The DAPA-HF trial marks the beginning of a new era in the treatment of heart failure with reduced ejection fraction

Despite significant advances, heart failure remains a significant cause of death and disability worldwide. Unfortunately, the problem is growing and accordingly the cost of chronic care and hospitalization are escalating. Novel approaches are needed to reduce the burden of heart failure as well as improve the quality of life of these patients. The DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial is a landmark study that marks the beginning of a completely new era in the treatment of heart failure with reduced ejection fraction.1 In this global study, 4744 patients with heart failure and reduced ejection fraction (EF < 45%) were randomized to receive the sodium-glucose transport protein 2 inhibitor (SGLT2i) dapagliflozin 10 mg daily or matching placebo. In addition to evidence of reduced ejection fraction, patients were enrolled if they were symptomatic despite optimal heart failure therapy, had evidence of moderately elevated natriuretic peptides levels, and had an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2. Diabetes was neither an inclusion nor exclusion criteria. Dapagliflozin reduced the primary outcome—a composite of worsening heart failure or cardiovascular death—by 26% [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.65–0.85; P < 0.001]. Individual components of the primary outcome were reduced—worsening heart failure by 30% (HR 0.70, 95% CI 0.59–0.83) and cardiovascular mortality by 18% (HR 0.82, 95% CI 0.69–0.98). Importantly, all-cause mortality was reduced by 17% (HR 0.83, 95% CI 0.71–0.97). The key findings are summarized in Figure 1. Remarkably, these benefits were observed in addition to excellent standard of care which included angiotensin-converting enzyme inhibitors (56%), angiotensin receptor blocker (28%), beta-blockers (96%), and mineralocorticoid receptor antagonists (72%). Furthermore, in post hoc analyses, consistent benefits were observed in those treated with and without sacubitril–valsartan (HR 0.75, 95% CI 0.50–1.13 and HR 0.74, 95% CI 0.65–0.86, respectively). Most intriguingly, the benefits were entirely consistent in those with and without type 2 diabetes (HR 0.75, 95% CI 0.63–0.90 among those with type 2 diabetes and HR 0.73, 95% CI 0.60–0.88 among those without type 2 diabetes) and were similar across the entire spectrum of glycated haemoglobin (A1C, assessed either continuously or categorically). From a safety standpoint, rates of discontinuation were low and similar between both groups, and there were no excess volume depletion or renal side effects. Treatment with dapagliflozin was also associated with a significant improvement in patient-reported outcomes as assessed by the Kansas City Cardiomyopathy Questionnaire.2 Recent sub-analyses from the trial demonstrate efficacy and safety across the broad range of patient age,3 eGFR,4 and ejection fraction.2 Strikingly, the benefit was statistically significant by 28 days after treatment initiation.5

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