stroke/systemic embolism and bleeding than renal impairment per se.¹¹⁷² In RCTs of OAC for stroke prevention in AF, renal function was usually estimated using the Cockcroft–Gault formula for CrCl, and a CrCl cut-off of <50 mL/min was used to adapt NOAC dosage.

In patients with mild-to-moderate CKD (CrCl 30 − 49 mL/min), the safety and efficacy of NOACs vs. warfarin was consistent with patients without CKD in landmark NOAC trials^1173–1176, hence the same considerations for stroke risk assessment and choice of OAC may apply.

In patients with CrCl 15 − 29 mL/min, RCT-derived data on the effect of VKA or NOACs are lacking. These patients were essentially excluded from the major RCTs. The evidence for the benefits of OAC in patients with end-stage kidney disease with CrCl≤15 mL/min or on dialysis is even more limited, and to some extent controversial. There are no RCTs, whereas observational data question the benefit of OAC in this patient population. Data from observational studies suggest possible bleeding risk reduction in patients with end-stage kidney disease taking a NOAC compared with VKA,⁴³⁵^,¹¹⁷⁷ but there is no solid evidence for a reduction in embolic events with either NOACs or VKAs, as recently shown in a systematic review.¹¹⁷⁸ Notably, NOACs have not been approved in Europe for patients with CrCl ≤15 mL/min or on dialysis.

Several RCTs are currently assessing OAC use and comparing NOACs with VKAs in patients with end-stage renal disease (NCT02933697, NCT03987711). The RENAL-AF trial, investigating apixaban vs. warfarin in AF patients on haemodialysis, was terminated early with inconclusive data on relative stroke and bleeding rates.¹¹⁷⁹

There are no RCT data on OAC use in patients with AF after kidney transplantation. The prescription and dosing of NOACs should be guided by the estimated glomerular filtration rate of the transplanted kidney and taking into account potential interactions with concomitant medication.

Particular attention must be given to the dosing of NOACs in patients with CKD (Supplementary Table 9).

11.9 Atrial fibrillation and peripheral artery disease

Patients with AF often have atherosclerotic vascular disease. With the inclusion of asymptomatic ankle-brachial index≤0.90 in the definition PAD, the prevalence of vascular disease increased significantly.¹¹⁸⁰ In a systematic review and meta-analysis, the presence of PAD was significantly associated with a 1.3- to 2.5-fold increased risk of stroke.³⁴⁷ Complex aortic plaque in the descending aorta, as identified on TOE, is also a significant vascular stroke risk factor (section 10.1.1).

In patients with asymptomatic PAD, the risk of cardiovascular events progressively increases with increasing vascular disease burden.⁴⁷⁰ Therefore, PAD patients should be opportunistically screened for AF. Patients with AF and PAD should be prescribed OAC, unless contraindicated. Those with stable vascular disease (arbitrarily defined as no new vascular event in the past 12 months) should be managed with OAC alone (section 11.3), as concomitant use of antiplatelet therapy has not been shown to reduce stroke or other cardiovascular events, but may increase serious bleeds, including ICH.

The principles of rate and rhythm control outlined in section 10.2 also apply for AF patients with PAD. Special considerations include possibly limited exercise capacity in these patients, owing to intermittent claudication. Beta-blockers may exacerbate PAD symptoms in some patients, in whom NDCC blockers may be more appropriate for rate control.

11.10 Atrial fibrillation and endocrine disorders

Electrolyte disturbances and altered glucose and/or hormone levels in endocrine disorders such as thyroid disorders, acromegaly, pheochromocytoma, diseases of adrenal cortex, parathyroid disease, or pancreas dysfunction including diabetes mellitus may contribute to development of AF. Data on management of AF in these settings are limited.³ Diabetes is discussed in section 10.3.2.4. Stroke prevention should follow the same principles as in other AF patients, with risk stratification using the CHA₂DS₂-VASc score.³^,¹¹⁸¹ In AF patients with hyperthyroidism, spontaneous conversion of AF often occurs once a euthyroid state is achieved.¹¹⁸² Withdrawal of amiodarone is mandatory in hyperthyroidism. AF catheter ablation should be performed under stable electrolytic and metabolic conditions and should not be carried out during active hyperthyroidism.

11.11 Atrial fibrillation and gastrointestinal disorders

While gastrointestinal lesions can lead to bleeding events in anticoagulated AF patients, some gastrointestinal conditions such as active inflammatory bowel disease increase the risk of AF and stroke.¹¹⁸³ Gastrointestinal bleeding is a well-known complication of OAC. Overall, NOAC use is associated with an increased risk of gastrointestinal bleeding,¹¹⁸⁴^,¹¹⁸⁵ but in patients treated with apixaban or dabigatran 110 mg the risk is similar to warfarin.⁴¹⁹^,⁴²¹ Bleeding lesions can be identified in more than 50% of cases of major gastrointestinal bleeding.¹¹⁸⁶ After correction of the bleeding source, OAC should be restarted, as this strategy has been associated with decreased risks of thrombo-embolism and death.¹¹⁸⁷

Patients treated with dabigatran may experience dyspepsia (about 11% in the RE-LY trial, and 2% discontinued the drug because of gastrointestinal symptoms⁴¹⁹). After-meal ingestion of dabigatran and/or the addition of proton-pump inhibitors improves symptoms.¹¹⁸⁸

Management of AF patients with liver disease is challenging, owing to increased bleeding risk (associated with decreased hepatic synthetic function in advanced liver disease, thrombocytopenia, and gastrointestinal variceal lesions), as well as increased ischaemic risk¹¹⁸⁹^,¹¹⁹⁰). Patients with hepatic dysfunction were generally excluded from the RCTs,¹¹⁹¹ especially those with abnormal clotting tests, as such patients may be at higher risk of bleeding on VKA, possibly less so on NOACs. Despite the paucity of data, observational studies did not raise concerns regarding the use of NOACs in advanced hepatic disease.¹¹⁹² In a recent study, AF patients with liver fibrosis had no increase in bleeding on NOACs compared with VKAs.⁴⁷⁰ Other reassuring data for NOACs come from a large nationwide cohort.⁴⁷² A number of patients may be started on a NOAC while having unrecognized significant liver damage and, in cirrhotic patients, ischaemic stroke reduction may outweigh bleeding risk.⁴⁷¹ NOACs are contraindicated in patients within Child-Turcotte-Pugh C hepatic dysfunction, and rivaroxaban is not recommended for patients in the Child-Turcotte-Pugh B or C category.¹¹⁹³

11.12 Atrial fibrillation and haematological disorders

Anaemia is an independent predictor of OAC-related major bleeding.³⁹³^,⁴⁰² In a population-based AF cohort, anaemia was associated with major bleeding and lower TTR, whereas OAC use in AF patients with moderate or severe anaemia was associated with more major bleeding but no reduction in thrombo-embolic risk.¹¹⁹⁴ Thrombocytopenia is also associated with increased bleeding risk. Before and during anticoagulation treatment, both anaemia and thrombocytopenia should be investigated and corrected, if possible. Decision making on OAC use in patients with platelet counts <100/µL requires a multidisciplinary approach including haematologists, balancing thrombotic and bleeding risks and addressing modifiable bleeding risk factors. Some chemotherapeutic drugs may increase the risk of incident AF (e.g. ibrutinib, melphalan, anthracyclines)^1195–1197 or impair platelet function, thus increasing the risk of bleeding (e.g. ibrutinib).¹¹⁹⁸^,¹¹⁹⁹

11.13 The elderly and frail with atrial fibrillation

The prevalence of AF increases progressively with age⁶⁷^,^1200–1206, and age is an independent risk factor for adverse outcomes in AF.³⁷²^,¹²⁰⁰^,¹²⁰⁷^,¹²⁰⁸ Older people are less likely to receive OAC^1209–1216 despite sufficient evidence supporting the use of OAC in this population. Frailty, comorbidities, and increased risk of falls^1217–1219 do not outweigh the benefits of OAC given the small absolute risk of bleeding in anticoagulated elderly patients.³³⁹^,³⁹⁰^,³⁹¹^,^1220–1223 Evidence from RCTs,⁴⁴¹^,¹²²⁴ meta-analyses⁴²³^,¹²²⁵ and large registries³³⁹^,⁴³³^,¹²⁰⁹^,¹²²⁶ support the use of OAC in this age group. Antiplatelets are neither more effective nor safer than warfarin and may even be harmful,⁴³³ whereas NOACs appear to have a better overall risk–benefit profile compared with warfarin.⁴²³^,⁴³³^,⁴⁴¹^,¹⁰³⁵^,¹²²⁵^,^1227–1236 Prescribing a reduced dose of OAC is less effective in preventing AF adverse outcomes.¹¹⁰⁷^,¹²¹¹^,¹²³⁷^,¹²³⁸

