The clinical implication of pure heart rate reduction in CAD management: future directions



Interview with K. Fox, United Kingdom

Kim FOX, MD
Professor of Clinical Cardiology – Imperial College London and Consultant Cardiologist Department of Cardiology – Royal Brompton Hospital – London, UK

Despite all the therapeutic advances in the prevention and treatment of coronary artery disease (CAD), the disease remains the leading cause of death and disability worldwide. Epidemiological studies have demonstrated that an elevated heart rate is an independent predictor of cardiovascular events in CAD patients. The results of themorBidity–mortality EvAl- UaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) have shown that patients with elevated heart rate (≥70 bpm) are clearly at high risk for all cardiovascular events. Thus reducing the elevated heart rate in CAD patients could be an additional approach to lowering their risk of cardiovascular events. Ivabradine is the first of a new class of heart rate–lowering agents that act specifically on the sinoatrial node, and it has been well documented to provide antianginal and antiischemic efficacy in stable CAD patients. Furthermore, in stable CAD patients with associated left ventricular dysfunction and a baseline heart rate of 70 bpm or above, the use of ivabradine on top of the guideline-recommended optimal preventive therapy leads to a significant reduction in coronary events. Because of these promising results with ivabradine, and given the association between heart rate and cardiovascular events in all CAD patients, the evaluation of ivabradine in acute coronary syndromes and in stable coronary patients with preserved left ventricular ejection fraction is clearly warranted. Two specific clinical studies have been designed for this purpose.

Medicographia. 2009;31:410-413 (see French abstract on page 413)

What further clinical perspectives are there for pure heart rate
reduction with ivabradine in the management of CAD?

Heart rate reduction is a well accepted approach to relieving ischemia and angina in stable coronary artery disease (CAD) patients. Large scale epidemiological studies have also shown a positive association between elevated baseline heart rate and the increased risk of cardiovascular events in stable CAD patients.1

The results of BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) have shown prospectively that in CAD patients with associated left ventricular dysfunction (LVD), those with a baseline heart rate of 70 beats per minute (bpm) or above have a significantly higher risk of cardiovascular morbidity and mortality.2

Ivabradine is the first of a new class of heart rate–lowering agents that act specifically on the sinoatrial node, and the drug has been well documented to provide antianginal and antiischemic efficacy in monotherapy3-5 and in combination with â-blockers6 in stable CAD patients. Furthermore, in stable CAD patients with associated LVD and a baseline heart rate of 70 bpm or above, the use of ivabradine on top of the guidelinerecommended optimal preventive therapy led to a significant reduction in coronary events (Figure).7

Considering the emerging role of heart rate reduction as a therapeutic approach in CAD management, and the background of the important benefits of pure heart rate reduction with ivabradine in stable CAD patients, it was felt necessary to evaluate the effect of ivabradine 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 evaluating the efficacy and safety of ivabradine in patients with acute ST-segment– elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention. To evaluate the efficacy of heart rate reduction with ivabradine in the reduction of cardiovascular outcomes in stable coronary patients with preserved ejection fraction, we have designed another morbidity-mortality study—SIGNIFY (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease).

Figure
Figure. The effect of ivabradine on hospitalization for fatal and nonfatal myocardial infarction (MI) in patients with a heart rate ≥70 beats per minute.

Based on data from reference 7.

What is the rationale for ivabradine treatment in patients with acute coronary syndromes? When do you expect the results of VIVIFY?

Elevated heart rate is frequently observed in patients with acute myocardial infarction, and this can further aggravate the myocardial ischemia by increasing the oxygen demand and further lowering the myocardial oxygen perfusion. There is good evidence to suggest that the beneficial effects of â-blockers after acute myocardial infarction are primarily due to heart rate reduction.8 The use of early β-blocker therapy in patients with acute myocardial infarction has been shown to reduce the risk of reinfarction and ventricular fibrillation, but to increase the risk of cardiogenic shock, especially during the first day after admission.9 The use of ivabradine in these patients could be advantageous, as ivabradine reduces the heart rate without any negative inotropic effect,10 and ivabradine can also be used in patients in whom β-blockers are contraindicated or not well tolerated.11 Hence, VIVIFY was designed to evaluate the efficacy and safety of ivabradine in patients with acute STEMI who undergo a percutaneous coronary intervention. VIVIFY is a placebo-controlled randomized international trial. The first patient was recruited in May 2006 and the results are expected to be available by the end of 2009.

What could the impact be of the expected results of VIVIFY on the management of acute coronary patients? Slowing the heart rate has always been considered as a useful approach in acute coronary patients. The results of VIVIFY have the potential to reinforce this approach and to demonstrate the safety and potential benefits of ivabradine for the first time in an acute coronary setting.

What is the rationale and objective of SIGNIFY?

