Impact of ivabradine on the cardiac function of chronic heart failure reduced ejection fraction: Meta‐analysis of randomized controlled trials

Abstract Elevated resting heart rate in chronic heart failure (HF) patients has been associated with higher mortality and poor prognosis. Ivabradine is a new pure bradycardic agent that has been used to treat angina or heart failure reduced ejection fraction (HFrEF) with sinus heart rate above 70 beats per minute. However, the effect of ivabradine for chronic HF patients on rehospitalization and cardiac function is still inconsistent. Thus, this meta‐analysis aimed to elucidate the effect of Ivabradine in chronic HFrEF patients. We systematically searched PubMed, Medline, Clinical Trials.gov , and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) of ivabradine with search terms Ivabradine (MeSH Terms), chronic heart failure and beta‐blocker. The primary endpoints of the study include the impact of Ivabradine on heart rate, left ventricle ejection fraction (LVEF), left ventricular remodeling, exercise capacity, and quality of life (QoL) in patients with chronic HFrEF. Secondary endpoints were safety analysis of Ivabradine including cardiovascular mortality, worsening HF readmission, visual disturbances, and asymptomatic bradycardia. The analysis was done by Review Manager 5.4 Analyzer, to analyze the mean differences (MD) for continuous data and risks ratio (RR) for dichotomous data. A total of six RCTs and one subgroup analysis showed add of Ivabradine to standard HF therapy was associated with greater resting heart rate reduction (MD = −9.57; 95% CI ‐11.15, −8.00), improved LVEF (MD = 3.89; 95% CI 2.61, 5.17), left ventricular reverse remodeling improvement (MD = −3.73; 95% CI ‐4.25, −3.21, LVESV; MD = −17.00, 95%CI ‐29.65, −4.35, LVEDD; MD = −1.43, 95%CI ‐2.78, −0.08, LVEDV; MD = −14.75, 95%CI ‐34.36, 4.87), increased exercise capacity (exercise duration; MD = 8.52; 95%CI 0.09, 16.94), and significant reduction on rehospitalization due to worsening HF (RR = 0.76, 95%CI 0.69, 0.84). However, Ivabradine has no significant effect on the quality of life (MD = 0.65; 95%CI ‐10.52, 11.82), and cardiovascular mortality (RR = 0.92; 95%CI 0.82, 1.03). Moreover, there were some events of visual disturbances and asymptomatic bradycardia observed in the Ivabradine group compared to the placebo group (RR = 4.76; 95%CI 3.03, 7.48; RR = 3.78; 95%CI 2.77, 5.15, respectively). Addition of Ivabradine to standard HF therapy is associated with cardiac function improvement, reduction on worsening HF readmission, greater HR reduction, and better exercise capacity in chronic HFrEF patients, although it cannot reduce cardiovascular mortality or improve the quality of life.