Impact of Ivabradine on Central Aortic Blood Pressure and Myocardial Perfusion in Patients With Stable Coronary Artery Disease

Abstract

Abstract-Treatment of hypertensive patients with β-blockers reduces heart rate and decreases central blood pressure less than other antihypertensive drugs, implying that reducing heart rate without altering brachial blood pressure could increase central blood pressure, explaining the increased cardiovascular risk reported with β-blocker. We describe a randomized, double-blind study to explore whether heart rate reduction with the I f inhibitor ivabradine had an impact on central blood pressure. We included 12 normotensive patients with stable coronary artery disease, heart rate ≥70 bpm (sinus rhythm), and stable background β-blocker therapy. Patients received ivabradine 7.5 mg BID or matched placebo for two 3-week periods with a crossover design and evaluation by aplanation tonometry. Treatment with ivabradine was associated with a significant reduction in resting heart rate after 3 weeks versus no change with placebo (−15. Methods Study Design and PatientsThis randomized, double-blind, crossover study was performed in 3 centers in Paris, Dublin, and Rome. The trial was conducted in accordance with the ethical principles laid out in the Declaration of Helsinki (sixth revision, 2008). Ethics committee approval was obtained in all centers before the start of the study, and all patients provided written informed consent before enrollment. Eligible men and women were outpatients with stable CAD, documented by a history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft at least 3 months before selection; angiographic evidence of ≥50% narrowing of at least 1 major coronary artery; a positive noninvasive stress test, stress echocardiography, or scintigraphic evidence of stress-induced ischemia; or discharge from hospital with a diagnosis of unstable angina within 12 months and at least 3 months before selection. They were aged at least 30 years and were in sinus rhythm with resting heart rate ≥70 bpm on ECG at both selection and inclusion. They had systolic blood pressure/diastolic blood pressure (SBP/DBP) <140/90 mm Hg and normal laboratory values considering their disease. They had been receiving β-blocker for at least 3 months at doses estimated appropriate by the investigator. The original protocol sought to include only patients with type 2 diabetes mellitus but was amended during the study to include nondiabetic patients.Reasons for nonselection or exclusion included a history of central neuropathy, symptomatic orthostatic hypotension, or severe hypotension; treatment with ivabradine; myocardial infarction, revascularization, stroke, or transient ischemic attack in the past 3 months; scheduled for percutaneous coronary intervention or coronary artery bypass graft; patients with a heart transplant, an implanted pacemaker or cardioverter defibrillator, or cardiac resynchronization therapy; valvular disease likely to require surgery within 1 year; permanent atrial fibrillation or flutter, sick sinus syndrome, sinoatrial block, congenital long QT, substance-induced long QT...

Selective Heart Rate Reduction With Ivabradine Increases Central Blood Pressure in Stable Coronary Artery Disease

“…23 This in turn was presumably the principle reason in ASCOT for atenololbased therapy being less efficacious than amlodipine-based therapy in reducing morbidity and mortality. 24 Our findings are apparently in contrast with the recently published study of Dillinger et al, 25 who in controlled hypertensive patients with CAD failed to observe an increase in central pressure after HR reduction with ivabradine. This could be explained by some important clinical and methodological differences between their study and our findings.…”

Impact of Ivabradine on Inflammatory Markers in Chronic Heart Failure

“…The present study demonstrated a significant decrease in diastolic blood pressure in patients with HCM. Interestingly, this differs from results of former studies that did not observe an effect of ivabradine on blood pressure [23]. The reason for this discrepancy is not clear, but a diastolic dip of blood pressure might be the result of the prolonged diastole with increased preload.…”

Efficacy Profile of Ivabradine in Patients with Heart Failure plus Angina Pectoris

“…Prior studies have suggested that β-blockers can increase pulse wave reflections/arterial stiffness, thereby negating the blood-pressure-lowering effects on cardiovascular mortality and specifically precluding the reduction of central aortic blood pressure, which may be attributable in part to heart rate reduction [17]. However, a cross-over study specifically examining ivabradine versus β-blockers showed no effect of ivabradine on central aortic pressure [18]. Therefore, central pulse wave reflections and blood pressure effects are unlikely to explain the results of SIGNIFY or to negate the results of SHIFT in patients with CAD with or without angina.…”