From coronary artery disease to heart failure: potential benefits of ivabradine
Department of Medicine, Montreal Heart Institute, 5000 Belanger Street, Montreal, Canada H1T 1C8
* Corresponding author. Tel: +1 514 376 3330 ext. 3612, fax: +1 514 593 2500. E-mail address: jean-claude.tardif{at}icm-mhi.org
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Abstract |
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 Top Abstract Heart rate and cardiovascular...Heart rate and atherosclerosis...If current inhibition with...Ivabradine post-discharge after...If current inhibition with...If current inhibition with...ConclusionReferences |
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In addition to the beneficial effects of heart rate reduction for the prevention of angina, a lower heart rate is also associated with a more favourable prognosis in patients with coronary artery disease (CAD). A high resting heart rate is a strong predictor for cardiovascular mortality and morbidity in patients with CAD. Patients with resting heart rate above 77 bpm are also prone to more re-hospitalizations for cardiovascular reasons, independently of major risk factors compared with patients with lower resting heart rates. These issues are clinically important because they support the relevance of testing the effect of lowering heart rate to reduce cardiovascular mortality and morbidity. The value of ivabradine for reduction in hard cardiovascular events in patients with ischaemic heart disease is presently being tested in the ongoing large-scale BEAUTIFUL (morBidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study. Also, the prognostic value of heart rate in patients with heart failure and the lack of intrinsic negative inotropic effects of ivabradine have prompted its evaluation in addition to modern multifaceted therapy of heart failure in the Systolic Heart failure treatment with If inhibitor ivabradine Trial (SHIFT). These large-scale clinical trials will help to determine whether the spectrum of patients benefiting from a pure heart rate-reducing agent, such as ivabradine, goes beyond those with angina and whether the clinical benefits are much greater than prevention of angina and extend to reduction in cardiovascular mortality and morbidity.
Key Words: If current • Ivabradine • Myocardial infarction • Stunning • Heart rate • Angina • Atherosclerosis • Heart failure
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Heart rate and cardiovascular mortality and morbidity in patients with coronary artery disease |
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TopAbstractHeart rate and cardiovascular...Heart rate and atherosclerosis...If current inhibition with...Ivabradine post-discharge after...If current inhibition with...If current inhibition with...ConclusionReferences |
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Many large observational studies have shown a link between increased heart rate and all-cause mortality and cardiovascular events in patients with hypertension and metabolic syndrome and in the elderly.1–3 Recently, we have assessed the relationship between resting heart rate and future cardiovascular events in a population of 24 913 patients with suspected or proven coronary artery disease (CAD).4 Over a median follow-up of 14.7 years, resting heart rate was a predictor of overall and cardiovascular mortality, even after adjusting for age, sex, diabetes, hypertension, cigarette smoking, left ventricular ejection fraction, number of clinically significant diseased coronary vessels, type of recreational activity, and concomitant treatments (including beta-blockers). Patients with resting heart rate between 77 and 82 bpm had a significantly higher risk for total mortality [hazard ratio (HR)=1.16, 99% confidence interval (CI) 1.04–1.28] and the effect was even larger for patients with a resting heart rate
83 bpm, with an HR of 1.32 (CI 1.19–1.47; Figure 1). The association between heart rate and total mortality held true in all analysed subgroups: patients treated with beta-blockers vs. those without such a treatment, men vs. women, age above or below 65 years, diabetics vs. non-diabetics, hypertensives vs. normotensives, body mass index above or below 27, and those with left ventricular ejection fraction above or below 50%. In addition, resting heart rate was a risk factor for time to cardiovascular re-hospitalizations (Figure 2). When comparing patients with heart rates between 77–82 and 83 bpm with patients with a heart rate of 
62 bpm, the HRs for time to first re-hospitalization due to any cardiovascular event were, respectively, 1.11 (CI 1.00–1.24) and 1.14 (CI 1.02–1.27) (P<0.0001 for both). A high resting heart rate was also an independent predictor of time to first re-hospitalization due to angina and congestive heart failure (CHF).
