Clinical benefits of pure heart rate reduction with Corlentor: evidence and perspectives

by I . Elyubaeva, France

Servier International – Division of Medical Information – Suresnes, FRANCE

Despite many therapeutic advances in the field of cardiology, coronary artery disease (CAD) remains the leading cause of death and disability worldwide. Reduction of elevated resting heart rate is a well-established approach to relieving angina and ischemia, and has long been advocated as a therapeutic approach in the management of cardiovascular disease. A large body of evidence indicates that high resting heart rate is a risk factor for adverse outcomes in a variety of populations. Recent evidence from morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) demonstrated that elevated heart rate (≥70 beats per minute; bpm) increases cardiovascular risk. Corlentor is the only agent to have been approved for clinical practice that has a unique action on cardiac pacemaker activity, based on selective and specific If current inhibition. The clinical efficacy and safety of Corlentor has been demonstrated in comparison with placebo and well-established antianginal drugs such as β-blockers and calcium antagonists. The recent study, evaluation of the Antianginal efficacy and Safety of the asSociation Of the If Current inhibitor IvabrAdine with a beTa-blockEr (ASSOCIATE), demonstrated that in patients with stable angina receiving the β-blocker atenolol, Corlentor produced a significant reduction in heart rate and improvement in all exercise capacity parameters. The BEAUTIFUL results suggest that Corlentor could have a role not only in symptomatic treatment, but also in prevention of coronary events in CAD patients with a heart rate ≥70 bpm, over and above routine preventive therapy. Other ongoing trials should provide important evidence and insights that will enhance the care and management of patients with stable CAD or heart failure.

Medicographia. 2009;31:403-409 (see French abstract on page 409)

Despite all the therapeutic advances in the field of cardiology, cardiovascular diseases, in particular coronary artery disease (CAD), remain the leading cause of death and disability worldwide, thereby underlining the importance of acquiring new therapeutic options in this field.1 Reduction of elevated resting heart rate has long been postulated as a therapeutic approach in the management of cardiovascular diseases.

Figure 1
Figure 1. The central role of heart rate in the pathophysiology of coronary artery disease.

CV, cardiovascular.

A high heart rate leads to both greater myocardial oxygen consumption and decreased myocardial perfusion, the latter via shortening of the duration of diastole, which can induce or exacerbate myocardial ischemia. Furthermore, experimental data and clinical observations support the notion of the importance of heart rate in the pathophysiology of atherosclerosis and plaque rupture. An elevated heart rate enhances mechanical arterial wall stress and prolongs the exposure of coronary endothelium to systolic low and oscillatory shear stress. All these processes induce structural and functional changes in endothelial cells, which accumulate over time in atherosclerosis-prone regions, promoting atherosclerosis.2 Moreover, elevated heart rate caused by mechanical stress may promote weakening of the fibrous cap, ultimately increasing the risk of plaque disruption and the onset of an acute coronary syndrome. Elevated resting heart rate has been demonstrated to be a significant predictor of all-cause and cardiovascular mortality in the general population and in patients with cardiovascular disease.3-5 Analysis from the Coronary Artery Surgery Study (CASS) involving 24 913 patients with suspected or proven CAD who were followed up for 14.7 years demonstrated that both all-cause and cardiovascular mortality were directly and independently related to resting heart rate at study entry.4 Patients with resting heart rates of 77 beats per minute (bpm) or above were at an elevated risk of total and cardiovascular mortality after adjustment for other clinical variables. Another retrospective analysis from the randomized controlled INternational VErapamil SR-Trandolapril STudy (INVEST) in CAD patients with hypertension demonstrated an increased risk of cardiovascular mortality and morbidity with increasing baseline resting heart rate. This association was evident in patients with a baseline heart rate of above 70 bpm.5Recently, prospective results from BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) showed that patients with heart rates of 70 bpm or greater have 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).6 Thus reducing elevated heart rate could reduce the risk of cardiovascular events. Consistent with this understanding of the important role of elevated heart rate in the pathophysiology of CAD, heart rate reduction should clearly be considered as a key therapeutic goal in patients with CAD: the short-term implication is better prevention of ischemia, and the long-term implication is better preventionof cardiovascular events (Figure1).

