Reviewer: : Dr. Levent PAY

Name of the Study: Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

Link : doi: 10.1056/NEJMoa2206286.

Background: Few pharmacological treatment options are available for heart failure patients with mildly reduced or preserved left ventricular ejection fraction. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death in patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Recently, treatment with the SGLT2 inhibitor empagliflozin has been shown to reduce the risk of hospitalization for heart failure or cardiovascular death in patients with heart failure and a left ventricular ejection fraction greater than 40%. The DELIVER study was conducted to test the hypothesis that the SGLT2 inhibitor dapagliflozin would reduce the risk of worsening heart failure or cardiovascular death in patients with mildly reduced or preserved ejection fraction.

Methods: The DELIVER trial was an international, multicenter, parallel group, event-driven, double-blind, randomized, controlled trial in which patients with chronic heart failure and left ventricular ejection fraction greater than 40% were treated with dapagliflozin or placebo. 6263 patients with heart failure and left ventricular ejection fraction greater than 40% were randomly assigned to receive dapagliflozin or corresponding placebo in addition to their current therapy. The primary endpoint was a composite of worsening heart failure, defined as unplanned hospitalization for heart failure or an emergency hospital admission for heart failure, or cardiovascular death. The secondary endpoint was the total number of worsening heart failure events and cardiovascular deaths, change from baseline in the total symptom score on the Kansas City Cardiomyopathy Questionnaire at month 8, cardiovascular death, and death from any cause.

Results: Between 27 August 2018 and 30 December 2020, a total of 10,418 patients were screened in 353 centers in 20 countries; 6263 of these patients were randomly assigned to receive dapagliflozin or matched placebo. Over a mean of 2.3 years, primary outcome was achieved in 512 (16.4%) of 3131 patients in the dapagliflozin group and 610 (19.5%) of 3132 patients in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0, 73 to 0.92; P<0.001). Results were similar between patients with a left ventricular ejection fraction of 60% or greater and a left ventricular ejection fraction of less than 60%. The incidence of components of the primary outcome was lower in the dapagliflozin group both in the general population and in those with a left ventricular ejection fraction less than 60%, including worsening heart failure and cardiovascular death (hazard ratio in the general population, 0.79; 95% [CI] 0.69 to 0.91).

Conclusion: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death in patients with heart failure and mildly decreased or preserved ejection fraction. These data provide further evidence to support the use of an SGLT2 inhibitor as the mainstay therapy in patients with heart failure, regardless of the presence or absence of type 2 diabetes mellitus or left ventricular ejection fraction.

Interpretations: In this randomized, placebo-controlled study of patients with heart failure and patients with slightly reduced or preserved ejection fraction, dapagliflozin resulted in a lower primary composite outcome, worsening heart failure, or risk of cardiovascular death than placebo. Although the EMPEROR-Preserved study suggested some potential benefit reduction in the highest part of the ejection fraction range, no evidence of heterogeneity was observed in the DELIVER study with respect to left ventricular ejection fraction. This finding suggests that the benefit of SGLT2 inhibition will likely extend across the entire ejection fraction range.

In addition, a meta-analysis of DAPA-HF and DELIVER studies was conducted with the study "Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER". A patient-level pooled meta-analysis of two studies testing dapagliflozin in participants with heart failure and different left ventricular ejection fraction ranges (≤40% and >40%) was performed to test the consistency of dapagliflozin's effect to examine its effect on treatment endpoints. As endpoints; death from cardiovascular causes; death from any cause; total hospitalization for heart failure; death from cardiovascular causes was determined as the composite of death from myocardial infarction or stroke. A total of 11,007 participants with a mean ejection fraction of 44% were included in the study. In conclusion, dapagliflozin reduced the risk of death from cardiovascular causes, death from any cause, and total hospitalization for heart failure. There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient-level pooled meta-analysis covering all ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospitalization for heart failure.