Giuseppe M. C. RosanoIRCCS San Raffaele Pisana, Roma, ItalySan Raffaele Sulmona, Sulmona, Italy

Cristiana Vitale ∙ Maurizio VolterraniIRCCS San Raffaele Pisana, Roma, Italy

Giuseppe M. C. Rosano ()Department of Medical Sciences, IRCCS San Raffaele Roma, Via della Pisana, 235, 00163 Roma, Italy. E-mail: giuseppe.rosano@sanraffaele.it

Adv Ther (2010) 27(4): 9.DOI 10.1007/s12325-010-0030-9

REVIEW

Heart Rate in Ischemic Heart Disease. The Innovation of Ivabradine: More Than Pure Heart Rate Reduction

Giuseppe M. C. Rosano ∙ Cristiana Vitale ∙ Maurizio Volterrani

Received: March 15, 2010 / Published online: © Springer Healthcare 2010

ABSTRACT

A wealth of data suggests that heart rate (HR) is an independent predictor of cardiovascular and all-cause mortality in men and women of all ages with and without cardiovascular disease. Data gathered from clinical trials suggest that HR reduction is an important mechanism of benefit of HR-lowering drugs. A high HR has direct detrimental effects not only on myocardial ischemia but also on the progression of atherosclerosis, ventricular arrhythmias, and on left ventricular function. The risk increases with HR >60 b.p.m. Ivabradine, a drug that slows HR though an effect on the If channels, has been approved for the control of myocardial ischemia in patients with coronary artery disease intolerant to beta-blockers. More recently, the

indication of ivabradine has been extended for use in association with beta-blockers in patients with coronary artery disease. The effects of ivabradine on myocardial ischemia are greater than those predicted by pure HR reduction with beta-blockers, suggesting additional mechanisms of action.

Keywords: acute myocardial infarction; coronary artery disease; heart rate; myocardial ischemia

INTRODUCTION

Elevated heart rate (HR) has long been thought to be a negative prognostic marker of future cardiovascular events. Data from population studies and patient cohorts have shown that HR is a prognostic indicator of all-cause mortality in subjects with cardiovascular diseases as well as in the general population.1-5 The relationship between resting HR and coronary artery disease (CAD), as well as cardiovascular and all-cause mortality, is strong and independent from other risk factors both in patients with cardiovascular disease and in the general population.1-5 Several studies have suggested that resting HR plays an important role in the pathophysiology of atherosclerosis, myocardial ischemia, and in

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the clinical manifestations of CAD and heart failure.6-10 The BEAUTIFUL study has recently shown that in patients with CAD and left ventricular dysfunction, HR values above the cut-off set by the investigators (70 b.p.m.) is associated with an increased risk of future cardiovascular events.11-13 Other studies, however, have shown that in patients with CAD total and cardiovascular mortality increases with HR >50 b.p.m.2-8 Elevated HR is also an important predictor of future adverse events in patients with heart failure. The prognostic value of elevated HR in patients with heart failure has been confirmed by several clinical trials evaluating the effect of HR-lowering agents. These trials have shown that a reduction in resting HR is associated with an improvement in future cardiovascular events.12-16

In patients with CAD and in those with heart failure already treated with up-titrated doses of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers are used with the understanding that the reduction in HR would protect from episodes of myocardial ischemia and therefore improve prognosis.15,16 However, although beta-blockers represent the mainstay of treatment for patients suffering from CAD and heart failure according to current guidelines, these drugs are most often under-titrated or even not prescribed both in patients with CAD and in those with heart failure.17-20 Therefore, patients rarely reach therapeutic target doses suggested by clinical trials. Lower use of beta-blockers is observed in the elderly and in patients with comorbidities despite no clear contraindications.19,20

BENEFITS OF HR REDUCTION

HR can be reduced pharmacologically by beta-blockers, nondihydropyridine calcium channel blockers, and by class I and III antiarrhythmic drugs. Beta-blockers have been shown to reduce

future events in patients with recent acute myocardial infarction (AMI) or in those with heart failure treated with ACE inhibitors.21-27

However, the evidence of an effect of beta-blockers on long-term prognosis in patients with chronic CAD is lacking.

