DELIVER study - dapagliflozin in heart failure with mildly reduced or preserved ejection fraction

DELIVER study - Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

Treatment with the SGLT2 inhibitor empagliflozin was shown to reduce the combined risk of hospitalization for heart failure or cardiovascular death among patients with heart failure and a left ventricular ejection fraction of more than 40%, a finding that suggests that the benefits of SGLT2 inhibition may extend to all patients with heart failure, regardless of the left ventricular ejection fraction (1).

The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) study investigated the use of dapagliflozin in heart failure with mildly reduced or preserved ejection fraction:

Methodology:

• randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy
• primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis

Study Results:

• over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001)
  • worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91)
  • cardiovascular death occurred in 231 patients in the dapagliflozin group (7.4%) and 261 patients (8.3%) in the placebo group, respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05)
  • total events and symptom burden were lower in the dapagliflozin group than in the placebo group
  • results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes
  • incidence of adverse events was similar in the two group

Conclusion:

• dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction
• a pre-specified analysis showed that benefit of dapagliflozin was consistent across range of frailty studied & improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with greater frailty (3)
• treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared with those without, and has the additional benefit of causing modest weight loss (4)
  • applying the HR for the trial overall to each BMI category gave an NNT for the primary outcome in patients with Class III obesity of only 22 (over the median DELIVER follow up of 2.3 years), compared with 31 in patients with a normal weight, indicating a greater absolute benefit in obese individuals because of their higher absolute risk of this outcome
  • patients with greater obesity had markedly worse health status at baseline and, importantly, this was improved following randomization to dapagliflozin
    • the improvement was greatest in patients with the highest BMI
• a prespecified analysis of the DELIVER RCT found dapagliflozin reduced the risk of the composite of cardiovascular death and heart failure events similarly across the spectrum of baseline kidney function; and slowed the rate of eGFR decline versus placebo (5)

Reference:

• Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451-1461
• Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, Jhund PS, Belohlavek J, Chiang CE, Borleffs CJW, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer-Gamba MA, Al Habeeb W, Han Y, Cabrera Honorio JW, Janssens SP, Katova T, Kitakaze M, Merkely B, O'Meara E, Saraiva JFK, Tereshchenko SN, Thierer J, Vaduganathan M, Vardeny O, Verma S, Pham VN, Wilderäng U, Zaozerska N, Bachus E, Lindholm D, Petersson M, Langkilde AM; DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Aug 27.
• Butt JH et al. Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure: A Prespecified Analysis of the DELIVER Trial. Circulation. 2022 Aug 27
• Adamson C et al. Dapagliflozin for heart failure according to body mass index: the DELIVER trial, European Heart Journal, 2022;, ehac481, https://doi.org/10.1093/eurheartj/ehac481
• Mc Causland FR, Claggett BL, Vaduganathan M, et al. Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol. Published online November 03, 2022.