The burden of coronary artery disease (CAD) remains high across Europe and the rest of the world. CAD continues to be the main cause of death and a major cause of morbidity and loss of quality of life. The decline in age-standardized mortality rates and in incidence of CAD in many countries illustrates the potential for prevention of premature deaths and for prolonging life expectancy. New therapeutic options for prevention and treatment of CAD have resulted in an increasing number of patients who survive a cardiovascular event; in developed countries the burden has shifted from the middle-aged to the elderly and the prevalence of CAD increases exponentially with aging. CAD is a leading public health problem accounting for a significant proportion of total societal costs and representing 27% of total cardiovascular disease costs. Together with cerebrovascular diseases, CAD accounts for 64% of all cardiovascular deaths. There are a number of lifestyle changes that can be implemented to improve the prognosis of patients with stable CAD, including smoking cessation, adoption of a Mediterranean diet, body weight reduction, and increased physical activity. Concomitant risk factors such as diabetes, dyslipidaemia, and hypertension should be managed aggressively. Current treatment options for stable CAD involve a two-pronged approach combining antianginal treatment to improve symptoms and quality of life along with a cardioprotective treatment to prevent cardiovascular events. Optimal medical treatment should be the initial management approach in the majority of patients with stable CAD, even if extensive and multi-vessel atherosclerosis is involved. A large body of evidence suggests that high resting heart rate (HR) is a potential risk factor for mortality and morbidity in various populations, including patients with CAD. Experimental evidence indicates that high HR plays a role in endothelial dysfunction and atherosclerosis progression. An HR ≥70 b.p.m. is associated with an increased cardiovascular risk. Ongoing randomized trials are evaluating the role of selective HR reduction in improving cardiovascular outcomes. These trial data will be complemented by CLARIFY, a large-scale international registry of outpatients with stable CAD which will analyse not only the baseline characteristics and management practices but will also capture all suspected important determinants of outcomes including resting HR.
Epidemiology of coronary artery disease
The incidence of coronary artery disease (CAD) is apparent from community surveys. The Bromley Coronary Registry is a contemporary community registry used to identify all symptomatic medical presentations of CAD in one population.1 All incident (first) presentations of exertional angina, acute coronary syndromes, and sudden cardiac death were recorded for the Bromley Health Authority in South East London (population 186 053, in men and women aged 25–74 years) for the period from 1996 to 1998. In the ARIC study in participants aged from 45 to 64 years, the average age-adjusted CAD incidence rates per 1000 person-years were 12.5 in white men and 10.6 in black men.2 According to AHA Heart Disease and Stroke statistics, it is estimated that 770 000 Americans had a new coronary attack in 2008, and 430 000 had a recurrent attack. It is estimated that 190 000 additional silent first acute myocardial infarctions (MIs) occur each year. Approximately every 26 s, an American will have a coronary event, and about every minute someone will die of one.3
There are marked variations in the epidemic of CAD among regions of the world, nations, and even between regions within a country.4 The age-standardized death rates from CAD are declining in many developed countries, but are increasing in developing and transitional countries, partly as a result of demographic changes, urbanization, and lifestyle changes. Nowadays ∼3.8 million men and 3.4 million women worldwide die each year from CAD.5 According to the Global Burden of Disease Study,6 the developing countries contributed 3.5 million of the total number of 6.2 million deaths from CAD in 1990. The projections estimate that these countries will account for 7.8 million of the 11.1 million deaths due to CAD in 2020. According to global and regional projections of mortality and burden of disease, CAD will remain the leading cause of death for the next 20 years.7 In the USA and in most countries in the European Union, the age-standardized CAD mortality rates have decreased significantly. This may lead paradoxically to an increase in the prevalence of CAD; indeed a better survival of CAD patients and demographic changes result in more elderly people suffering from CAD. Today CAD is the most important major killer of both American men and women, causing approximately one of every five deaths in the USA in 2005.8 Approximately 37% of the people who have a coronary event in a given year will die of it. In 2005 the overall CAD death rate was 144.4 per 100 000 population. The death rates were 187.7 for white males and 213.9 for black males; for white females the rate was 110.0 and for black females 140.99. In the European Union, CAD is also the single most common cause of death. One in five to one in seven women die of CAD; in men CAD accounts for one in four to one in six of all deaths. Age-standardized and gender-specific CAD mortality rates have significantly decreased during recent decades in many countries in the north, west and south of Europe. However, the decline was less apparent or absent in central and eastern Europe. Thus, the Russian Federation, Belarus, Ukraine, and Central Asian republics show the highest CAD mortality rates ever seen, significantly higher even than recognized peaks in the USA, Australia, New Zealand, Finland, and Scotland.9,10 Furthermore, population aging represents a major challenge. Thus, even if age-specific mortality rates continue to decline, the absolute number of cardiovascular disease (CVD) deaths will increase. Predictions up to 2030 suggest that even with an annual decline in mortality rates of about 1%, the absolute number of deaths will increase, attributable solely to population aging.7
