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Editor in chief

Roberto Ferrari

Associate Editors

Francisco Fernández-AvilésJeroen BaxMichael BöhmThomas F. LüscherFrank Ruschitzka


Published on behalf of

Heart rate management in coronary artery disease: the CLARIFY registry

Philippe Gabriel Steg
DOI: http://dx.doi.org/10.1093/eurheartj/sup017 D13-D18 First published online: 1 September 2009


Coronary artery disease (CAD) is and will remain the first cause of death worldwide. With progress made in treatment, an increasing number of patients survive acute coronary syndromes and will live as outpatients with or without anginal symptoms. The characteristics, management, and outcomes of patients with chronic stable CAD are not well known, because most of the information available stems from the highly selected patient populations enrolled in randomized clinical trials or from hospital-based cohorts and was gathered almost exclusively in Europe and North America. Finally, a large fraction of the information available relates to patients with anginal symptoms. To better characterize these patients, a large international observational registry will be launched: CLARIFY aims to enrol in more than 30 countries over four continents ∼25 000 outpatients with stable CAD, defined as history of documented myocardial infarction (of more than 3 months), prior coronary revascularization, chest pain with documented myocardial ischaemia or coronary stenosis of >50% proven by angiography. Patients will be followed up annually to 5 years, with collection of information regarding risk factors, medical history, anthropometric indices, blood pressure, and heart rate, laboratory measurements, treatments and cardiovascular events and procedures. Establishing the determinants of prognosis and particularly the impact of resting heart rate is among the main goals. CLARIFY will provide contemporary information regarding characteristics management and outcomes of patients with stable CAD. This should help improve care and ultimately the outcomes of these patients.

  • Coronary artery disease
  • Heart rate
  • Epidemiology
  • Prognosis
  • Registry

Coronary artery disease (CAD) remains the leading cause of death worldwide.1 Despite a steady decline in industrialized countries, cardiovascular mortality has increased in low- and middle-income countries, as these countries are undergoing a rapid epidemiological transition to a Western lifestyle and its attendant high rates of cardiovascular disease. Therefore, despite the tremendous progress made in prevention and cure of cardiovascular diseases, projections are that cardiovascular disease will remain the leading cause of death in 2020–30. Among cardiovascular causes, CAD was and will remain the first cause of death and stroke the second.2 For these reasons, any insight into how to improve care and outcomes of patients with CAD is of tremendous value to public health and to patients.

Current prognosis of coronary artery disease

It is now recognized that CAD is a chronic disease, which remains silent for several decades, as atherosclerotic plaque builds up in the coronary arteries but in which acute coronary syndromes (i.e. acute myocardial infarction and unstable angina) are precipitated by plaque rupture or erosion causing thrombosis. In the intervals between acute episodes, the disease may become silent again or the patient may suffer from myocardial ischaemia, generally triggered by exercise or emotions and which may be (but not necessarily) associated with anginal symptoms. These intervals between acute exacerbations of the disease are generally designated as chronic stable CAD. In the past 30 years, there has been enormous progress in the diagnosis and management of acute coronary syndromes, which have translated into major reductions in the acute and chronic mortality rates associated with these.3 In addition, secondary prevention of acute coronary syndromes has also made giant strides, with a series of large randomized clinical trials establishing the value of anti-platelet therapy, statins, and angiotensin-converting enzyme inhibitors in order to prevent adverse cardiac events in these patients.4,5 Because of the major improvement in the initial outcomes and the survival from acute episodes, the overall pool of patients with established CAD has enlarged. This group of patients remains at high risk of subsequent cardiovascular events. Their management is now rather well codified. Essentially, the lifestyle interventions and drugs used for secondary prevention are similar across all types of acute coronary syndromes (with or without ST-segment elevation).