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Several studies conducted before the thrombolysis era have demonstrated that a high heart rate during hospitalization increases overall mortality up to 2 years after myocardial infarction.5 In patients with no or mild heart failure, mortality was more than doubled (P<0.001) for patients with heart rate >90 min–1 vs. those with <90 min–1. Disegni et al.6 reported similar results in 1044 patients who survived an acute myocardial infarction. Overall mortality was 4.3, 8.7, and 11.8% for patients with resting heart rate <70, 70–90, and >90 min–1 at discharge, respectively. For patients without clinical signs of heart failure during hospitalization, the 1-year mortality was 2.8, 5.1, and 6.6% for patients with discharge resting heart rate <70, 70–90, and >90 min–1, respectively. A retrospective analysis of data from the second Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI-2) study in patients treated with thrombolysis for acute myocardial infarction was also published.7 The overall 6-month mortality was 0.8% for those with heart rate below 60 bpm at discharge and 14.3% for those with a heart rate above 100 bpm. Resting heart rate remained an independent prognostic factor in a multivariable analysis.
These data demonstrate a strong link between heart rate and cardiovascular morbidity and mortality. A high heart rate may reflect an imbalance of the autonomic nervous system and may therefore be a marker of sympathetic overactivity.8–10 Some investigators have hypothesized that many of the risk factors (hypertension, diabetes, dyslipidaemia, smoking, and sedentarity) are also related to sympathetic overactivity.10–12 In addition, agents that induce tachycardia have been found to have neutral or deleterious effects on mortality, whereas several of those that reduce heart rate have been shown to improve survival. The relationship between reduction in heart rate and decrease in mortality has indeed been well established with beta-blockers after myocardial infarction and in patients with heart failure.13
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Heart rate and atherosclerosis progression: a target for ivabradine? (Table 1) |
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TopAbstractHeart rate and cardiovascular...Heart rate and atherosclerosis...If current inhibition with...Ivabradine post-discharge after...If current inhibition with...If current inhibition with...ConclusionReferences |
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Secondary prevention is central to the therapeutic strategy in patients with CAD. Prevention of atherosclerosis progression and stabilization of plaque are indeed of paramount importance to prevent recurrent clinical events in long-term follow-up. Heart rate is significantly correlated with the severity and progression of atherosclerosis on coronary angiography among men who had developed myocardial infarction at a young age.14 Experimental data have also demonstrated that a reduction in heart rate can delay the progression of coronary atherosclerosis in monkeys.15,16 Beere et al.15 showed that male cynomolgus monkeys subjected to sinus node ablation or those with innately low heart rates had significantly less coronary atherosclerosis than did animals with higher heart rates. Atherosclerosis was also inhibited when cardiac responses to stress were inhibited in monkeys fed with an atherogenic diet.16 Stress-related tachycardia has been used to investigate the mechanisms of enhanced atherogenesis at high heart rates. The proportion of dysfunctional coronary artery endothelial cells in monkeys exposed to behavioural stress was much higher in untreated, tachycardic animals than in those treated with a beta-blocker.17 This coronary artery endothelial dysfunction associated with high heart rates, which was also observed by Skantze et al.,18 may represent an important mechanism of increased atherogenesis. These observations are supported by results from the Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS), a randomized trial that showed that a beta-blocker reduced the rate of progression of carotid-intima thickness in asymptomatic patients.19 More recently, a heart rate above 80 bpm has also been shown to be an independent predictor of coronary atherosclerotic plaque disruption with an odds ratio of 3.19 in a multivariable analysis.20
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By virtue of its pure heart rate-reducing effect, the If current inhibitor ivabradine may therefore potentially improve outcomes of patients with CAD by reducing atherosclerotic progression and by preventing plaque rupture. The value of ivabradine for reduction in hard cardiovascular events in patients with ischaemic heart disease and left ventricular dysfunction is being tested in the BEAUTIFUL study (MorBidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), an ongoing large-scale, multicentre, placebo-controlled, randomized trial (registred in www.ClinicalTrials.gov).
