Analysis Details Effects of Dapagliflozin on Total Events in HFmrEF, HFpEF

John McMurray, MD
Credit: European Society of Cardiology

A prespecified analysis of the DELIVER trial is offering more insight into the effects of dapagliflozin on total events and cardiovascular death for patients with heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF).

Results of the study, which used the proportional rates approach of Lin, Wei Yang, and Ying (LWYY) and a joint frailty model to estimate effects of use, demonstrate use was associated with a reduction in the rate of total heart failure events, regardless of patient characteristics, including ejection fraction.

“In patients with HFmrEF or HFpEF, dapagliflozin reduced the risk of total HF events, ie, repeated in addition to first events. This benefit was observed in all the prespecified DELIVER subgroups and across the spectrum of EF,” investigators wrote. “The characteristics associated with multiple HF events in this population with HFmrEF or HFpEF were similar to those in patients with HFrEF experiencing multiple hospitalizations.”

The SGLT2 inhibitor class, led by dapagliflozin and empagliflozin, have reshaped the modern understanding and approach to management of cardiometabolic disease.² Although the agent has yet to receive an expanded indication for those with an elevated ejection fraction, the class received a Class 1 recommendation in heart failure with reduced ejection fraction and a Class 2a recommendation in HFpEF in the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America heart failure guidelines.³

Launched in 2018 after proving benefit in heart failure with reduced ejection (HFrEF), the DELIVER trial was designed with the intent of exploring the effects of dapagliflozin on a composite endpoint of cardiovascular death and worsening heart failure relative to placebo therapy among a cohort of patients with ejection fractions greater than 40%.⁴

The trial enrolled 6263 patients from August 27, 2017-December 30, 2020, and randomized them in a 1:1 ratio to 10 mg dapagliflozin once-daily or matching placebo. The initial results of the DELIVER trial, which were presented at the European Society of Cardiology 2021 Congress, demonstrated use of dapagliflozin was associated with an 18% relative reduction in risk of the trial’s primary composite endpoint of worsening heart failure and cardiovascular death. During the trial, a total of 1057 heart failure events and cardiovascular deaths occurred among the placebo group as compared to the dapagliflozin group.⁴

The current study, which was led by John McMurray, MD, of the British Heart Foundation Cardiovascular Research Centre at the University of Glasgow, was a prespecified analysis aimed at evaluating the effects of dapagliflozin use on total episodes of worsening heart failure and cardiovascular death in groups stratified according to ejection fraction. With this in mind, the analysis was designed to calculate proportional rates using the LWYY approach and a joint frailty model to examine the effects on total events and cardiovascular death.¹

Upon analysis, results indicated patients with more heart failure events had similar ejection fractions as those with no heart failure events, but did have features of more severe heart failure, including greater N-terminal pro–B-type natriuretic peptide level, worse kidney function, more prior heart failure hospitalizations, and longer duration of heart failure. In the LWYY model, results suggested the rate ratio for total events and cardiovascular death for dapagliflozin relative to placebo was 0.77 (95% Confidence interval [CI], 0.67-0.89; P <.001). Investigators pointed out the hazard ratio in a traditional time to first event analysis was 0.82 (95% CI, 0.73-0.92; P <.001).¹

In the joint frailty model, results suggested the rate ratio for total events among those using dapagliflozin relative to placebo therapy was 0.72 (95% CI, 0.65-0.81; P <.001). The ratio for cardiovascular death was 0.87 (95% CI, 0.72-1.05; P=.14). Further analysis suggested results were similar for total hospitalizations and cardiovascular death and in all subgroups.¹

“The reduction in burden of total HF events with dapagliflozin was evident regardless of the method used to analyze the total events and whether we examined total [heart failure] events including urgent [heart failure] visits or [heart failure] hospitalizations without urgent visits,” investigators added.¹

References:

1. Jhund PS, Claggett BL, Talebi A, et al. Effect of Dapagliflozin on Total Heart Failure Events in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Trial. JAMA Cardiol. Published online April 26, 2023. doi:10.1001/jamacardio.2023.0711
2. Campbell P. 10 years of SGLT2 inhibitors: A Decade of Redefining Cardiometabolic Care. HCP Live. https://www.hcplive.com/view/10-years-of-sglt2-inhibitors-a-decade-of-redefining-cardiometabolic-care. Published March 29, 2023. Accessed April 26, 2023.
3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2022 May 3;145(18):e1033] [published correction appears in Circulation. 2022 Sep 27;146(13):e185] [published correction appears in Circulation. 2023 Apr 4;147(14):e674]. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
4. Dapagliflozin proves HFPEF benefit in deliver trial. HCP Live. https://www.hcplive.com/view/dapagliflozin-proves-hfpef-benefit-in-deliver-trial. Published August 22, 2022. Accessed April 26, 2023.