Heart rate in registries: an important, yet still neglected opportunity

Philippe Gabriel STEG,MD
AP-HP, Hôpital Bichat
Université Paris Diderot Sorbonne Paris Cité

Heart rate in registries: an important, yet still neglected opportunity

by P. G. Steg, France

Registries are the key to understanding the characteristics, management, and outcomes of patients with coronary artery disease (CAD), particularly since information gathered from randomized clinical trials often has limited external validity given the stringent selection criteria used to select trial participants. Resting heart rate is emerging as a key prognostic determinant of outcomes, particularly cardiovascular mortality in patients with stable and unstable forms of CAD and heart failure. Yet, while heart rate is the most commonly measured physiological parameter, surprisingly little information has been gathered regarding actual heart rate in patients with CAD and its relation to the use of heart rate–lowering medications (particularly β-blockers) and subsequent outcomes. In recent years, many registries from various countries in Europe and elsewhere have gathered information on the characteristics of patients with CAD. They have consistently found that although the majority of patients receive β-blockers, resting heart rate is very frequently above 70 bpm. In addition, they have showed that elevated resting heart rate is associated with a greater prevalence of anginal symptoms and, more importantly, with increased cardiovascular mortality. In patients with acute coronary syndromes, however, very low heart rates were also associated with increased mortality, suggesting that the relationship between heart rate and survival in CAD may follow a “J curve.” The large international CLARIFY registry (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease), which has enrolled more than 33 000 patients worldwide, will provide robust information about resting heart rate in relation to anginal symptoms, the use of heart rate–lowering agents—particularly β-blockers— and, most importantly, clinical outcomes up to 5 years.

Medicographia. 2012;34:454-459 (see French abstract on page 459)

Cardiovascular medicine has made major strides in the past 30 years, with substantial progress in the diagnosis, evaluation, management, and prevention of cardiovascular disease. In fact, progress in the field of cardiovascular disease accounts for most of the increase in life expectancy witnessed in the Western world between 1970 and 2000.1 Advances have largely stemmed from evidence accumulated via large randomized clinical trials (RCTs) testing new interventions, devices, and drugs. While randomized clinical trials provide the highest level of evidence regarding the value of interventions, they have some important shortcomings.

First, they tend to recruit highly selected patient populations who are more compliant with medical care and therapies than the average patient encountered in routine clinical practice. Additionally, because of the often stringent inclusion and exclusion criteria, patients enrolled in RCTs tend to be healthier and suffer from fewer comorbidities than patients encountered in routine care. It is therefore important to complement the information gathered from randomized clinical trials with additional information, more representative of routine clinical practice and collected via observational registries. Registries have important additional advantages over RCTs: they are much cheaper and thus can be conducted on a very large scale. They do not require the same level of training or infrastructures as RCTs and can enroll patients from all types of hospitals (not necessarily academic or tertiary institutions), from both hospital and outpatient settings, and can gather data from broad geographic sources. They can collect comprehensive information regarding the clinical characteristics of patients, their management, and their outcomes, and they tend to have greater external validity than RCTs.2 External validity is critical to the interpretation and application of evidence-based medicine: there is ample evidence that patients enrolled in clinical trials tend to have better clinical outcomes than patients in routine practice. Yet, we tend to extend the results of RCTs to patients from routine clinical practice who have characteristics similar to those of the participants in RCTs. There have been demonstrations, for example in ST-segment elevation myocardial infarction (STEMI),3 that even “trial-eligible patients” from registries actually experience much worse outcomes than actual trial participants.

