1. In this pooled analysis of 11,007 patients with heart failure in the DAPA-HF and DELIVER trials, treatment with dapagliflozin was associated with a 14% lower risk of cardiovascular death regardless of ejection fraction, due to lower rates of sudden death and HF death.

2. No difference was found between dapagliflozin vs placebo in rates of non-CV death.

Evidence Rating Level: 2 (Good)

Study Rundown: Recent clinical trials of patients with chronic heart failure (HF) across the spectrum of ejection fraction (EF) have associated sodium-glucose cotransporter 2 (SGLT-2) inhibitors with a reduction in the risk of worsening HF events or death due to cardiovascular (CV) causes. However, there is a lack of evidence examining the effects of SGLT-2 inhibitors on overall mortality and specific causes of death. Hence, the objective of this pooled secondary analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) and Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) was to examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF. The intervention in the trials examined was dapagliflozin vs placebo. The main outcomes were more death in relation to baseline EF, as well as the effect of randomized treatment on cause-specific death. A total of 11,007 patients were included in the pooled data set. During follow-up, there were 1628 deaths, of which 872 were ascribed to CV deaths. Of the CV deaths, 289 were due to HF, 441 were sudden, 69 were due to stroke, 47 were due to myocardial infarction (MI), and 26 were due to other CV causes. Treatment with dapagliflozin was found to significantly reduce the risks of CV death by 14%, predominantly due to lower rates of sudden death and death from progressive HF. A strength of this study was its large sample size; however, a limitation was that due to the absence of autopsy data, the cause of death was ascertained based on clinical inference made with limited data regarding the circumstances of death, which may have impacted results.

Click to read the study in JAMA Cardiology

Relevant Reading: Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER

In-Depth [meta-analysis]: In this participant-level, pooled, prespecified secondary analysis of data from the DAPA-HF and DELIVER randomized trials, a total of 11,007 patients were included in the pooled data set (mean [SD] age, 71.7 [10.3] years; 1139 male [70.0%]). This study investigated the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF. During follow-up, there were a total of 1628 deaths, and of those who died, 872 (53.5%) were ascribed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) due to unknown causes. Of the CV deaths specifically, 289 (33.1%) were due to HF, 441 (50.6%) were sudden, 69 (7.9%) were due to stroke, 47 (5.4%) due to MI, 26 (3.0%) were due to other CV causes. Across the spectrum of EF in the pooled population, treatment with dapagliflozin compared with placebo was associated with lower rates of CV death (hazard ratio [HR], 0.86; 95% CI, 0.75-0.98; P = .02), and this was attributed to lower rates of sudden death (HR, 0.84; 95% CI, 0.70-1.01; P = .07) and HF death (HR, 0.88; 95% CI, 0.70-1.11; P = .30). No difference was found between dapagliflozin and placebo in rates of non-CV death (HR, 1.01; 95% CI, 0.84-1.20; P = .94).

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