Resting heart is an independent predictor of all-cause mortality and cardiovascular mortality. In patients with coronary artery disease and left ventricular dysfunction, the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) trial showed that a heart rate of 70 b.p.m. or greater is an independent predictor of cardiovascular events. In patients with moderate-to-severe heart failure, the SHIFT (Systolic Heart failure treatment with the If inhibitor Trial) showed also that heart rate was a predictor of cardiovascular death and heart failure hospitalisation. Heart rate plays an important role in the pathophysiology of atherosclerosis. The BEAUTIFUL trial and SHIFT provide evidence for the benefits of heart rate reduction using the new heart rate-lowering agent ivabradine, even in patients on beta-blockers. The BEAUTIFUL trial showed that in patients with a heart rate of 70 b.p.m. or more, ivabradine significantly reduced hospitalisation for fatal and non-fatal myocardial infarction or hospitalisation for heart failure and coronary revascularisation. In the SHIFT, heart rate reduction with ivabradine improved clinical outcomes. Therefore, high heart rate represents an important risk factor the effects of which can be reversed by ivabradine in patients with coronary artery disease or heart failure with or without background beta-blocker therapy.
The most worrisome manifestation of atherosclerosis is coronary artery disease (CAD), which has two major clinical presentations: stable angina pectoris related to myocardial ischaemia and acute myocardial infarction (MI). Among the possible complications of MI, two are life-threatening: ventricular arrhythmias with the risk of sudden cardiac death and loss of myocardial tissue leading to ventricular remodelling, ventricular enlargement and heart failure.
CAD is an important public health burden and a major cause of mortality worldwide. Although in recent years a decrease in the incidence of CAD has been noted in Western countries,1 the increase in other parts of the world still makes it a major cause of death. In the Framingham study, the lifetime risk of CAD for individuals at age 40 was 49% in men and 32% in women.2 Furthermore, the World Health Organization prediction is that CAD will remain the leading cause of death for the next 20 years, accounting for 13.4% of total mortality, followed by cerebrovascular disease (10.6%).3 The REduction of Atherothrombosis for Continued Health Registry (REACH) enrolled prospectively a cohort of 68 236 patients with either established atherosclerotic arterial disease or at least three risk factors for atherothrombosis. For patients with CAD, the yearly cardiovascular death, MI or stroke rates were 4.52% and the incidences of the endpoint of cardiovascular death, MI, or stroke or of hospitalization for atherothrombotic event(s) were 15.20%, underlining the yearly high cardiovascular event rates in this population of patients.4 Therefore, there is a need to improve the prognosis of CAD by preventing death and MI and to improve quality of life by reducing the severity and/or the frequency of symptoms, including angina and heart failure and related hospitalizations.5 Patients with left ventricular dysfunction or ischaemic cardiomyopathy are at even higher risk of ischaemic events and/or cardiovascular death. Consequently, identification of risk factors and their possible modification becomes essential for improving the quality of life and the prognosis of these patients. In this paper, we will review the value of heart rate as a prognostic factor of mortality and morbidity, particularly in patients with CAD and in patients with heart failure, and the beneficial effects of pure heart rate reduction using the new heart rate-lowering agent ivabradine on patient outcomes in the light of recently published trials.