Information on patients with coronary artery disease is limited

Despite a steady decline in the Western world over the past 30 years, coronary artery disease (CAD) is still the first cause of death worldwide4 and is expected to remain so due to an epidemic of coronary heart disease in emerging countries. Yet, our knowledge of the clinical epidemiology of CAD remains limited. Much of the information available predates the emergence of percutaneous coronary intervention (PCI) as the dominant form of revascularization, and therefore, reflects patient profiles that differ markedly from current clinical practice. Most of the information stems from highly selective RCTs or from registries enrolling patients hospitalized for an acute coronary event or a procedure (PCI or coronary artery bypass grafting [CABG]). This wealth of data regarding patients who are admitted to hospital for an acute event does not necessarily reflect the situation of stable outpatients. There are some large registries, but they have focused mostly on patients with anginal symptoms, such as, for example, the Euro Heart Survey on stable angina, which enrolled patients with angina.5 Finally, most of the information comes from sources located in North America or Europe, overlooking the important differences in patient characteristics, management, and environment in other regions of the world. The fact is that our knowledge of the global characteristics of patients with CAD is scant. Little is known about their clinical characteristics, functional status, quality of life, clinical management (including the use of functional testing and imaging) and the use of evidence-based therapies and medications and their outcomes. Gathering such information is critical to identifying gaps in evidence as well as gaps between evidence and routine clinical practice, which can then inform quality assurance initiatives.

Heart rate is emerging as an important prognostic and physiological parameter in coronary artery disease and chronic heart failure

Heart rate is probably the most frequently measured physiological parameter. Despite its considerable variability, it is emerging as a parameter of utmost physiological and prognostic importance in cardiovascular disease. It is one of the major determinants of myocardial oxygen consumption, and therefore, increased heart rate is an important precipitating factor for myocardial ischemia and anginal symptoms. Indeed, some of the most effective treatments to prevent or treat myocardial ischemia and angina, such as β-blockers or some (but not all) calcium channel blockers, act by lowering the heart rate. In fact, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of patients with angina recommend targeting a heart rate of less than 60 beats per min (bpm) for patients with stable angina.6

In addition, despite the short-term variability in heart rate, large epidemiological observational studies, such as the Chicago epidemiological studies7 or other large studies in apparently healthy individuals,8 have consistently linked resting heart rate with long-term cardiovascular risk in subjects without established cardiovascular disease: the higher the heart rate, the greater the risk of cardiovascular and even all-cause mortality.9 An analysis of the CASS registry (Coronary Artery Surgery Study)10 also showed the long-term prognostic value of resting heart rate in patients with suspected or proven CAD: 24 913 patients from the CASS registry were followed for a median duration of 14.7 years. All-cause mortality and cardiovascular mortality increased with increasing heart rate. This persisted after adjustment for multiple baseline clinical variables (Figure 1). Likewise, Copie et al showed that resting heart rate and heart rate variability were important predictors of outcomes after myocardial infarction.11 More recently, prespecified analyses of the placebo arm of the BEAUTIFUL randomized trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) in patients with CAD and left ventricular dysfunction examined the relationship between heart rate at enrollment and subsequent outcomes.12 After adjustment for baseline characteristics, patients with heart rates of 70 bpm or greater (n=2693) had an increased risk of cardiovascular death (34%; P=0.0041), admission to hospital for heart failure (53%; P<0.0001), admission to hospital for myocardial infarction (46%; P=0.0066), and coronary revascularization (38%; P=0.037) than those with heart rates below 70 bpm (n=2745). For every increase of 5 bpm, there were increases in cardiovascular death (8%; P=0.0005), admission to hospital for heart failure (16%; P<0.0001), admission to hospital for myocardial infarction (7%; P=0.052), and coronary revascularization (8%, P=0.034). In patients with CAD and left ventricular systolic dysfunction, elevated heart rate (70 bpm or greater) identifies those at increased risk of cardiovascular outcomes. Similar observations regarding the prognostic importance of heart rate in congestive heart failure were made in the SHIFT randomized trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial).13 SHIFT was a double-blind placebo-controlled trial comparing ivabradine—a specific If inhibitor (which is a pure heart rate–reducing agent)—with placebo, in addition to optimal medical therapy in patients with chronic heart failure.14 In the placebo group, patients with the highest heart rates (≥87 bpm) had a more than 2-fold higher risk of cardiovascular death or hospital admission for worsening heart failure than patients with the lowest heart rates (70 to <72 bpm; hazard ratio, 2.34; 95% CI, 1.84-2.98; P<0.0001). The risk increased by 3% with every bpm increase from baseline heart rate. Ivabradine improved outcomes with an 18% relative reduction in cardiovascular deaths or hospital admissions for heart failure (P<0.0001). Interestingly, the effect of ivabradine was accounted for by heart rate reduction, as shown by the neutralization of the treatment effect after adjustment for change in heart rate after 4 weeks of treatment (hazard ratio, 0.95; 95% CI, 0.85-1.06, P=0.352).