For the past few decades, β-blockers have been used widely as effective heart rate–lowering drugs. However, in addition to heart rate reduction, β-blockers have numerous other cardiac and extra-cardiac effects that may not necessarily be clinically beneficial. Furthermore, recent studies have suggested that after a myocardial infarction, only approximately 60% of patients receive β-blockers.7 Thus specific heart rate– lowering agents that could be used with or without β-blockers could be clinically useful. Corlentor (ivabradine) is a selective heart rate–lowering agent that acts by inhibiting the pacemaker ionic current If in sinoatrial node cells. At therapeutic concentrations, Corlentor acts by selectively and specifically binding to f-channels to inhibit the If current in a dose-dependent manner, with no effects on other cardiac ionic currents.8,9

Hence, in contrast with β-blockade, selective heart rate reduction with Corlentor preserves myocardial contractility, isovolumic ventricular relaxation, and coronary vasodilation, and therefore ensures the full benefits of prolonged diastole on coronary blood flow supply. Thus in addition to lowering myocardial oxygen demand, Corlentor increases diastolic perfusion time and improves oxygen supply while preserving cardiac stroke volume at rest and during exercise.10-12 These pharmacological effects translate into tangible clinical advantages in CAD patients. It is a very well accepted approach to the relief of angina and ischemia in symptomatic CAD patients.

Clinical benefits of exclusive heart rate reduction with Corlentor

The clinical development program of Corlentor involved patients across various stages of the cardiovascular disease spectrum, with the first phase of the development program being carried out in more than 5000 patients with chronic stable angina pectoris. The program was focused on several international, multicenter, randomized, double-blind, parallelgroup trials.

Figure 2
Figure 2. Change in total exercise duration (TED) per 1-beat heart rate reduction at peak exercise after 4 months’ treatment with atenolol 100 mg once daily (n=300) and Corlentor 7.5 mg twice daily.

Antianginal and anti-ischemic efficacy

The first large-scale study of Corlentor was an international, multicenter, double-blind trial, in which 360 patients with a history of chronic stable angina were randomized to placebo or Corlentor. Corlentor dose-dependently reduced heart rate, which was associated with a significant increase in the time to 1-mm ST-segment depression and time to limiting angina (P<0.005). Data from the subsequent open and runout periods showed that both the antianginal and antiischemic benefits of Corlentor persisted without the development of pharmacological tolerance.13 These encouraging results compared with placebo supported the rationale for testing Corlentor versus other antianginal anti-ischemic drugs like β-blockers and calcium channel blockers.14,15 The INternatIonal TrIal of the AnTianginal effects of IVabradinE compared with atenolol (INITIATIVE) compared the anti-ischemic and antianginal efficacy of Corlentor 7.5 mg and 10 mg twice daily and atenolol 100 mg once daily in 939 stable angina pectoris patients.14 After 4 months of treatment, Corlentor increased total exercise duration by 86.8 seconds, compared with 78.8 seconds for atenolol (P<0.001 for non-inferiority). Major improvements were also noted in time to limiting angina (91.8-96.9 seconds vs 85.4 seconds for atenolol; P<0.001) and time to angina onset (139.6-145.2 seconds vs 135.2 seconds for atenolol; P<0.001). Moreover, the improvement in exercise capacity for each beat of heart rate reduction was greater for Corlentor than atenolol (Figure 2). This difference may be due to the greater anti-ischemic efficiency of the exclusive heart rate reduction with Corlentor. Clinically, this means that patients treated with Corlentor can adapt better to exercise, while also gaining the full benefits of heart rate reduction.

In another comparative study, 1195 stable angina patients received either Corlentor (7.5 mg twice daily or 10 mg twice daily) or amlodipine 10 mg once daily for 3 months.15 Time to 1-mm ST-segment depression increased by 45 seconds with Corlentor versus a 40-second increase with amlodipine (P<0.001), and both treatments decreased the anginal attack frequency by two-thirds. In addition, Corlentor had a superior effect on the reduction of rate-pressure product (a surrogate marker of myocardial oxygen consumption) compared with amlodipine, and a similar safety profile. Importantly, the efficacy of Corlentor in reducing heart rate and the frequency of angina was demonstrated across a wide range of populations with stable angina, including the elderly, females, and patients with asthma/chronic obstructive pulmonary disease, making it suitable for most stable coronary patients, including also those with contraindications or an intolerance to β-blockers.16 Analysis of the efficacy of Corlentor in diabetic patients with stable angina indicates that Corlentor retains its antianginal efficacy in diabetic patients and is devoid of the undesirable metabolic effects in diabetics that can be seen with β-blockers or dihydropyridine calcium channel blockers.17

Antianginal and anti-ischemic efficacy of Corlentor in combination with β-blockers

In routine clinical practice, stable angina patients may not be controlled with one drug alone. Though combination therapy is recommended to improve symptomatic management,18 most clinical studies have demonstrated only modest improvement in exercise tolerance test parameters with combination therapy compared with monotherapy at the peak of drug activity, with no significant differences 6 hours after drug intake.1