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If current inhibition with ivabradine during in-hospital course after myocardial infarction |
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TopAbstractHeart rate and cardiovascular...Heart rate and atherosclerosis...If current inhibition with...Ivabradine post-discharge after...If current inhibition with...If current inhibition with...ConclusionReferences |
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Patients with recent myocardial infarction generally benefit from heart rate reduction both through a decrease in myocardial oxygen requirement and through a lengthening in the duration of diastole and myocardial perfusion. However, the negative inotropic and hypotensive effects of beta-blockers contraindicate their use in patients with pulmonary congestion, borderline blood pressure, overt pulmonary oedema, or cardiogenic shock. These effects of beta-blockers probably explain their failure to improve in-hospital outcomes after myocardial infarction in the recently published Comprehensive Multidisciplinary Intervention Trial (COMMIT) that involved 45 852 patients.21 The reductions in re-infarctions and cardiac arrests were indeed counterbalanced by a significant increase in cardiogenic shock with beta-blockade, with no difference in overall mortality in COMMIT.21
Ischaemic left ventricular dysfunction is also often accompanied by diastolic dysfunction. Because excessive tachycardia has deleterious consequences on diastolic function, heart rate reduction is important to achieve. However, the negative lusitropic effects of beta-blockers may represent another disadvantage in this setting. Ivabradine offers pure heart rate reduction without affecting haemodynamic parameters such as ejection fraction, blood pressure, contractility, atrioventricular conduction, or coronary vasomotion. The absence of effects on systolic and diastolic function and blood pressure places ivabradine in a unique position to control heart rate in unstable patients. Further clinical studies will need to be performed to demonstrate the benefits of ivabradine in this setting.
Although beta-blockers have several side effects, bronchospasm and atrioventricular block constitute the most relevant adverse reactions that limit their use in the emergency setting. Although asthma or chronic obstructive pulmonary disease represent only relative contraindications to beta-blockade, some patients clearly develop bronchospasm and wheezing with beta-blockers, which require dose reduction or abrupt withdrawal. Such patients who require heart rate reduction would clearly benefit from the lack of this side effect with ivabradine.
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Ivabradine post-discharge after myocardial infarction |
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TopAbstractHeart rate and cardiovascular...Heart rate and atherosclerosis...If current inhibition with...Ivabradine post-discharge after...If current inhibition with...If current inhibition with...ConclusionReferences |
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The potential role of ivabradine in the treatment of patients discharged following a myocardial infarction must take into account several considerations: (i) the prognostic value of resting heart rate and the relationship between heart rate reduction and decrease in mortality post-discharge after myocardial infarction shown with beta-blockers; (ii) the prevalence of residual angina and/or ischaemia after myocardial infarction even when patients undergo revascularization; (iii) side effects such as fatigue, depression, and sexual dysfunction may limit long-term compliance with beta-blockers; and (iv) ivabradine has shown anti-anginal and anti-ischaemic properties22 that are not inferior to those of the beta-blocker atenolol.23 It is particularly relevant to note that more than half of the 939 patients involved in the International Trial of the Antianginal effects of Ivabradine compared to atenolol (INITIATIVE) trial23 comparing ivabradine with atenolol (discussed in the article by Steg and Tchetche in this supplement) had previously suffered a myocardial infarction.
Ivabradine shares with beta-blockers the property of decreasing heart rate and oxygen demand from the ischaemic heart, which is presumably fundamentally important in mediating anti-ischaemic effects. In addition, Colin et al.24 compared the effects of ivabradine, atenolol, and placebo on oxygen consumption and supply during exercise in dogs. For a given heart rate, left ventricular ejection time was longer with atenolol than with ivabradine because of the negative inotropic effects of atenolol. As a consequence, the increase in diastolic time and coronary blood flow was greater with ivabradine compared with atenolol. Furthermore, in contrast to beta-blockers, ivabradine has also been shown not to limit the decrease in coronary resistance induced by exercise.25
Given the absence of cardiac effects other than exclusive heart rate lowering, ivabradine is potentially suitable after myocardial infarction for patients with residual angina or ischaemia in whom beta-blockers should be avoided (those with atrioventricular block, peripheral vascular disease, and chronic obstructive pulmonary disease) and in those not well tolerating beta-blockers or calcium antagonists. Unlike beta-blockers, ivabradine may be used in vasospastic angina because it does not increase coronary vasomotor tone.