Figure 1
Figure 1. Survival curves for overall mortality (A) and cardiovascular mortality (B) in the Coronary Artery Surgery Study (CASS) registry.

A high resting heart rate is an independent predictor of mortality in coronary artery disease patients.
Data from the CASS registry in 24 913 patients, with 14.7 years of follow-up.
After reference 10: Diaz et al. Eur Heart J. 2005;26:967-974. © 2005, European Society of Cardiology.

Heart rate in coronary artery disease registries

As surprising as it may seem, there is relatively little largescale data on the resting heart rate of patients with CAD. In addition, interpretation of heart rate data requires access to information regarding the use of β-blockers and other heart rate–lowering agents as well as information on the doses and types of β-blockers used as some β-blockers may exhibit sympathomimetic activity and therefore not result in heart rate lowering at rest.

Stable angina registries>

In the European Heart Survey of stable angina the mean baseline heart rate in patients with stable CAD was 73 bpm and approximately half of the patients had a baseline heart rate above 70 bpm,15 despite the fact that some guidelines recommend a target heart rate of 55 to 60 bpm for patients with stable angina on β-blockers.6 Interestingly, over half of the patients were not on any chronotropic medication (ie, no β-blockers or any other heart rate–lowering medication). Among patients receiving β-blockers, the doses used were lower than those found to be effective in clinical trials. Finally, a higher heart rate at baseline was associated with higher rates of mortality and hospitalization for heart failure at follow-up.

Figure 2
Figure 2. Risk calculator for 6-month
postdischarge mortality after hospitalization
for acute coronary syndrome.

Computation of the GRACE (Global Registry of
Acute Coronary Events) risk score, a validated risk
prediction model, to predict 6-month post discharge
outcomes after acute coronary syndrome.
After reference 25: Eagle et al. JAMA.
2004;291:2727-2733. © 2004, American
Medical Association.

In a British registry of 500 patients with chronic stable angina,16 a large proportion of patients did not achieve the target resting heart rate of <60 bpm; 27% had a resting heart rate >70 bpm and an additional 40% had a heart rate between 60 and 69 bpm, despite the fact that 78% of patients were receiving β-blockers. The resting heart rate was not related to the dose of β-blocker. Similar or higher proportions of patients with elevated heart rate and similar rates of β-blocker use were seen in other studies from Portugal, Italy, France, Austria, and Poland.17-21 Studies focusing on older patients tend to find lower rates of β-blocker use.22 The Lhycorne registry enrolled 8922 hypertensive patients with stable CAD.23 In this study, the mean resting heart rate was 70 ± 6 bpm, with 54% of the patients having a heart rate ≥70 bpm and 62% of the population receiving β-blockers. In the above-mentioned studies, patients with higher resting heart rates experienced more frequent anginal symptoms. One study found that the link between a higher resting heart rate and adverse clinical outcomes in patients with stable CAD may be limited to patients with diabetes mellitus, possibly because it reflects autonomic disturbances.24 This study was, however, limited by a relatively short follow-up of only 1 year.

Acute coronary syndromes registries

Heart rate is an independent predictor of outcomes in patients with acute coronary events. For example, the GRACE risk score (Global Registry of Acute Coronary Events), the most widely recommended risk score for acute coronary syndromes, collects information regarding heart rate at presentation and correlates this with the in-hospital risk of death and myocardial infarction. Interestingly, heart rate does not solely predict in-hospital outcomes in ACS, but also post discharge outcomes, indicating that it is a robust marker of long-term outcomes (Figure 2).25 Likewise, heart rate is also a predictor of outcomes in the PURSUIT risk score (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy).26 In the GRACE risk prediction model, the risk of events increases by 30% for every 30-beat increase in heart rate. An analysis of the large CRUSADE acute coronary syndromes quality improvement initiative (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines?) found that the relationship between resting heart rate at presentation and cardiovascular outcomes follows a “J-shaped” curve, with higher event rates at high heart rates, but also at very low heart rates (below 60 beats per minute), even after controlling for baseline variables.27 The lowest risk of adverse outcomes was seen in patients with a resting heart rate between 60 and 69 bpm. One issue requiring clarification is that of the extent to which the detrimental prognostic impact of heart rate may have been confounded by heart failure and whether more modern studies of acute coronary syndromes in which PCI is widely used may fail to show a link between resting heart rate and survival. In a recent analysis of 1453 STEMI patients treated with primary PCI, Antoni et al found that heart rate at discharge after STEMI is a strong predictor of mortality following STEMI, with patients with a heart rate ≥70 bpm having twice the mortality of patients with a lower heart rate, at 1 and 4 years. Every increase of 5 bpm in heart rate at discharge was associated with a 29% and 24% increased risk of cardiovascular mortality at 1 and 4 years of follow-up, respectively.28

