Effect of ivabradine on cardiovascular outcomes in patients with stable angina: meta-analysis of randomized clinical trials

Abstract

BackgroundAlthough there are established drugs for treatment of cardiovascular diseases, due to adverse effects these drugs may not be clinically applicable to all patients. Recent trends have seen the emergence of drugs which act on funny current channels to induce selective heart rate reduction. Ivabradine is one such drug developed for coronary artery disease and heart failure. There is inconsistent evidence about the effect of this selective inhibitor in reduction of cardiovascular related mortality and morbidity. Such an inconsistency warrants the need for a meta-analysis to consider the effectiveness and efficacy of Ivabradine in the treatment of coronary artery disease and heart failure.MethodsRandomized controlled trials with a minimum follow-up period of one year were searched in Pub Med/Medline, Embase, Cochrane Central Register of Controlled Trials published between 1980 and 2016.Each eligible study was assessed for risk of bias by using the Cochrane Risk of Bias Assessment tool. The outcomes assessed in this study included: all cause mortality, cardiovascular-related mortality, hospitalization for new or worsening heart failure, and adverse events. Subgroup analysis and publication bias were assessed. We used Mantel-Haenszel method for random-effects. Analysis was done using RevMan5.1™.This study was registered in PROSPERO as [PROSPERO 2016:CRD42016035597].ResultThree trials with a total of 36,577 participants met the meta-analysis criteria. Pooled analysis showed that ivabradine is not effective in reducing cardiovascular deaths (OR: 1.02; CI:0.91–1.15,P = 0.74), all-cause mortality (OR:1.00; CI:0.91–1.10,P = 0.98), coronary revascularization (OR: 0.93, CI: 0.77–1.11, P = 0.41) and hospital admission for worsening of heart failure (OR: 0.94, CI: 0.71–1.25, P = 0.69). However, the drug was found to significantly increase adverse events: phosphenes (OR:7.77, CI: 4.4–14.6,P < 0.00001), blurred vision (OR:3.07,CI:2.18–4.32,P < 0.00001), symptomatic bradycardia (OR: 6.23, CI: 4.2–9.26, P < 0.00001), and atrial fibrillation (OR: 1.35, CI: 1.19–1.53, P < 0.0001). Subgroup analysis by duration of follow up on cardiovascular outcomes found that there is no difference in effect of ivabradine depending on the duration of follow up. There was no publication bias in reporting of included studies.ConclusionThis meta-analysis suggests that ivabradine is not effective in reducing cardiovascular-related morbidity and mortality unless used for specific conditions. On the contrary, the use of this drug was strongly associated with the onset of untoward and new adverse events. This finding strongly supports previous findings and further informs the rational and evidence-informed clinical use of ivabradine.Electronic supplementary materialThe online version of this article (doi:10.1186/s12872-017-0540-3) contains supplementary material, which is available to authorized users.

The Use of Selective Inhibitor of If-Channels Ivabradine in Patients with Ischemic Heart Disease, Heart Failure with High Heart Rate

“…Патогенетически ХСН характеризуется хроническим дисбалансом нейрогуморальных систем с гиперактивацией ренин-ангиотензин-альдостероновой и симпато-адреналовой систем, что приводит к увеличению ЧСС в покое [21].…”

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

“…BRAKE-AF project will compare ivabradine to digoxin in 232 patients with permanent AF and poor rate control despite beta-blocker or calcium channel blocker administration [ 160 ]. A meta-analysis of three RCTs (36,577 participants) suggests that ivabradine administration is associated with symptomatic bradycardia and atrial fibrillation (OR: 6.23; CI: 4.2–9.26; p < 0.00001 and OR: 1.35; CI: 1.19–1.53; p < 0.0001, respectively) [ 161 ]. Before putting ivabradine to the test against rate control, these findings necessitate further elucidation.…”

Effect of ivabradine on major adverse cardiovascular events and mortality in critically ill patients: a systematic review and meta-analyses of randomised controlled trials with trial sequential analyses

“…In a meta-analysis 43 including all patients (n¼36 577) from three large RCTs 18 19 44 of ivabradine vs placebo in patients with stable coronary artery disease with a follow-up of at least 1 yr, ivabradine was not associated with improvements in cardiovascular outcomes and was associated with higher risk of atrial fibrillation and symptomatic bradycardia. Of note, this meta-analysis included patients from the SIGNIFY trial that received a large dose of ivabradine (7.5e10 mg twice daily) 44 and a doseeeffect analysis was not performed.…”