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Aims: Among patients with heart failure (HF) and reduced ejection fraction (HFrEF), those with atrial fibrillation (AF) may respond differently to certain treatments than patients without AF. We investigated the efficacy and safety of dapagliflozin in patients with HFrEF with and without AF in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF). We also examined the effect of dapagliflozin on new‐onset AF. Methods and results: The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized, 1910 (40.3%) had 'any AF' (history of AF or AF on enrolment electrocardiogram). Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in patients with and without any AF [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.62–0.92 and 0.74, 95% CI 0.62–0.88, respectively; p for interaction = 0.88]. Consistent benefits were observed for the components of the primary outcome, all‐cause mortality, and improvement of Kansas City Cardiomyopathy Questionnaire total symptom score. Among patients without AF at baseline, dapagliflozin did not significantly reduce the risk of new‐onset AF compared with placebo (HR 0.86, 95% CI 0.60–1.22). However, patients with new‐onset AF had a 5 to 6‐fold higher risk of adverse outcomes when compared to those without incident AF. Conclusions: Dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all‐cause death, and improved symptoms, in patients with and without AF. Dapagliflozin did not reduce the risk of new‐onset AF. [ABSTRACT FROM AUTHOR]

Aims: Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis. We studied the relationship between HF diagnosis, use of LD, and outcomes in patients with type 2 diabetes mellitus (T2DM) enrolled in the EMPA-REG OUTCOME trial.Methods and Results: The relationship between HF diagnosis, use of LD, and outcomes was evaluated in four patient subgroups with T2DM: (i) investigator-reported HF on LD, (ii) investigator-reported HF not on LD, (iii) no HF on LD, and (iv) no HF and not on LD, and we assessed their risk of cardiovascular events. Of 7020 participants, 706 (10%) had a diagnosis of HF at baseline, of whom 334 were prescribed LD. However, 755 (11%) patients who did not have a diagnosis of HF were prescribed LD. Compared to those with neither HF nor prescribed LD (reference group; placebo), those with both HF and receiving LD had the highest rates for all-cause [hazard ratio (HR) (95% confidence interval) 3.19 (2.03-5.01)] and cardiovascular mortality [3.83 [(2.28-6.44)], and HF hospitalizations [9.51 (5.61-16.14)]. Patients without HF but prescribed LD had higher rates for all three outcomes [1.62 (1.10-2.39); 1.97 (1.26-3.08); 3.20 (1.90-5.39)], which were similar to patients with HF who were not receiving LD [1.42 (0.78-2.57); 1.56 (0.78-3.11); 3.00 (1.40-6.40)]. Empagliflozin had similar benefits regardless of subgroup (P for interaction >0.1 for all outcomes).Conclusion: Patients with T2DM prescribed LD are at greater risk of cardiovascular events even if they are not reported to have HF; this might reflect under-diagnosis. Empagliflozin was similarly effective in all subgroups investigated. [ABSTRACT FROM AUTHOR]

Aim: Anaemia is common in heart failure and associated with worse outcomes. We examined the effect of dapagliflozin on correction of anaemia in patients with heart failure (HF) and reduced ejection fraction in DAPA‐HF. We also analysed the effect of dapagliflozin on outcomes, according to anaemia status at baseline. Methods and results: Anaemia was defined at baseline as a haematocrit <39% in men and <36% in women. Resolution of anaemia was defined as two consecutive haematocrit measurements above these thresholds at any time during follow‐up. The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized in DAPA‐HF, 4691 had a haematocrit available at baseline, of which 1032 were anaemic (22.0%). The rate of the primary outcome was higher in patients with anaemia (16.1 per 100 person‐years) compared with those without (12.9 per 100 person‐years). Anaemia was corrected in 62.2% of patients in the dapagliflozin group, compared with 41.1% of patients in the placebo group. The effect of dapagliflozin on the primary outcome was consistent in anaemic compared with non‐anaemic patients [hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.52–0.88 vs. HR 0.76, 95% CI 0.65–0.89; interaction P = 0.44]. Similar findings were observed for cardiovascular death, HF hospitalization, and all‐cause mortality. Patients with resolution of anaemia had better outcomes than those in which anaemia persisted. Conclusion: Patients with anaemia had worse outcomes in DAPA‐HF. Dapagliflozin corrected anaemia more often than placebo and improved outcomes, irrespective of anaemia status at baseline. