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Background: In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy following randomization to dapagliflozin or placebo. Methods: We examined the effects of study treatment in the following subgroups: no diuretic, diuretic dose equivalent to furosemide <40mg daily, 40mg daily and >40mg daily at baseline. We examined the primary composite endpoint of cardiovascular (CV) death or a worsening HF event, its components, all-cause death and symptoms. Results: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40mg, 1365 (29.6%) on 40 mg and 1204 (26.1%) of patients were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint across each of these subgroups: hazard ratio [HR]: 0.57 (95% CI 0.36-0.92), 0.83 (0.63-1.10), 0.77 (0.60-0.99) and 0.78 (0.63-0.97), respectively (P-interaction 0.61). The HR in patients taking any diuretic was 0.78 (0.68-0.90). Improvement in symptoms and treatment toleration was consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up and mean diuretic dose did not differ between the dapagliflozin and placebo group after randomization. Conclusions: The efficacy and safety of dapagliflozin was consistent across the diuretic subgroups examined in DAPA-HF. Clinical Trial Registration: DAPA-HF: ClinicalTrials.gov Identifier NCT03036124

Aims Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of ‘health deficits’ across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results Using a cumulative deficits approach, we constructed a 42‐item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM‐HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non‐frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI >0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all‐cause death or all‐cause hospitalization: 40.7 (39.1–42.4) vs. 22.1 (21.2–23.0) per 100 person‐years in the non‐frail; adjusted hazard ratio 1.63 (1.53–1.75) (P < 0.001). The rate of all‐cause hospitalizations, taking account of recurrences, was 61.5 (59.8–63.1) vs. 31.2 (30.3–32.2) per 100 person‐years (incidence rate ratio 1.76; 1.62–1.90; P < 0.001). Conclusion Frailty is highly prevalent in HFrEF and associated with greater deterioration in quality of life and higher risk of hospitalization and death. Strategies to prevent and treat frailty are needed in HFrEF.

Background Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure hospitalization in patients with heart failure and reduced ejection fraction.Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown. MethodsWe assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF trial, a 4744 patient trial comparing dapagliflozin to placebo in patients with heart failure and reduced ejection fraction. We evaluated whether treatment with sacubitril/valsartan at baseline modified the efficacy and safety of dapagliflozin, examining the primary and secondary efficacy endpoints and predefined safety assessments. Results 508 patients (10.9%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fraction, systolic and diastolic blood pressure, but were similar with respect to age, NYHA class, history of diabetes and use of other evidence-based heart failure therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (HR 0.75, 95% CI, 0.50, 1.13), compared with those not taking sacubitril/valsartan (HR 0.74, 95% CI, 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening heart failure; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to

Background: To describe characteristics and outcomes in women and men with heart failure (HF) and preserved ejection fraction (HFpEF). Methods & Results: Baseline characteristics (including biomarkers and quality-of-life) and outcomes (primary outcome: composite of first HF hospitalization or cardiovascular [CV] death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (EF ≥ 45%), I-Preserve and TOPCAT-Americas. Women were older and more often obese and hypertensive, but less likely to have coronary artery disease and atrial fibrillation. Women had more symptoms and signs of congestion, and worse quality-of-life. Despite this, the risk of the primary outcome was lower in women (HR 0.80; 95% CI 0.73-0.88), as was the risk of CV death (HR 0.70; 95% CI 0.62-0.80) but there was no difference in the rate for first hospitalization for HF (HR 0.92; 95% CI 0.82-1.02). The lower risk of CV death in women, compared with men, was in part explained a by a substantially lower risk of sudden death (HR 0.53, 0.43-0.65; P<0.001). E/A ratio was lower in women (1.1 vs 1.2). Conclusions: There are significant differences between women and men with HFpEF. Despite worse symptoms, more congestion, and lower quality-of-life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men.