It has been estimated that 30–43% of patients who were asymptomatic after an MI had silent myocardial ischaemia in the initial 30-day period after the infarct, based on stress test data or Holter monitoring.11,12 A recently published analysis in 937 outpatients with stable CAD from the Heart and Soul Study demonstrated that 14% of outpatients had angina alone, 20% had inducible ischaemia alone, and 4% had both angina and ischaemia. Recurrent CAD events occurred in 7% of participants without angina or inducible ischaemia, 10% of those with angina alone, 21% of those with inducible ischaemia alone, and 23% of those with both angina and inducible ischaemia.13
Coronary atherosclerosis most commonly presents in the community as angina pectoris, followed by acute coronary syndromes (MI and unstable angina), and finally as sudden cardiac death. When the acute manifestations of CAD—sudden cardiac death and MI—are considered together, one in two patients with new or recurrent disease die within 30 days of their acute clinical presentation.14–17 About 69% die in the community, 29% die in hospital, and the other 2% die within 30 days of discharge. The prognosis of patients with chronic CAD is not uniform. It depends on several factors, including the underlying coronary anatomy, left ventricular (LV) function, and comorbidities. The data concerning prognosis in clinical trials are of limited value due to the highly selective nature of populations included in such studies. Large population-based studies could help to increase our understanding of the differences in prognosis between CAD manifestations. The recently published data on cardiovascular event rates from the REACH (Reduction of Atherothrombosis for Continued Health) registry in stable CAD outpatients (n = 38 602 patients) has confirmed that patients with established stable CAD had the highest non-fatal MI rate and the highest non-fatal stroke rate. The registry reported annual event rates of 15.2% for death, stroke, MI, or hospitalization for an atherothrombotic event, 6.4% for unstable angina, 4.5% for death, acute MI, and stroke, and 3.8% for revascularization by percutaneous coronary intervention (PCI).18 Thus, ∼3 of 20 patients with established CAD had a major event or had been hospitalized within a year of follow-up. The high event rates observed in the subgroup of patients with established CAD in this large contemporary cohort indicate that continued efforts are needed to improve secondary prevention and clinical outcomes.
The appropriate management of CAD entails costs for non-invasive diagnostic and follow-up tests, as well as for medical and interventional therapy. All these factors lead to significant direct and indirect costs. The treatment of stable CAD aims to prevent serious cardiovascular events such as MI or death and to improve quality of life by reducing the symptoms caused by myocardial ischaemia. The economic costs of CAD include health care expenditure and non-health service costs. Health care expenditures comprise primary care activities, accident and emergency care, hospital inpatient care, outpatient care, and medications. Non-health service costs comprise informal care costs, and productivity costs attributable to mortality and morbidity. Informal care costs are equivalent to the opportunity cost of unpaid care, i.e. the time (work and/or leisure) that carers forego, valued in monetary terms, to provide unpaid care for relatives suffering from CAD. Productivity costs include the foregone earnings related to CAD-attributable mortality and morbidity. A recent study estimated economic costs of CVD in the enlarged European Union and the proportion of these costs attributable to CAD.19 CAD cost the health care systems of the European Union just under 23 billion euros in 2003. The major component of health expenditure was inpatient care, which accounted for 62% (14 billion euros) of costs, followed by pharmaceutical expenditure which represented 23% (5.4 billion euros) of total health care costs. Primary, outpatient, and emergency care accounted for ∼16% of health care costs. Over 678 000 people provided care to CAD patients, representing 702 million hours of care, which was estimated to cost the European Union 6.8 billion euros. Approximately one million working years were lost because of CAD mortality, accounting for 44% of all working years lost because of cardiovascular deaths, with a cost of 11.7 billion euros. Additionally, 90 million working days were lost because of CAD morbidity, representing a cost of 3.5 billion euros after adjusting costs using the friction period. Overall, CAD is estimated to have cost European Union 45 billion euros in 2003—one-quarter of the overall cost of CVD. Over half of these costs (51%) were incurred in health care, 34% in productivity losses, and 15% in informal care.