The effect of beta-blockers on prognosis is associated, at least in part, with the drug-mediated HR reduction. Indeed, there is good evidence to suggest that the beneficial effects of beta-blockers after AMI are closely related to reduction in HR. A review of early randomized trials in AMI where beta-blockers were administered within 6 hours of the onset of symptoms showed that the reduction in infarct size was directly related to the reduction in HR.14 Similarly, the review of 11 long-term trials of beta-blockers after AMI involving more than 16,000 patients found a significant association between the reduction in HR and reduction in mortality.14 The Norwegian Timolol Multicenter Study15 also showed similar results in that and the HR reduction during follow-up was a significant predictor of overall mortality. Although in the study timolol treatment was associated with a 41.6% reduction in mortality, the mortality at a given HR was similar in the timolol and placebo groups, suggesting that the major effect of the beta-blocker on mortality was to be attributed to its effect on HR.

The effect of beta-blockers on angina and myocardial ischemia in patients with CAD seems largely related to the anti-ischemic effect of HR reduction.28,29 Also, the reduction in angina episodes is related to HR reduction in patients with chronic CAD.28 Studies comparing the anti-ischemic effect of beta-blockers and calcium channel blockers found that the improvement in myocardial ischemia and exercise duration were related to the degree of HR reduction, and studies comparing different calcium channel blockers on the same endpoints showed that the

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beneficial anti-ischemic effect of the drugs was largely dependent on their effect on HR.28,29

As for patients with AMI, in patients with heart failure HR reduction is associated with a beneficial effect on mortality.27 Furthermore, in patients with heart failure the use of drugs that increase HR increases mortality, further supporting the importance of HR reduction.30 In the CIBIS (Cardiac Insufficiency Bisoprolol Study) trial, bisoprolol reduced HR by almost 15 b.p.m. compared with placebo, and HR reduction was concluded to be the most powerful predictor of survival.22 In the CIBIS II trial,25 baseline HR and HR change both were significant predictors of mortality; patients with the lowest baseline HR and with the greatest HR reduction had the lowest mortality.

In the COMET (Carvedilol or Metoprolol European Trial) study, HR achieved during beta-blocker therapy was a significant independent predictor of mortality.26 However, in the MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) study, the benefits of metoprolol were greater than those expected from the change in HR,23

suggesting that mechanisms acting on top of HR reduction are also important for the benefit of beta-blockers in heart failure.

HR REDUCTION AND MYOCARDIAL ISCHEMIA

Ischemic heart disease and ischemic left ventricular dysfunction are the leading cause of death in patients with cardiovascular disease. In these patients, episodes of myocardial ischemia lead to a progressive deterioration of left ventricular function and/or to an acute event. Myocardial ischemia occurs from a mismatch between myocardial oxygen demand and supply. Both factors are influenced by HR. Early studies have shown that the increase in HR is

associated with an increase in oxygen demand, even at a constant external work performed by the heart.31-33 This is mainly due to the greater oxygen requirement for excitation-contraction coupling. Furthermore, as myocardial perfusion occurs predominantly during diastole, the fraction of the cardiac cycle occupied by diastole increases as HR decreases.

In patients with CAD, most episodes of myocardial ischemia are preceded by an increase in HR.34 The likelihood of developing ischemia in these patients is related to both the baseline HR and the magnitude and duration of the increase.29,35 Patients with HR >80 b.p.m. experience ischemia almost twice as often as those with HR <70 b.p.m.29 It is becoming clear that the control of HR is of pivotal importance in the therapeutic approach of patients with ischemic heart disease, as well as in those with ischemic left ventricular dysfunction.

In patients in sinus rhythm, HR control can be obtained by modulating the activity of the sinoatrial node. The depolarization rate of the sinoatrial node is largely determined by the activity of the autonomic nervous system. Therefore, HR unquestionably is directly related to sympathetic activity or autonomic imbalance. An important unresolved issue is the extent to which HR mediates the deleterious effects of sympathetic hyperactivity. It is clear that the majority of the benefit of beta-1-adrenergic blockade is mediated via HR reduction, but beta-blockers have, along with beneficial effects, some undesirable cardiac and noncardiac side effects.36 Understanding the contribution of HR per se is likely to be particularly useful in managing the large number of patients who might expect to benefit from HR reduction but who do not or cannot receive intensive beta-blocker therapy.