Recently, the anti-ischemic efficacy of Corlentor in combination with â-blocker therapy was investigated in a 4-month study of 889 stable angina patients already receiving atenolol 50 mg/day.20 This study, ASSOCIATE (evaluation of the Antianginal efficacy and Safety of the asSociation Of the If Current inhibitor IvabrAdine with a beTa-blockEr), included patients who had a positive symptom-limited exercise test on atenolol 50 mg once daily. Patients were randomly assigned to treatment with Corlentor 5 mg twice daily uptitrated to 7.5 mg twice daily after 2 months (n=449), or placebo (n=440), in addition to the β-blocker. In the Corlentor group, 90% of patients were uptitrated to receive 7.5 mg twice daily. The baseline resting heart rate in these patients was 67 bpm. Corlentor reduced the baseline heart rate by 9 bpm at the end of the study, which was associated with a statistically significant improvement in all exercise test parameters recorded at the trough of activity at the end of 4 months. Total exercise duration, which was the primary efficacy criteria, increased threefold compared with placebo (Figure 3).

Figure 3
Figure 3. Changes in total exercise duration from baseline to month 4 among stable angina patients treated with the addition of either Corlentor (5 mg twice daily for 2 months increased to 7.5 mg twice daily for 2 months; n=449) or placebo (n=440) to β-blocker therapy (atenolol 50 mg once daily).

This study is one of the largest studies of combination therapy for angina pectoris, and the effects achieved were demonstrated at the trough of drug activity, which signifies that the combination works all the time. This study clearly demonstrates that in patients with stable angina receiving the β-blocker atenolol, Corlentor provides a significant improvement in total exercise duration, as demonstrated using the standardized Bruce protocol for exercise testing, in which higher workloads are reached more rapidly than in the modified Bruce protocol. The more demanding standard Bruce protocol was chosen in view of the fact that patients were receiving background therapy known to improve exercise capacity. In terms of the size of the trial, compliance with regulatory recommendations, and the consistency of the significant improvements across all exercise tolerance test criteria and time points, this trial may represent the most compelling demonstration of the benefits of any combination of antianginal drugs published to date.

The long-term anti-ischemic and antianginal efficacy of Corlentor

The long-term antianginal efficacy of Corlentor was investigated in a population of 386 stable angina patients, in whom Corlentor 5 mg twice daily or Corlentor 7.5 mg twice daily was added to other therapies.21 After 12 months, mean heart rate had significantly reduced from baseline by 10 bpm in the Corlentor 5 mg twice daily group, and by 12 bpm in the 7.5 mg twice daily group. The heart rate–lowering efficacy of Corlentor was associated with significant antianginal efficacy. The mean number of angina attacks per week decreased by 50% (P<0.001) with Corlentor. This sustained reduction in angina attack frequency was consistent with that observed in previous controlled studies. Reduction in the frequency of angina attacks in patients who were still symptomatic at inclusion and who were being treated with other antianginal drugs, in whom Corlentor was given as add-on therapy, provided a good representation of the effects of Corlentor under the usual prescribing conditions in clinical practice. The sustained efficacy of Corlentor throughout the study was consistent with the absence of pharmacological tolerance, providing proof that stable coronary patients can be optimally treated with Corlentor over the long term.

Reduction of coronary events with Corlentor

The two aims in treating a patient with CAD are to relieve anginal symptoms and to prevent cardiovascular events.18 The ability of Corlentor to reduce cardiovascular events has been evaluated in BEAUTIFUL. BEAUTIFUL was carried out in 10 917 patients with documented CAD and associated left ventricular systolic dysfunction, and was the first prospective, randomized, controlled study that assessed whether Corlentor reduces cardiovascular events in such patients.22 Most of the study patients were already receiving guideline-recommended cardiovascular therapy: antiplatelet agents (94%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (90%), β-blockers (87%), as well as lipid-lowering agents (76%). The mean heart rate in these patients was 71.6 bpm despite the fact that 87% were on â-blockers, and 50% of the patients had a heart rate above 70 bpm. This baseline heart rate in BEAUTIFUL was similar to that in observational studies in CAD patients. The first important finding from BEAUTIFUL is that patients with an elevated heart rate (≥70 bpm) are clearly at a very high risk for cardiovascular events such as myocardial infarction (46% increased risk, P=0.0066), coronary revascularization (38%, P=0.037), or cardiovascular death (34%, P=0.0041).6

In the overall study population, treatment with Corlentor did not result in a significant change in the primary composite end point of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for heart failure. However in a pre-specified subgroup of patients with heart rate ≥70 bpm, treatment with Corlentor resulted in a significant reduction in the composite coronary end point defined as a composite of hospitalization for myocardial infarction (fatal or nonfatal) or unstable angina (relative risk reduction, 22%; P=0.023). In the Corlentor group, there was a significant 36% relative risk reduction in hospitalization for fatal or nonfatal myocardial infarction (Figure 4) (P=0.001) and a 30% reduction in hospitalization for coronary revascularization, which includes percutaneous coronary interventions as well as coronary artery bypass grafts (P=0.016). It is important to note that these results were obtained when the majority of patients were already receiving currently recommended optimal preventive therapy and that the results emerged in just 2 years of follow-up. BEAUTIFUL is the first demonstration that in coronary patients already receiving optimal preventive therapy, an antianginal drug can reduce the risk of myocardial infarction and revascularization.

