Summary of DAPA-HF: dapagliflozin in patients with heart failure and reduced ejection fraction

Summary of DAPA-HF: dapagliflozin in patients with heart failure and reduced ejection fraction
McKenzie Moore, PharmD, St. Cloud VA

Background: Patients with type 2 diabetes mellitus treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to have a reduced risk of hospitalization for heart failure in clinical trials. This finding was largely driven by preventing heart failure as the majority of patients included in previous trials did not have a history of heart failure. Although SGLT2 inhibitors were previously untested in this population, patients with a history of heart failure without a diagnosis of diabetes may benefit from the use of SGLT2 inhibitors considering the diuretic and related hemodynamic actions of this medication class.  

Objective: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was designed to determine if the SGLT2 inhibitor dapagliflozin (FarxigaⓇ) could be used safely and efficaciously in the treatment of patients with heart failure and reduced ejection fraction, regardless of diabetes history.

Study Design: DAPA-HF was a randomized, placebo-controlled trial. Patients were required to have an ejection fraction of 40% or less and meet specified N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels that varied based on history of hospitalization or presence of atrial fibrillation. Those with type one diabetes, symptomatic hypotension or systolic blood pressure less than 95 mmHg, or severe renal disease (eGFR <30 ml/min) were excluded. Patients were stratified based on diagnosis of diabetes. Standard heart failure device therapy such as implantable cardioverter-defibrillator and/or cardiac resynchronization therapy and guideline directed medical treatment were required. For patients with diabetes included in the study, additional glucose-lowering therapies were adjusted if necessary. Due to extensive exclusion criteria, 40% of patients screened did not meet eligibility criteria. A total of 4,744 patients were randomly assigned to receive either dapagliflozin 10 mg daily or matching placebo. The primary outcome was a composite of worsening heart failure (unplanned hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or death from cardiovascular causes.  Secondary outcomes also included a composite of worsening renal function and the change from baseline to 8 months in the total symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a self-administered questionnaire used to evaluate symptoms, limitations, and quality of life in patients with congestive heart failure.

Results: The mean ejection fraction in both treatment and placebo groups was approximately 31% and each group included 45% with diabetes. The primary composite outcome of worsening heart failure or death from cardiovascular causes occurred in 386 patients (16.3%) in the dapagliflozin group and in 502 patients (21.2%) in the placebo group (HR 0.74 [95% CI 0.65 – 0.85] P<0.001). Each component of the primary composite outcome favored dapagliflozin over placebo. During the median trial period of 18 months, the number needed to treat was 21 patients to prevent one primary event [95% CI 15-38]. Results of total symptom score on the KCCQ were improved in the dapagliflozin group with increase in score of at least 5 points in 58.3% of dapagliflozin patients and 50.9% in the placebo group (OR 1.15 [95% CI 1.08 – 1.23] P<0.001). The composite of worsening renal function did not differ between groups. Safety outcomes were similar in dapagliflozin and placebo groups with 111 and 116 patients discontinuing treatment due to adverse events, respectively (P=0.79). Major hypoglycemia, defined as requiring assistance from another person, was reported in 4 patients in each group and all occurred in patients with diabetes at baseline.  Volume depletion related adverse events occurred in 29 (1.2%) dapagliflozin patients and 40 (1.7%) placebo patients (P=0.23). Fournier’s gangrene was also included in the prespecified safety analysis with only one reported case seen in the placebo group.

Conclusions: In patients with reduced ejection fraction heart failure receiving dapagliflozin in addition to standard therapy, risk of worsening heart failure or death from cardiovascular disease is decreased and symptom scores are improved. These benefits are seen regardless of history of diabetes. The mechanism for benefit is still unclear at this time with many possibilities proposed and further research needed.  More studies will be necessary to establish a place for SGLT2 inhibitors in heart failure therapy. This trial did not report dosing of standard heart failure therapy to determine if target doses had been reached. Additionally, few patients were included with severe heart failure and subgroup analysis suggests benefit may be less in those with NYHA functional class III and IV compared to class II. Trials currently underway will evaluate the role of other SGLT2 inhibitors in patients with reduced and preserved ejection fraction both with and without diabetes.     

Key Point: Regardless of presence or absence of diabetes, dapagliflozin use decreased the incidence of worsening heart failure or death from cardiovascular causes. Although the place in heart failure therapy for SGLT2 inhibitors is not yet defined, pharmacists should be aware of the potential benefit of adding dapagliflozin, particularly for patients with mild heart failure.

Reference:

  1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction [published online September 19, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1911303.