Sodium–glucose co-transporter-2 (SGLT2) inhibitors are now established to reduce the risk of heart failure (HF) hospitalization and cardiovascular death across the spectrum of left ventricular ejection fractions. However, scant evidence is available to support starting HF therapies in hospitalized or recently discharged patients with preserved ejection fraction.
In a prespecified secondary analysis of the DELIVER trial, Scott D. Solomon, MD, director of the Clinical Trials Outcomes Center at Brigham and Women’s Hospital, and colleagues found that starting dapagliflozin during or shortly after hospitalization for HF is safe and effective for patients with mildly reduced or preserved ejection fraction. The research team published their results in the Journal of the American College of Cardiology.
The multicenter, double-blind DELIVER trial compared dapagliflozin 10 mg daily with placebo in 6,263 patients with HF who had mildly reduced, preserved, or improved ejection fraction.
654 patients were randomized while hospitalized for HF or within 30 days of hospital discharge. They were required to have been clinically stable and off intravenous HF therapies for at least 12 hours before enrollment and 24 hours before randomization.
The primary outcome for the current analysis and the main trial was a composite of cardiovascular death or a worsening HF event. The latter was defined as either HF hospitalization or an urgent outpatient visit for HF.
Patients with recent HF hospitalization experienced significantly higher rates of rehospitalization and death than patients not recently hospitalized (P<0.001 for all comparisons):
- Primary composite outcome—HR, 2.21
- Cardiovascular death—HR, 2.11
- Worsening HF event—HR, 2.30
- HF hospitalization—HR, 2.42
- All-cause mortality—HR, 1.68
- Total (first and recurrent) worsening HF events and cardiovascular deaths (rate ratio, 2.44)
The greater risk of all outcomes persisted after adjustment for 14 preselected covariates: age, sex, geographic region, history of atrial fibrillation or flutter, stroke, type 2 diabetes, chronic obstructive pulmonary disease, coronary artery disease, smoking status, New York Heart Association functional class III or IV compared with II, ejection fraction, systolic blood pressure, estimated glomerular filtration rate, and N-terminal prohormone of B-type natriuretic peptide concentration.
Relative Efficacy of Dapagliflozin
Dapagliflozin had a beneficial effect on clinical outcomes regardless of recent HF hospitalization:
- Primary composite outcome—HR, 0.78 in recently hospitalized patients vs. 0.82 in those without recent hospitalization (P=0.71), with no evidence of effect modification by ejection fraction
- HF hospitalization—HR, 0.76 vs. 0.77 (P=0.90)
- Cardiovascular death—HR, 0.85 vs. 0.89 (P=0.77)
- All-cause mortality—HR, 0.96 vs. 0.94 (P=0.95)
- Total worsening HF events and cardiovascular deaths—rate ratio, 0.69 vs. 0.79 (P=0.46)
Dapagliflozin compared with placebo similarly improved the total symptom score on the Kansas City Cardiomyopathy Questionnaire at 32 weeks after randomization.
Relative Safety of Dapagliflozin
In patients with recent HF hospitalization, rates of serious adverse events were statistically similar between treatment groups, including volume depletion, diabetic ketoacidosis, and renal events. Rates of adverse events leading to study drug discontinuation were also similar.
Better Uptake of SGLT2 Inhibitors Needed
Many clinical trials of HF drugs have excluded recently hospitalized patients, so, understandably, physicians may hesitate to start new therapies during this vulnerable period. However, this analysis indicates dapagliflozin was well tolerated. The overall findings are consistent with those of the SOLOIST-WHF and EMPULSE trials of other SGLT2 inhibitors in hospitalized patients with worsening HF.
Physicians can feel reassured by the evidence that it is appropriate to consider initiating an SGLT2 inhibitor for patients with HF regardless of the clinical setting (in-hospital, shortly after discharge, or in the outpatient setting).