The benefits of ivabradine are independent of resting heart rate

Evaluation of: Tardif JC, Ponikowski P, Kahan T; on behalf of the ASSOCIATE investigators. Effects of ivabradine in patients with stable angina receiving betablockers according to baseline heart rate: an ana-lysis of the ASSOCIATE study. Int. J. Cardiol. pii: S0167-5273(12) 01385-X (2012). Chronic stable angina pectoris is the most common manifestation of coronary artery disease. A large body of evidence points to high resting heart rate (HR) as a risk factor for mortality in various populations, including patients with cardiovascular disease. Elevated HR is an important pathophysiological variable that increases myocardial oxygen demand and also limits tissue perfusion by reducing the duration of diastole, during which most myocardial perfusion occurs. Large epidemiological trials have established that elevated resting HR is a prognostic factor for cardiovascular events and mortality in healthy individuals and in patients with myocardial infarction, stable coronary artery disease and heart failure. The classical treatments for HR reduction show such negative aspects. beta-blocker therapy exerts negative effects on regional myocardial blood flow and function when HR reduction is eliminated by atrial pacing. Calcium channel antagonists functionally antagonize coronary vasoconstriction mediated through alpha-adrenoreceptors and are thus devoid of this undesired effect, but the compounds are nevertheless negative inotrope. Ivabradine (IVA), a pure HR-lowering drug, reduces the myocardial oxygen demand of exercise and contributes to the restoration of oxygen balance, which has demonstrated a benefit in chronic cardiovascular disease. No relevant negative effects are evidenced on cardiac conduction, contractility, relaxation or repolarization, or blood pressure. In this post-hoc analysis, the authors show that IVA treatment, compared with the placebo group, had no significant impact on systolic or diastolic blood pressure at rest or during exercise and reduces HR in all stages of physical exercise and during the treatment period. These benefits are independent of baseline HR, both at rest and during physical exercise, confirming that HR reduction with IVA is beneficial in all patients, even with b-blocker therapy, if their resting HR is above 60 bpm.