Prognostic factors in coronary artery disease

Starting with the Framingham study, there is a host of data to compute the risk of ischaemic heart disease in healthy individuals, using scores such as the Framingham risk score, the European SCORE project,6 and similar types of scores. Likewise, there have been many studies of the determinants of prognosis in patients hospitalized for acute coronary syndromes (acute myocardial infarction or unstable angina).4,5 Using data from the TIMI repository of randomized clinical trials, the TIMI group has devised a series of TIMI scores to predict outcomes in STEMI and in non-ST-segment elevation ACS.7 Using data from the international Global Registry of Acute Coronary Events (GRACE), the GRACE investigators designed several scores to compute the risk of adverse outcomes for the whole spectrum of ACS. There is one score to predict short-term outcomes,8 one score to predict post-discharge outcomes up to 6 months9 and one score to compute overall risk.10 These scores have been shown to be robust11 and to retain validity over time despite changes in management and outcomes.12 For individuals with established cardiovascular disease, there is much less data available on how to compute prognosis in a 'secondary prevention setting'. The Framingham study has created a score for predicting the risk of subsequent cardiovascular event in patients with established cardiovascular disease.13 Likewise, the REACH registry analysed a large cohort of stable outpatients with established atherothrombosis (CAD, cerebrovascular disease or peripheral arterial disease) to predict the subsequent probability of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.14

The role of heart rate as a prognostic factor

Heart rate as a predictor for cardiovascular disease in healthy individuals

Epidemiological studies have shown that resting heart rate is a predictor of cardiovascular mortality in healthy individuals1521 and in hypertensive patients.2224 In addition, resting heart rate was also found to be a predictive factor for sudden death.25

Heart rate among patients with established coronary artery disease

The prognostic importance of heart rate in acute coronary syndrome has been underscored by the fact that it was incorporated in prognostic scores such as the GRACE risk score, to predict hospital and post-discharge mortality across all types of acute coronary syndrome,810 or the simplified TIMI index for ST-segment elevation myocardial infarction.2628

There has also been a large body of evidence to support the association between resting heart rate and mortality in patients with established stable CAD, starting with observations from the trials of beta-blockade after acute myocardial infarction29,30 to the fact that heart rate was associated with the incidence of new coronary events in patients undergoing Holter ECG monitoring31 and to subsequent strong evidence of the association between heart rate and mortality in patients with stable CAD.32,33 More recently, the placebo arm of the randomized BEAUTIFUL trial allowed prospective study of the prognostic role of resting heart rate in patients with CAD and left ventricular systolic dysfunction and showed that elevated heart rate was associated with an increased risk of adverse fatal and non-fatal cardiac events. More importantly, in that trial, ivabradine, a pure heart rate-lowering agent, was associated with a reduction in the risk of coronary events, particularly fatal and non-fatal myocardial infarction, among patients with a baseline heart rate above 70 b.p.m., providing additional validation that elevated heart rate is indeed in the causal pathway from CAD to cardiac events. While many studies had demonstrated clinical benefits using drugs which lowered heart rate, such as beta-blockers, these effects could not easily be separated from the important benefits related to blockade of the sympathetic nervous system3438 Studies of ivabradine test the concept that heart rate lowering per se is therapeutic. The mechanisms by which heart rate reduction in general and by ivabradine in particular may play a beneficial role in preventing cardiovascular death or myocardial infarction are multiple and have been reviewed elsewhere.3946

The need for reliable registry data in stable coronary artery disease

Most of the data pertaining to patients with stable CAD come from randomized clinical trials of drugs used in the secondary prevention of cardiovascular events, such as EUROPA,47 CHARISMA,48 TNT,49 etc. An important limitation of such datasets derived from randomized clinical trials is the highly selective nature of randomized trials, which are known to involve a selected patient population, with more favourable baseline demographics, risk characteristics, and outcomes than the general population. Typically, randomized clinical trials also tend to underrepresent elderly patients (often due to the co-morbidities frequently present), women or patients with lower socioeconomic status. All of these selection biases create issues regarding the generalization of the results of randomized clinical trials.50 In addition, even patients from routine clinical practice who mimic the characteristics of trial participants tend to have better outcomes than actual trial participants.51 Therefore, it is important to complement the observations made in highly selected randomized clinical trial populations with data from more representative studies, such as large-scale registries.

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, or only on patients with anginal symptoms. In addition, some studies are cross-sectional and therefore do not allow us to establish links between baseline characteristics, management, and subsequent outcomes. Therefore, it would be important to have longitudinal observation of a representative large cohort of patients with stable CAD, spanning several geographic regions, focussing on stable outpatients (as opposed to patients hospitalized or recently discharged from hospitals for acute manifestations of the disease), and including both symptomatic and asymptomatic patients. It would also be important that such a database captures all suspected important determinants of outcomes in order to analyse not only the baseline characteristics and management practices but also outcomes and prognostic determinants, including heart rate. Finally, the measurement of heart rate is not well standardized and can fluctuate substantially. Therefore, using a dataset in which resting heart rate is carefully and reliably measured will be critical when trying to assess the precise role of heart rate in prognosis.

