Dapagliflozin cuts risk of total HF events, CV deaths in HF patients

In a prespecified analysis of the DELIVER* study, the sodium glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduced the rate of total** heart failure (HF) events or cardiovascular (CV) deaths in HF patients with mildly reduced or preserved ejection fraction (HFmrEF or HFpEF).

“The efficacy of dapagliflozin in reducing the number of these events is consistent across a broad range of subgroups and the spectrum of EF,” said the researchers. “The reduction in the burden of total HF events with dapagliflozin was evident regardless of the method used to analyse total events and whether we examined total HF events including urgent HF visits or HF hospitalizations without urgent visits.”

The researchers evaluated 6,263 participants (mean age 71.7 years, 44 percent female) who were randomized to dapagliflozin 10 mg QD or placebo. During a median follow-up of 2.3 years, fewer patients in the dapagliflozin vs placebo arm had ≥1 nonfatal worsening HF events (n=368 vs 454). The total number of events was also lower in the treatment arm (n=584 vs 796), as was the number of additional CV deaths and HF events (n=815 vs 1,057). [JAMA Cardiol 2023;8:554-563]

In the LWYY*** model, rate ratio (RR) for total HF events and CV death with dapagliflozin was 0.77. In a traditional time-to-first-event analysis, the hazard ratio was 0.82 (p<0.001 for both).

In the joint frailty model, RR was 0.72 (p<0.001) for total HF events and 0.87 (p=0.14) for CV death. The results were similar for total HF hospitalizations (without urgent HF visits) and CV death and in all subgroups, including those defined by EF.

The point estimates were more favourable than what was obtained in the time-to-first-event analysis (the study’s primary outcome, ie, no reduction in efficacy in reducing second or subsequent events with dapagliflozin). [N Engl J Med 2022;387:1089-1098] These were also consistent with other SLGT2 inhibitor trials on patients with HFmrEF and HFpEF. [N Engl J Med 2021;385:1451-1461]

On exploratory post hoc analysis, AUC^# was shorter with dapagliflozin than placebo (5.7 vs 7.8 months; p<0.001). This corresponded to an absolute increase of 2.2 months and an RR of 0.72, translating to a 28-percent reduction in the cumulative burden of HF events and CV death over time, in favour of dapagliflozin. “These results support those by the prespecified procedures,” the researchers said.

The major driver of HF burden

Recurrent hospitalizations, which account for a greater fraction of the burden of disease in HFmrEF or HFpEF, are the major driver of HF burden on patients and healthcare systems and are tied to a higher subsequent risk of death. [Circulation 2007;116:1482-1487]

“The gradient of risk is linear: as the number of repeated hospitalizations increases, the subsequent risk of both CV and all-cause mortality also increases,” the researchers explained.

However, the study’s follow-up was limited, hence “we do not know what the full lifetime burden of HF events or deaths was in each treatment arm and how this may affect the treatment benefit in the longer term,” said the researchers. The findings may not be generalizable to all HFmrEF or HFpEF patients in the broader population given the specific inclusion and exclusion criteria.

“[Nonetheless,] one attraction of a recurrent or total events analysis is that they describe the full burden of disease and are potentially more meaningful to patients, representing the full disease experience. Therefore, describing reductions in total events may be helpful to explain treatment effects to patients,” they said.