Rate control is traditionally the preferred strategy, but evidence informing the choice between rate and rhythm control in the elderly is insufficient.^1239–1242 Limited evidence on other AF treatments supports the use of all rate and rhythm control options, including cardioversion, pacemaker implantation, and AF catheter ablation without any age discrimination. AF catheter ablation may be an effective and safe option in selected older individuals with success rates comparable to younger patients^1243–1255 and acceptable complication rates.¹²⁴³^,^1245–1247^,^1249–1260 Nevertheless, age was a predictor of complications in AF catheter ablation in some studies^1261–1263 and longer follow-up studies suggested an age-related increase in multivariable-adjusted risk for AF/AFL recurrence, death, and major adverse cardiac events.¹²⁵⁷

11.14 Patients with cognitive impairment/dementia

Evidence regarding effective prevention of cognitive impairment in AF is derived mainly from observational studies, suggesting that OAC could play a protective role in AF patients with stroke risk factors, not only for stroke prevention but also for prevention of cognitive decline.¹²⁶⁴ The quality of anticoagulation with VKAs (i.e. TTR) seems to play an additional role: low TTR and supratherapeutic INR values were associated with higher risk of dementia.¹²⁶⁵^,¹²⁶⁶ Limited evidence suggests that NOACs may be superior to VKA for preventing cognitive impairment in some,¹²⁶⁷^,¹²⁶⁸ but not all, studies.¹²⁶⁹ Recent observational data indicate a protective effect of OAC even in low-risk AF patients who do not need OAC for stroke prevention.¹²⁷⁰ A number of RCTs with cognitive function as an endpoint are ongoing and will provide more insights into the role of anticoagulation (NOACs and VKAs) for prevention of cognitive impairment in AF.⁸⁶

Conversely, cognitive impairment can influence treatment adherence,¹²⁷¹^,¹²⁷² thus affecting outcomes in AF patients. After AF catheter ablation, silent brain lesions are detected by MRI, but this has not led to cognitive impairment in the AXAFA–AFNET 5 trial, although underpowered.⁸⁸⁰

11.15 Atrial fibrillation and congenital heart disease

Survival of patients with congenital heart disease has increased over time, but robust data on the management of AF are missing and available evidence is derived mainly from observational studies and/or extrapolation from large clinical trials.

In patients with AF (or AFL or intra-atrial re-entrant tachycardia) and congenital heart disease, OAC treatment is recommended for all patients with intracardiac repair, cyanotic congenital heart disease, Fontan palliation, or systemic right ventricle.¹²⁷³ Patients with AF and other congenital heart diseases should follow the general risk stratification for OAC use in AF. Notably, NOACs are contraindicated in patients with mechanical heart valves,¹¹⁶⁵ whereas they seem safe in those with a valvular bioprosthesis.¹²⁷⁴^,¹²⁷⁵

Rate control drugs such as beta-blockers, verapamil, diltiazem, and digitalis can be used with caution due to the risk of bradycardia and hypotension. Rhythm control strategies (i.e. amiodarone) may be effective. In Fontan patients, sodium-channel blockers suppress half of the atrial arrhythmias, but caution is needed for proarrhythmia. When cardioversion is planned, both 3 weeks of anticoagulation and TOE may be considered as thrombi are common in patients with congenital heart disease and atrial tachyarrhythmias.¹²⁷⁶^,¹²⁷⁷

In patients with atrial septal defect, closure may be considered before the fourth decade of life to decrease the risk of AF or AFL.¹²⁷⁸ Patients with stroke who underwent closure of the patent foramen ovale may have an increased risk of AF,¹²⁷⁹ but in patients with patent foramen ovale and AF, closure is not recommended for stroke prevention; and OAC use should be decided using the conventional stroke risk assessment tool. In patients with a history of AF, AF surgery or AF catheter ablation should be considered at the time of closure of the septal defect.^1280–1282 AF catheter ablation of late atrial arrhythmias is likely to be effective after surgical atrial septal defect closure.¹²⁸³

Recommendations for the management of AF in patients with congenital heart disease

AF = atrial fibrillation; AFL = atrial flutter; TOE = transoesophageal echocardiography.

a

Class of recommendation.

b

Level of evidence.

11.16 Atrial fibrillation in inherited cardiomyopathies and primary arrhythmia syndromes

A higher incidence and prevalence of AF have been described in patients with inherited cardiomyopathies and primary arrhythmia syndromes.^1284–1318 Sometimes AF is the presenting or only clinically overt feature,^1319–1323 is often associated with adverse clinical outcomes,¹²⁹²^,¹²⁹⁹^,¹³⁰¹^,¹³⁰⁷^,¹³⁰⁸^,¹³¹⁰^,^1324–1329 and has important implications:

The use of AADs may be challenging. In congenital long QT syndrome, many drugs are contraindicated owing to increased risk of QT prolongation and torsade de pointes (http://www.crediblemeds.org/); in Brugada syndrome, class I drugs are contraindicated (http://www.brugadadrugs.org/). Owing to its long-term adverse effects, chronic use of amiodarone is problematic in these typically young individuals.
In patients with an implantable cardioverter defibrillator, AF is a common cause of inappropriate shocks.¹³⁰⁷^,¹³¹¹^,^1330–1333 Programming a single high-rate ventricular fibrillation zone ≥210 − 220 bpm with long detection time is safe,¹²⁹⁵^,¹²⁹⁶^,¹³³⁴ and is recommended in patients without documented slow monomorphic ventricular tachycardia. Implantation of an atrial lead may be considered in case of significant bradycardia under beta-blocker treatment.

Supplementary Table 14 summarizes the main clinical features of AF in patients with inherited cardiac diseases.

Patients with Wolff−Parkinson−White syndrome and AF are at risk of fast ventricular rates resulting from rapid conduction of atrial electrical activity to the ventricles via the accessory pathway, and at increased risk of ventricular fibrillation and sudden death.¹³³⁵^,¹³³⁶ Electrical cardioversion should be readily available for haemodynamically compromised patients with pre-excited AF, and atrioventricular node-modulating drugs (e.g. verapamil, beta-blockers, digoxin) should be avoided.¹³³⁷^,¹³³⁸ Pharmacological cardioversion can be attempted using ibutilide,¹³³⁹ whereas AADs class Ia (procainamide) and Ic (propafenone, flecainide) should be used with caution owing to their effect on the atrioventricular node.^1340–1343 Amiodarone may not be safe in pre-excited AF as it may enhance pathway conduction.¹³⁴³

11.17 Atrial fibrillation during pregnancy

AF is one of the most frequent arrhythmias during pregnancy,¹³⁴⁴ especially in women with congenital heart disease¹³⁴⁵^,¹³⁴⁶ and in older gravidae,¹³⁴⁴^,¹³⁴⁷^,¹³⁴⁸ and is associated with increased risk of death.¹³⁴⁴ Rapid atrioventricular conduction may have serious haemodynamic consequences for mother and foetus.

Pregnancy is associated with a hypercoagulable state and increased thrombo-embolic risk. Given the lack of specific data, the same rules for stroke risk assessment should be used as in non-pregnant women.¹³⁴⁹ Detailed practical recommendations on oral and parenteral anticoagulation regimens depending on the pregnancy trimester, such as low- and high-dose VKA use during the second and third trimesters, timing of low-molecular-weight heparin (LMWH) to unfractionated heparin (UFH) relative delivery, and control of therapeutic effects are given in the recent ESC Pregnancy Guidelines.¹³⁴⁹ Immediate anticoagulation is required in clinically significant mitral stenosis, using LMWH at therapeutic doses in the first and last trimesters, and VKA with the usual INR targets or LMWH for the second trimester. Use of NOACs is prohibited during pregnancy. Vaginal delivery should be advised for most women but is contraindicated while the mother is on VKAs because of the risk of foetal intracranial bleeding.¹³⁴⁹

Intravenous beta-blockers are recommended for acute rate control. Beta-1 selective blockers (e.g. metoprolol and bisoprolol) are generally safe and are recommended as the first choice.¹³⁴⁹ If beta-blockers fail, digoxin and verapamil should be considered for rate control.

Rhythm control should be considered the preferred strategy during pregnancy. Electrical cardioversion is recommended if there is haemodynamic instability or considerable risk for mother or foetus. It can be performed safely without compromising foetal blood flow¹³⁵⁰ and the consequent risk for foetal arrhythmias or preterm labour is low.¹³⁵¹^,¹³⁵² The fetal heart rate should routinely be controlled after cardioversion.¹³⁵³ Cardioversion should generally be preceded by anticoagulation (section 10.2.2.6).¹³⁴⁹ In haemodynamically stable patients without structural heart disease, i.v. ibutilide or flecainide may be considered for termination of AF but experience is limited.¹³⁵⁴^,¹³⁵⁵ Flecainide, propafenone, or sotalol should be considered to prevent AF if atrioventricular nodal-blocking drugs fail. AF catheter ablation has no role during pregnancy.