CLARIFY: the protocol

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, ∼25 000 subjects will be followed up for 5 years and data will be collected prospectively at annual visits. Because of substantial geographic variations in the epidemiology of stable CAD, this registry will be international, in order to generate reliable data on several geographic regions of the world. This strategy will enhance the value of the results and yield data on international variability in disease presentation, management, and outcomes.

Subject selection

Inclusion criteria: the study will enrol outpatients with stable CAD, proven by history of at least one of the following criteria (Table 1):

  • Documented myocardial infarction (more than 3 months ago)

  • Coronary stenosis of more than 50% proven by coronary angiography

  • Chest pain with myocardial ischaemia, proven by stress ECG, stress echocardiography, or myocardial imaging

  • Coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (more than 3 months ago).

The study will exclude:

  • Patients hospitalized for cardiovascular disease within last 3 months (including revascularization)

  • Patients with planned revascularization

  • Conditions hampering the participation or the 5-year follow-up such as limited cooperation, limited legal capacity, serious non-cardiovascular disease or conditions interfering with life expectancy (cancer, drug abuse, etc.), or severe cardiovascular disease (advanced heart failure, severe valve disease, history of valve repair/replacement, etc.).

View this table:
Table 1

Selection criteria

Inclusion criteria: outpatients with stable CAD, proven by history of at least one of the following criteria
 Documented myocardial infarction (more than 3 months ago)
 Coronary stenosis of more than 50% proven by coronary angiography
 Chest pain with myocardial ischaemia, proven by stress ECG, stress echocardiography, or myocardial imaging
 Coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI) (more than 3 months ago)
Exclusion criteria
 Patients hospitalized for cardiovascular disease within last 3 months (including revascularization)
 Patients with planned revascularization
 Conditions hampering the participation or the 5-year follow-up such as limited cooperation, limited legal capacity, serious non-cardiovascular disease, or conditions interfering with life expectancy (cancer, drug abuse, etc.) or severe cardiovascular disease (advanced heart failure, severe valve disease, history of valve repair/replacement, etc.)

Study setting and site selection

To ensure that the study population is representative of the real-life community of stable CAD outpatients, the recruitment of sites and subjects should be based on two principles: predefined selection of physician types and consecutive enrolment of subjects. Selection of participating sites will be ensured by a two-tiered process: first, in each participating country, the types (primary care, internists, cardiologists, or other specialties) and practice settings (hospital-based as opposed to ambulatory practice) of physicians who are in charge of CAD patients will be determined, using the best epidemiological sources as well as market research data. This will allow targeting of an appropriate proportion of each of these physician types and settings. Ultimately, site selection will be done, using this information, by the National Coordinator in each country. Each physician will recruit a maximum of 15 outpatients with stable CAD as defined by the inclusion criteria. Patients will be enrolled in each practice setting over a brief period of time, suggesting near, if not consecutive, patient enrolment and limiting ‘cherry picking'. Enrolment will take place worldwide between October 2009 and April 2010 (implying that the last patient will end follow-up around April 2015). Cardiologists as well as office-based primary care physicians, including general practitioners, internists, and physicians based in hospitals with outpatient clinics will be involved in the registry. Finally, to ensure that a balanced representation of participating countries, a general target enrolment for any participating country is 25 patients per million inhabitants (range 12.5–50).

Data collection and evaluation

The data will be collected anonymously using electronic forms at baseline and annually for 5 years to ascertain clinical events, hospitalization, employment status, or sick leave. Between annual visits, a 6-monthly phone call will help maximize follow-up and retention rates.

Information collected at baseline will include demographics, medical history, risk factors, employment status, physical examination, heart rate (determined by both pulse palpation and 12-lead electrocardiography) using the most recent ECG within 6 months in clinically stable patients, laboratory values (if available), and current chronic medical treatments.

Each annual follow-up visit will collect information regarding clinical events occurring since the last visit, hospitalizations, interventions, death, employment status, physical examination, heart rate, laboratory values (if available), and current medical therapy (cardiovascular and non-cardiovascular). In addition, quality of life data will be collected at baseline and at follow-up using the simplified EQ-5D tool.