Management of traditional risk factors
Risk factor control in patients with established CAD remains poor, especially for obesity, smoking, and blood pressure, in spite of guidelines. The 2007 European Guidelines on CVD prevention in clinical practice have adopted a more aggressive approach for the treatment of cardiovascular risk factors.20 Smoking cessation and avoidance of exposure to environmental tobacco smoke at work and home is recommended. Follow-up, referral to special programs, and/or pharmacotherapy (including nicotine replacement) are recommended, as is a stepwise strategy for smoking cessation. Patients should initiate and/or maintain lifestyle modifications—weight control, increased physical activity, moderation of alcohol consumption, limited sodium intake, and maintenance of a diet high in fresh fruits, vegetables, and low-fat dairy products. Combination antihypertensive treatment is frequently needed to control blood pressure. Drugs that have a long-lasting effect and a documented ability to lower blood pressure effectively over 24 h with once-a-day administration are preferred. Long-acting drugs also minimize blood pressure variability and this may offer protection against progression of target-organ damage and risk of cardiovascular events. According to Joint National Conference VII guidelines, blood pressure <140/90 mmHg, or <130/80 mmHg for patients with diabetes or chronic kidney disease, is recommended.21 Dietary therapy for all patients should include reduced intake of saturated fats (to <7% of total calories), trans fatty acids, and cholesterol. Daily physical activity and weight management are recommended for all patients. Statin therapy should always be considered for patients with established CAD, based on their benefits in the reduction of the risk of atherosclerotic complications. Current European guidelines on CVD prevention suggest a target value of <4.5 mmol/L (175 mg/dL) for total cholesterol with an option of 4.0 mmol/L (155 mg/dL) if feasible, and 2.5 mmol/L (10 mg/dL) for LDL cholesterol an option of 2.0 mmol/L (80 mg/dL) if feasible in patients with established CVD.20
Physical activity should be encouraged, as it increases exercise tolerance, reduces symptoms of angina, and has a favourable effect on weight, blood lipids, blood pressure, glucose tolerance, and insulin sensitivity. The recent ACC/AHA update of the Guidelines for the Management of Patients With Chronic Stable Angina recommends physical activity of 30–60 min, 7 days per week (minimum 5 days per week).22 All patients should be encouraged to do 30–60 min of moderate-intensity aerobic activity, such as brisk walking, on most and preferably all days of the week, supplemented by an increase in daily activities (walking breaks at work, gardening, or household work). Patients should be advised to adopt a ‘Mediterranean’ diet, with vegetables, fruit, fish, and poultry. Body mass index and waist circumference should be assessed regularly. On each patient visit, it is useful to consistently encourage weight maintenance/reduction through an appropriate balance of physical activity, caloric intake, and formal behavioural programmes when indicated to achieve and maintain a body mass index between 18.5 and 24.9 kg/m2. Diabetes management should include lifestyle and pharmacotherapy measures to achieve a near-normal HbA1c. In type 1 diabetes, glycemic control requires appropriate insulin therapy and concomitant professional dietary therapy. In type 2 diabetes, professional dietary advice, weight reduction, and increased physical activity should be the first treatment, followed by pharmacological treatment (oral hypoglycemic treatment and insulin when needed) aiming at good glucose control. Current European guidelines on CVD prevention suggest a target HbA1c value of <6.5% if feasible, <6.0 mmol/L (110 mg/dL) for fasting/preprandial plasma glucose and <7.5 mmol/L (135 mg/dL) for postprandial plasma glucose if feasible.20 In addition, psychological risk factors should also be addressed, such as excessive anxiety or depression.
