Dapagliflozin Associated with Lower Risk of CV Death Across Ejection Fraction Spectrum

Akshay S. Desai, MD, MPH

In a new pooled analysis of patients with heart failure (HF) from the DAPA-HF and DELIVER trials, dapagliflozin was found to significantly reduce the risk of cardiovascular death.

The treatment effects appeared consistent across ejection fraction (EF) levels, although higher rates of overall CV, sudden, and HF-associated deaths were observed among those with lower EF.

The reductions in CV death from dapagliflozin were principally driven by lower rates of sudden death and death from progressive HF.

“These data provide further evidence of CV death reductions with dapagliflozin across the spectrum of EF and offer additional mechanistic insights into the clinical benefits of SGLT2 inhibition in chronic HF,” said Akshay S. Desai, MD, MPH, Cardiovascular Division, Brigham and Women’s Hospital in a presentation at the Heart Failure Society of America (HFSA) 2022 annual scientific meeting.

Treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of the composite of worsening HF events or death from CV causes in previous trial findings, but specific causes of death were not measured.

In a prespecified analysis, Investigators pooled data from the DAPA-HF (n = 4,744 patients) and DELIVER (n = 6,263 patients) trials to uncover the effects of dapagliflozin on cause-specific mortality across the spectrum of EF.

Each trial randomly assigned patients with symptomatic HF to treatment with dapagliflozin (10 mg daily) or placebo, but enrolled adjacent populations with HF and reduced EF (EF ≤40%) and HF with mildly reduced or preserved ejection fraction (EF >40%), respectively.

The prespecified secondary analysis examined the adjudicated mode of death (CV, non-CV, undetermined) and the specific causes of CV death (HF, sudden death, myocardial infarction, stroke, or other CV) in the pooled populations of the 2 trials and its subgroups. Effects of randomized treatment on cause-specific mortality were estimated in Cox proportional hazards models.

Among a total of 11,007 patients in the pooled analysis, there were 1628 deaths during follow-up (mean age, 71.7 years; 1139 male [70.0%]). Of these deaths, 872 (53.5%) were attributed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) to undetermined causes.

From the CV deaths, 289 (33.1%; 17.8% of total deaths) were due to HF, 441 (50.6%; 27.1% of total deaths) were sudden, 69 (7.9%; 4.2% of total deaths) were due to stroke, 47 (5.4%; 2.9% of total deaths) to myocardial infarction, and 26 (3.0%; 1.6% of total deaths) were due to other CV causes.

Investigators noted the proportion of deaths attributed to CV causes (overall and specific cause) was inversely correlated with EF, due to higher proportions of sudden and HF death in the lower EF categories.

In the pooled population, dapagliflozin was associated with lower rates of all-cause death, CV death (HR, 0.86; 95% CI, 0.75 - 0.98; P = .02), and the composite of CV or unknown death.

Reductions in CV death were driven principally by 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). There were little differences observed in the rates of death from stroke or myocardial infarction.

The study, “Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction,” was published in JAMA Cardiology.