Main outcomes to be collected

Five-year follow-up of patients will be undertaken to collect morbidity/mortality data, particularly cardiovascular death [divided into fatal myocardial infarction, sudden death, and other cardiovascular deaths (fatal stroke, heart failure, ruptured aneurysm, pulmonary embolism, cardiac investigation/procedure/operation)], non-cardiovascular deaths, and cardiovascular morbidity (i.e. hospitalization for non-fatal myocardial (re)infarction, unstable angina, new-onset or worsening heart failure, coronary revascularization (PTCA or CABG), non-fatal stroke, and other vascular events or procedures).

Statistical considerations

The data will be collected and analysed by an independent statistics centre at the Robertson Centre for Biostatistics, University of Glasgow, UK. The main analyses are designed to describe patient characteristics at baseline (including resting heart rate, other risk factors, and medical therapy) and to estimate the annual cardiovascular event rates, and the outcome event rates by region and country. Finally, another goal for CLARIFY is to develop predictive models based on resting heart rate to estimate the risk of subsequent cardiovascular events in patients with CAD.

Determination of sample size

CLARIFY is an observational registry, and the size of the population is not based on treatment comparison. The number of patients that must be included depends on cardiovascular event rates, number of subjects lost to follow-up, and study duration. It is assumed that CLARIFY will screen and enrol ∼25 000 subjects and follow them up for 5 years with a loss to follow-up rate of no greater than 5% per annum. Taking a conservative approach and assuming that 1500 cardiovascular deaths occur, there is ample power (at least 80%) to identify a 20% increase in mortality when comparing highest to lowest quartiles of heart rate, if it is studied as a categorical variable. Treating heart rate as a continuous variable, we would have 90% power with a 5% alpha error to detect an underlying hazard ratio of 1.06 per 10 b.p.m. increase in heart rate.

Event rates will be estimated using the Kaplan–Meier approach and using estimated cumulative incidence functions. The relationship between baseline heart rate (from the ECG) and cardiovascular outcomes will be modelled using parametric and semi-parametric models (Cox proportional hazard models). Assumptions and goodness-of-fit will be assessed using appropriate statistical methods. Heart rate will be modelled as a continuous variable and after categorization. The additional prognostic value of heart rate will be determined using statistical tests of nested models and using the c-index.

Data management and ethical considerations

All data will be entered into an electronic case report form and sent electronically by each country to the data management centre where checks for completeness, internal consistency, and accuracy will be run. Each site will obtain written consent from subjects, verify inclusion criteria, and collect baseline data prospectively by questioning the subject. Pulse palpation and the data from the most recent ECG within 6 months in clinically stable patients will be used to obtain resting heart rate.

Data quality control will be performed onsite in 5% of sites chosen at random in each country. At these sites, 100% of case report forms for patients enrolled at that site will be monitored for source documentation and accuracy. Data quality control will be done at face-to-face quality control visits and will involve review of source documents supporting the adequacy and accuracy of data collected on the case report forms.

The study will be approved by local institutional review boards and all patients will give informed consent in accordance with national and local guidelines. Patient confidentiality will be ensured by utilizing patient identification code numbers to correspond to the computer files.

Anticipated insights from CLARIFY

CLARIFY will constitute the first large-scale international registry of outpatients with stable CAD and provide contemporary information about the characteristics, management, and outcomes of these patients across a variety of geographic and practice settings. It will also collect information regarding quality of life and its changes over time. It will help identify gaps between evidence-based guidelines and clinical practice and avenues for potential improvement, and should help clarify the prognostic indicators in this population. Additionally, it will provide an opportunity to test prospectively the importance of carefully collected resting heart rate as a predictor of future cardiac events in that population. This information should help improve the care and ultimately the clinical outcomes of this large group of patients who continue to remain, despite medical progress, at high risk of adverse clinical outcomes and death.

Conflict of interest: P.G.S. receiving research grant from sanofi-aventis (1999–2008) (significant), speakers bureau (all modest) in Boehringer-Ingelheim, BMS, GSK, Menarini, Medtronic, Nycomed, Pierre Fabre, sanofi-aventis, Servier, The Medicines Company, consulting/advisory board (all modest) in Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Daiichi-Sankyo, Endotis, GSK, Medtronic, MSD, Nycomed, sanofi-aventis, Servier, The Medicines Company and stockholding Aterovax.


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