Ivabradine and Bisoprolol on Doppler-derived Coronary Flow Velocity Reserve in Patients with Stable Coronary Artery Disease: Beyond the Heart Rate

Abstract

IntroductionCoronary flow velocity reserve (CFVR) is an important prognostic marker in patients with stable coronary artery disease (CAD). Beta-blockers and ivabradine have been shown to improve CFVR in patients with stable CAD, but their effects were never compared. The aim of the current study was to compare the effects of bisoprolol and ivabradine on CFVR in patients with stable CAD.MethodsPatients in sinus rhythm with stable CAD were enrolled in this prospective, randomized, double-blind trial. Patients had to be in a stable condition for at least 15 days before enrollment, on their usual therapy. Patients who were receiving beta-blockers or ivabradine entered a 2-week washout period from these drugs before randomization. Transthoracic Doppler-derived CFVR was assessed in left anterior descending coronary artery, and was calculated as the ratio of hyperemic to baseline diastolic coronary flow velocity (CFV). Hyperemic CFV was obtained using dipyridamole administration using standard protocols. After CFVR assessment, patients were randomized to ivabradine or bisoprolol and entered an up-titration phase, and CFVR was assessed again 1 month after the end of the up-titration phase.ResultsFifty-nine patients (38 male, 21 female; mean age 69 ± 9 years) were enrolled. Transthoracic Doppler-derived assessment of CFV and CFVR was successfully performed in all patients. Baseline characteristics were similar between the bisoprolol and ivabradine groups. No patient dropped out during the study. At baseline, rest and hyperemic peak CFV as well as CFVR was not significantly different in the ivabradine and bisoprolol groups. After the therapy, resting peak CFV significantly decreased in both the ivabradine and bisoprolol groups, but there was no significant difference between the groups (ivabradine group 20.7 ± 4.6 vs. 22.8 ± 5.2, P < 0.001; bisoprolol group 20.1 ± 4.1 vs. 22.1 ± 4.3, P < 0.001). However, hyperemic peak CFV significantly increased in both groups, but to a greater extent in patients treated with ivabradine (ivabradine: 70.7 ± 9.4 vs. 58.8 ± 9.2, P < 0.001; bisoprolol: 65 ± 8.3 vs. 58.7 ± 8.2, P < 0.001). Accordingly, CFVR significantly increased in both groups (ivabradine 3.52 ± 0.64 vs. 2.67 ± 0.55, P < 0.001; bisoprolol 3.35 ± 0.70 vs. 2.72 ± 0.55, P < 0.001), but it was significantly higher in ivabradine group, despite a similar decrease in heart rate (63 ± 7 vs. 61 ± 6; P not significant).ConclusionIvabradine improves hyperemic peak CFV and CFVR to a greater extent than bisoprolol in patients with stable CAD, despite a similar decrease in heart rate. These data demonstrate that the benefits from ivabradine therapy go beyond the heart rate. This could be due to a different mechanism such as diastolic perfusion time, isovolumic ventricular relaxation, end-diastolic pressure, and collaterals.FundingServier.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0237-x) contains supplementary material, which is available to authorized users.

A 'diamond' approach to personalized treatment of angina

“…In addition, ivabradine increases coronary flow reserve and collateral perfusion, promoting the development of coronary collaterals and maintaining endothelial function in patients with chronic stable angina 47,48 . The antianginal effects of ivabradine have been documented in several randomized clinical trials against placebo, various active comparators, and in addition to β-blockers, as well as in unselected studies reflecting routine clinical practice 29,49 .…”

“…Subsequently, in a double-blind, placebo-controlled, crossover study conducted in women with effort angina but no obstructive coronary artery disease, ranolazine produced no significant benefits except in some patients with impaired coronary flow reserve 65 . Analogously, ivabradine has been shown to improve coronary collateral flow and coronary flow reserve in patients with microvascular angina 47,48 . The effects of ivabradine were superior to those of bisoprolol, despite similar degrees of heart-rate reduction 48 .…”

“…Analogously, ivabradine has been shown to improve coronary collateral flow and coronary flow reserve in patients with microvascular angina 47,48 . The effects of ivabradine were superior to those of bisoprolol, despite similar degrees of heart-rate reduction 48 . Therefore, treatment of microvascular angina is extremely challenging and necessarily empirical.…”

Effectiveness of Ivabradine Treatment in Different Subpopulations with Stable Angina in Clinical Practice: A Pooled Analysis of Observational Studies

“…The mechanisms of anti-ischemic and antianginal efficacy of ivabradine were first elucidated in experimental studies [5] and confirmed in recent clinical trials. This includes an increase in myocardial diastolic perfusion time [6], enhancement in coronary flow reserve [7], improvement in endothelial function [8], and enhancement in coronary collateral flow in patients with chronic stable coronary artery disease [9]. This makes ivabradine an important antianginal and anti-ischemic therapeutic strategy.…”

Treatment of Angina: Where Are We?

“…Furthermore, in contrast to beta-blockers and to non-dihydropyridines calcium antagonists, ivabradine has no negative inotropic or lusitropic effects. Recently, ivabradine has also been shown to increase coronary collateral perfusion and the coronary flow reserve [85-87]. In addition, ivabradine does not unmask α-adrenergic vasoconstriction and, unlike beta-blockers, it maintains the physiological coronary dilation during exercise.…”