Heart rate as an independent risk factor of mortality
In the general population
Epidemiological studies have consistently shown that resting heart rate is a predictor of all-cause mortality and cardiovascular mortality.6–9 The ‘Chicago People Gas Company Study’ followed up for up to 17 years men belonging to the ‘Chicago Western Electric Company’ and the ‘Chicago Heart Association Detection Project’ and found a statistically significant relation between resting heart rate and both cardiovascular mortality and total mortality.9 Using a multivariate analysis, they found that even when other CAD risk factors such as age, blood pressure, total blood cholesterol, smoking and body weight were taken into account, heart rate still appeared as an independent risk factor of sudden coronary death and of non-cardiovascular mortality in 2 of the 3 cohorts studied. In the Framingham study, a significant relationship was also found with a 30-year follow-up, between high resting heart rate and increase in cardiovascular mortality, coronary heart disease and sudden coronary death both in men and women.10 In a study including a large cohort of ‘white collar’ employees in France, followed up over a 20-year period, heart rate was found to be a predictive factor of non-cardiovascular mortality in both men and women.11 The MATISS Project, which included men aged 40–69 years followed up for a total of 24 457 subject-years, showed that heart rate was an independent predictor of total mortality, cardiovascular mortality and non-cardiovascular mortality.12 In a French population of 7079 subjects aged 42–53 years, followed up for an average of 23 years, the risk of sudden death increased linearly with the level of resting heart rate in men.13 Taking into account age, body mass index, systolic blood pressure, tobacco consumption, parental history of MI and parental history of sudden death, cholesterol level, diabetic status, and sport activity, an elevated heart rate still appeared as an independent risk factor for sudden death, but not for MI. Therefore, in a population of apparently healthy individuals, these studies are consistent in showing that heart rate is an independent predictor of total mortality and cardiovascular mortality
Resting heart rate in hypertension
In hypertensive patients (defined as with a systolic blood pressure ≥140 mm Hg or a diastolic ≥90 mm Hg), 4530 subjects from the Framingham Study aged 35–74 years who were not on antihypertensive medication were evaluated. Biennial mortality rates were assessed using pooled logistic regression.14 An increment of heart rate of 40 b.p.m. was associated with an odds ratio for total mortality of 2.18 (1.68–2.83, CI: 95%) for men and 2.14 (1.59, 2.88 CI: 95%) for women. For cardiovascular mortality the odds ratios were 1.68 (1.19, 2.37) for men and 1.70 (1.08, 2.67) for women. The authors conclude that heart rate may be an independent risk factor for cardiovascular death in patients with hypertension.
Resting heart rate in coronary artery disease
In CAD patients, increased heart rate is a well-known precipitating factor for ischaemia and anginal pain. Diaz et al.15 analysed a registry of 24 913 patients with suspected or proven CAD referred for coronary angiography and followed up for an average of 14.1 years. They found that resting heart rate was an independent risk factor for total and cardiovascular mortality in men and women. The better prognosis observed in patients with lower resting heart rate may not be ascribed to beta-blocker therapy as it was also observed in patients not taking beta-blockers.15,16 Heart rate risk was independent of hypertension, diabetes and smoking. The relation between heart rate and cardiovascular mortality was also true when powerful markers such as ejection fraction or the number of diseased coronary vessels were taken into account. Furthermore, patients with a heart rate ≥83 b.p.m. had a higher risk of hospital admission for cardiovascular cause than those with a heart rate ≤62 b.p.m.
In an attempt to characterize the relation between heart rate on hospital admission and heart rate after discharge from hospital and total mortality from Day 2 to 1 year, 1807 patients with acute myocardial infarction with and without heart failure were reviewed.17 It was found that in-hospital and post-discharge mortality increased with increasing heart rate on admission. The total mortality was 15% for patients with an admission heart rate ranging between 50 and 60 b.p.m., 41% for heart rates >90 b.p.m. and 48% for heart rates ≥110 b.p.m. Mortality from hospital discharge to 1 year was also related to the maximal heart rate observed in the coronary care unit and to heart rate at discharge. In patients with severe heart failure, cumulative mortality was high (60–68%) regardless of the level of heart rate on admission. In patients with moderate heart failure (grade 2 pulmonary venous congestion), the cumulative mortality for patients with an admission heart rate ≥90 b.p.m. was more than double that of patients with an admission heart rate <90 b.p.m. (39 vs. 18%). The same trend in cumulative mortality was observed in patients with mild or no heart failure (18 vs. 10%).