Recommendations for the management of AF during pregnancy

AF = atrial fibrillation; ECG = electrocardiogram; US FDA = United States Food and Drug Administration; i.v. = intravenous; LV = left ventricular; HCM = hypertrophic cardiomyopathy; QTc = corrected QT interval; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

Cardioversion of AF should generally be preceded by anticoagulation.

d

Atenolol has been associated with higher rates of foetal growth retardation and is not recommended.¹³⁵⁶

e

Flecainide and propafenone should be combined with atrioventricular nodal-blocking drugs, but structural heart disease, reduced LV function, and bundle branch block should be excluded.

f

Class III drugs should not be used in prolonged QTc.

g

Atrioventricular nodal-blocking drugs should not be used in patients with pre-excitation on resting ECG or pre-excited AF.

Note that the former A to X categories of drugs—the classification system for counselling of pregnant women requiring drug therapy—was replaced by the Pregnancy and Lactation Labelling Rule, which provides a descriptive risk summary and detailed information on animal and clinical data, by the US FDA in June 2015.

11.18 Atrial fibrillation in professional athletes

Moderate physical activity improves cardiovascular health and prevents AF, whereas intense sports activity increases the risk of AF.³⁵^,¹³⁵⁷ Athletes have an approximate five-fold increased lifetime risk of AF compared with sedentary individuals despite a lower prevalence of conventional AF risk factors.³⁵^,¹⁰²⁰ Risk factors for AF in athletes include male sex, middle age, endurance sports, tall stature, and total lifetime exercise dose exceeding 1500 − 2000 hours.¹⁰²⁰^,^1358–1361 Endurance sports such as running, cycling, and cross-country skiing³⁵^,¹³⁶² carry the highest risk.

In the absence of RCTs, recommendations for AF management in athletes are based largely on evidence in non-athletes, observational data, and expert consensus.¹⁴³ The need for anticoagulation is determined by clinical risk factors. Sports with direct bodily contact or prone to trauma should be avoided in patients on OAC. As athletes have a high prevalence of sinus bradycardia and sinus pauses, medical therapy is frequently contraindicated or poorly tolerated.¹⁰²¹^,¹³⁶³ Digoxin and verapamil are often ineffective for rate control during exertional AF, whereas beta-blockers may not be well tolerated or are sometimes prohibited. Pill-in-the-pocket therapy has been used, but sports activity should be avoided after ingestion of flecainide or propafenone until AF ceases and two half-lives of the drug have elapsed.⁵⁸⁶ AF catheter ablation is often preferred by athletes and was similarly efficacious in both the athletic and non-athletic populations in small studies.¹³⁶⁴^,¹³⁶⁵

Recommendations for sports activity in patients with AF

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

11.19 Postoperative atrial fibrillation

Perioperative AF describes the onset of the arrhythmia during an ongoing intervention. This is most relevant in patients undergoing cardiac surgery. While multiple strategies to reduce the incidence of perioperative AF with pretreatment or acute drug treatment have been described, there is lack of evidence from large RCTs. Amiodarone is the most frequently used drug for prevention of perioperative AF.¹³⁶⁹

Postoperative AF, defined as new-onset AF in the immediate postoperative period, is a clinically relevant problem,¹³⁷⁰^,¹³⁷¹ occurring in 20 − 50% of patients after cardiac surgery,¹³⁷²^,¹³⁷³ 10 − 30% after non-cardiac thoracic surgery,¹³⁷⁴ and in 5 − 10% after vascular or large colorectal surgery,¹³⁷⁵ with peak incidence between postoperative day 2 and 4.¹³⁷⁶ Intra- and postoperative changes affecting AF triggers and pre-existing atrial substrate may increase atrial vulnerability to AF. Many episodes of postoperative AF are self-terminating and some are asymptomatic, but postoperative AF has been associated with a four- to five-fold risk of recurrent AF in the next 5 years.¹³⁷⁷^,¹³⁷⁸ It has also been shown to be a risk factor for stroke, myocardial infarction, and death compared with non-postoperative AF patients.¹³⁷⁹^,¹³⁸⁰

Other adverse consequences of postoperative AF include haemodynamic instability, prolonged hospital stay, infections, renal complications, bleeding, increased in-hospital death, and greater healthcare costs.¹³⁷¹^,¹³⁸¹^,¹³⁸² Management of postoperative AF is shown in Figure 23.

$Management of postoperative AF. AAD = antiarrhythmic drug; bpm = beats per minute; CCB = calcium channel blocker; ECV = electrical cardioversion; LVEF = left ventricular ejection fraction; Mg2+ magnesium; OAC = oral anticoagulation; PCV = pharmacological cardioversion; PUFA=polyunsaturated fatty acid.$

Figure 23

Management of postoperative AF. AAD = antiarrhythmic drug; bpm = beats per minute; CCB = calcium channel blocker; ECV = electrical cardioversion; LVEF = left ventricular ejection fraction; Mg²⁺ magnesium; OAC = oral anticoagulation; PCV = pharmacological cardioversion; PUFA=polyunsaturated fatty acid.

11.19.1 Prevention of postoperative AF

Preoperative beta-blocker (propranolol, carvedilol plus N-acetyl cysteine) use in cardiac and non-cardiac surgery is associated with a reduced incidence of postoperative AF,^1383–1386 but not major adverse events such as death, stroke, or acute kidney injury.¹³⁸⁷ Notably, in non-cardiac surgery, perioperative metoprolol was associated with increased risk of death in a large RCT.¹³⁸⁸ In a meta-analysis, amiodarone (oral or i.v.), and beta-blockers were equally effective in reducing postoperative AF,¹³⁸⁹ but their combination was better than beta-blockers alone.¹³⁹⁰ Lower cumulative doses of amiodarone (<3000 mg) could be effective, with fewer adverse events.^1391–1393 Data for other interventions such as statins⁹⁷⁴^,,¹³⁹⁴ magnesium,¹³⁹⁵ sotalol,¹³⁸⁵ colchicine,¹³⁹⁶ posterior pericardiotomy,¹³⁹⁷^,¹³⁹⁸ (bi)atrial pacing,¹³⁸⁵ and corticosteroids¹³⁹⁹ are not robust. Two large RCTs showed no significant effect of i.v. steroids on the incidence of postoperative AF after cardiac surgery,¹⁴⁰⁰^,¹⁴⁰¹ and colchicine is currently being investigated in the prevention of postoperative AF [COP-AF (Colchicine For The Prevention Of Perioperative Atrial Fibrillation In Patients Undergoing Thoracic Surgery): NCT03310125].

11.19.2 Prevention of thrombo-embolic events

In a large meta-analysis, patients with postoperative AF had a 62% higher odds of early and 37% higher risk of long-term stroke compared with those without postoperative AF (≥1-year stroke rates were 2.4% vs. 0.4%, respectively), as well as 44% higher odds of early and 37% higher risk of long-term mortality; long-term stroke risk was substantially higher with non-cardiac than cardiac postoperative AF (HR 2.00; 95% CI 1.70–2.35 for non-cardiac vs. HR 1.20; 95% CI 1.07–1.34 for cardiac postoperative AF; P for subgroup difference <0.0001).¹³⁷⁹

Nevertheless, the evidence on OAC effects in patients with postoperative AF is not very robust.¹³⁸²^,^1402–1407 Observational data¹⁴⁰⁸ suggest that although coronary artery bypass graft-related postoperative AF might not be equivalent to non-surgery AF regarding the long-term risk of adverse outcomes, OAC use during follow-up was associated with a significantly lower risk of thrombo-embolic events in both postoperative AF and non-surgery AF compared with no OAC.¹⁴⁰⁸ Reportedly, postoperative AF occurring after non-cardiac surgery was associated with a similar long-term thrombo-embolic risk to non-surgery AF, and OAC therapy was associated with comparably lower risk of thrombo-embolic events and all-cause death in both groups.¹⁴⁰⁹ Ongoing RCTs in cardiac [PACES (Anticoagulation for New-Onset Post-Operative Atrial Fibrillation After CABG); NCT04045665] and non-cardiac (ASPIRE-AF; NCT03968393) surgery will inform optimal long-term OAC use among patients developing postoperative AF.

In haemodynamically unstable patients with postoperative AF, emergency electrical cardioversion (or i.v. administration of amiodarone¹³⁸⁵ or vernakalant,⁵⁸³ if consistent with the clinical situation) is indicated. In a recent RCT of postoperative AF patients after cardiac surgery, neither rate nor rhythm control showed net clinical advantage over each other.¹³⁷³ Hence, rate or rhythm control treatment decisions should be based on symptoms, and non-emergency cardioversion should follow the principles of peri-cardioversion anticoagulation outlined in section 10.2.