Resting heart rate has been shown to be a strong predictor of overall and cardiovascular mortality in a wide range of patients, including patients with CAD and post–myocardial infarction.1,2 The results of BEAUTIFUL have shown that in stable CAD patients with associated LVD, heart rate reduction with ivabradine leads to a significant reduction in all coronary events in the group of patients with a baseline heart rate of 70 bpm or more. Considering the positive results with ivabradine on the coronary end points and the neutral results on the heart failure end points in CAD patients with LVD,7 one can postulate that ivabradine could be more beneficial in reducing cardiovascular events in CAD patients with preserved ejection fraction and a baseline heart rate of more than 70 bpm. Recent studies have also demonstrated the promising anti-atherosclerotic properties of ivabradine,12,13 once again highlighting the prominent role of ivabradine in the prevention of cardiovascular events in CAD patients. With this background in mind, we designed SIGNIFY to assess the efficacy of ivabradine compared with placebo in the prevention of cardiovascular events in patients with stable CAD without clinical heart failure, on top of guideline-recommended optimal preventive therapy. The primary end point of the study is a composite of cardiovascular death and nonfatal acute myocardial infarction.

Which patients will be included in SIGNIFY and how long will the follow-up be?

The inclusion and exclusion criteria of SIGNIFY have been designed to identify a group of patients who have documented stable CAD without clinical signs of heart failure and who are in normal sinus rhythm with a baseline heart rate of 70 bpm or more. The documentation of CAD will be based on previous documented myocardial infarction or previous revascularization (percutaneous intervention or coronary artery bypass graft) in two or more major coronary arteries, at least 3 months ago, or the imaging evidence of at least 50% narrowing of at least one or more major coronary arteries and a positive noninvasive stress test (exercise tolerance test, perfusion scintigraphy, or stress echocardiogram/hospitalization with documented clinical diagnosis of unstable angina within 12 months prior to selection). The left ventricular function of all patients will be assessed, and only patients with a left ventricular ejection fraction >40% will be enrolled. In addition, the presence of cardiovascular risk factor(s) will be required at inclusion: either at least one of the following—Canadian Cardiovascular Society class II (or higher) symptomatic angina, objective evidence of myocardial ischemia induced by stress testing, documented diagnosis of major coronary event (acute myocardial infarction/unstable angina) within 12 months prior to selection; or at least two of the following—documented low HDL cholesterol and/or documented high LDL cholesterol, type 1 or 2 diabetes treated with an oral hypoglycemic or insulin, documented peripheral artery disease, current smoker, age >70 years. All patients would be expected to follow a stable conventional treatment regimen that is considered optimal by the treating physician.

Apart from the usual exclusion criteria as in any clinical trial, the main exclusion criteria in SIGNIFY are related to the stability and severity of the CAD. Patients will not be included if they have had a myocardial infarction or coronary revascularization within 3 months of randomization; if they have a history of stroke or cerebral transient ischemic attack within the previous 3 months; if they have severe liver or renal disease; or if they are planning to have a revascularization procedure. Patients with clinical signs of heart failure will be excluded.

Patients meeting the inclusion criteria will be randomized to ivabradine 7.5 mg twice daily (with the possibility of uptitration to 10 mg twice daily or downtitration to 5 mg twice daily depending on the resting heart rate and the presence or absence of symptomatic bradycardia) or matching placebo on top of optimal preventive therapy and will be followed up for a maximum period of 42 months. We plan to follow up all patients for a minimum period of 18 months.

When do you expect the results of SIGNIFY?

The recruitment for SIGNIFY is expected to begin in October 2009. To obtain the necessary statistical power we need to recruit around 12 000 patients. Assuming that the recruitment goes as per our expectations, the study should be completed by 2013.

How will SIGNIFY advance the management of patients with stable CAD?

If the results, as expected, show that ivabradine treatment reduces morbidity and mortality in patients with resting heart rates above 70 bpm despite conventional therapy, this trial will constitute a breakthrough in treatment strategies for all stable CAD patients.

It must be acknowledged that huge strides have already been made in the prevention and treatment of CAD patients. Today, CAD patients are treated with a range of therapies that include β-blockers. Unfortunately, despite the effectiveness of these treatments, there are a large number of patients whose resting heart rate remains above 70 bpm and these patients are at a higher risk in terms of morbidity and mortality.

Specific heart rate–reducing effects may provide the advance in therapeutic strategies that is needed. With the results of BEAUTIFUL, it is already known that ivabradine reduces coronary events in stable CAD patients with associated LVD and heart rate ≥70 bpm. The results of SIGNIFY could reinforce the benefits observed in BEAUTIFUL and expand them to all CAD patients with preserved left ventricular function and a baseline heart rate of 70 bpm or more. These results could confirm that all stable CAD patients with preserved left ventricular function and a baseline heart rate ≥70 bpm could receive ivabradine as an essential part of their treatment plan in addition to their routine therapy. _

References

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2. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and leftventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
3. Tardif JC, Ford I, Tendera M, et al; INITIATIVE study investigators group. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.
4. Ruzyllo W, Ford I, Tendera M, et al. Antianginal and anti-ischemic affects of the If current inhibitor ivabradine compared to amlodipine as monotherapy in patients with chronic stable angina: A 3-month randomised, controlled, doubleblind, multicenter trial. Drugs. 2007;67:393-405.
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7. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL investigators. Ivabradine for patients with stable coronary artery disease and left ven tricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo- controlled trial. Lancet. 2008;372:807-816.
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10. Vilaine JP, Bidouard JP, Lesage L, et al. Antiischemic effects of ivabradine, a selective heart rate reducing agent, in exercise-induced myocardial ischemia in pigs. J Cardiovascular Pharmacol. 203;42:688-696.
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