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Dapagliflozin and Cause-Specific Mortality in HF Across Spectrum of EF
Quick Takes
- The reductions in CV death with dapagliflozin were driven principally by lower rates of sudden death and, to a lesser extent, death from progressive HF.
- These treatment effects appeared to be consistent across EF levels, despite higher rates of overall CV, sudden, and HF-associated deaths among patients with lower EF.
- These data provide support for the use of SGLT2 inhibitors to treat patients with symptomatic HF, regardless of LVEF.
Study Questions:
What are the effects of dapagliflozin on cause-specific cardiovascular (CV) and non-CV mortality across the spectrum of ejection fraction (EF)?
Methods:
The investigators conducted a participant-level, pooled, prespecified secondary analysis of data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial (participant left ventricular EF [LVEF] ≤40%), and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial (participant LVEF >40%), to assess the effects of randomized treatment on cause-specific mortality. The trials assigned adjacent populations of patients with chronic heart failure (HF), New York Heart Association class II-IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The primary outcome for each study was a composite of worsening HF events (hospitalization or urgent HF visits) or CV death. Clinical outcomes, including all deaths, were adjudicated as to cause by clinical endpoints committees blinded to treatment assignment. The mode of death in relation to baseline EF was examined, as well as the effect of randomized treatment on cause-specific death in Cox regression models. Relationships with continuous EF were modeled using Poisson regression.
Results:
Of 11,007 patients in the pooled dataset, there were 1,628 deaths during follow-up (mean [standard deviation] age, 71.7 [10.3] years; 1,139 male [70.0%]). Of those who died, 872 (53.5%) were ascribed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) to undetermined causes. Of CV deaths, 289 (33.1%; this represented 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. The proportion of non-CV deaths was higher in those with higher EF. In the pooled population, across the spectrum of EF, treatment with dapagliflozin was associated with lower rates of CV death (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.98; p = 0.02), principally due to lower rates of sudden death (HR, 0.84; 95% CI, 0.70-1.01; p = 0.07) and HF death (HR, 0.88; 95% CI, 0.70-1.11; p = 0.30), with little difference in rates of death from stroke or MI.
Conclusions:
The authors concluded that dapagliflozin significantly reduced risks of CV death with contributions from lower rates of sudden death and death from progressive HF across the full spectrum of LVEF.
Perspective:
This prespecified secondary analysis of cause-specific mortality in the DAPA-HF and DELIVER randomized clinical trials reports that the reductions in CV death with dapagliflozin were driven principally by lower rates of sudden death and, to a lesser extent, death from progressive HF. Furthermore, these treatment effects appeared to be consistent across EF levels, despite higher rates of overall CV, sudden, and HF-associated deaths among patients with lower EF. Overall, these data reinforce the consistent benefits of dapagliflozin on CV mortality regardless of EF and provide additional support for the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors to treat patients with symptomatic HF, regardless of LVEF.
Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure
Keywords: Death, Sudden, Geriatrics, Heart Failure, Metabolic Syndrome, Myocardial Infarction, Natriuretic Peptides, Secondary Prevention, Sodium-Glucose Transporter 2 Inhibitors, Stroke, Stroke Volume
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