Beta-blockers are the conventional negative chronotropic agents and they are the recommended first-line therapy for angina by

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principal guidelines.37 However, beta-blockers are often underused and under-titrated because of the lack of tolerability.38,39 This underuse results in an inadequate control of HR control and incomplete antianginal effect. Absolute and relative contraindications, physician concerns, and medication intolerance are among the major reasons for low doses or nonprescription of beta-blocker therapy35,40 and may preclude optimal management for many patients. There is no evidence to show that the addition of antianginal drugs with hemodynamic action, like long-acting nitrates, or dihydropyridine calcium antagonists, to beta-blockers may improve symptoms and objective markers of myocardial ischemia.35,37,41-44 There is, therefore, a clinical need for pharmacologic strategies alternative and/or adjunctive to beta-blockade that will enable adequate control of HR and reduction of myocardial ischemia.

IVABRADINE: MORE THAN PURE HR CONTROL IN CAD

Ivabradine is a novel HR-reducing agent, which modulates the rate of spontaneous diastolic depolarization through selective If current inhibition in sinoatrial pacemaker nodal cells, and thereby induces a decrease in HR without any negative inotropic or dromotropic effects.45-51 This effect of ivabradine on sinus node electrophysiology flattens the spontaneous depolarization phase of pacemaker cells, thereby increasing the time taken to reach the voltage threshold for the initiation of action potential. The increase in spontaneous depolarization time induced by ivabradine causes an increase in R wave (RR) interval and reduces HR.

Unlike beta-blockers, ivabradine reduces HR without any negative effect on coronary artery diameters.51 In conscious chronically instrumented dogs randomized to receive

propranolol, saline, or ivabradine infusion, Simon et al.51 have shown that beta-blockade with propranolol reverses the physiological exercise-induced increase in diameter into a decrease, unmasking alpha-adrenoceptor-mediated coronary vasoconstriction. In contrast, ivabradine induces an exercise-induced increase in coronary artery diameter similar to that observed with saline. Therefore, for a similar degree of HR reduction ivabradine has a greater effect on coronary artery perfusion compared to beta-blockers. Coronary artery perfusion with ivabradine is 30%-40% greater than that obtained with beta-blockers during exercise.

It is recommended that ivabradine is administered orally twice daily at a dose of 5 or 7.5 mg depending on HR reduction. An intravenous formulation of ivabradine is yet to be approved for clinical use. In patients with CAD and stable angina pectoris, treatment with ivabradine reduces resting HR, HR during exercise, and rate-pressure product (HR × systolic blood pressure), resulting in a reduction in cardiac workload and myocardial oxygen consumption.52 A significant and dose-dependent improvement in total exercise capacity, as well as a significant decrease in the number of anginal episodes and use of short-acting nitrates, has been observed with ivabradine.

More than 2900 patients with CAD and stable angina pectoris have been treated with ivabradine in phase 3 development studies.53

Adverse events with ivabradine are rare and are mainly visual, while signs or symptoms related to excessive bradycardia are extremely rare. Visual symptoms consist mainly of phosphenes (transient enhanced brightness in the visual fields). They are generally mild and well tolerated, and fade away with treatment in the majority of patients.54 These effects are related to the action of ivabradine on Ih current, which is present in the retina and shares extensive homology with

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cardiac If. Visual symptoms have led to changes in daily activities or to discontinuation of the study treatment in less than 1% of patients.

The INITIATIVE trial54 compared the anti-ischemic effect of ivabradine (up-titrated to either 5 or 7.5 mg twice daily) and atenolol (up-titrated to 100 mg/day) in a randomized parallel study conducted in 939 patients with CAD and stable angina. The study was designed to test noninferiority between the two anti-ischemic agents and showed similar anti-ischemic effect of ivabradine to atenolol on time to 1 mm ST segment depression, time to angina, and exercise time (Figure 1). Furthermore, the study showed that for similar degree of HR reduction the anti-ischemic effect of ivabradine was more pronounced (up to twofold). This effect is most probably related to a greater coronary artery perfusion obtained with ivabradine compared to beta-blockers for similar degree of HR reduction. The INITIATIVE trial was the pivotal study that granted ivabradine the approval of the European Medicine Agency for the treatment of myocardial ischemia in patients intolerant to beta-blockers.

