Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo‐controlled trial

Aims This randomized, double‐blind, placebo‐controlled trial assessed whether heart rate ( HR ) reduction with ivabradine improves cardiac function in heart failure with preserved ejection fraction ( HFpEF ). Methods and results The prEserveD left ventricular ejectIon fraction chronic heart Failure with ivabradine studY ( EDIFY ) included 179 patients in New York Heart Association ( NYHA ) classes II and III , in sinus rhythm, with HR of ≥70 b.p.m., NT‐proBNP of ≥220 pg/ mL ( BNP ≥80 pg/ mL ) and left ventricular ejection fraction of ≥45%. Ivabradine (or placebo) was titrated to 7.5 mg b.i.d. Patients were followed for 8 months on the change and assessed for three co‐primary endpoints: echo‐Doppler E/e′ ratio, distance on the 6‐min walking test ( 6MWT ), and plasma NT‐proBNP concentration. At baseline, median E/e′ was 12.8 [interquartile range ( IQR ): 9.9–16.3], median distance on the 6MWT was 320 m ( IQR : 247–375 m), and median NT‐proBNP was 375 pg/ mL ( IQR : 253–701 pg/ mL ). Baseline median HR was 75 b.p.m. ( IQR : 70–107 b.p.m.). A total of 171 patients (87 in the ivabradine group, 84 in the placebo group) were evaluated for treatment efficacy. After 8 months of treatment, findings showed a median change in HR of −13.0 b.p.m. ( IQR : −18.0 to −6.0 b.p.m.) in the ivabradine group and −3.5 b.p.m. ( IQR : −11.5 to 3.0 b.p.m.) in the placebo group [estimated between‐group difference: 7.7 b.p.m.; 90% confidence interval ( CI ) −10 to −5.4; P  < 0.0001]. No evidence of improvement was found in any of the three co‐primary endpoints. There was almost no change in median E/e′ in either of the two groups [median change: +1.0 ( IQR : −0.8 to 2.9) in the ivabradine group; −0.6 ( IQR : −2.2 to 1.4) in the placebo group; estimated between‐group difference: 1.4, 90% CI 0.3–2.5; P  = 0.135]. There were no meaningful changes in the other co‐primary endpoints and no apparent trends. There was no significant safety concern. Conclusions In patients with HFpEF , HR reduction with ivabradine did not improve outcomes. These findings do not support the use of ivabradine in HFpEF .