Impact of dapagliflozin on cardiometabolic outcomes after myocardial infarction according to baseline left ventricular ejection fraction: a DAPA-MI substudy

Abstract Background Dapagliflozin improved cardiometabolic outcomes compared with placebo following acute myocardial infarction (MI) in participants without prior diabetes mellitus (DM) or chronic heart failure (HF) in the DAPA-MI trial. Purpose Cardiometabolic outcomes were assessed in the DAPA-MI trial according to left ventricular ejection fraction (EF) at randomisation. Methods Participants were categorised according to whether baseline EF was ≥50 or <50%. Those without a baseline EF result and those who did not receive a dose of study drug were excluded. The primary objective was to determine the clinical effect of dapagliflozin 10 mg versus placebo assessed using a hierarchical composite outcome and analysed by the win ratio method. The primary outcome was the hierarchical composite, by order of perceived clinical importance, of death, hospitalization for HF (HHF), nonfatal MI, atrial fibrillation/flutter event, new diagnosis of type 2 DM, NYHA functional class at the last trial visit, and body weight decrease of ≥5% from baseline to the last trial visit. Time to first event of NYHA class II-IV or HHF and time to first event of NYHA class III-IV or HHF were assessed as endpoints of special interest. Hazard ratios (HR) with 95% confidence intervals (CI) were determined using Cox proportional hazards models. The main subgroup variable (baseline EF ≥50 or <50) and its interaction with treatment (P int) were included. Results 838 participants had EF≥50 and 2913 had EF<50 at baseline. The primary hierarchical composite outcome resulted in a win ratio for those with EF≥50 of 1.32 (CI 1.00-1.73) and 1.38 for those with EF<50 (CI 1.21-1.57; P int 0.8) (Figures). There were no significant interactions by EF for any of the secondary outcomes. In those with EF<50, a first event of NYHA class II-IV or HHF occurred in 435 (29.4%) participants in the dapagliflozin group and 485 (33.8%) in the placebo group (absolute risk difference [ARD] 4.4%; HR 0.83, CI 0.73-0.94, P<0.01). In those with EF≥50, this occurred in 81 (19.7%) and 93 (21.8%), respectively (ARD 2.1%; HR 0.96, CI 0.65-1.41, P=0.7; P int 0.47). In those with EF<50, a first event of NYHA class III-IV or HHF occurred in 77 (5.2%) in the dapagliflozin and 115 (8.0%) in the placebo groups (ARD 2.2%; HR 0.64, CI 0.48-0.85, P<0.01). In those with EF≥50, this occurred in 14 (3.4%) and 19 (4.4%), respectively (ARD 1.0%; HR 0.80, CI 0.40-1.60, P=0.5; P int 0.55). There was no significant effect of dapagliflozin on death/MI/stroke in either subgroup (EF<50: HR 0.96, CI 0.65-1.41; EF≥50: HR 0.83, CI 0.38-1.84; P int 0.75). Dapagliflozin increased the incidence of 5% weight loss in both of the EF subgroups with no significant interaction. Conclusions Dapagliflozin resulted in significant benefit in cardiometabolic outcomes compared with placebo regardless of baseline EF. The absolute reduction in HF symptoms or HHF with dapagliflozin, compared with placebo, was greatest in those with baseline EF<50.Figures