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If current inhibition with ivabradine and limitation of myocardial stunning |
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TopAbstractHeart rate and cardiovascular...Heart rate and atherosclerosis...If current inhibition with...Ivabradine post-discharge after...If current inhibition with...If current inhibition with...ConclusionReferences |
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Post-ischaemic myocardial dysfunction, or myocardial stunning, can result in systolic and/or diastolic ventricular dysfunction in different settings, such as at the time of reperfusion after myocardial infarction but also after periods of ischaemia in patients with chronic angina. Monnet et al.26 demonstrated the benefit of ivabradine on myocardial stunning in dogs compared with atenolol and placebo. Time to recovery of myocardial contractility after exercise-induced stunning is indeed better with ivabradine than with placebo and atenolol, and this holds true whether the drugs were infused before or after exercise. Under atrial pacing, the negative effects of atenolol on systolic function during stunning were amplified. These results demonstrate that ivabradine enhances recovery of myocardial stunning after exercise-induced ischaemia in dogs, whereas atenolol has deleterious effects related to its negative inotropic properties. Thus ivabradine has the potential to improve myocardial stunning in patients with ischaemic heart disease, potentially in several different clinical settings as described earlier.
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If current inhibition with ivabradine in patients with heart failure |
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TopAbstractHeart rate and cardiovascular...Heart rate and atherosclerosis...If current inhibition with...Ivabradine post-discharge after...If current inhibition with...If current inhibition with...ConclusionReferences |
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The anti-ischaemic and anti-anginal properties of ivabradine have been demonstrated and summarized in another article of this supplement. In particular, the efficacy of ivabradine 5 and 7.5 mg twice daily was demonstrated in the INITIATIVE trial, a non-inferiority study vs. atenolol conducted in 939 patients with stable angina.23 These results, along with heart rate reduction, were obtained with ivabradine without any negative inotropic effects.25,27 The absence of deleterious effects of ivabradine on left ventricular function supports its evaluation in patients with CHF.
The prevalence of heart failure is rising, due to the ageing of the population and to the improved survival from conditions such as CAD. Heart failure is a very disabling condition, associated with repeated hospitalizations and substantially reducing quality of life. Heart failure consumes 1–2% of total healthcare expenditure in industrialized countries. Current therapeutic guidelines in systolic heart failure recommend a combination of angiotensin-converting enzyme (ACE)-inhibitors and/or angiotensin receptor antagonists, beta-blockers, with or without diuretics and digoxin. Aldosterone inhibitors are recommended for patients with severe symptoms of heart failure persisting after treatment with ACE-inhibitors and beta-blockers. Finally, cardiac resynchronization therapy using biventricular pacing can be considered in patients with ventricular dyssynchrony who remain symptomatic.
Despite advances in the treatment of CHF over the past decade, mortality and morbidity remain high, with annual mortality rates of 8–10% in recent clinical trials involving patients with systolic dysfunction.28–30 The 5-year mortality rates were 35–40% in the Carvedilol Or Metoprolol European Trial (COMET)30 involving patients with moderately severe CHF (New York Heart Association classes II and III) and left ventricular ejection fraction below 35%. In this clinical trial, the beta-blocker agents (carvedilol or metoprolol) were permanently discontinued by a large number of patients (32% in both groups). Thus, despite the beneficial effects of beta-blockers on heart rate, neurohormonal activation, and left ventricular remodelling, a significant number of patients actually do not receive an agent of this class. The numbers are even higher in the community.31 The high mortality rates in patients with heart failure despite modern multidrug therapy, the prognostic value of heart rate in this population, the adverse effects of beta-blockers, and the relative difficulty in reaching optimal doses of beta-blockers have been behind the interest in testing a different heart rate lowering strategy, If inhibition with ivabradine.