The prognostic significance of heart rate in acute myocardial infarction was also assessed in 8915 patients belonging to the GISSI-2 study and treated with fibrinolytic therapy.18 Increased heart rate on admission was associated with a progressive increase in in-hospital mortality (7.1% for heart rate <60 b.p.m. to 23.4% for heart rate >100 b.p.m.). Heart rate at discharge from the hospital was available in 7831 patients. A progressive increase of 6-month mortality was noted with increasing heart rate (from 0.8% for heart rates <60 b.p.m. to 14.3% for heart rates >100 b.p.m.). Multivariate analysis showed that heart rate is an independent prognostic factor of mortality. Similar results were found in the SPRINT 2 trial (Secondary Prevention Reinfarction Israeli Nifedipine Trial) performed before the thrombolytic era which showed that heart rate on admission to coronary care units was related to total mortality and to the occurrence of complications.19
In a large cohort of 22 192 patients with hypertension and CAD, the INVEST (INternational VErapamil-SR/trandolapril STudy) study examined the relationship between resting heart rate both at baseline and at follow-up and adverse outcomes. The latter included all-cause death, non-fatal MI and non-fatal stroke. Patients were treated either with verapamil or with atenolol. Resting heart rate was found to predict adverse events, but heart rate on treatment was even more predictive than baseline resting heart rate. Although atenolol was more effective than verapamil in lowering heart rate, the effect on adverse outcome was similar.20
In 1975 Fox et al.21 suggested that beta blockade by lowering heart rate may protect against myocardial infarction, but it was not until the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study that this became established. The BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study offered a unique opportunity to evaluate prospectively the effect of heart rate as a prognostic factor by analysing the effect of elevated heart rate on cardiovascular events in the placebo arm in patients with CAD and left ventricular dysfunction.22,23 The population of the placebo group was subdivided into 2 subgroups one with baseline heart rate below 70 b.p.m. (n = 2745) and the other with a baseline heart rate of 70 b.p.m. or above (2693 patients). The results of this analysis showed that increased heart rate was a strong predictor of outcome. After adjustment for baseline characteristics in patients with heart rates of 70 b.p.m. or greater, importantly, admission to the hospital for fatal and non-fatal myocardial infarction was higher by 46%. Also, cardiovascular death was increased by 34% (HR, 1.34, CI, 1.10–1.36, P = 0.004), hospitalization or new or worsening of heart failure by 53% (HR, 1.53, 95% CI, 1.25–1.88, P < 0.0001), and coronary revascularization was higher by 38%. Based on these results, one may postulate that ivabradine, which is a pure heart rate-lowering agent, should be able to shift the patients from the high-risk to the low-risk group.
Role of high heart rate in the development of coronary events
Heart rate may intervene to promote cardiovascular disease along a chain of events, which constitute the so-called cardiovascular continuum. The role of heart rate in myocardial ischaemia as seen in patients with stable angina and those who suffered a myocardial infarction is well known. Several mechanisms may account for the increase in heart rate, including catecholamine discharge. Heart rate may also be involved at different phases of the development of atherosclerosis, in plaque erosion and plaque rupture resulting in coronary thrombosis and in acute coronary events (Figure 1). Therefore, heart rate reduction may play an important role in the cardiovascular disease continuum.
A high resting heart rate may induce or exacerbate ischaemia and angina as it both increases oxygen demand and decreases coronary perfusion by shortening the duration of diastole. Therefore, reduction of resting heart rate should be viewed as an attractive therapeutic target in CAD patients.
Resting heart rate in heart failure
In the CIBIS II trial which randomized patients with heart failure to bisoprolol or placebo, the relationship between baseline heart rate, heart rate changes and outcomes, such as mortality and hospitalization for heart failure was evaluated in the placebo group. Multivariate analysis showed that baseline heart rate and heart rate changes were both significantly related to survival and hospitalization for worsening heart failure.24 The lowest baseline heart rates and the largest heart rate changes in the placebo group were associated with the best survival and with a reduction of hospital admissions. Bisoprolol further improved survival to a similar extent at all levels of baseline heart rate or heart rate changes.
