Influence of background therapy on efficacy of dapagliflozin in patients with heart failure and improved ejection fraction

Abstract

Abstract Introduction Heart failure with improved ejection fraction (HFimpEF), defined as prior reduced left ventricular EF (LVEF) ≤40% with a subsequent measurement LVEF >40%, is growing in prevalence, in part because of effective guideline directed medical therapy (GDMT) initiated when LVEF was ≤40%. These patients have been largely excluded from major HF clinical trials. The DELIVER trial demonstrated dapagliflozin to be beneficial in patients with symptomatic HFimpEF; whether this benefit differs by background medical therapy is unclear. Purpose We investigated the efficacy and safety of dapagliflozin in patients with HFimpEF by background HF GDMT (beta-blocker [BB], mineralocorticoid receptor antagonist [MRA], and ACEi/ARB/ARNI at baseline). Methods The DELIVER trial randomized patients with symptomatic heart failure and LVEF>40% to dapagliflozin or placebo. Treatment effects on the primary endpoint, worsening heart failure or cardiovascular (CV) death, and its components were assessed by a GDMT composite score. We assigned 1 point each for baseline use of ACEi/ARB, evidence-based BB, or MRA, and 2 points for sacubitril/valsartan. The composite GDMT score could range from 0 (no GDMT) to 4 (triple therapy inclusive of sacubitril/valsartan). Results Among the 6,263 patients randomized, 1,151 (18%) had HFimpEF. Of those, 2% of patients were on no GDMT, 14% were on 1 GDMT, 47% were on 2 GDMT therapies, and 37% were on triple therapy at baseline (Figure 1). Patients treated with triple therapy, compared to those on less than 3 therapies, were younger, more likely male, have a history of myocardial infarction, less likely to have diabetes, had a lower baseline LVEF and systolic blood pressure, and higher eGFR. During 2.2 years of median follow-up, the incidence rate was 9.8 per 100 person-years among those on 1 or no medications at baseline compared with 8.6 per 100 person-years among those on 2 or 3 therapies. Relative benefits of dapagliflozin on the primary outcome were not significantly modified by baseline GDMT score (Pinteraction = 0.11), but absolute benefits appeared more pronounced in those receiving 1 or no medications at baseline (Figure 2). Serious adverse events were well-balanced between treatment arms in the HFimpEF cohort, including among those already treated with triple therapy. Conclusions In patients with HFimpEF, the benefits of dapagliflozin are similar irrespective of background GDMT. Dapagliflozin was safe and did not lead to higher risk of adverse events among those with HFimpEF, including those already treated with triple therapy.Figure 1Figure 2