Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction

Abstract

ImportanceIn 2 trials enrolling patients with heart failure (HF) across the spectrum of ejection fraction (EF), dapagliflozin has been shown to reduce the rate of the composite of worsening HF events or death from cardiovascular (CV) causes.ObjectiveTo examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF.Design, Setting, and ParticipantsThis was a participant-level, pooled, prespecified secondary analysis of data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, or DAPA-HF trial (participant left ventricular EF [LVEF] ≤40%), and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure, or DELIVER trial (participant LVEF >40%), to assess the effects of randomized treatment on cause-specific mortality. The trials assigned adjacent populations of patients with chronic 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 heart failure visits) or CV death. Clinical outcomes, including all deaths, were adjudicated as to cause by clinical end points committees blinded to treatment assignment.InterventionDapagliflozin vs placebo.Main Outcomes and MeasuresThe 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.ResultsOf 11 007 patients in the pooled data set, there were 1628 deaths during follow-up (mean [SD] age, 71.7 [10.3] years; 1139 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% CI, 0.75-0.98; P = .02), principally due 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), with little difference in rates of death from stroke or MI.Conclusions and RelevanceIn a pooled analysis of patients with HF in the DAPA-HF and DELIVER randomized clinical trials, across the full spectrum of LVEF, dapagliflozin significantly reduced risks of CV death with contributions from lower rates of sudden death and death from progressive HF.Trial RegistrationClinicalTrials.gov Identifier: NCT03036124, NCT03619213

Efficacy of SGLT2-inhibitors across different definitions of heart failure with preserved ejection fraction

“…Conversely, cardiovascular death was not significantly less frequent with SGLT2i than with placebo. This is not surprising, as non-cardiovascular death is predominant in HFpEF 30 and the influence of SGLT2i on mortality is limited 31 . Interestingly, it has recently been suggested that SGLT2i may affect the risk of sudden cardiac death in HFpEF 32 .…”

“…This is not surprising, as non-cardiovascular death is predominant in HFpEF 30 and the influence of SGLT2i on mortality is limited. 31 Interestingly, it has recently been suggested that SGLT2i may affect the risk of sudden cardiac death in HFpEF. 32 As this meta-analysis was based on aggregate data with no distinction of the modes of death, we cannot address this observation.…”

Unsupervised Clustering Applied to Electronic Health Record-derived Phenotypes in Patients with Heart Failure

“…24 The limitations of LVEF in categorizing HF are well-recognized 28 , and several therapies have been proven to be of benefit regardless of LVEF. 29,30 Recent changes in the nomenclature of HF subtype classification 31 have signaled a reconsideration of the determinants of patient eligibility for HF therapies. The results of our cluster analysis align with this position by demonstrating the importance of the underlying pathophysiological features of HF.…”

Cardiac assessment and management in older surgical patients

“…61 A major recent change has been sodium-glucose cotransporter 2 inhibitors (eg, empagliflozin, dapagliflozin), which improve outcomes in both HFpEF and HFrEF. 61,65,66 Preexisting HF is a recognized risk factor for postoperative mortality and morbidity. 67 The associated risks of 90-day mortality are even higher for individuals with symptomatic versus asymptomatic HF, and individuals with progressively reduced systolic dysfunction.…”

“…Importantly, most medical therapy for improving morbidity and mortality in HF has only shown efficacy in HFrEF, including ACE inhibitors, ARBs, and beta-blockers 61. A major recent change has been sodium-glucose cotransporter 2 inhibitors (eg, empagliflozin, dapagliflozin), which improve outcomes in both HFpEF and HFrEF 61,65,66…”