SHIFT (Systolic Heart failure treatment with the If inhibitor Trial) was a large randomized, placebo-controlled trial, which investigated whether ivabradine improves cardiovascular outcomes in moderate-to-severe heart failure related to systolic dysfunction (ejection fraction ≤35%) and a resting heart rate ≥70 b.p.m.25 In the placebo group of the SHIFT, heart rate was found to be a predictor of cardiovascular death and of heart failure hospitalizations. The risk increased by 3% for a 1 b.p.m. increase in heart rate and by 16% for a 5 b.p.m. increase in heart rate.26
Benefits of heart rate reduction
Beta-blockers have been shown to reduce total mortality and sudden cardiac death after myocardial infarction and at least part of their beneficial effects has been ascribed to their effect on heart rate.27 Furthermore, a recent meta-regression of randomized clinical trials of beta-blockers and calcium channel blockers in post-myocardial infarction patients strongly suggests that the beneficial effect of these agents is proportionally related to resting heart rate reduction.28 The mechanisms by which heart rate improves the outcome has not been completely unravelled. It is well known that exercise training is associated with lower resting heart rate. In fact, exercise capacity was found to be a strong predictor of mortality.29 Heart rate is also determined by the influence of the autonomic nervous system balance. The major effect of beta-blockers is heart rate reduction, but other actions may operate. A significant proportion of patients with MI or myocardial ischaemia do not receive beta-blockers, probably because their use is limited by the common occurrence of side effects or by contraindications in patients with asthma, hypotension, atrioventricular conduction disorders, and by their negative inotropic effect.
Therefore, patients with CAD and left ventricular systolic dysfunction may derive benefit from heart rate reduction and ivabradine would offer a possibility with or without background beta-blockers.
A new approach: ivabradine and pure heart rate reduction
Ivabradine has heart rate-lowering properties similar to those of beta-blockers, but is devoid of their side effects. Ivabradine is the first of a new class of agents that act specifically on the sino-atrial node by inhibiting the If current of cardiac pacemaker cells without affecting other cardiac ionic currents. Ivabradine has a unique pharmacodynamic profile as heart rate reduction is not associated with vasodilation or negative inotropic effects.30 Ivabradine has been investigated in patients with CAD. A double-blind, placebo-controlled study in patients with chronic stable angina showed that ivabradine produced dose-dependent improvements in exercise tolerance and time to development of exercise-induced ischaemia.31 Ivabradine was compared with atenolol in a double-blinded trial using treadmill exercise tests. The study included patients with stable angina randomized to receive ivabradine or atenolol and was found to be as effective as atenolol and to prolong exercise test duration.32 In the ASSOCIATE study ivabradine improved exercise capacity in patients with CAD and stable angina pectoris treated with commonly used therapeutic dose of beta-blocker.33
In a rat model of congestive heart failure, Mulder et al.34 showed that chronic administration of ivabradine induced a dose-dependent reduction in heart rate without modification of systemic haemodynamics. Cardiac output was preserved despite the decrease of heart rate because stroke volume is increased owing to a decrease in left ventricular end-systolic diameter. This improvement in left ventricular function was attributed to a possible modification of left ventricular structure.
