Patient Population: Adults (≥18 years) with ejection fraction (EF) ≤ 40%, NYHA II-IV symptoms, NT-proBNP ≥ 600 pg/mL (≥ 400 pg/mL if heart failure (HF) hospitalization in last year; ≥ 900 pg/mL if AFib/flutter) receiving standard HF device (ICD, CRT, or both) and standard drug therapy (angiotensin converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB) or angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, unless contraindicated or not tolerated, with mineralocorticoid receptor antagonist (MRA) use encouraged). Those with recent treatment with or intolerance to an SGLT2 inhibitor, T1DM, hypotension symptoms or SBP < 95 mmHg, eGFR < 30 mL/min/1.73m2, or rapidly declining renal function were excluded.

Intervention (n = 2,373): Dapagliflozin 10 mg PO daily

Comparison (n = 2,371): Matching placebo PO daily

Outcome: Primary outcome: composite of worsening HF (unplanned hospitalization or urgent visit for IV HF therapy) or death from cardiovascular causes over a median of 18 months

Categories for risk of bias include:

Low risk of bias (green), unclear/possible risk of bias (yellow), high risk of bias (red)

The primary outcome was a composite of worsening HF, including either an unplanned hospitalization or an urgent visit resulting in IV HF therapy, or death from cardiovascular causes. Worsening HF (hospitalization or urgent visit resulting in IV therapy for heart failure occurred in 386 patients (16.3%) in the dapagliflozin group and 502 patients (21.2%) in the placebo group (HR 0.74; 95% CI 0.65–0.85; P <0.001). A first worsening HF event occurred in 237 patients (10%) in the dapagliflozin group and 326 patients (13.7%) in the placebo group (HR 0.70; 95% CI 0.59–0.83; P-value not given). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and 273 patients (11.5%) in the placebo group (HR 0.82; 95% CI 0.69–0.98; P value not given). It is evident that the event rates for all three components of the primary composite outcome favored dapagliflozin.

Most adverse events that were evaluated in this study were uncommon and not statistically different between study groups. However, serious renal adverse events were significantly lower in the dapagliflozin group compared with placebo. While serious volume depletion events were numerically lower in the dapagliflozin group, the difference between groups did not reach statistical significance.

Healthcare Professional Summary

The DAPA-HF trial evaluated the safety and efficacy of dapagliflozin in patients with HF with reduced ejection fraction regardless of the presence of diabetes. It was an international, multi-center, randomized, placebo-controlled study, with blinding of patients and all study personnel, a low percent of patients without final outcomes, and analyzed with the intention-to-treat principle. The primary outcome of the trial showed an absolute risk reduction of 4.9% and a relative risk reduction of 23.2%, with an NNT of 20, demonstrating that the composite outcome of worsening heart failure or death from cardiovascular causes was lower in the dapagliflozin group relative to placebo. Dapagliflozin was well tolerated with notable adverse reactions reported being volume depletion and renal adverse events in a similar number of events for both groups, and severe renal adverse events being lower with dapagliflozin. There are limitations when considering the generalizability of this study since the majority of the study population were classified as moderate heart failure. Additionally, the study demonstrated that there is a differential benefit between NYHA classes, with the primary benefit attributed to those classified as NYHA FC II. The ideal population for treatment with dapagliflozin are adults with HF with reduced ejection fraction and NYHA FC II–III symptoms, who are receiving standard HF device therapy (ICD, CRT or both) and standard drug therapy (ACEi/ARB/ARNI and beta-blocker unless contraindicated or resulting in unacceptable side effects), with MRA use being encouraged.

Patient Summary

Dapagliflozin is a medication that is taken once daily by mouth and is primarily used in patients with type 2 diabetes mellitus to lower blood sugar levels through the kidneys. Previous studies have shown that medications in the same class as dapagliflozin reduce the risk of hospitalization for heart failure. In this study, patients with a weak heart, known as, heart failure, with or without type 2 diabetes mellitus who took dapagliflozin had a lower chance of worsening heart failure (leading to a hospital admission or IV therapy) or death from heart-related problems including, heart attack, shock, and stroke compared with patients who took standard heart failure therapy. The main side effects of dehydration and kidney injury were not different between groups, and more serious kidney injury happened less often with dapagliflozin. While it may cost more to use dapagliflozin relative to other medications used to treat type 2 diabetes, this medication has the added benefit of lowering heart-related events in combination with standard treatment in patients with heart failure who may or may not have diabetes

About the Authors

Anthony Sengul, BSc, is a PharmD candidate at Western University of Health Sciences, California. He received his bachelor’s degree in biological sciences with concentration in medical biology in 2012 from the University of California, Riverside. He has no conflicts of interest to report.

Edison Escobar, BSc, is a PharmD candidate at Western University of Health Sciences, College of Pharmacy. He received his bachelor’s degree in biology in 2016 from California State University, Los Angeles. He has no conflicts of interest to report.

Cynthia Jackevicius, BScPhm, PharmD, MSc, BCPS, BCCP, FCSHP, FAHA, FCCP, FCCS, FACC, a Professor of Pharmacy Practice at Western University of Health Sciences, is the Evidence-Based Practice Section Editor. Dr. Jackevicius teaches evidence-based practice skills to health care professionals. She advocates for the adoption of an evidence-based practice, incorporating the best available evidence, patients’ values and preferences, and clinicians’ expertise into clinical decision-making. She has no conflicts of interest to report.

Citation: McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008.