Dapagliflozin therapy helps reduce CV mortality in heart failure with improved ejection fraction: JAMA

The findings, published in JAMA Cardiology, support current guideline recommendations for using sodium-glucose transport protein 2 inhibitor therapy.

In the post-hoc analysis, including 6263 participants, 1151 participants had HFimpEF. The researchers showed a similar distribution of mode of death in those with HFimpEF compared with those with left ventricular ejection fraction (LVEF) consistently greater than 40%. Dapagliflozin was associated with less cardiovascular death compared to placebo in HFimpEF, primarily due to lower sudden death rates.

Heart failure with improved ejection fraction, defined as a prior LVEF of 40% or lower that has increased to greater than 40%, is understudied. These patients experience similar rates of adverse nonfatal clinical outcomes as those with HF with mildly reduced or preserved ejection fraction (HFpEF). Not much is known regarding the potential benefit of initiating new therapies in those with LVEF that has improved to greater than 40%.

In the DELIVER randomized clinical trial, dapagliflozin reduced worsening HF or cardiovascular death in patients with HFimpEF to a similar extent as in those with LVEF consistently greater than 40%. In the post hoc report, Orly Vardeny, University of Minnesota, Minneapolis, and colleagues evaluated the mode of death of patients with HFimpEF versus those with LVEF consistently greater than 40%. They also assessed the association of dapagliflozin with reductions in cause-specific death in patients with HFimpEF.

The DELIVER trial included patients with HF with LVEF greater than 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides. They were randomly assigned to treatment with dapagliflozin (10 mg, once daily) or placebo. HFimpEF presence was captured through study case report forms.

The study's primary outcome was a composite of worsening heart failure events (hospitalization or urgent HF visits) or cardiovascular death. Clinical outcomes were adjudicated by a blinded clinical endpoints committee.

The researchers examined the mode of death with HFimpEF status and the association of randomized treatment with cause-specific death in Cox regression models.

The study led to the following findings:

• Of 1151 patients with HFimpEF in DELIVER, 190 died, compared with 833 patients of 5112 with LVEF consistently greater than 40%.
• The overall distribution of mode of death was similar in those with HFimpEF compared with those with LVEF consistently greater than 40% (noncardiovascular death: 54% versus 51%]; cardiovascular death: 46% vs 49%, respectively).
• Most deaths in individuals with HFimpEF were noncardiovascular (54%).
• For cardiovascular deaths, sudden deaths were most common (19%), followed by HF-related (15%).
• Among patients with HFimpEF, treatment with dapagliflozin was associated with lower rates of cardiovascular death relative to placebo, a difference primarily due to lower rates of sudden death (hazard ratio, 0.38).

The study showed that patients with HFimpEF enrolled in the DELIVER trial carried a similar death risk as those who had LVEF consistently over 40%. Dapagliflozin was linked with a decrease in cardiovascular death among those with HFimpEF, which appeared primarily driven by a lower residual risk of sudden death.

"These data support current guideline recommendations for SGLT2i use across the spectrum of LVEF and further suggest that the new addition of SGLT2i to other guideline-directed medical therapies may help reduce cardiovascular mortality in HFimpEF patients," the researchers concluded.

Reference:

Vardeny O, Desai AS, Jhund PS, et al. Dapagliflozin and Mode of Death in Heart Failure With Improved Ejection Fraction: A Post Hoc Analysis of the DELIVER Trial. JAMA Cardiol. Published online January 24, 2024. doi:10.1001/jamacardio.2023.5318