Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction

Abstract

IMPORTANCEWomen may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men.OBJECTIVE 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 (DAPA-HF).DESIGN, SETTING, AND PARTICIPANTS Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021.INTERVENTIONS Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MAIN OUTCOMES AND MEASURESThe primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.RESULTS A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of Ն5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of Ն5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women.CONCLUSIONS AND RELEVANCE Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex.

Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction

“…A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years (eFigure 2 in Supplement 2). Baseline demographic characteristics of the study population have been previously reported . The distribution of age at randomization and at the time of a primary composite end point and death from any cause are shown in eFigure 3 in Supplement 2.…”

Efficacy of Implantable Cardioverter Defibrillator in Nonischemic Systolic Heart Failure According to Sex: Extended Follow-Up Study of the DANISH Trial

“…21–24 This is expected as women more often have HFrEF due to nonischemic causes than men. 2,8 The present analysis demonstrated substantial differences in the clinical profile between sexes, most of which confirmed known sex differences in HFrEF. 2,7,8 An interesting finding was the significantly higher proportion of women who had a CRT device.…”

“…2,8 The present analysis demonstrated substantial differences in the clinical profile between sexes, most of which confirmed known sex differences in HFrEF. 2,7,8 An interesting finding was the significantly higher proportion of women who had a CRT device. The high use of CRT in women is particularly striking because they seem to derive greater benefit from this therapy than men.…”

“…19 Whether this complex relationship is further modified by sex and (perhaps more interesting from a clinical perspective) whether the age cutoff for the effectiveness of ICD therapy is similar in men and women, is important to investigate given that women with HFrEF are older than men with this condition. 2,8…”

Dapagliflozin: A Review in Symptomatic Heart Failure with Reduced Ejection Fraction

“…In general, the effect of dapagliflozin on the primary composite endpoint was consistent across numerous prespecified patient subgroups, including age (≤ 65 vs > 65 years), body mass index (BMI; < 30 vs ≥ 30 kg/ m 2 ), LVEF (≤ vs > median), and NT-proBNP level (≤ vs > median) [13]. In prespecified analyses, dapagliflozin significantly reduced the risk of worsening HF or CV death regardless of gender [19], presence of T2DM [20], MRA use [21], etiology (ischemic vs non-ischemic HF) [22], and eGFR (< 60 vs ≥ 60 mL/min/1.73 m 2 ) [23]. In an exploratory analysis, dapagliflozin increased event-free survival from a primary composite event by 2.1 years for a patient aged 65 years [24].…”