Heart rate as an emerging cardiovascular risk factor
Heart rate (HR), a simple and easily measurable clinical parameter, has been found to be a risk predictor of mortality and morbidity in various populations. Heart rate has already appeared in European guidelines on CVD prevention.20 This consideration is based on a large body of evidence from epidemiological studies reporting an association between elevated HR and increased risk of all-cause mortality and cardiovascular mortality and morbidity in the general population, hypertensives, diabetics, and those with CAD.23 The relationship between HR and cardiovascular mortality has been shown in 14 epidemiological studies over the last 25 years carried out in the general population and in subjects with hypertension, including a total of more than 155 000 patients followed up for between 8 and 36 years.24 The Framingham study, which included 5070 subjects followed up for 30 years, evidenced a progressive and significant increase in all-cause mortality in relation to HR in both men and women.25 Several studies of healthy men and women found that elevated resting HR was an independent risk predictor of sudden death. A recently published study of 5139 healthy French men found that resting HR and its change over 5 years were both predictors of death, independent of standard risk factors.26 After adjustments were made for confounding factors, including baseline HR at rest, and compared with subjects with unchanged HR, those with HR that decreased during the 5 years had a 14% decreased mortality risk (P = 0.05), whereas men whose HR increased over the 5 years had a 19% increased mortality risk (P = 0.012).
In patients with acute MI, Hjalmarson et al.27 demonstrated that in-hospital mortality and post-discharge mortality increased with increasing HR on admission. Total mortality was 15% for patients with an admission HR ranging between 50 and 60 b.p.m., 41% for HR > 90 b.p.m. and 48% for HR > 110 b.p.m. Mortality from hospital discharge to 1 year was also related to the maximal HR observed in the coronary care unit and to the HR at discharge. The prognostic significance of HR was also assessed in the GISSI-2 study in 8915 patients with acute MI and treated with fibrinolytic therapy.28 Increased HR on admission was associated with a progressive increase in in-hospital mortality (from 7.1% for HR < 60 b.p.m. to 23.4% for HR > 100 b.p.m.). A progressive increase of 6-month mortality was noted with increasing HR at discharge (from 0.8% for HR ≤ 60 b.p.m. to 14.3% for HR > 100 b.p.m.). Tardif and colleagues29 found that resting HR was an independent risk predictor of total and cardiovascular mortality in 24 913 men and women with suspected or proved CAD followed for an average of 14 years. The prognostic value of HR held true when controlling for hypertension, diabetes, and smoking, as well as powerful markers such as the LV ejection fraction and the number of diseased coronary vessels. Patients with an HR ≥ 83 b.p.m. also had a significantly higher risk of hospital admissions for cardiovascular causes than those with an HR < 62 b.p.m. In a post hoc analysis from the INVEST (INternational VErapamil-SR/Trandolapril) study, the relationships between resting HR at baseline and at follow-up and adverse outcomes (all-cause death, non-fatal MI, and non-fatal stroke) were evaluated in 22 192 patients with hypertension and CAD treated either with verapamil or with atenolol. Resting HR was found in this study to predict adverse events, and on-treatment HR was even more predictive than baseline resting HR.30
The BEAUTIFUL (MorBidity-mortality EvAlUaTion of the If inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction) investigators have also added to current knowledge concerning the prognostic value of elevated HR by conducting a prospective analysis of the data from the placebo arm of the study to assess the association of HR with different clinical outcomes.31 The results of this analysis in the placebo arm (n = 5438) showed that an elevated resting HR (≥70 b.p.m.) is a strong predictor of outcome in patients with stable CAD and LV dysfunction. This was the case for all of the outcomes assessed in the study. Patients with an HR of 70 b.p.m. or more were 34% more likely to die of cardiovascular causes (P = 0.0041) and 53% more likely to be hospitalized for new or worsening heart failure (P<0.0001) than those with values <70 b.p.m. Similarly, an elevated HR (≥70 b.p.m.) was associated with a 46% increase in the risk of fatal and non-fatal MI (P = 0.0066) and a 38% increase in the need for coronary revascularization (P = 0.037). These data were adjusted for all the variables that differed between the two groups at baseline, including beta-blocker intake and other background therapy.