The BEAUTIFUL study was a multinational, multicentre, randomized, double-blind, placebo-controlled trial conducted in 781 centres worldwide whose main objective was to examine the effects of ivabradine on cardiovascular events in stable CAD patients with left ventricular systolic dysfunction.22 The primary endpoint was a composite of cardiovascular death, admission to hospital for MI or worsening of heart failure. The study included 10 917 patients with CAD and left ventricular dysfunction (ejection fraction <40%), and was conducted between December 2004 and December 2006. One arm of 5479 patients received the initial dose of 5 mg of ivabradine b.i.d. with the aim of reaching the target dose of 7.5 mg b.i.d. after 15 days of treatment, and the other arm of 5438 received placebo b.i.d. on top of conventional cardiovascular treatment as recommended by guidelines, throughout the study. Optimal preventive therapy in the ivabradine arm included aspirin or another antithrombotic agent in 94% of patients, statins in 74%, angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) or both in 90% and beta-blockers in 87%. These figures were similar in the placebo group and better than those of other large trials on beta-blockers or on ACE inhibitors or ARBs. The mean duration of the study was 19 months with a maximum of 35 months. The mean age of the population was 65 years and 82% were men. The mean heart rate at baseline was 71.6 b.p.m. and mean ejection fraction was 32.4%. Ivabradine reduced the mean resting heart rate from 72 b.p.m. at baseline to 61 b.p.m. after 30 days and to 64 b.p.m. at the end of the study. The composite primary endpoint in the ivabradine group was similar to that of the placebo group. In discussing the results the BEAUTIFUL study investigators underlined that the heart rate in the total population was low at baseline leading to insufficient heart rate reduction with ivabradine and therefore limiting the impact of this If inhibitor on the primary composite endpoint. The incidence of endpoints related to CAD was significantly (P = 0.001) reduced in patients with baseline heart rate of 70 b.p.m. or above. There was a 36% reduction in the relative risk for fatal and non-fatal MI (Figure 2). Ivabradine reduced the need for coronary revascularization most likely because of the well-established effect of ivabradine on anginal pain in patients with stable angina. Ivabradine was also associated with a 22% reduction in hospitalisation for fatal and non-fatal MI or unstable angina despite the fact that this population received an optimal treatment as mentioned above. It seems that ivabradine shifts the patients from high risk to low risk, as suggested in Figure 3. The effect of ivabradine on coronary outcomes is important as it extends the efficacy of this agent beyond the symptomatic improvement of anginal or ischaemic symptoms.
SHIFT was a large international trial in 6505 patients with moderate-to-severe heart failure, an ejection fraction ≤35% and a heart rate ≥70 b.p.m. who were randomized to ivabradine 5 mg b.i.d. (n = 3268) or placebo (n = 3290).25 The patients were on optimal medical treatment, including beta-blockers (ivabradine group: 89%, placebo group: 90%) ACE inhibitors and/or ARBs (91% in both groups) and diuretics (84 and 83%, respectively). Ivabradine was increased to 7.5 mg b.i.d. in 70% of patients to achieve a mean heart rate of 67 b.p.m. at 32 months. Patients were followed up for a mean of 22.9 months. The primary endpoint was a composite of cardiovascular death and hospitalization for worsening of heart failure. The cumulative primary endpoint showed a reduction of 18% as shown in Figure 4. Deaths due to heart failure occurred in 5% of patients in the placebo group and in 3% of the ivabradine group, a reduction of 26%. (P < 0.014), as shown in Figure 5. Admissions for worsening of heart failure occurred in 21% in the placebo group and in 16% in the ivabradine group, a reduction of 26% (Figure 6), which was highly significant (P < 0.0001). There were fewer serious adverse events in patients on ivabradine than in those on placebo. This trial strongly supports the use of ivabradine in patients with heart failure with systolic dysfunction and a heart rate ≥70 b.p.m.
A large body of evidence supports high resting heart rate as a risk factor of total mortality and cardiovascular mortality in various populations including patients with hypertension, CAD or heart failure. Experimental evidence supports the role of high heart rate in endothelial dysfunction and atherosclerotic lesions. The results of the BEAUTIFUL study confirmed that high heart rate was an independent risk factor in the placebo arm in patients with CAD and left ventricular systolic dysfunction. In the ivabradine arm, there was in patients with a heart rate of 70 b.p.m. or greater a reduction in admission to hospital for fatal and non-fatal myocardial infarction or unstable angina and in the need for coronary revascularization. The SHIFT study in patients with moderate-to-severe heart failure related to systolic dysfunction showed also in improvement of clinical outcomes.
Therefore, resting heart rate should not be overlooked as a risk factor in CAD or heart failure patients. Reduction of resting heart rate using ivabradine should be viewed as an attractive therapeutic target in patients with CAD and in patients with heart failure.
Conflict of interest: none declared.
The author has received fees, honoraria and research grants from Servier.