Recommendations for postoperative AF

AF = atrial fibrillation; OAC = oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

12 Prevention of atrial fibrillation

12.1 Primary prevention of atrial fibrillation

Primary prevention of AF refers to the implementation of preventive measures in patients at risk but without previous documentation of AF. This strategy relies on the identification and management of risk factors and comorbidities predisposing to AF, before the development of atrial remodelling and fibrosis⁹⁶⁴^,.¹⁴¹¹ Upstream therapy refers to the use of non-AADs that modify the atrial substrate or target-specific mechanisms of AF to prevent the occurrence or recurrence of the arrhythmia. The key targets of upstream therapy are structural changes in the atria (e.g. fibrosis, hypertrophy, inflammation, oxidative stress), but effects on atrial ion channels, gap junctions, and calcium handling are also evident.⁹⁶⁴

Adequate management of hypertension and HF may prevent AF by reducing atrial stretch, but inhibition of the renin-angiotensin-aldosterone system may exert an additional protective role by suppressing electrical and structural cardiac remodelling.⁹⁶⁴^,¹⁴¹¹^,¹⁴¹² Large RCTs and meta-analyses have yielded equivocal results, either in favour^1413–1416 or against^1417–1421 statin use for primary prevention of AF. Controversial results have also been reported for the effects of fish oils on primary prevention of AF.¹⁴²²

For primary prevention of postoperative AF after cardiac and non-cardiac surgery, see section 11.19.

12.2 Secondary prevention of atrial fibrillation

For secondary AF prevention see section 11.3 and Supplementary section 12.

13 Sex-related differences in atrial fibrillation

Female patients are generally under-represented in RCTs, including AF trials. Sex-related differences in the epidemiology, pathophysiology, clinical presentation, and prognosis of AF that are consistently reported¹⁹^,¹⁰⁷^,¹²⁴^,¹⁴²³^,¹⁴²⁴ may influence the effectiveness of AF treatment, and hence should be considered in a personalized, individual patient-centred approach to AF management in clinical practice.¹⁴²⁵ Understanding the underlying pathophysiological mechanisms and biology may help to improve personalized treatments. Adequate representation of women in future AF trials is recommended, as well as the identification and resolution of sex-specific barriers to implementation of guideline-recommended treatments for AF.

Women presenting with AF are older, have a higher prevalence of hypertension, VHD, and HFpEF, and a lower prevalence of CAD compared with men. Women with AF are more often symptomatic than men with AF, with greater symptom severity.¹⁴²³^,¹⁴²⁶

Female sex is a stroke risk modifier that increases the risk of AF-associated stroke in the presence of other stroke risk factors.³⁵³ Women with AF have a greater stroke severity and permanent disability than men with AF.¹⁴²⁷ Anticoagulation with warfarin may be less well controlled in women, and they have a greater residual stroke risk even with well-controlled VKAs.¹⁴²⁸ The efficacy and safety of NOACs in landmark RCTs were consistent in both sexes, but women were largely under-represented.⁴²³

In women with AF, the use of AADs for rhythm control is associated with significantly higher rates of life-threatening adverse events (e.g. acquired long QT syndrome with class Ia or III AADs)¹⁴²⁹^,¹⁴³⁰ or sinus-node disease/bradyarrhythmia requiring pacemaker implantation¹⁹ compared with male patients. Women with AF are less likely to undergo electrical cardioversion,¹⁴²⁶ and are referred for AF catheter ablation later than men, possibly reflecting AF occurrence later in life among women.¹⁰⁷^,¹⁴³¹^,¹⁴³² The result of PVI may be less favourable in women,¹⁴³¹^,¹⁴³² with higher rates of procedure-related complications.¹⁴³¹ Women are more likely to undergo atrioventricular nodal ablation for AF than men.¹²⁴ Sex-specific data on cardiovascular risk management in women with AF are lacking. Principles outlined in section 11.3 apply to women with AF.

Recommendations pertaining to sex-related differences in AF

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

14 Implementation of the atrial fibrillation guidelines

Guideline-adherent care (i.e. the implementation of guideline-recommended management to individual AF patients) aims to improve patient outcomes and reduce healthcare costs,¹²³⁸^,¹⁴³⁴^,¹⁴³⁵ but adherence to guidelines is modest worldwide.¹²⁴^,^1436–1439^,¹⁴⁴⁰^,¹⁴⁴¹ Reportedly, the adoption of NOACs as first-line therapy has been associated with increasing guideline-adherent stroke prevention.¹⁴⁴²^,¹⁴⁴³

Guideline non-adherence is multifactorial,¹²¹⁵^,¹⁴⁴⁴^,¹⁴⁴⁵ including physician/healthcare professional- and healthcare system-related factors.¹⁴⁴⁶ Integrated AF management may facilitate adherence to guidelines. Various educational interventions²⁸⁰^,²⁸⁴^,²⁹⁰^,¹⁴⁴⁷^,¹⁴⁴⁸ based on guideline-provided recommendations²⁸⁴ and tailored to close specific knowledge gaps among healthcare professionals and/or AF patients¹⁴⁴⁶ may facilitate the implementation of guideline-based AF management to improve patient outcomes.²⁷⁷^,^1449–1452 Further research is needed to identify the cost-effective intervention type(s) that would more effectively improve patient clinical outcomes, medication adherence, and QoL.

15 Quality measures and clinical performance indicators in the management of atrial fibrillation

Measurable service quality has been identified as a cornerstone for optimal AF management and is a mandatory step towards value-based healthcare. Quality and performance indicator sets should provide practitioners and institutions with the tools to measure the quality of care (e.g. adherence to guideline class I recommendations upon discharge/end of visit, complications after procedures, access/waiting list times) and identify opportunities for improvement. They should capture important aspects of care quality, including structure, process, outcome measures, and patient-centrednes, while the reporting burden for hospitals, practices, and practitioners should be kept to a minimum.⁶⁵⁸^,^1453–1455

A collaborative effort involving the ESC, EHRA, Asia Pacific Heart Rhythm Society, Heart Rhythm Society, and Latin American Heart Rhythm Society was put in place to develop quality indicators for the diagnosis and management of AF; a summary form of these quality indicators is provided in Table 22, with the full set published separately.³¹⁷ The ESC quality indicators are intended for quality improvement and performance measurement through meaningful surveillance, as well as for integration within registries that specifically aim to identify areas for improvement in clinical practice and are not intended for ranking healthcare professionals/providers or payment incentives.

Table 22

Summary of quality indicators for the diagnosis and management of AF

Domain: Patient assessment (at baseline and follow-up)

Main quality indicator: CHA₂DS₂-VASc cardioembolic risk assessment.

Main quality indicator: bleeding risk assessment using a validated method such as the HAS-BLED score.

Numerator: Number of AF patients who have their respective score documented at the time of diagnosis and at every follow-up appointment.

Denominator: Number of AF patients.

Domain: Anticoagulation

Main quality indicator: inappropriate prescription of anticoagulation to patients with a CHA₂DS₂-VASc score of 0 for men and 1 for women.

Numerator: number of AF patients with CHA₂DS₂-VASc score of 0 for men and 1 for women, who are inappropriately prescribed anticoagulation.

Denominator: number of AF patients with CHA₂DS₂-VASc score of 0 for men and 1 for women who do not have other indication for anticoagulation.

Main quality indicator: proportion of patients with a CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.

Numerator: Number of AF patients with CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.

Denominator: Number of AF patients with CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are eligible for anticoagulation with no contraindication or refusal.

Domain: rate control

Main quality indicator: inappropriate prescription of AADs^a to patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned).

Numerator: Number of patients with permanent AF who are prescribed one or more AADs^a for rhythm control.

Denominator: Number of patients with permanent AF.

Domain: rhythm control

Main quality indicator: inappropriate prescription of class IC AADs to patients with structural heart disease.

Numerator: number of AF patients with structural heart disease who are inappropriately prescribed class IC AADs.

Denominator: number of AF patients with structural heart disease.

Main quality indicator: proportion of patients with symptomatic paroxysmal or persistent AF who are offered AF catheter ablation after failure of/intolerance to one class I or class III AAD.

Numerator: Number of patients with paroxysmal or persistent AF who are offered catheter ablation after the failure of, or intolerance to, at least one class I or class III AAD.

Denominator: Number of patients with paroxysmal or persistent AF with no contraindications (or refusal) to catheter ablation who remain symptomatic on, or intolerant to at least one class I or class III AAD.

Domain: risk factor management

Main quality indicator: Proportion of patients who have their modifiable risk factors identified.

Numerator: number of AF patients who have their modifiable risk factors (e.g. BP, obesity, OSA, alcohol excess, lack of exercise, poor glycaemic control and smoking) identified

Denominator: number of AF patients.

Domain: outcomes

Main quality indicator: ischaemic stroke or TIA.

Main quality indicator: life-threatening or major bleeding events.^b

Numerator: number of AF patients who have a documented ischaemic or bleeding event

Denominator: number of AF patients or number of patients prescribed an OAC, respectively.

Domain: Patient assessment (at baseline and follow-up)

Main quality indicator: CHA₂DS₂-VASc cardioembolic risk assessment.

Main quality indicator: bleeding risk assessment using a validated method such as the HAS-BLED score.

Numerator: Number of AF patients who have their respective score documented at the time of diagnosis and at every follow-up appointment.