Role of heart rate in the development of atherosclerosis and coronary events
The most common coronary manifestations of atherosclerosis are stable angina pectoris and acute coronary syndromes. The role of HR in myocardial ischaemia in patients with stable angina and those who suffer an MI is well known. An increased HR contributes to an imbalance between myocardial oxygen demand and supply, by causing both an increase in myocardial oxygen demand and a decrease in coronary blood supply (the latter via a shorter duration of diastole, the period during which most of the myocardial perfusion occurs). Thus, the likelihood of myocardial ischaemia is related to baseline resting HR, and is two times higher in patients with baseline HR of 89 b.p.m. or more compared with those with HR of 60 b.p.m.32 Experimental evidence also supports the role of HR in endothelial dysfunction and progression of atherosclerosis. A higher HR is associated with a shortened diastole and more time spent in systole during which coronary shear stress is lower.33 Reduced shear stress is associated with enhanced endothelial expression of pro-inflammatory molecules and predisposition to atherosclerosis. An increased HR may also be involved at the later stages of atherosclerosis and has been associated with greater risk of plaque rupture.34 Consistent with this understanding of the importance of HR in the pathophysiology of CAD, HR reduction is considered as a potential therapeutic goal in coronary patients; the short-term implication is prevention of ischaemia, and the long-term implication is potential prevention of cardiovascular events.
Heart rate reduction and decreased cardiovascular risk
Several studies have shown that beta-blockers are able to reduce total mortality and sudden cardiac death after MI. These beneficial effects have been ascribed at least in part to the reduction of HR.35 Furthermore, a recent meta-regression of randomized clinical trials of beta-blockers and calcium channel blockers in post-MI patients strongly suggests that resting HR reduction could be a major determinant of the clinical benefits seen in these trials.36 Recently, the BEAUTIFUL investigators have contributed to the understanding of the importance of HR reduction for prevention of coronary events. Treatment with ivabradine, a pure HR-reducing agent, provides an opportunity to assess the effects of selectively lowering HR without altering other aspects of cardiac function.37 The prospective analysis of data from the placebo arm of BEAUTIFUL demonstrated that elevated resting HR (≥70 b.p.m.) is a strong independent predictor of clinical outcomes. Consistent with these data, ivabradine significantly improved coronary outcomes in these patients with an HR ≥70 b.p.m. Compared with placebo, there was a 36% reduction in relative risk of hospitalization for fatal and non-fatal MI in these patients with HR ≥ 70 b.p.m. treated with ivabradine (P = 0.001) and a 30% relative risk reduction in coronary revascularization (P = 0.016). Treatment with ivabradine was also associated with a 22% reduction in the relative risk of the composite endpoint of hospitalization for fatal and non-fatal MI and unstable angina pectoris (P = 0.023) as compared with placebo.
Aspirin irreversibly inhibits platelet cyclooxygenase and, as a consequence, reduces the synthesis of thromboxane. At low doses (75–150 mg/day), chronic therapy with aspirin remains the best pharmacological option for the prevention of arterial thrombosis.38 Outside this dose range, the advantage conferred by treatment with aspirin may be lower.39 Low-dose aspirin is therefore to be recommended in all patients, provided they do not present specific contraindications.38 The antiplatelet agents clopidogrel and ticlopidine are more expensive than aspirin, but have a similar overall safety profile and may be good options in cases of aspirin intolerance (e.g. patients with bronchospasm). They have antithrombotic effects comparable to those of aspirin.40 The CAPRIE trial demonstrated the benefits of long-term treatment with clopidogrel by reducing the combined risk of ischaemic stroke, MI, or vascular death.41 High-risk patients may benefit from combination of aspirin with an anticoagulant agent such as warfarin. However, unless there is a specific separate indication, anticoagulants should be avoided in stable CAD.
There is a strong association between increased low-density lipoprotein (LDL) cholesterol levels and the risk of CVD.42 Cholesterol lowering reduces the risk of atherosclerosis progression43 and the currently recommended treatment goals are lower for patients with established CAD and those considered to be at high risk. The Heart Protection Study clearly demonstrated that lipid-lowering treatment was beneficial in patients with a history of CAD, and such therapy should be an integral part of the management of all CAD patients.44 Statins have been reported to decrease cardiovascular complications by up to 30%, even in the elderly (>70 years) and patients with diabetes.44,45 It is known that the deleterious effects of serum cholesterol begin at low-normal levels,46 and pre-treatment cholesterol level does not determine the benefits of long-term statin therapy; treatment is therefore useful in patients with normal cholesterol levels but high cardiovascular risk.47 This explains why it is currently recommended to treat patients at high cardiovascular risk with a statin, even if they have normal or near-normal LDL cholesterol levels.
Angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of hypertension and heart failure. Trials in patients with heart failure and post-MI reported reduced cardiac mortality and MI with ACE inhibition,48–50 which ultimately led to the investigation of the role of these agents in secondary prevention for CAD patients without heart failure. In the EUropean trial of Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA), there was a 20% relative risk reduction in the composite primary endpoint of cardiovascular death, MI, or resuscitated cardiac arrest in the perindopril treatment group.48 Results in favour of ACE inhibition also came from the Heart Outcomes Prevention Evaluation (HOPE) study with ramipril, in which there was a 22% reduction in the composite primary endpoint of cardiovascular death, MI, and stroke.49 The conclusion drawn from these studies is that ACE inhibition with perindopril or ramipril could have additional cardiovascular effects via mechanisms other than reduction of blood pressure.51–53 Secondary prevention with ACE inhibition is therefore recommended for patients with proved CAD, if they have had a previous MI, or have diabetes, concomitant hypertension, heart failure, or asymptomatic LV dysfunction.38
Beta-blockers can reduce the risk of cardiovascular death or MI by about 30% in post-MI populations.54 Beta-blockers are currently recommended in such patients, and in patients with heart failure. Beta-blockers reduce HR at rest and during exercise, and are the standard choice for the symptomatic treatment of stable angina and ischaemia, provided the agent is initiated carefully and titrated progressively to full dose to achieve resting HR less than 60 b.p.m.55 Uptitration of beta-blockers might be limited by side effects, such as fatigue, depression, lethargy, insomnia, nightmares, and worsening claudication.
If current inhibitor ivabradine
If current inhibitor ivabradine selectively inhibits the If cardiac pacemaker current, thus exerting selective HR reduction while preserving LV contractility and relaxation.56 It provides powerful anti-ischaemic and antianginal efficacy in patients with stable angina.57–60 The recent ASSOCIATE study clearly demonstrated that treatment with ivabradine in patients with stable angina receiving the beta-blocker atenolol resulted in a significant reduction in HR and improvement in all parameters of exercise capacity.61 The results of the BEAUTIFUL study suggest that ivabradine has the ability to affect not only symptoms of myocardial ischaemia, but also potentially to improve coronary outcomes in patients with elevated HR (≥70 b.p.m.), which makes it an interesting agent for the management of patients with CAD.37
Calcium channel blockers
Calcium channel blockers (CCBs), through selective inhibition of the L-type calcium channels, lead to dilation of the coronary and other arteries, which decreases cardiac work and counteracts vasospasm. The non-dihydropyridine CCBs (e.g. verapamil and diltiazem) reduce HR, myocardial contractility, and atrioventricular nodal conduction. Calcium channel blockers reduce the frequency and severity of anginal attacks, but there is no evidence supporting their use to improve prognosis in stable CAD patients. ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system) found no benefit of nifedipine over placebo in stable angina in terms of composite endpoints, including death, MI, refractory angina, and heart failure.62
Nicorandil is a potassium channel opener with a nitrate-like effect. The IONA (Impact Of Nicorandil in Angina) study showed fewer major coronary events in patients treated with nicorandil vs. placebo, but significance was driven mainly by a reduction in ‘hospital admission for cardiac chest pain’. The risk of death and non-fatal MI was unaffected.63
Revascularization includes either PCI, usually with stent implantation, or coronary artery bypass graft (CABG) surgery. The results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, published in 2007, showed no benefit in terms of all-cause mortality, MI, or other major cardiovascular events of adding PCI in stable CAD patients receiving optimized medical therapy.64 Moreover, the marginal quality of life benefit obtained by revascularization in that trial had completely disappeared after 3 years.65 A remarkable finding from COURAGE is that the majority of patients had substantial improvements in health status (with contemporary treatment) that were sustained for several years. At the same time, the rapid improvement with optimal medical therapy alone suggests that antianginal medications are underused in practice. The COURAGE trial redefines the contemporary roles of optimal medical therapy and PCI in the management of patients with stable CAD. It suggests the complementary role of optimal medical therapy as first-line therapy, with PCI reserved for patients who do not respond or who have severe symptoms. In some circumstances, for example in patients with severe lesions in coronary arteries that supply a large area of the myocardium, revascularization can improve prognosis by increasing the effectiveness of the existing perfusion or providing alternative routes of perfusion. Whatever the decision—to revascularize or not—the patient should be advised that secondary preventative pharmacological therapy will continue to be necessary, even after the intervention. The risks and benefits of surgery or PCI should also be carefully discussed with the patient.