_ How does Corlentor prevent coronary events?
The reduction in coronary events with Corlentor could be explained by its exclusive heart rate reduction, which leads to superior anti-ischemic efficacy,10-12 and the prevention of atherosclerosis development and progression.23,24 The prevention of endothelial dysfunction—the first step in the development of atherosclerosis—was demonstrated with Corlentor in a transgenic model of dyslipidemia and endothelial dysfunction. Three-month treatment with Corlentor preserved the endothelium-mediated vasodilation in the renal and cerebral arteries of mice expressing human apolipoprotein B (apoB-100).24 Corlentor restored the endothelium-dependent vasodilation in cerebral vessels, whereas in the same animal model, metoprolol did not restore endothelial function to the same degree.21 This was possibly because of inhibitory effects of metoprolol on â-adrenoreceptor–mediated activation of endothelial nitric oxide synthase.25,26 Pre-clinical studies have also demonstrated that Corlentor reduces the atherosclerotic plaque size in the aortic root and ascending aorta by 40% and 70%, respectively (P<0.05). Corlentor also markedly reduced vascular oxidative stress, nicotinamide adenine dinucleotide phosphate oxidase activity, superoxide production, and lipid peroxidation.23 These factors could contribute clinically to the prevention of the progression of atherosclerosis. These experiments support the rationale for heart rate reduction with Corlentor as an intervention to improve endothelial function and to attenuate the progression of atherosclerosis and cardiovascular event prevention.

The safety profile of Corlentor

The large clinical development program of Corlentor has provided a solid demonstration of its tolerability. The most frequently encountered adverse events sinus bradycardia and visual disturbances are related to the drug’s mechanism of action; ie, inhibition of sinus node f-channels and inhibition of h-channels in retinal rods and cones, though their incidence is low. In BEAUTIFUL, the incidence of symptomatic sinus bradycardia (heart rate <55 bpm) was 3%. In patients with stable angina receiving β-blockers and Corlentor, withdrawal due to sinus bradycardia was 1.1% in the Corlentor group. The rate of visual symptoms (phosphenes, blurred vision, and visual disturbances) was also very low in BEAUTIFUL and led to discontinuation in only 0.5% of patients receiving Corlentor (28 patients) versus 0.2% of patients receiving placebo (9 patients). Importantly, the abrupt discontinuation of Corlentor has not resulted in a rebound angina phenomenon.

Current place of Corlentor in clinical practice and future perspectives

Corlentor is currently recommended in the symptomatic treatment of CAD patients.18 The results of BEAUTIFUL suggest that Corlentor could have a role not only in symptomatic treatment, but also in the prevention of coronary events particularly in CAD patients with a heart rate ≥70 bpm, over and above routine preventive therapy. A large proportion of stable angina patients in clinical practice have a resting heart rate above this threshold.27

Considering the emerging role of heart rate reduction as a therapeutic approach in CAD management, it was felt necessary to evaluate the effect of Corlentor in acute coronary syndromes, as well as in CAD patients with documented preserved left ventricular ejection fraction. EValuation of the IntraVenous If inhibitor ivabradine after ST-segment elevation mYocardial infarction (VIVIFY) is an ongoing trial that is evaluating the efficacy and safety of Corlentor in patients with acute myocardial infarction with ST-segment–elevation who are undergoing percutaneous coronary intervention. To evaluate the efficacy of heart rate reduction with Corlentor in the reduction of cardiovascular outcomes in stable coronary patients with preserved left ventricular ejection fraction, another morbidity-mortality study has been designed—Study assess- InG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY).

In patients with congestive heart failure, heart rate lowering using β-blockers is associated with a reduction in mortality.28 Pilot studies with Corlentor in patients with moderate left ventricular dysfunction have shown that Corlentor reduced left ventricular end-systolic and end-diastolic volumes, suggesting a preserving effect on cardiac function.29

These results have formed the basis of the Systolic Heart failure with the If inhibitor ivabradine Trial (SHIFT), which is currently investigating the effects of Corlentor in congestive heart failure. The objective is to evaluate if the addition of Corlentor to standard therapy results in a further reduction of cardiovascular events in heart failure patients.

These ongoing trials should provide important evidence and insights that will enhance the care and management of patients with CAD or heart failure. _


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