Resting heart rate is thought to have an independent prognostic value in heart failure, across a large spectrum of severity of the disease. Recent studies have suggested that lowering heart rate in patients with CHF might have a favourable effect on prognosis.32 Patients with CHF at the highest ranges of resting heart rate more often have diabetes, lower ejection fractions, and more severe symptoms.33 Those variables are independent markers of poor prognosis, but they are also related to an autonomic imbalance with increased sympathetic activity and reduced vagal activity. This imbalance has been proposed as the pathophysiological basis for the relationship between a high resting heart rate and a poor prognosis. The increased cardiac sympathetic stimulation leads to an increased myocardial metabolic rate and chronic ischaemia and hypoxia at the cellular level. The increase in heart rate and plasma norepinephrine is also associated with reduced heart rate variability, the latter being correlated with a poor prognosis.34,35 The clinical consequences of sustained sympathetic stimulation include vasoconstriction, progressive impairment of left ventricular function, and an increased risk of arrhythmias. The rationale for adding a pure heart rate-lowering agent such as ivabradine to a beta-blocker is to further reduce the consequences of excessive sympathetic stimulation in those patients who still have increased adrenergic tone (reflected by a relatively high resting heart rate) despite beta-blockade. The absence of vasodilation associated with ivabradine could provide an advantage for the combination with beta-blockers, as preserving blood pressure may prevent hypoperfusion of peripheral organs such as the kidneys.
Preliminary preclinical and clinical data support the safety of ivabradine in systolic heart failure and its beneficial effects on left ventricular size and function. Ivabradine improved left ventricular function and structure and increased stroke volume in a rat model of cardiac failure using coronary ligation (Figure 3).36 In patients with systolic dysfunction, a single intravenous dose of ivabradine induced heart rate reduction while preserving left ventricular function.27 Ivabradine given orally during 3 months in patients with stable class II CHF and a history of CAD tended to have beneficial effects on left ventricular ejection fraction as well as on end-systolic and end-diastolic volumes.37 In particular, clinically relevant decreases in ventricular volumes and increase in ejection fraction were observed in patients with more significant systolic dysfunction (left ventricular ejection fraction 35%) at baseline.
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The safety of combining a beta-blocker with ivabradine is currently being assessed in an ongoing study in patients with stable angina (Efficacy and Safety of Ivabradine on Top of Atenolol in Stable Angina Pectoris, clinical study registred in www.ClinicalTrials.gov). In another ongoing trial, the BEAUTIFUL study, morbidity/mortality benefits from heart rate reduction with ivabradine are being evaluated in patients with CAD and left ventricular systolic dysfunction treated with background therapy based on current guidelines, which can also include a beta-blocker. The effect of ivabradine on morbidity/mortality in patients with moderate to severe heart failure will be evaluated soon in a large-scale randomized clinical trial called SHIFT.
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Conclusion |
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TopAbstractHeart rate and cardiovascular...Heart rate and atherosclerosis...If current inhibition with...Ivabradine post-discharge after...If current inhibition with...If current inhibition with...ConclusionReferences |
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Heart rate reduction is an integral part of an optimal pharmacological strategy to restore the balance between myocardial oxygen demand and supply. In addition to the beneficial effects of heart rate reduction for prevention of angina, a lower heart rate is also associated with a more favourable prognosis in patients with CAD. A high resting heart rate is a strong predictor for cardiovascular mortality and morbidity in patients with CAD. Patients with resting heart rate above 77 bpm are also prone to more re-hospitalizations for cardiovascular reasons, independently of major risk factors compared with patients with lower resting heart rates. These issues are clinically important because they support the relevance of testing the effect of lowering heart rate to reduce cardiovascular mortality and morbidity. The value of ivabradine for reduction in hard cardiovascular events in patients with ischaemic heart disease is presently being tested in the ongoing large-scale BEAUTIFUL study. Finally, the prognostic value of heart rate in patients with heart failure and the lack of intrinsic negative inotropic effects of ivabradine have also prompted its evaluation in addition to modern multifaceted therapy of heart failure in SHIFT. These large-scale clinical trials will help to determine whether the spectrum of patients benefiting from a pure heart rate-reducing agent such as ivabradine goes beyond those with angina and whether the clinical benefits are much greater than prevention of angina and extend to reduction of cardiovascular mortality and morbidity.
Conflict of interest: J.-C.T. has received honoraria from Servier.
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