A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS EVALUATING IVABRADINE IN HEART FAILURE

New guidelines on the management of heart failure (HF) recommend ivabradine, a pure negative chronotropic drug, for symptomatic patients with HF and a reduced left ventricular ejection fraction (LVEF) in sinus rhythm >70 bpm. In making this recommendation, they only reference the SHIFT trial. Aiming to summarize the whole body of evidence, we performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing ivabradine with placebo/control in patients with HF. We searched MEDLINE, EMBASE and Cochrane CENTRAL to July 2018 for RCTs comparing ivabradine to placebo/control in patients with HF. We imposed no restriction on the type of HF and HF was defined as by study authors. We performed screening, full-text eligibility assessment, risk of bias evaluation and data collection independently and in duplicate. We pooled study results using a fixed-effect model. We evaluated the risk of bias for individual studies with the Cochrane tool and the overall quality of evidence with the GRADE framework. We screened 2,323 references and evaluated the full-text of 224 potentially relevant studies, 58 of which were included in the analysis. Ivabradine led to a significant reduction in the risk of hospitalization (14 RCTs, n=18,691, RR 0.90 95% CI [0.86,0.95], I2=52%, high quality evidence, Figure 1). Most of the data (10 RCTs, n=18,094, RR 0.92 95% CI [0.87, 0.97], I2=36%, high quality evidence) was from patients with HF with reduced LVEF (HFrEF), although one RCT (n=100) demonstrated a significant reduction in hospitalization in HF patients with preserved LVEF (HFpEF) (RR 0.76, 95% CI [0.59, 0.96]). Three RCTs (n=487) that included both HFrEF and HFpEF patients also demonstrated a lower risk of hospitalization (RR 0.42, 95% CI [0.24, 0.71]). The risk of mortality did not differ significantly in patients randomized to ivabradine compared to placebo/control (RR 0.95, CI [0.88, 1.02], I2=0%, high quality evidence); this was consistent regardless of the type of HF. Compared to placebo/control, a greater improvement in LVEF was observed in patients randomized to ivabradine (n=2,484, mean difference in change in EF: 2.67%, 95% CI [1.51, 3.82], I2=88); this was consistently observed in both the HFrEF (n=1,892: 2.87%, 95% CI [1.39, 4.36],I2=89%) and HFpEF (n=298: 2.63%, 95% CI [1.12,4.13 ], I2=0%) subgroups (test for interaction: p=0.10). Ivabradine decreases hospitalizations in patients with HF without impacting mortality. Evidence predominantly comes from patients with a reduced LVEF, but these findings may extend to patients with a preserved LVEF.