The CLARIFY registry: rationale and objectives
Coronary artery disease is and will remain for the foreseeable future the first cause of death worldwide. With improvements in treatment, an increasing number of patients survive acute coronary syndromes and will live as outpatients with or without anginal symptoms.
Need for worldwide contemporary data on outpatients with stable coronary artery disease
Data available today on disease presentation and management of patients with stable CAD come mainly from clinical trials or registries. Clinical trials often have stringent inclusion and exclusion criteria, and thus do not adequately represent populations with stable CAD, particularly in terms of age, comorbidity, and concomitant therapy, and often do not reflect daily practice. This is emphasized by the under-representation of women and ethnic minorities in trial populations, and by the tendency for trial patients to be free from important comorbidities. Furthermore, patients followed up in the large centres typically participating in clinical trials may not resemble those in the outpatient community. However, some registries have attempted to capture the patient population with stable CAD, but often focus on a single country or geographic region, or on acute manifestations of the disease,66 or only on patients with anginal symptoms.67 In addition, some studies are cross-sectional and therefore do not establish links between baseline characteristics, management, and subsequent outcomes. Therefore, the generalizability of findings from randomized clinical trials and most registries is often limited. Finally, due to the important changes in management and outcome of CAD patients, there is a need for contemporary data. It is therefore important to have longitudinal observations of a representative large cohort of patients with stable CAD, spanning several geographic regions, focusing on stable outpatients (as opposed to patients hospitalized or recently discharged from hospital for acute manifestations of the disease), and including both symptomatic and asymptomatic patients.
Need to evaluate determinants of long-term prognosis, including heart rate, in patients with stable coronary artery disease
It is also important that such a database captures all suspected important determinants of outcomes in order to analyze not only the baseline characteristics and management practices, but also outcomes and prognostic determinants including resting HR. In spite of extensive evidence for the importance of HR in the prognosis of stable CAD, HR is not yet a routine component of cardiovascular risk assessment. We also lack data on HRs actually achieved in practice. Therefore, using a dataset in which resting HR is carefully and reliably measured will be critical when trying to assess the role of HR in prognosis in stable CAD patient populations. Therefore, large outpatient-based registries are needed to increase understanding of the characteristics, management, outcomes, and determinants of prognosis, including HR, of contemporary outpatients with stable CAD. The CLARIFY registry has been set up to improve knowledge about the contemporary stable CAD population.68 CLARIFY is an international, prospective, observational, longitudinal registry in stable CAD outpatients with 5-year follow-up. The study will be approved by local institutional review boards and all patients will give informed consent in accordance with national and local guidelines. The registry will provide important data on the demographic and clinical profile of the stable CAD outpatient population, current treatment in daily practice, adherence to guidelines, evidence-based practice, changing patterns of stable CAD management during registry follow-up, variations in management of CAD patients according to geography, type of physician, and patient characteristics, and the determinants of long-term prognosis, including the role of resting HR. The population of CLARIFY is intended to reflect the entire spectrum of outpatients with CAD. This information will help to improve the management of patients with CAD.
The main objectives of CLARIFY are (i) to characterize contemporary CAD patients in terms of demographic characteristics, clinical profiles, management and outcomes and to identify gaps between treatment and evidence, and (ii) to determine the long-term prognostic determinants in this population, including resting HR, with a view to developing a risk prediction model.
