Physicians' Academy for Cardiovascular Education

SGLT2i reduces specific causes of CV death in HF across wide LVEF spectrum

Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction: A Participant-Level Pooled Analysis of DAPA-HF and DELIVER

Literature - Desai AS, Jhund PS, Claggett BL, et al. - JAMA Cardiol. 2022 Dec 1;7(12):1227-1234. doi: 10.1001/jamacardio.2022.3736

Introduction and methods


Recently, dapagliflozin was shown to reduce the rate of the composite outcome of worsening HF events or CV death in 2 international RCTs, namely the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials [1-4]. However, the effect of dapagliflozin on specific causes of death has not been examined.

Aim of the study

In a pooled analysis of the DAPA-HF and DELIVER trials, the effect of dapagliflozin versus placebo on cause-specific CV and non-CV mortality in HFrEF, HFmrEF, and HFpEF patients was examined.


In this participant-level, pooled, prespecified secondary analysis, data from the DAPA-HF trial (LVEF ≤40%; n=4744) and the DELIVER trial (LVEF >40%; n=6263) were combined. Both trials had randomized patients with chronic HF, NYHA class II–IV symptoms, and elevated NT-proBNP levels to treatment with dapagliflozin 10 mg once daily or placebo. Median follow-up duration was 18.2 (DAPA-HF trial) or 27.6 months (DELIVER trial).

The authors assessed the mode of death (CV, non-CV, undetermined) and the specific causes of CV death (HF, sudden death, MI, stroke, other CV causes), as a whole and across different baseline LVEF categories (≤40%, 41%–49%, 50%–59%, ≥60%).


The primary endpoint in both trials was time to the first occurrence of the composite outcome of adjudicated worsening HF events (i.e., hospitalization or urgent visits for HF) or CV death.

Main results


In a pooled analysis of the DAPA-HF and DELIVER trials, dapagliflozin reduced the risk of CV death and all-cause mortality in HF patients compared with placebo. The reduction in CV deaths with dapagliflozin was primarily due to lower, albeit nonsignificant, rates of sudden death and, to a lesser extent, death from progressive HF.

The authors believe these results support the consistent beneficial effects seen with dapagliflozin on CV mortality, regardless of LVEF. They also note that “[t]he higher proportionate contribution of non-CV death with rising EF may be partly responsible for the limited progress in reducing the burden of overall mortality in patients with HF and preserved EF using CV therapies.”


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Find this article online at JAMA Cardiol.

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