UK: Findings from a Post Hoc Analysis of the DAPA-HF Trial

Findings from a post hoc analysis of the DAPA-HF trial suggest that the protective effects of dapagliflozin in patients having heart failure with reduced ejection fraction (HFrEF) are maintained regardless of frailty. The study appears in Annals of Internal Medicine.

The study further reveals that the greatest benefit is derived by the most-frail patients, with regards to outcomes like worsening heart failure, cardiovascular death, symptoms, and quality of life.

Background

Previous studies have shown frailty to modify the risk-benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments. Considering this, Jawad H. Butt, University of Glasgow, Glasgow, United Kingdom, and colleagues aimed to investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure).

The study was a post hoc analysis of a phase 3 randomized clinical trial conducted across 410 sites in 20 countries. Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide were included. They were randomized to addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. Worsening HF or cardiovascular death was the primary outcome.

Findings

• Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI ≤0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI ≥0.311; most frail). The median follow-up time was 18.2 months.
• Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class.
• The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were −3.5, −3.6, and −7.9.
• Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients.
• Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class.

Conclusion

The researchers conclude, "Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients."

The main limitation of the study was that the enrollment criteria precluded the inclusion of very high-risk patients.

Reference

Butt JH, Dewan P, Merkely B, Belohlávek J, Drożdż J, Kitakaze M, Inzucchi SE, Kosiborod MN, Martinez FA, Tereshchenko S, Ponikowski P, Bengtsson O, Lindholm D, Langkilde AM, Schou M, Sjöstrand M, Solomon SD, Sabatine MS, Chiang CE, Docherty KF, Jhund PS, Køber L, McMurray JJV. Efficacy and Safety of Dapagliflozin According to Frailty in Heart Failure With Reduced Ejection Fraction: A Post Hoc Analysis of the DAPA-HF Trial. Ann Intern Med. 2022 Apr 26. doi: 10.7326/M21-4776. Epub ahead of print. PMID: 35467935.