The CLARIFY registry

CLARIFY (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) is an ongoing international, prospective, observational, longitudinal cohort study in stable CAD outpatients, with a 5-year follow-up. The study rationale and methods have been published previously.29 The enrolled population is representative of the broad spectrum of CAD patients and detailed information on heart rate was collected at baseline and will continue to be collected on a yearly basis for up to 5 years. CLARIFY will provide a robust database to assess the determinants of outcomes in CAD, prospectively explore the role of heart rate, and evaluate the degree of heart rate reduction achieved with the different types of heart rate–lowering medications used at various doses. In particular, it will help build a robust model of outcomes in CAD and test the importance of heart rate.

Patients were enrolled in 45 countries in Africa, Asia, Australia, Europe, the Middle East, and North, Central, and South America. These patients are being treated according to usual clinical practice at each participating institution, with no specific tests or therapies defined in the study protocol. Patients eligible for enrollment were outpatients with stable CAD proven by a history of at least one of the following: documented myocardial infarction (>3 months before enrollment); coronary stenosis >50% on coronary angiography; chest pain with myocardial ischemia proven by stress electrocardiogram, stress echocardiography, or myocardial imaging; and history of CABG or PCI (performed >3 months before enrollment).

Patients hospitalized for cardiovascular disease within the previous 3 months (including for revascularization), patients for whom revascularization was planned, and patients with conditions expected to hamper participation in the 5-year follow up (eg, limited cooperation or legal capacity, serious non cardiovascular disease, conditions limiting life expectancy, or severe cardiovascular disease [advanced heart failure, severe valve disease, history of valve repair/replacement, etc]) were excluded from the study.

In order to enroll a population of stable CAD outpatients that mimicked the epidemiological patterns of each country, recruitment was based on a predefined selection of physician specialties (cardiologists, internists, and primary care physicians) and aimed for consecutive enrollment of eligible patients. Physician selection was based on the best available sources—either local or regional—of epidemiological and medical care data, including available market data and epidemiological surveys. A general target of 25 patients per million inhabitants was used (range, 12.5-50) to ensure a balanced representation of the participating countries. Each physician recruited between 10 and 15 outpatients with stable CAD, as defined by the inclusion criteria, over a brief period of time, in order to avoid selection bias. Information collected at baseline included: demographics, medical history, risk factors and lifestyle, results of physical examination, heart rate (determined by both pulse palpation and the results of the most recent electrocardiogram performed with in the previous6months), current symptoms, laboratory values (eg, fasting blood glucose, hemoglobin A1c, cholesterol, triglycerides, serum creatinine, hemoglobin, if available), and current chronic medical treatments.

Data are collected centrally using an electronic, standardized, international case report form (translated into local languages) and sent electronically to the data management center, where checks for completeness, internal consistency, and accuracy are run. Data quality control is performed onsite in 5% of sites chosen at random in each country with, at each site, monitoring of 100% of case report forms for source documentation and accuracy. All patients gave written informed consent to participate, in accordance with national and local guidelines. The CLARIFY registry is registered in the ISRCTN registry of clinical trials with the number ISRCTN43070564. All CLARIFY data are collected and analyzed at an independent academic statistics center at the Robertson Centre for Biostatistics, University of Glasgow, UK. The baseline data and 1-year outcome data from CLARIFY were presented at the 2011 and 2012 European Society of Cardiology (ESC) congresses, respectively.30,31 _

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Keywords: clinical outcome; coronary artery disease; heart failure; heart rate; mortality; registry