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of incident heart failure hospitalization in individuals with type 2 diabetes who have, or are at high risk of, cardiovascular disease. Most patients in these trials did not have heart failure at baseline and the effect of SGLT2 inhibitors on outcomes in individuals with established heart failure (with or without diabetes) is unknown.Design and Methods: The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) is an international, multicentre, parallel group, randomized, double-blind, study in patients with chronic heart failure, evaluating the effect of dapagliflozin 10 mg, compared with placebo, given once daily, in addition to standard care, on the primary composite outcome of a worsening heart failure event (hospitalization or equivalent event, i.e. an urgent heart failure visit) or cardiovascular death. Patients with and without diabetes are eligible and must have a left ventricular ejection fraction ≤ 40%, a moderately elevated N-terminal pro B-type natriuretic peptide level, and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 . The trial is event-driven, with a target of 844 primary outcomes. Secondary outcomes include the composite of total heart failure hospitalizations (including repeat episodes), and cardiovascular death and patient-reported outcomes. A total of 4744 patients have been randomized.Conclusions: DAPA-HF will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in a broad spectrum of patients with heart failure and reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to examine whether left ventricular ejection fraction (LVEF) modified efficacy and safety of dapagliflozin 10 mg compared with placebo in the 4744 patients with LVEF ≤40% randomized in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).Methods and Results: We examined whether LVEF, analysed categorically or continuously, modified the effect of dapagliflozin. The primary efficacy outcome was the composite of a worsening heart failure (HF) event (unplanned HF hospitalization/an urgent HF visit requiring intravenous therapy) or cardiovascular death. Mean LVEF was 31.1% and LVEF categories analysed were: <26% (n = 1143), 26-30% (n = 1018), 31-35% (n = 1187), and >35% (n = 1396). Each 5% decrease in LVEF was associated with a higher risk of the primary outcome [hazard ratio (HR) 1.18; 95% confidence interval (CI) 1.13-1.24]. The benefit of dapagliflozin was consistent across the spectrum of LVEF: the dapagliflozin vs. placebo HR was 0.75 (95% CI 0.59-0.95) for LVEF <26%, 0.75 (0.57-0.98) for LVEF 26-30%, 0.67 (0.51-0.89) for LVEF 31-35%, and 0.83 (0.63-1.09) for LVEF >35% (P for interaction = 0.762). Similarly, the effect of dapagliflozin on the components of the primary endpoint was not modified by baseline LVEF (P for interaction for cardiovascular death = 0.974, and for worsening HF = 0.161). Safety of dapagliflozin was also consistent across the range of LVEF and neither efficacy nor safety were modified by diabetes status.Conclusion: Left ventricular ejection fraction was a significant predictor of hospitalization and mortality in patients with HF with reduced ejection fraction but did not modify the beneficial effect of dapagliflozin, overall or separately, in patients with and without diabetes.Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03036124. [ABSTRACT FROM AUTHOR]

Aims: Atrial fibrillation (AF) is common in patients with diabetes and heart failure (HF) and increases the future risk of adverse cardiovascular (CV) outcomes. This analysis from the EMPA-REG OUTCOME trial explores CV and renal outcomes in patients with vs. without AF at baseline and assesses the benefits of empagliflozin.Methods and Results: Analyses were conducted on patients distinguished by the presence (n = 389) or absence (n = 6631) of AF at baseline. Outcome events were more frequent in patients with AF than those without AF. Empagliflozin compared to placebo reduced CV death or HF hospitalisation consistently in patients with AF [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.36-0.92] and without AF (HR 0.67, 95% CI 0.55-0.82, Pinteraction  = 0.56). Similar results were observed for the components of this endpoint, all-cause mortality, new or worsening nephropathy, first introduction of loop diuretics, or occurrence of oedema. The absolute number of prevented events was higher in patients with AF, resulting in larger absolute treatment effects of empagliflozin. New loop diuretics or oedema were associated with increased rates of subsequent events, and rates appeared lower in those randomised to empagliflozin.Conclusions: In patients with type 2 diabetes mellitus and established CV disease, those with AF at baseline had higher rates of adverse HF outcomes than those without AF. Irrespective of the presence of AF, empagliflozin reduced HF-related and renal events. The absolute number of prevented events is higher in patients with AF than without AF. Patients with diabetes, CV disease and AF may especially benefit from use of empagliflozin. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to: (i) report the baseline characteristics of patients enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial, (ii) compare DAPA-HF patients to participants in contemporary heart failure (HF) registries and in other recent HF trials, and (iii) compare individuals with diabetes, pre-diabetes and a normal glycated haemoglobin (HbA1c) in DAPA-HF.Methods and Results: Adults with HF in New York Heart Association functional class ≥ II, a left ventricular ejection fraction ≤ 40%, an elevated N-terminal pro-B-type natriuretic peptide concentration and receiving standard treatment were eligible for DAPA-HF, which is comparing dapagliflozin 10 mg once daily to matching placebo. In patients without a history of diabetes, previously undiagnosed diabetes was defined as a confirmed HbA1c ≥ 6.5%. Among patients without known or undiagnosed diabetes, pre-diabetes was defined as a HbA1c ≥ 5.7% The remainder of patients, with a HbA1c < 5.7%, were defined as normoglycaemic. Of the 4744 patients (mean age 66 years; 23% women) randomized, 42% had known diabetes and 3% undiagnosed diabetes. Of the remainder, 67% had pre-diabetes and 33% normal HbA1c. Overall, DAPA-HF patients were generally similar to those in recent registries and in relevant trials and had high levels of background therapy: 94% angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 96% beta-blocker, and 71% mineralocorticoid receptor antagonist; 26% had a defibrillator. Patients with diabetes had worse HF status, more co-morbidity, and greater renal impairment but received similar HF therapy. Patients with diabetes received non-insulin hypoglycaemic therapy alone in 49%, insulin alone in 11%, both in 14%, and none in 26%.Conclusions: Patients randomized in DAPA-HF were similar to those in other contemporary HF with reduced ejection fraction (HFrEF) registries and trials. These patients were receiving recommended HFrEF therapy and those with diabetes were also treated with conventional glucose-lowering therapy. Consequently, DAPA-HF will test the incremental efficacy and safety of dapagliflozin in HFrEF patients with and without diabetes.Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03036124. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions The primary aim was to evaluate the effect of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction (LVEF), given that prolongation of QRS duration is associated with less favourable ventricular remodelling with pharmacological therapy and worse outcomes.A pooled analysis of the DAPA‐HF and DELIVER trials, excluding patients with a paced rhythm and cardiac resynchronization therapy. Overall, 4008 patients had heart failure (HF) with reduced ejection fraction (HFrEF), and 5816 had HF with mildly reduced/preserved ejection fraction (HFmrEF/HFpEF). QRS duration was <120 ms in 7039 patients (71.7%), 120–149 ms in 1725 (17.6%), and ≥150 ms in 1060 patients (10.8%). The median follow‐up time was 23 months. The rate of the primary composite outcome of cardiovascular death or worsening HF was 9.2 (95% confidence interval [CI] 8.7–9.7), 14.3 (13.0–15.7), and 15.9 (14.1–17.9) per 100 patient‐years in the <120, 120–149, and ≥150 ms groups, respectively. This gradient in event rates was observed both in HFrEF and HFmrEF/HFpEF. Dapagliflozin, compared with placebo, reduced the risk of the primary outcome consistently across the QRS duration subgroups (hazard ratio [95% CI] 0.75 [0.67–0.85], 0.79 [0.65–0.96], and 0.89 [0.70–1.13] in the <120, 120–149, and ≥150 ms groups, respectively; p for interaction = 0.28). The effect of dapagliflozin on the primary outcome was consistent across the QRS duration regardless of HF phenotype that is, HFrEF or HFmrEF/HFpEF.Prolongation of QRS duration is associated with worse outcomes irrespective of HF phenotype. Dapagliflozin reduced the risk of the primary outcome, regardless of QRS duration, in DAPA‐HF and DELIVER. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Methods and results Conclusions Although much is known about the usefulness of heart failure (HF)‐specific instruments for assessing patient well‐being, less is known about the value of generic instruments for the measurement of health‐related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5‐dimension 5‐level (EQ‐5D‐5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores.We performed a patient‐level pooled analysis of the DAPA‐HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ‐5D‐5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator‐reported (New York Heart Association class) and patient‐self‐reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N‐terminal pro‐B‐type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ‐5D‐5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72–0.91) in Q2, 0.74 (0.65–0.84) in Q3, and 0.62 (0.54–0.72) in Q4. The risk of each component of the composite outcome, and all‐cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ‐5D‐5L VAS and index scores across the range of ejection fraction.Both higher (better) EQ‐5D‐5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ‐5D‐5L VAS and index scores, irrespective of ejection fraction. [ABSTRACT FROM AUTHOR]