Dapagliflozin Reduces Risk of Worsening HF and CV Death in HFrEF in Both Sexes

Hospital readmission rates for heart failure common.
Hospital readmission rates for heart failure common.
The objective of this study was to investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial.

Dapagliflozin is associated with a reduced risk for worsening heart failure (HF), cardiovascular death, and all-cause death in both men and women with heart failure with reduced ejection fraction (HFrEF), according to research results published in JAMA Cardiology.

Researchers sought to evaluate the efficacy and safety of dapagliflozin 10 mg vs placebo in a randomized, double-blind, placebo-controlled trial of patients with HFrEF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF], ClinicalTrials.gov Identifier NCT03036124).

The primary study outcome was the composite of an episode of worsening HF or cardiovascular death; secondary outcomes included HF hospitalization or cardiovascular death, total HF hospitalizations or cardiovascular death, change from baseline to 8 months in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), overall summary score (KCCQ-OSS), and clinical summary score (KCCQ-CSS).

The total cohort included 4744 patients (23.4% women); women within this cohort were older; more likely to be Black; and less likely to have atrial fibrillation (AF), chronic obstructive pulmonary disease, and anemia; and had a lower estimated glomerular filtration rate (eGFR). Women also had higher systolic blood pressure, heart rate, and baseline NT-proBNP.

Women in the cohort typically had a higher ejection fraction with lower KCCQ scores and worse New York Heart Association functional class compared with men and were more frequently treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

Investigators found that women had a lower risk for worsening HF or cardiovascular death (adjusted hazard ratio [aHR], 0.72; 95% CI, 0.61-0.85) and for the expanded composite outcome of the primary endpoint plus episodes of outpatient worsening (aHR, 0.80; 95% CI, 0.69-0.92) compared with men. These risks remained lower even after adjusting for prognostic variables including left ventricle ejection fraction and NT-proBNP.

In terms of the primary outcome, dapagliflozin reduced the risk associated with worsening HF or cardiovascular death to the same extent in both men and women (HR, 0.73 vs 0.79); no interaction was noted between sex and treatment effect. Dapagliflozin effect was consistent between men and women for all secondary endpoints. Mean increase in KCCQ-TSS from baseline to 8 months was 6.0 and 6.1, respectively, in the placebo and dapagliflozin groups; in men, the mean increase was 2.5 and 6.1 in these same groups. However, mean increases in KCCQ-CSS and KCCQ-OSS during this same time period were higher in the dapagliflozin group, with similar effects across men and women.

Researchers noted an initial increase in eGFR with dapagliflozin therapy in both men and women. Systolic blood pressure decreased in both groups, with no interaction between sex and dapagliflozin effect. Body weight also declined in both groups.

In patients with and without diabetes, dapagliflozin reduced risks for worsening HF, cardiovascular death, and all-cause death, regardless of sex.

In terms of safety, proportions of patients who discontinued initial treatment or experienced adverse events were similar by sex, but women were more likely than men to discontinue the study drug “for any reason.”

Study limitations include post hoc assessments of secondary and exploratory clinical outcomes by sex, a lower proportion of women in DAPA-HF, and a lack of generalizability to populations that include hospitalized or other very high-risk patients.

“In DAPA-HF, dapagliflozin…reduced the risk of worsening HF events, cardiovascular death, and all cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women,” the researchers concluded. “These findings provide further support for dapagliflozin as a new treatment option for patients with HFrEF.”

Disclosure: This clinical trial was supported by AstraZeneca. Please see the original reference for a full list of authors’ disclosures.


Butt JH, Docherty KF, Petrie MC, et al. Efficacy and safety of dapagliflozin in men and women with heart failure with reduced ejection fraction: a prespecified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial. JAMA Cardiol. Published online March 31, 2021. doi:10.1001/jamacardio.2021.0379