Early and sustained clinical benefits with SGLT2i in HFmrEF/HFpEF

Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial

Literature - Vaduganathan M, Claggett BL, Jhund P, et al. - JAMA Cardiol. 2022 Dec 1;7(12):1259-1263. doi: 10.1001/jamacardio.2022.3750

Introduction and methods

Background

Recently, the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial showed that dapagliflozin reduced the incidence of CV death or worsening HF events compared with placebo in patients with HFmrEF or HFpEF [1]. While prevention of worsening HF is a priority in the comprehensive management of this patient population [2], it is uncertain when worsening HF events may occur. Knowledge of the expected time course to disease stabilization or even clinical improvement may be of interest to both patients and their treating physicians.

Aim of the study

In a prespecified secondary analysis of the DELIVER trial, the authors aimed to evaluate the time course of benefits of dapagliflozin treatment on clinically relevant outcomes in patients with HFmrEF or HFpEF.

Methods

The DELIVER trial was a global, event-driven, phase 3 RCT in which 6263 patients with symptomatic HFmrEF or HFpEF (LVEF >40%) were randomized to dapagliflozin 10 mg once daily or matching placebo between August 2018 and December 2020. The timeline to onset of clinical benefit with dapagliflozin versus placebo was assessed, whereby data were truncated at every day postrandomization.

Outcome

The primary endpoint was a composite outcome of time to first occurrence of CV death or worsening HF (i.e., hospitalization for HF or urgent HF visit requiring intravenous HF therapies).

Main results

  • During a median follow-up time of 2.3 years (IQR: 1.7–2.8), 1122 primary end-point events (incidence rate: 8.7 per 100 patient-years; 95%CI: 8.2–9.2), 823 first worsening HF events (incidence rate: 6.4 per 100 patient-years; 95%CI: 6.0–6.8) and 747 first HF hospitalizations (incidence rate: 5.7 per 100 patient-years; 95%CI: 5.3–6.2) occurred.
  • Time to first nominal statistical significance for the primary end point for dapagliflozin versus placebo was 13 days (HR: 0.45; 95%CI: 0.20–0.99; P=0.046). Sustained statistical significance (i.e., time point at which upper bounds of treatment CI remained below unity for remainder of trial) started at day 15.
  • For worsening HF events, time to first nominal statistical significance for dapagliflozin versus placebo was 16 days (HR: 0.45; 95%CI: 0.21–0.96; P=0.04), and statistical significance was sustained from this day onwards as well.
  • For HF hospitalizations, time to first nominal statistical significance for dapagliflozin versus placebo was 16 days (HR: 0.42; 95%CI: 0.18–0.96; P=0.04), which was sustained thereafter.
  • Significant benefits of dapagliflozin over placebo for the primary end point and worsening HF events were sustained at 30 days, 90 days, 6 months, 1 year, 2 years. At final follow-up, dapagliflozin reduced the occurrence of the primary endpoint by 18% (HR: 0.82; 95%CI: 0.73–0.92; P<0.001) and worsening HF events by 21% (HR: 0.79; 95%CI: 0.69–0.91; P=0.001) compared with placebo.

Conclusion

In this prespecified analysis of the DELIVER trial, dapagliflozin treatment led to early and sustained reductions in the incidence of CV death or worsening HF in patients with HFmrEF or HFpEF compared with placebo. Within 2 weeks of treatment initiation, a statistically significant reduction in the primary endpoint was seen. The authors acknowledge that “[f]or less frequent events in HFmrEF/HFpEF, such as CV death or kidney disease progression, the anticipated timeline to clinical benefit and duration necessary to demonstrate statistical significance may be longer.”

References

1. Solomon SD, McMurray JJV, Claggett B, et al; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. Published online August 27, 2022. doi:10.1056/NEJMoa2206286

2. Butler J, Braunwald E, Gheorghiade M. Recognizing worsening chronic heart failure as an entity and an end point in clinical trials. JAMA. 2014;312(8):789-790. doi:10.1001/jama.2014.6643

Find this article online at JAMA Cardiol.

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