Denominator: Number of AF patients.

Domain: Anticoagulation

Main quality indicator: inappropriate prescription of anticoagulation to patients with a CHA₂DS₂-VASc score of 0 for men and 1 for women.

Numerator: number of AF patients with CHA₂DS₂-VASc score of 0 for men and 1 for women, who are inappropriately prescribed anticoagulation.

Denominator: number of AF patients with CHA₂DS₂-VASc score of 0 for men and 1 for women who do not have other indication for anticoagulation.

Main quality indicator: proportion of patients with a CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.

Numerator: Number of AF patients with CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.

Denominator: Number of AF patients with CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are eligible for anticoagulation with no contraindication or refusal.

Domain: rate control

Main quality indicator: inappropriate prescription of AADs^a to patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned).

Numerator: Number of patients with permanent AF who are prescribed one or more AADs^a for rhythm control.

Denominator: Number of patients with permanent AF.

Domain: rhythm control

Main quality indicator: inappropriate prescription of class IC AADs to patients with structural heart disease.

Numerator: number of AF patients with structural heart disease who are inappropriately prescribed class IC AADs.

Denominator: number of AF patients with structural heart disease.

Main quality indicator: proportion of patients with symptomatic paroxysmal or persistent AF who are offered AF catheter ablation after failure of/intolerance to one class I or class III AAD.

Numerator: Number of patients with paroxysmal or persistent AF who are offered catheter ablation after the failure of, or intolerance to, at least one class I or class III AAD.

Denominator: Number of patients with paroxysmal or persistent AF with no contraindications (or refusal) to catheter ablation who remain symptomatic on, or intolerant to at least one class I or class III AAD.

Domain: risk factor management

Main quality indicator: Proportion of patients who have their modifiable risk factors identified.

Numerator: number of AF patients who have their modifiable risk factors (e.g. BP, obesity, OSA, alcohol excess, lack of exercise, poor glycaemic control and smoking) identified

Denominator: number of AF patients.

Domain: outcomes

Main quality indicator: ischaemic stroke or TIA.

Main quality indicator: life-threatening or major bleeding events.^b

Numerator: number of AF patients who have a documented ischaemic or bleeding event

Denominator: number of AF patients or number of patients prescribed an OAC, respectively.

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; OAC = oral anticoagulant; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

a

Flecainide, propafenone, amiodarone, dronedarone, sotalol and disopyramide.

b

Using the definitions of the International Society of Thrombosis and Haemostasis.¹⁴⁵⁶^,¹⁴⁵⁷

Table 22

Summary of quality indicators for the diagnosis and management of AF

Domain: Patient assessment (at baseline and follow-up)

Main quality indicator: CHA₂DS₂-VASc cardioembolic risk assessment.

Main quality indicator: bleeding risk assessment using a validated method such as the HAS-BLED score.

Numerator: Number of AF patients who have their respective score documented at the time of diagnosis and at every follow-up appointment.

Denominator: Number of AF patients.

Domain: Anticoagulation

Main quality indicator: inappropriate prescription of anticoagulation to patients with a CHA₂DS₂-VASc score of 0 for men and 1 for women.

Numerator: number of AF patients with CHA₂DS₂-VASc score of 0 for men and 1 for women, who are inappropriately prescribed anticoagulation.

Denominator: number of AF patients with CHA₂DS₂-VASc score of 0 for men and 1 for women who do not have other indication for anticoagulation.

Main quality indicator: proportion of patients with a CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.

Numerator: Number of AF patients with CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.

Denominator: Number of AF patients with CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are eligible for anticoagulation with no contraindication or refusal.

Domain: rate control

Main quality indicator: inappropriate prescription of AADs^a to patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned).

Numerator: Number of patients with permanent AF who are prescribed one or more AADs^a for rhythm control.

Denominator: Number of patients with permanent AF.

Domain: rhythm control

Main quality indicator: inappropriate prescription of class IC AADs to patients with structural heart disease.

Numerator: number of AF patients with structural heart disease who are inappropriately prescribed class IC AADs.

Denominator: number of AF patients with structural heart disease.

Main quality indicator: proportion of patients with symptomatic paroxysmal or persistent AF who are offered AF catheter ablation after failure of/intolerance to one class I or class III AAD.

Numerator: Number of patients with paroxysmal or persistent AF who are offered catheter ablation after the failure of, or intolerance to, at least one class I or class III AAD.

Denominator: Number of patients with paroxysmal or persistent AF with no contraindications (or refusal) to catheter ablation who remain symptomatic on, or intolerant to at least one class I or class III AAD.

Domain: risk factor management

Main quality indicator: Proportion of patients who have their modifiable risk factors identified.

Numerator: number of AF patients who have their modifiable risk factors (e.g. BP, obesity, OSA, alcohol excess, lack of exercise, poor glycaemic control and smoking) identified

Denominator: number of AF patients.

Domain: outcomes

Main quality indicator: ischaemic stroke or TIA.

Main quality indicator: life-threatening or major bleeding events.^b

Numerator: number of AF patients who have a documented ischaemic or bleeding event

Denominator: number of AF patients or number of patients prescribed an OAC, respectively.

Domain: Patient assessment (at baseline and follow-up)

Main quality indicator: CHA₂DS₂-VASc cardioembolic risk assessment.

Main quality indicator: bleeding risk assessment using a validated method such as the HAS-BLED score.

Numerator: Number of AF patients who have their respective score documented at the time of diagnosis and at every follow-up appointment.

Denominator: Number of AF patients.

Domain: Anticoagulation

Main quality indicator: inappropriate prescription of anticoagulation to patients with a CHA₂DS₂-VASc score of 0 for men and 1 for women.

Numerator: number of AF patients with CHA₂DS₂-VASc score of 0 for men and 1 for women, who are inappropriately prescribed anticoagulation.

Denominator: number of AF patients with CHA₂DS₂-VASc score of 0 for men and 1 for women who do not have other indication for anticoagulation.

Main quality indicator: proportion of patients with a CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.

Numerator: Number of AF patients with CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.

Denominator: Number of AF patients with CHA₂DS₂-VASc score of ≥1 for men and ≥2 for women who are eligible for anticoagulation with no contraindication or refusal.

Domain: rate control

Main quality indicator: inappropriate prescription of AADs^a to patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned).

Numerator: Number of patients with permanent AF who are prescribed one or more AADs^a for rhythm control.

Denominator: Number of patients with permanent AF.

Domain: rhythm control

Main quality indicator: inappropriate prescription of class IC AADs to patients with structural heart disease.

Numerator: number of AF patients with structural heart disease who are inappropriately prescribed class IC AADs.

Denominator: number of AF patients with structural heart disease.

Main quality indicator: proportion of patients with symptomatic paroxysmal or persistent AF who are offered AF catheter ablation after failure of/intolerance to one class I or class III AAD.

Numerator: Number of patients with paroxysmal or persistent AF who are offered catheter ablation after the failure of, or intolerance to, at least one class I or class III AAD.

Denominator: Number of patients with paroxysmal or persistent AF with no contraindications (or refusal) to catheter ablation who remain symptomatic on, or intolerant to at least one class I or class III AAD.

Domain: risk factor management

Main quality indicator: Proportion of patients who have their modifiable risk factors identified.

Numerator: number of AF patients who have their modifiable risk factors (e.g. BP, obesity, OSA, alcohol excess, lack of exercise, poor glycaemic control and smoking) identified

Denominator: number of AF patients.

Domain: outcomes

Main quality indicator: ischaemic stroke or TIA.

Main quality indicator: life-threatening or major bleeding events.^b

Numerator: number of AF patients who have a documented ischaemic or bleeding event

Denominator: number of AF patients or number of patients prescribed an OAC, respectively.

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; OAC = oral anticoagulant; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

a

Flecainide, propafenone, amiodarone, dronedarone, sotalol and disopyramide.

b

Using the definitions of the International Society of Thrombosis and Haemostasis.¹⁴⁵⁶^,¹⁴⁵⁷

Recommendations for quality measures in patients with AF

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

16 Epidemiology, clinical implications, and management of atrial high-rate episodes/ subclinical atrial fibrillation

The incidence of AHRE/subclinical AF in patients with a pacemaker/implanted device is 30–70%, but it may be lower in the general population.¹⁴⁵⁸ Very short episodes (≤10 − 20 s/day) are considered clinically irrelevant, as they are not significantly associated with longer episodes or an increased risk of stroke or systemic embolism.¹⁴⁵⁹ However, longer episodes of AHRE/subclinical AF (minimum of 5 − 6 min) are associated with an increased risk of clinical AF,⁴⁶⁷^,⁴⁶⁹ ischaemic stroke,¹⁶⁸^,⁴⁶⁷ major adverse cardiovascular events,¹⁴⁶⁰ and cardiovascular death.¹⁴⁶¹

Overall, the absolute risk of stroke associated with AHRE/subclinical AF may be lower than with clinical AF.¹⁶⁰^,¹⁶⁸^,²²⁶^,⁴⁶⁷ The temporal dissociation from acute stroke suggests that AHRE/subclinical AF may represent a marker rather than a risk factor for stroke⁴^,⁷^,¹⁴⁶² (Supplementary Box 6).