In order to test the effect of ivabradine when given in association with beta-blockers, the

ASSOCIATE study investigators performed a randomized double-blind placebo-controlled trial to determine the effect of ivabradine on exercise capacity, myocardial ischemia, and anginal symptoms in 889 patients with chronic stable angina, already receiving atenolol (50 mg daily).55 After a run-in phase during which all received atenolol 50 mg, patients were randomized to receive atenolol plus placebo or atenolol plus ivabradine (up to 7.5 mg). The addition of ivabradine (7.5 mg) to atenolol (50 mg) induced a 9 b.p.m. reduction in HR compared to baseline treatment with atenolol and an 8 b.p.m. reduction in HR compared with patients randomized to atenolol plus placebo. Patients receiving both atenolol and ivabradine reached, after 4 months of treatment, a mean HR of 58 b.p.m. Combination therapy with ivabradine and atenolol was associated with a significant improvement in exercise time, time to angina and ischemic threshold compared to atenolol alone (Figure 2). The combination of ivabradine and atenolol was well tolerated as withdrawal from the study due to symptomatic bradycardia occurred in only 1.1% of patients. This study granted ivabradine the extension of

Total exercise duration P<0.0001

Ivabradine 7.5 mg bidbetter

Atenolol 100 mg odbetter

–35 sec 0Equivalence limits

+35 sec

Time to limiting angina

Time to angina onset

Time to 1 mm ST-segmentdepression

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P<0.0001

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Figure 1. INITIATIVE study: evaluation of the efficacy of ivabradine vs atenolol in 939 patients with chronic stable angina treated for 4 months. Exercise tolerance test parameters at trough of drug activity over 4 months of treatment. Treatment with ivabradine 7.5 mg/bd was comparable to atenolol 100 mg/daily on ischemia-related endpoints. For all endpoints evaluated ivabradine showed a significant trend for better anti-ischemic potency. Adapted from: Tardif JC, et al. Eur Heart J. 2009;30:540-548.55

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indication of its marketing authorization by the European Medicines Agency to the treatment of angina in patients already receiving beta-blockers. This new indication for ivabradine opens new strategies for the treatment of chronic coronary artery disease. Until now, calcium channel blockers, nicorandil, and nitrates were all used in combination with beta-blockers despite the lack of evidence of an additive effect. The only drug that has shown an additive effect on improving angina and myocardial ischemia in ischemic patients receiving beta-blockers is trimetazidine.56 As previously mentioned, the BEAUTIFUL study has shown that HR >70 b.p.m. is a risk factor for future events in patients with CAD and left ventricular dysfunction, and that HR reduction with ivabradine improves ischemia-related endpoints.11-13 Furthermore, a recent analysis of 1507 patients with limiting angina at baseline included in the BEAUTIFUL study showed that treatment with ivabradine, in combination with cardiovascular therapy, was associated with

a 24% reduction in risk for the primary endpoint (P=0.05) and a 42% reduction in the risk for hospitalization for fatal and nonfatal MI (P=0.02) in patients with limiting angina.11-13 Therefore, the strategy of treatment of patients with CAD should now include the combination of beta-blockers plus ivabradine as first-line therapy.

The improvement in myocardial ischemia observed with ivabradine is greater than the one expected by pure HR reduction on the basis of historical data with beta-blockers. This suggests that the improvement in myocardial ischemia is obtained by ivabradine through a mechanism that unlike beta-blockers couples HR reduction with coronary dilation during stress thereby allowing better coronary artery perfusion for similar degree of HR reduction. Furthermore, unlike beta-blockers, ivabradine preserves diastolic relaxation which further increases coronary diastolic filling. These mechanisms, along with some mechanisms still not completely elucidated, explain the

Figure 2. ASSOCIATE study: evaluation of the efficacy of ivabradine plus atenolol compared to atenolol plus placebo in 889 patients with chronic stable angina treated for 4 months. Combination therapy was superior to atenolol alone on all ischemia-related endpoints. ETT=exercise tolerance test. Adapted from: Tardif JC, et al. Eur Heart J. 2009;30:540-548.55

0

Ivabradine + atenolol

Total exerciseduration

Time to limitingangina

Time to anginaonset

Time to 1-mmST-segment depression

10

20

30

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60Placebo + atenolol

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Cha

nge i

n ET

T cr

iteri

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effectiveness of ivabradine in the treatment of myocardial ischemia.

CONCLUSION

HR reduction is the primary aim of medical therapy for patients with ischemic heart disease. Beta-blockers are effective in controlling symptoms and ischemic episodes but are often underused because of their side effects. Ivabradine selectively reduces HR and it has been initially been approved as an alternative to beta-blockers in patients who were intolerant. However, the recent extension of its therapeutic indication places ivabradine along with beta-blockers as first-line therapy for patients with CAD with or without left ventricular dysfunction.

ACKNOWLEDGMENTS

This manuscript was supported in part by a grant of the Italian Ministry of Health (Ricerca Corrente 2009).

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