More Evidence For the Newest Guideline Directed Medical Therapy Pillar – Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (The DELIVER Trial)

By Jamie Diamond, MD on

Key Points:

  • The use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) has been previously established, but evidence in patients who are peri-hospitalization and with improved EF is lacking
  • The Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) Trial shows that dapagliflozin resulted in a lower risk of the primary composite (including cardiovascular death, HF hospitalization or urgent HF visit) in patients with HF and mildly reduced or preserved EF
  • Benefit of dapagliflozin was seen irrespective of EF and with no attenuation of treatment benefit in patients with highest EF or in inpatient setting
  • Dapagliflozin was proven to be effective among patients with a prior reduced EF which had recovered to >40%

Last year’s European Society of Cardiology (ESC) Congress brought exciting news for heart failure patients and practioners alike when the EMPEROR trial demonstrated a benefit for the use of empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), in patients with heart failure with preserved ejection fraction (HFpEF). This landmark trial led to the US Food and Drug Administration’s decision to include HFpEF in the drug’s indications. This evidence was also incorporated into the updated American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) Guidelines for the Management of HF, published in 2022. These guidelines give SGLTis a COR 2a recommendation for use in patients with HFpEF, stating that, “SGLT2i can be beneficial in decreased HF hospitalization and cardiovascular mortality”. Despite strong evidence for SGLT2i use in HF there are certain populations for whom evidence gaps remain, including patients with high EFs (>40%), those initiated on SGLT2i treatment in peri-hospitalization period, and patients who have HF with recovered EF.

This year’s late breakers at ESC includes the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) Trial (NCT03619213). Presented by Scott Solomon, MD (Harvard Medical School and Brigham and Women’s Hospital, Boston, MA), DELIVER is an international, multicenter, parallel-group, event-driven, randomized, double-blind study evaluating the effect of dapagliflozin 10 mg versus placebo on patients with mildly reduced or preserved EF. Eligibility criteria included patients ≥40 years with NYHA class II-IV HF, LVEF >40% (even if previously EF had been lower), structural heart disease (defined by left ventricular hypertrophy or left atrial enlargement), and elevated natriuretic peptides. Patients could be enrolled from either the inpatient or outpatient setting, which is a key difference than the EMPEROR-Preserved Trial. In his presentation, Dr. Solomon notes that DELIVER was novel in including a broader range of patients than prior trials since hospitalized or recently hospitalized patients as well as those who had previously reduced EF but improvement to ≥40% were also included. Ultimately 6,263 patients were randomized to the dapagliflozin or placebo arms. There was a ~14% discontinuation rate in both arms.

The DELIVER Trial showed that the primary endpoint which included cardiovascular (CV) death, HF hospitalization or urgent HF visit (deemed “worsening HF”) occurred in 9.6% per 100py in the placebo group vs. 7.8% per 100py in the dapagliflozin group (HR 0.82; 95% CI 0.73-0.92, p=0.0008, NNT =32). Curves diverge around the 6 month point and continue until 3 years post-randomization. In the breakdown of the primary composite, there is a signal for decreased CV death in the LVEF ≥60% group (HR 0.68, 95% CI 0.46-0.99). Several subgroups were evaluated during the trial and Dr. Solomon notes, “there is remarkable consistency among subgroups favoring dapagliflozin over placebo”. Notably, there was no attenuation of signal for patients with higher EFs and patients who were enrolled during or within 30 days of a HF hospitalization had a signal favoring dapagliflozin. Adverse event rates were similar in the 2 groups. Dr. Solomon therefore concludes that these data provide strong evidence supporting SGLT2i use in all HF patients, regardless of inpatient status, EF or absence of diabetes.

Look out for more exciting DELIVER news during this year’s 2022 ESC Congress as there will be additional studies released which involve prespecified meta-analyses combining DELIVER and DAPA-HF and the other DELIVER and EMPEROR.

The results were published in the New England Journal of Medicine today.

Written By:
Jamie Diamond, MD, MPH