Whereas current data were obtained mostly from pacemakers/implantable cardioverter defibrillators or post-stroke patients, AHRE/subclinical AF is increasingly reported in a variety of patients undergoing cardiac monitoring. Clinical AF will reportedly develop in 1 in 5 - 6 of patients within 2.5 years after diagnosing AHRE/subclinical AF.¹⁶⁸ Notwithstanding that more high-quality evidence is needed to inform optimal management of these patients, more intense follow-up and monitoring to detect clinical AF early is prudent (preferably with the support of remote monitoring). Notably, the AHRE/subclinical AF burden is not static but may change on daily basis,⁴⁶⁹ hence should be regularly reassessed—the greater the AHRE/subclinical AF burden at diagnosis, the higher the risk of subsequent progression to longer episodes⁴⁶⁹ (Figure 24).

Progression of atrial high-rate episode burden (left panel) and stroke rates according to AHRE daily burden and CHA2DS2-VASc score (right panel). AHRE = atrial high-rate episodes; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); OAC = oral anticoagulant. aThe higher the burden at diagnosis, the greater the incidence of progression in the next 6 months and thereafter. bStroke rates above the threshold for OAC are shown in red.

Figure 24

Progression of atrial high-rate episode burden (left panel) and stroke rates according to AHRE daily burden and CHA₂DS₂-VASc score (right panel). AHRE = atrial high-rate episodes; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); OAC = oral anticoagulant. ^aThe higher the burden at diagnosis, the greater the incidence of progression in the next 6 months and thereafter. ^bStroke rates above the threshold for OAC are shown in red.

Whereas available evidence is insufficient to justify routine OAC use in patients with AHRE/subclinical AF, modifiable stroke risk factors should be identified and managed in each patient.

The use of OAC may be considered in selected patients with longer durations of AHRE/subclinical AF (≥24 h) and an estimated high individual risk of stroke,⁴^,¹⁴⁶² accounting for the anticipated net clinical benefit and informed patient’s preferences (Figures 24 and25). In the recent trials, OAC was initiated in 76.4% and 56.3% of patients with ≥2 clinical stroke risk factors and insertable cardiac monitor-detected physician-confirmed AF≥6 min, but follow-up bleeding rates were not reported.¹⁴⁶³^,¹⁴⁶⁴ In a large retrospective cohort study using remote monitoring data about daily AF burden, there was large practice variation in OAC initiation. Across increasing AF burden strata (from >6 min to >24 h) the risk of stroke in untreated patients increased numerically, and the strongest association of OAC with reduction in stroke was observed among patients with device-detected AF episodes of >24 h.⁵

Proposed management of AHRE/subclinical AF. AF = atrial fibrillation; AHRE = atrial high-rate episode; CKD = chronic kidney disease; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); f = female; LA = left atrium; LoE = level of evidence; m = male; OAC = oral anticoagulant; SCAF = subclinical atrial fibrillation. aHighly selected patients (e.g. with previous stroke and/or age ≥75 years, or ≥3 CHA2DS2-VASc risk factors, and additional non-CHA2DS2-VASc stroke factors such as CKD, elevated blood biomarkers, spontaneous echo contrast in dilated LA, etc); selected patients (e.g. with previous stroke and/or age ≥75 years, or ≥3 CHA2DS2-VASc risk factors , etc).

Figure 25

Proposed management of AHRE/subclinical AF. AF = atrial fibrillation; AHRE = atrial high-rate episode; CKD = chronic kidney disease; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); f = female; LA = left atrium; LoE = level of evidence; m = male; OAC = oral anticoagulant; SCAF = subclinical atrial fibrillation. ^aHighly selected patients (e.g. with previous stroke and/or age ≥75 years, or ≥3 CHA₂DS₂-VASc risk factors, and additional non-CHA₂DS₂-VASc stroke factors such as CKD, elevated blood biomarkers, spontaneous echo contrast in dilated LA, etc); selected patients (e.g. with previous stroke and/or age ≥75 years, or ≥3 CHA₂DS₂-VASc risk factors , etc).

Recommendations for management of patients with AHRE

AF = atrial fibrillation; AHRE = atrial high-rate episode; CIED = cardiac implantable electronic device; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

17 Atrial fibrillation and other atrial tachyarrhythmias (atrial flutter and atrial tachycardias)

Although AFL may exist as a solitary atrial arrhythmia, a significant proportion of patients will subsequently develop AF.^1466–1470 Typical AFL may occur in those taking class IC AADs or amiodarone.¹⁴⁶⁷^,¹⁴⁶⁸^,¹⁴⁷¹ The ABC pathway for integrated AF management largely applies to patients with AFL. It is recommended that stroke-prevention strategies in patients with solitary AFL, including periprocedural management of stroke risk, follow the same principles as in patients with AF.¹⁴⁷²

Rate control should be the first step in symptom management. However, cardioversion to sinus rhythm may be more effective, especially electrical cardioversion or (where feasible) high-rate stimulation.¹⁴⁷³^,¹⁴⁷⁴ Of note, the class III AADs dofetilide and ibutilide i.v. are very effective in interrupting AFL, whereas the class Ic drugs flecainide and propafenone^1475–1478 should not be used in the absence of atrioventricular-blocking drugs as they may slow the atrial rate, thus facilitating 1 : 1 atrioventricular conduction with a rapid ventricular rate.¹⁴⁷⁹^,¹⁴⁸⁰ AF catheter ablation of the CTI is the most effective rhythm control treatment for CTI-dependent AFL.⁷³²^,¹⁴⁸¹^,¹⁴⁸² When typical AFL develops in AF patients during treatment with class Ic drugs or amiodarone, CTI ablation should be considered to ensure that AADs can be continued for AF rhythm control.⁷³²^,¹⁴⁸¹

Atypical AFL (i.e. macro re-entrant atrial tachycardia) most commonly occurs in diseased or scarred atrial myocardium. Clinical management of atypical AFL/macro re-entrant atrial tachycardia broadly follows the principles of typical AFL management, but the use of AADs is often limited by significant structural heart disease, and ablation is more complex.¹³³⁶

Notably, the intervention to treat atrial tachycardias (AFL/macro re-entrant atrial tachycardia) occurring early after AF catheter ablation (or surgery) should be delayed, and initial rate control or the use of AADs should be considered instead, as some of these tachyarrhythmias are transient and cease after maturation of the lesions deployed by the index procedure.^1483–1485 For additional details about AFL, see Supplementary Box 7 and the 2019 ESC Guidelines on supraventricular tachycardias.¹³³⁶

18 Key messages

The diagnosis of AF needs to be confirmed by a conventional 12-lead ECG tracing or rhythm strip showing AF for ≥30 s.
Structured characterization of AF, including stroke risk, symptom severity, severity of AF burden, and AF substrate, helps improve personalized treatment of AF patients.
Novel tools and technologies for screening and detection of AF such as (micro-)implants and wearables substantially add to the diagnostic opportunities in patients at risk for AF. However, appropriate management pathways based on such tools are still incompletely defined.
Integrated holistic management of AF patients is essential to improving their outcomes.
Patient values need to be considered in treatment decision making and incorporated into the AF management pathways; the structured assessment of PRO measures is an important element to document and measure treatment success.
The ABC pathway streamlines integrated care of AF patients across healthcare levels and among different specialties.
Structured, clinical, risk-score−based assessment of individual thrombo-embolic risk, using the CHA₂DS₂-VASc score, should be performed as the first step in optimal thrombo-embolic risk management in AF patients.
Patients with AF and risk factors for stroke need to be treated with OAC for stroke prevention. In NOAC-eligible patients, NOACs are preferred over VKAs.
A formal structured risk-score−based bleeding risk assessment using, for example, the HAS-BLED score, helps to identify non-modifiable and address modifiable bleeding risk factors in AF patients.
An elevated bleeding risk should not automatically lead to withholding OAC in patients with AF and stroke risk. Instead, modifiable bleeding risk factors should be addressed, and high-risk patients scheduled for a more frequent clinical review and follow-up.
Rate control is an integral part of AF management and is often sufficient to improve AF-related symptoms.
The primary indication for rhythm control using cardioversion, AADs, and/or catheter ablation is reduction in AF-related symptoms and improvement of QoL.
The decision to initiate long-term AAD therapy needs to balance symptom burden, possible adverse drug reactions, particularly drug-induced proarrhythmia or extracardiac side-effects, and patient preferences.
Catheter ablation is a well-established treatment for prevention of AF recurrences. When performed by appropriately trained operators, catheter ablation is a safe and superior alternative to AADs for maintenance of sinus rhythm and symptom improvement.
Major risk factors for AF recurrence should be assessed and considered in the decision making for interventional therapy.
In patients with AF and normal LVEF, catheter ablation has not been shown to reduce total mortality or stroke. In patients with AF and tachycardia-induced cardiomyopathy, catheter ablation reverses LV dysfunction in most cases.
Weight loss, strict control of risk factors, and avoidance of triggers for AF are important strategies to improve outcome of rhythm control.
Identification and management of risk factors and concomitant diseases is an integral part of the treatment of AF patients.
In AF patients with ACS undergoing uncomplicated PCI, an early discontinuation of aspirin and switch to dual antithrombotic therapy with OAC and a P2Y₁₂ inhibitor should be considered.
Patients with AHRE should be regularly monitored for progression to clinical AF and changes in the individual thrombo-embolic risk (i.e. change in CHA₂DS₂-VASc score). In patients with longer AHRE (especially >24 h) and a high CHA₂DS₂-VASc score, it is reasonable to consider the use of OAC when a positive net clinical benefit from OAC is anticipated in a shared, informed, treatment decision-making process.

