Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients.

AIMS: The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the prospective comparison of ARNI with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of LCZ696 on mode of death. METHODS AND RESULTS: PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure, New York Heart Association Class II-IV symptoms, and left ventricular ejection fraction ≤40% receiving guideline-recommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72-0.89, P < 0.001). Among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68-0.94, P = 0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64-0.98, P = 0.034) were reduced by treatment with LCZ696 compared with enalapril. Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and distributed evenly between treatment groups, as were non-cardiovascular deaths. CONCLUSIONS: LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, NCT01035255.

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.

Importance: In 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. Objective: To examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF. Design, Setting, and Participants: This 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. Intervention: Dapagliflozin vs placebo. Main Outcomes and Measures: 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 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 Relevance: In 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 Registration: ClinicalTrials.gov Identifier: NCT03036124, NCT03619213.