CLARIFY study design
CLARIFY is an international, prospective, observational, longitudinal registry in stable CAD outpatients, with 5-year follow-up. This observational registry is designed to collect data on the current status of outpatients with stable CAD, including their demographic characteristics, clinical profiles, therapeutic strategies, and outcomes. This is not an interventional study to assess the impact of a predefined therapy. In this longitudinal study, a minimum of 30 000 subjects will be followed up for 5 years and data will be collected prospectively at annual visits at 12, 24, 36, 48, and 60 months. Because of substantial geographic variations in the epidemiology of stable CAD, this registry will be international to generate data on various countries and regions of the world. This strategy will enhance the value of the results and yield data on international variability in disease presentation and management.
Selection of subjects in the CLARIFY registry
The registry will attempt to collect representative data for each of the participating countries. Representativeness will be ensured by a two-tiered process: (i) determination of physician type in charge of CAD patients in a given country and targeting of an appropriate proportion of each of these physician specialties; (ii) enrolment of consecutive eligible patients is planned for each patient. Each physician will recruit 10–15 outpatients with stable CAD as defined by the inclusion criteria. Patients will be recruited at each practice setting over a brief period of time, suggesting consecutive (or nearly so) patient enrolment and ensuring representative inclusion of the overall population in each practice setting.
Inclusion and exclusion criteria
Outpatients with stable CAD proved by a history of at least one of the following criteria are eligible to enter CLARIFY: documented MI (more than 3 months ago), coronary stenosis of more than 50% proved by coronary angiography, chest pain with myocardial ischaemia proved by stress ECG, stress echocardiography or myocardial imaging, or CABG or PCI (more than 3 months ago). Patients cannot enter the study if they were hospitalized for CVD within the last 3 months before recruitment (including revascularization), are scheduled for revascularization, or have conditions hampering participation in the 5-year follow-up, such as limited cooperation, limited legal capacity, serious non-CVD or conditions interfering with life expectancy (cancer, drug abuse, etc.) or severe CVD (advanced heart failure, severe valve disease, history of valve repair/replacement).
Data collection and evaluation in CLARIFY
The data are collected anonymously at baseline and annually for 5 years to ascertain clinical events, hospitalization, employment status, or sick leave. Evaluations at baseline include demographic information, employment status, medical history, risk factors, physical examination, HR, pulse palpation, 12-lead electrocardiography (the most recent ECG within 6 months in clinically stable patients), laboratory values (if available), and current chronic medical treatments. Evaluations at the annual follow-up visit include clinical events occurring since last visit and other cases of hospitalization, death, employment status, medical history, physical examination, HR, pulse palpation, 12-lead ECG, laboratory values (if available), and current chronic medical treatments. A phone call between annual visits will be made 6 months after each annual visit to ascertain whether the patient has experienced major clinical events or been hospitalized. This will help to limit missing data and loss to follow-up. The main outcomes to be collected in CLARIFY for 5 years of follow-up are cardiovascular death [fatal MI, sudden death, and other cardiovascular death (fatal stroke, heart failure, ruptured aneurysm, pulmonary embolism, cardiac investigation/procedure/operation)], non-cardiovascular death, and cardiovascular morbidity [hospitalization for non-fatal MI, hospitalization for unstable angina, hospitalization for new-onset or worsening heart failure, coronary revascularization (PCI or CABG), hospitalization for non-fatal stroke, and other vascular events or procedures].
Cardiovascular diseases and CAD remain the leading cause of mortality in the world. In addition to the lifestyle and pharmacological approaches that are available to prevent and treat CAD, HR is emerging as a potential risk factor for CAD-related outcomes. Ongoing randomized trials are assessing the role of selective HR reduction in improving outcomes in patients with CVDs. Results from these trials will be complemented by CLARIFY, a large-scale international registry of outpatients with stable CAD that will assess baseline characteristics, management practices, and all potential outcome determinants including HR.
Conflict of interest: J.-C.T. has received honoraria from Servier.
- physical activity
- coronary arteriosclerosis
- mediterranean diet
- cardiovascular diseases
- diabetes mellitus
- cardiovascular disease risk factors
- heart rate
- endothelial dysfunction
- diabetes mellitus, type 2
- smoking cessation
- weight reduction
- cardiovascular system
- cause of death
- developed countries
- life expectancy
- antianginal therapy
- lifestyle changes
- cardiovascular event
- cardiovascular death
- management procedure
- medical management