19 Gaps in evidence

Whereas some progress has been made since publication of the 2016 ESC AF Guidelines, major gaps identified in those guidelines persist in 2020, calling for more intense research. In 2019, the EHRA published a white paper that covers major gaps in the field of AF in detail.¹⁴⁸⁶ The following bullet-list gives the most important knowledge gaps:

□ Major health modifiers causing atrial fibrillation

Mechanisms of AF are not yet fully understood. Improvement in understanding of these mechanisms in individual patients, e.g. patients with cardiac structural remodelling or HF, would allow better selection of treatments including the best rate and rhythm control strategies and OAC.

It is uncertain how educational interventions translate into actual behavioural change (patients and physicians) that leads to improvements in clinical management and outcomes, especially in the multimorbid AF patient.

□ Implementation of digital technologies for screening, diagnosis, and risk stratification in the atrial fibrillation patient

New techniques for digital ECG analysis (e.g. machine learning and artificial intelligence) and new technologies (e.g. wearables and injectables) have opened up potentially significant opportunities for the detection and diagnosis of AF. These innovations may help to personalize therapy and risk stratification. Studies are needed to evaluate such opportunities and to define for which groups of patients this is worthwhile.

□ Type of atrial fibrillation

There is a gap in knowledge regarding classification of AF. Recent data suggest that paroxysmal AF is not one entity. According to the pattern, type of therapy and outcome may differ.¹⁴⁸⁷ More studies are needed.

□ How much atrial fibrillation constitutes a mandate for therapy?

The threshold of AF burden at which to initiate OAC therapy needs to be defined more clearly. This knowledge gap has resulted in substantial variation in physician attitudes and practice patterns.⁵

We are still waiting for the results of two ongoing RCTs in subclinical AF patients who are detected with cardiac implantable electronic device (CIED) [(Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation) (NCT 01938248) and NOAH (Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) (NCT 02618577)].

□ Role of biomarkers in atrial fibrillation management

Although some studies have demonstrated an effective role of biomarkers (including natriuretic peptides and troponin) in AF risk assessment, there is uncertainty over the exact time point of biomarker assessment, optimal cut-offs, and the effect on management decision making based on changes in biomarker levels over time, especially with increasing age and incident comorbidities.

□ Stroke risk in specific populations

Some studies have tested the effect of biomarkers in predicting risk of AF-related complications, including stroke, in specific populations. However, it is unknown if biomarkers and biomarker-based scores practically help physicians in refining stroke risk, especially in prospective non-anticoagulated cohorts, particularly given the dynamic nature of stroke risk and how many current biomarkers are non-specific for AF or AF-related outcomes.

There is uncertainty of actual stroke risk in AHRE, compared with actual stroke risk in overt AF, in properly matched cohorts in similar settings, and the effect of appropriate management pathways.

The effect of sex in AF patients has been more investigated. Men with AF are less likely to have hypertension or VHD vs. women.¹⁴⁸⁸ Women often present with atypical symptoms related to AF. Further comparative studies are needed in different settings and ethnic groups on the effect of different stroke risk factors and female sex on stroke and bleeding risks.

□ Anticoagulant therapy in specific patients

There is a gap in knowledge regarding optimal NOAC dosing in specific groups, including those with mild-to-moderate CKD, with very low/high body mass index, and patients receiving medications with a high risk of metabolic interaction.¹⁴⁸⁹

In patients with CrCl ≤25 mL/min, RCT-derived data on the effect of VKA or NOACs is still lacking, due to the exclusion of these patients from the major RCTs. However, two RCTs (NCT02933697, NCT03987711) are currently assessing OAC use and comparing NOACs with VKAs in patients with end-stage renal disease.

□ Anticoagulation in patients with heart valve diseases

There are gaps in evidence on NOAC use in AF patients with rheumatic mitral valve disease and during the first 3 months after surgical or transcatheter implantation of a bioprosthesis; observational data regarding the use of NOACs after transcatheter aortic valve implantation are conflicting.¹¹⁶³

□ Anticoagulation in atrial fibrillation patients after a bleeding or stroke event

As high-quality RCT-derived evidence to inform optimal timing of anticoagulation after acute ischaemic stroke is lacking, OAC use in the early post-stroke period is currently based on expert consensus. Several ongoing RCTs [ELAN (NCT03148457), OPTIMAS (EudraCT, 2018-003859-3), TIMING (NCT02961348), and START (NCT03021928)] will try to assess the differences between the two approaches, including early (<1 week) vs. late NOAC initiation in patients with AF-related ischaemic stroke.

□ Left atrial appendage occlusion for stroke prevention

More studies have been conducted in this field. There is clearer evidence of the safety and possible complications of the LAA closure procedure.^450–454 However, there are still knowledge gaps to be addressed: (i) antithrombotic management after LAA occlusion has not been evaluated in a randomized manner; and (ii) the efficacy and safety of LAA closure vs. OAC therapy needs to be assessed in randomized trials.

LAA occluders have not been compared with NOAC therapy in patients at risk for bleeding, or with surgical LAA occlusion/exclusion.

□ Surgical exclusion of Left atrial appendage

Only limited RCT data are available^457–459 on surgical exclusion of the LAA. Although a large RCT in patients with an associated cardiac surgical procedure is ongoing,⁴⁶² adequately powered RCTs are needed.

There is the need for adequately powered trials to define the best indications for LAA occlusion/exclusion compared with NOAC therapy in patients with relative or absolute contraindications for anticoagulation, in those with an ischaemic stroke on anticoagulant therapy, and for assessment of the appropriate antithrombotic therapy after LAA occlusion.

□ Atrial fibrillation catheter ablation technique

The best approach to safely and expeditiously achieve permanent PVI in a single procedure is still one of the knowledge gaps in relation to emerging technologies for catheter ablation of AF. Moreover, it remains unknown if ablating additional targets will improve the outcomes of AF catheter ablation.¹⁴⁹⁰

□ Outcome of atrial fibrillation catheter ablation

The following issues need to be addressed in further studies:

The value of early AF ablation to prevent AF progression.
The optimal outcome measure (AF 30 s, AF burden, etc.) for AF-related outcome.
How much reduction in AF burden is needed to achieve an effect on hard endpoints, including survival, stroke, and comorbidity.
The main mechanism of PVI translating into freedom of AF.
The potential effect of cardiac structure and function on the likelihood of success of AF ablation.

Despite the publication of CABANA and CASTLE-AF, more data are needed on the effect of AF catheter ablation on clinical outcomes, including death, stroke, serious bleeding, AF recurrence, QoL, and cardiac arrest.

The relationship between the degree of atrial dilation/fibrosis and successful ablation of AF needs to be addressed. Additionally, the impact of specific components of structural heart disease, including LA structure/function, LV structure, etc., on the success of AF catheter ablation and the likelihood of recurrence requires further investigation.

□ Who may benefit less from atrial fibrillation catheter ablation

There are gaps in knowledge about subgroups of patients who may benefit less from AF catheter ablation, including (i) persistent and long-standing persistent AF; (ii) patients with enlarged atrial size and/or atrial fibrosis; (iii) patients with atypical AFL; and (iv) patients with risk factors for AF recurrence, including obesity or sleep apnoea.

□ Thoracoscopic ‘stand-alone’ atrial fibrillation surgery

There are no convincing data on the effects on stroke of surgical ablation as a stand-alone procedure or in combination with LAA occlusion or exclusion on various outcomes including QoL, stroke, and death.

□ Personalized therapy

The arrhythmia phenotype may differ among patients. Improved assessment of the pathophysiological process involved in the individual patient by using clinical characteristics, blood biomarkers, and non-invasive substrate determination (echo/MRI/CT) may improve personalized therapy (e.g. selection of rhythm control, yes or no; treatment of risk factors and comorbidities; type of antiarrhythmic drug; atrial ablation; and which type/techniques used for AF).

