Ivabradine added to usual care in patients with heart failure: a systematic review with meta-analysis and trial sequential analysis

Abstract

ObjectivesTo assess the beneficial and harmful effects of adding ivabradine to usual care in participants with heart failure.DesignA systematic review with meta-analysis and trial sequential analysis.Eligibility criteriaRandomised clinical trials comparing ivabradine and usual care with usual care (with or without) placebo in participants with heart failure.Information sourcesMedline, Embase, CENTRAL, LILACS, CNKI, VIP and other databases and trial registries up until 31 May 2021.Data extractionPrimary outcomes were all-cause mortality, serious adverse events and quality of life. Secondary outcomes were cardiovascular mortality, myocardial infarction and non-serious adverse events. We performed meta-analysis of all outcomes. We used trial sequential analysis to control risks of random errors, the Cochrane risk of bias tool to assess the risks of systematic errors and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of the evidence.ResultsWe included 109 randomised clinical trials with 26 567 participants. Two trials were at low risk of bias, although both trials were sponsored by the company that developed ivabradine. All other trials were at high risk of bias. Meta-analyses and trial sequential analyses showed that we could reject that ivabradine versus control reduced all-cause mortality (risk ratio (RR)=0.94; 95% CI 0.88 to 1.01; p=0.09; high certainty of evidence). Meta-analysis and trial sequential analysis showed that ivabradine seemed to reduce the risk of serious adverse events (RR=0.90; 95% CI 0.87 to 0.94; p<0.00001; number needed to treat (NNT)=26.2; low certainty of evidence). This was primarily due to a decrease in the risk of ‘cardiac failure’ (RR=0.83; 95% CI 0.71 to 0.97; p=0.02; NNT=43.9), ‘hospitalisations’ (RR=0.89; 95% CI 0.85 to 0.94; p<0.0001; NNT=36.4) and ‘ventricular tachycardia’ (RR=0.59; 95% CI 0.43 to 0.82; p=0.001; NNT=212.8). However, the trials did not describe how these outcomes were defined and assessed during follow-up. Meta-analyses showed that ivabradine increased the risk of atrial fibrillation (RR=1.19; 95% CI 1.04 to 1.35; p=0.008; number needed to harm (NNH)=116.3) and bradycardia (RR=3.95; 95% CI 1.88 to 8.29; p=0.0003; NNH=303). Ivabradine seemed to increase quality of life on the Kansas City Cardiomyopathy Questionnaire (KCCQ) (mean difference (MD)=2.92; 95% CI 1.34 to 4.50; p=0.0003; low certainty of evidence), but the effect size was small and possibly without relevance to patients, and on the Minnesota Living With Heart Failure Questionnaire (MLWHFQ) (MD=−5.28; 95% CI −6.60 to −3.96; p<0.00001; very low certainty of evidence), but the effects were uncertain. Meta-analysis showed no evidence of a difference between ivabradine and control when assessing cardiovascular mortality and myocardial infarction. Ivabradine seemed to increase the risk of non-serious adverse events.Conclusion and relevanceHigh certainty evidence shows that ivabradine does not seem to affect the risks of all-cause mortality and cardiovascular mortality. The effects on quality of life were small and possibly without relevance to patients on the KCCQ and were very uncertain for the MLWHFQ. The effects on serious adverse events, myocardial infarction and hospitalisation are uncertain. Ivabradine seems to increase the risk of atrial fibrillation, bradycardia and non-serious adverse events.PROSPERO registration number: CRD42018112082.

Agreement between mega-trials and smaller trials: a meta-research study

“…In the summary analysis, there was no noteworthy discrepancy observed between the results of the mega-trials and those of smaller trials (summary ROR 1.00, 95% confidence interval [CI] 0.97-1.04; I 2 =0.0, P-value for heterogeneity=0.478; Figure 2). In two instances when comparing ivabradine to placebo and new adenosine diphosphate receptor agonist versus clopidogrel, the disagreement between the mega-trials and the respective smaller trials was beyond chance (ROR 1.21, 95% CI, 1.0-1.47 and ROR 0.83, 95% CI, 0.73, 0.95, respectively) [21, 22].…”

Ivabradine in patients with heart failure: a systematic literature review

“…Authors showed that ivabradine does not affect the risks of all-cause death and CV death in patients with HF (regardless of LVEF). Furthermore, the effect of ivabradine on HRQoL was found to be small and potentially without relevance to patients [ 74 ]. A review by Benstoem et al [ 75 ] conducted two meta-analyses on individuals with HFrEF who underwent long-term treatment with ivabradine.…”

Terapia farmacológica en insuficiencia cardiaca fracción de eyección reducida: ¿cómo, cuánto, a quién?

“…Si bien se habría demostrado, mediante el estudio SHIFT disminución de mortalidad cardiovascular, metaanálisis de los ensayos para ivabradina (BEAUTIFUL y SHIFT) no lograron demostrar disminución significativa de la mortalidad global ni por eventos cardiovasculares. Por su mecanismo de acción, los principales efectos adversos son bradicardia, bloqueos auriculoventriculares y síncope (40,41) .…”