The effect of ivabradine therapy on heart failure patients with reduced ejection fraction: a systematic review and meta-analysis

Background Ivabradine is currently indicated to lower heart rate in Heart Failure with Reduced Ejection Fraction (HFrEF) patients. However its effect apart from beta-blockers is not clear. Aim of the review To study the additional effect of ivabradine, apart from the effect of beta-blockers, on cardiovascular death, all-cause mortality, hospitalization due to HF and heart rate in HFrEF population. Method Electronic searches were conducted up to June 2016 to include randomized controlled trials where ivabradine was compared to a control group. Relative risks RRs and their 95% confidence intervals (CI 95%) were pooled and the random and fixed effect were used to summarize the results according to heterogeneity levels. Heterogeneity among studies was measured by the I-squared statistic Results Of 1790 studies, seven met the inclusion criteria for the systematic review and meta-analysis. The population consisted of 17,747 patients. Risk of bias was generally high for beta-blocker doses lower than recommended. Interventions lasted 1.5–22.9 months and pooled relative risks RR (95%) for all-cause mortality, cardiovascular death and hospitalization for HF were 0.98 (0.90–1.06); 0.99 (0.91–1.08); and 0.87 (0.68–1.12) respectively. Heart rate (CI 95%) decreased by 8.7 (6.37–11.03) beats per minute with ivabradine compared to the control group. Subgroup analysis by beta-blocker dose showed that for patients on recommended treatment (at least 50% of the beta-blocker target dose), heart rate (CI 95%) decreased by 4.70 (3.67–5.73), whereas for patients not on recommended treatment or with unreported dose, heart rate decreased by 8.60 (8.13–9.08). Conclusion Ivabradine significantly reduced heart rate and its additional effect on heart rate appears to be inversely correlated with the dose of beta-blocker. It showed no significant effect for all-cause mortality, cardiovascular death and hospitalization due to HF. Unreported beta-blocker doses and beta-blocker doses lower than recommended limited the conclusions.