Management of AF. AAD = antiarrhythmic drug; AF = atrial fibrillation; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; CHA2DS2-VASc = Congestive HF, Hypertension, Age ≥75 years, diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CV = cardioversion; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TTR = time in therapeutic range; VKA = vitamin K antagonist.

Central Illustration

Management of AF. AAD = antiarrhythmic drug; AF = atrial fibrillation; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; CHA₂DS₂-VASc = Congestive HF, Hypertension, Age ≥75 years, diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CV = cardioversion; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TTR = time in therapeutic range; VKA = vitamin K antagonist.

20 ‘What to do’ and ‘what not to do’ messages from the Guidelines

AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; AFL = atrial flutter; AHRE = atrial high-rate episodes; BP = blood pressure; CCS = chronic coronary syndrome; CHA₂DS₂-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female); CIED = cardiac implantable electronic device; CrCl = creatinine clearance; ECG = electrocardiogram; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; i.v. = intravenous; INR = international normalized ratio; LMWH = low-molecular-weight heparin; LV = left ventricular; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; PRO = patient-reported outcome; PVI = pulmonary vein isolation; QoL = quality of life; TIA = transient ischaemic attack; TOE = transoesophageal echocardiography; TTR = time in therapeutic range; UFH = unfractionated heparin; VHD = Valvular heart disease; VKA = vitamin K antagonist.

21 Supplementary data

Supplementary Data with additional Supplementary Figures, Tables, and text complementing the full text are available on the European Heart Journal website and via the ESC website at www.escardio.org/guidelines.

The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website www.escardio.org/guidelines

ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers, and Author/Task Force Member affiliations: listed in the Appendix.

¹Representing the European Association for Cardio-Thoracic Surgery (EACTS)

ESC entities having participated in the development of this document:

Associations: Association for Acute CardioVascular Care (ACVC), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).

Councils: Council on Stroke, Council on Valvular Heart Disease.

Working Groups: Cardiac Cellular Electrophysiology, Cardiovascular Pharmacotherapy, Cardiovascular Surgery, e-Cardiology, Thrombosis.

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]).

Disclaimer The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

22 Appendix

Author/Task Force Member Affiliations: Nikolaos Dagres, Department of Electrophysiology, Heart Center Leipzig at the University of Leipzig, Leipzig, Germany; Elena Arbelo, Arrhythmia Department, Cardiovascular Institute, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain; Jeroen J. Bax, Cardiology, Leiden University Medical Center, Leiden, Netherlands; Carina Blomström-Lundqvist, Department of Medical Science and Cardiology, Medicine, Uppsala, Sweden; Giuseppe Boriani, Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy; Manuel Castella,¹ Cardiovascular Surgery, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gheorghe-Andrei Dan, Cardiology Department, Internal Medicine Clinic, ‘Carol Davila’ University of Medicine, Colentina University Hospital, Bucharest, Romania; Polychronis E. Dilaveris, 1^st University Department of Cardiology, National & Kapodistrian University of Athens School of Medicine, Athens, Attica, Greece; Laurent Fauchier, Department of Cardiology, Centre Hospitalier Universitaire Trousseau and University of Tours, Tours, France; Gerasimos Filippatos, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; Jonathan M. Kalman, Department of Cardiology, Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia; Mark La Meir,¹ Cardiac surgery, UZ Brussel, Brussels, Belgium; Deirdre A. Lane, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Jean-Pierre Lebeau, Department of General Practice, University of Tours, Tours, France; Maddalena Lettino, Cardiovascular, San Gerardo Hospital, ASST-Monza, Monza, Italy; Gregory Y. H. Lip, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Fausto J. Pinto, Cardiology, CCUL, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; G. Neil Thomas, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom; Marco Valgimigli, Cardiocentro Ticino, Lugano, Switzerland; Isabelle C. Van Gelder, Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Bart P. Van Putte,¹ Cardiothoracic Surgery, St Antonius Hospital, Nieuwegein, Netherlands; Caroline L. Watkins, Faculty of Health and Wellbeing, University of Central Lancashire, Preston, United Kingdom.

ESC Committee for Practice Guidelines (CPG): Stephan Windecker (Chairperson Switzerland), Victor Aboyans (France), Colin Baigent (United Kingdom), Jean-Philippe Collet (France), Veronica Dean (France), Victoria Delgado (Netherlands), Donna Fitzsimons (United Kingdom), Chris P. Gale (United Kingdom), Diederick E. Grobbee (Netherlands), Sigrun Halvorsen (Norway), Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni (Canada), Hugo A. Katus (Germany), Ulf Landmesser (Germany), Christophe Leclercq (France), Maddalena Lettino (Italy), Basil S. Lewis (Israel), Béla Merkely (Hungary), Christian Mueller (Switzerland), Steffen E. Petersen (United Kingdom), Anna Sonia Petronio (Italy), Dimitrios J. Richter (Greece), Marco Roffi (Switzerland), Evgeny Shlyakhto (Russian Federation), Iain A. Simpson (United Kingdom), Miguel Sousa-Uva (Portugal), Rhian M. Touyz (United Kingdom).

ESC National Cardiac Societies actively involved in the review process of the 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation.

Algeria: Algerian Society of Cardiology, Tahar Delassi; Armenia: Armenian Cardiologists Association, Hamayak S. Sisakian; Austria: Austrian Society of Cardiology, Daniel Scherr; Belarus: Belorussian Scientific Society of Cardiologists, Alexandr Chasnoits; Belgium: Belgian Society of Cardiology, Michel De Pauw; Bosnia and Herzegovina: Association of Cardiologists of Bosnia and Herzegovina, Elnur Smajić; Bulgaria: Bulgarian Society of Cardiology, Tchavdar Shalganov; Cyprus: Cyprus Society of Cardiology, Panayiotis Avraamides; Czech Republic: Czech Society of Cardiology, Josef Kautzner; Denmark: Danish Society of Cardiology, Christian Gerdes; Egypt: Egyptian Society of Cardiology, Ahmad Abd Alaziz; Estonia: Estonian Society of Cardiology, Priit Kampus; Finland: Finnish Cardiac Society, Pekka Raatikainen; France: French Society of Cardiology, Serge Boveda; Georgia: Georgian Society of Cardiology, Giorgi Papiashvili; Germany: German Cardiac Society, Lars Eckardt; Greece: Hellenic Society of Cardiology, Vassilios P. Vassilikos; Hungary: Hungarian Society of Cardiology, Zoltán Csanádi; Iceland: Icelandic Society of Cardiology, David O. Arnar; Ireland: Irish Cardiac Society, Joseph Galvin; Israel: Israel Heart Society, Alon Barsheshet; Italy: Italian Federation of Cardiology, Pasquale Caldarola; Kazakhstan: Association of Cardiologists of Kazakhstan, Amina Rakisheva; Kosovo (Republic of): Kosovo Society of Cardiology, Ibadete Bytyçi; Kyrgyzstan: Kyrgyz Society of Cardiology, Alina Kerimkulova; Latvia: Latvian Society of Cardiology, Oskars Kalejs; Lebanon: Lebanese Society of Cardiology, Mario Njeim; Lithuania: Lithuanian Society of Cardiology, Aras Puodziukynas; Luxembourg: Luxembourg Society of Cardiology, Laurent Groben; Malta: Maltese Cardiac Society, Mark A. Sammut; Moldova (Republic of): Moldavian Society of Cardiology, Aurel Grosu; Montenegro: Montenegro Society of Cardiology, Aneta Boskovic; Morocco: Moroccan Society of Cardiology, Abdelhamid Moustaghfir; Netherlands: Netherlands Society of Cardiology, Natasja de Groot; North Macedonia: North Macedonian Society of Cardiology, Lidija Poposka; Norway: Norwegian Society of Cardiology, Ole-Gunnar Anfinsen; Poland: Polish Cardiac Society, Przemyslaw P. Mitkowski; Portugal: Portuguese Society of Cardiology, Diogo Magalhães Cavaco; Romania: Romanian Society of Cardiology, Calin Siliste; Russian Federation: Russian Society of Cardiology, Evgeny N. Mikhaylov; San Marino: San Marino Society of Cardiology, Luca Bertelli; Serbia: Cardiology Society of Serbia, Dejan Kojic; Slovakia: Slovak Society of Cardiology, Robert Hatala; Slovenia: Slovenian Society of Cardiology, Zlatko Fras; Spain: Spanish Society of Cardiology, Fernando Arribas; Sweden: Swedish Society of Cardiology, Tord Juhlin; Switzerland: Swiss Society of Cardiology, Christian Sticherling; Tunisia: Tunisian Society of Cardiology and Cardio-Vascular Surgery, Leila Abid; Turkey: Turkish Society of Cardiology, Ilyas Atar; Ukraine: Ukrainian Association of Cardiology, Oleg Sychov; United Kingdom of Great Britain and Northern Ireland: British Cardiovascular Society, Matthew G. D. Bates; Uzbekistan: Association of Cardiologists of Uzbekistan, Nodir U. Zakirov.

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