SGLT2i’s effect on days of full health lost in patients with HFrEF

During the first 360 days of the DAPA-HF trial, dapagliflozin reduced the total number of days of full health lost due to death, hospitalization, and impaired well-being in HFrEF patients compared with placebo.

This summary is based on the publication of Kondo T, Mogensen UM, Talebi A, et al. - Dapagliflozin and days of full health lost through death, hospitalization, and impaired well-being in DAPA-HF. J Am Coll Cardiol. 2024 Mar 25:S0735-1097(24)06671-3 [Online ahead of print]. doi: 10.1016/j.jacc.2024.03.385

Introduction and methods

Background

Most trials evaluating new HF treatments use a composite endpoint, for example, time to first HF hospitalization or CV death [1-3]. However, this has several limitations, such as not accounting for recurrent events or the duration of hospitalization or not incorporating patient well-being. Alternatively, the number of potential follow-up days lost due to death and hospitalization can be counted, whereby the remaining potential days of healthy follow-up are adjusted for impaired well-being.

Aim of the study

The authors evaluated several integrated efficacy outcome measures that quantified the potential days of full health lost due to death, hospitalization, and impaired well-being.

Methods

This was a post-hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which showed that dapagliflozin 10 mg once-daily reduced the risk of the primary composite endpoint of worsening HF event or CV death and improved the NYHA class and several patient-reported outcomes compared with placebo in patients with HFrEF (NYHA class II–IV HF symptoms, LVEF ≤40%) (n=4744) [4-7]. Patient-reported well-being was evaluated using the KCCQ – Overall Summary Score (OSS) and EuroQol-5D visual analogue scale (EQ-5D VAS) score. In the current analysis, 4235 patients with ≥360 days of follow-up and data on hospitalization duration and their well-being were included.

Outcomes

The potential follow-up days of full health (and the proportion of days of full health) were evaluated using 6 integrated outcome measures: (1) days lost due CV death and HF hospitalization; (2) days lost due to any cause of death (CV and non-CV causes) and any hospitalization (HF and non-HF hospitalizations); and (3–6) days lost due to any cause of death, any hospitalization, and impaired well-being, with days of potential full health adjusted for KCCQ-OSS, EQ-5D VAS score, or NYHA class.

Main results

• At 360 days, the mean ± SE potential follow-up days lost due to CV death and HF hospitalization was 10.6 ± 1.0 days (2.9%) in patients treated with dapagliflozin (n=2127) and 14.4 ± 1.0 days (4.0%) in those receiving placebo (n=2108) (difference:–3.8 days; 95%CI: –6.6 to –1.0; P=0.009), resulting in a relative reduction of 26.4%.
• The mean number of potential days lost due to death and hospitalization for any cause or reason at 360 days was also smaller in the dapagliflozin group than in the placebo group (15.5 ± 1.1 (4.3%) vs. 20.3 ± 1.1 days (5.6%); difference: –4.8 days; 95%CI: –7.9 to –1.7; P=0.003), resulting in a 23.6% relative reduction.
• The mean number of potential days lost due to death, hospitalization, and impaired well-being adjusted for KCCQ-OSS was 110.6 ± 1.6 (30.7%) with dapagliflozin and 116.9 ± 1.6 days (32.5%) with placebo (difference: –6.3 days; 95%CI: –10.8 to –1.7; P=0.007), resulting in a 5.4% relative reduction. Adjustment for the EQ-5D VAS score or NYHA class showed similar results.
• For all 6 outcome measures, the difference in the number of days lost between the dapagliflozin and placebo groups increased proportionally over time. For example, the difference in the mean number of potential days lost due to any death and any hospitalization was –0.9 days (–0.7%) at 120 days, –2.3 days (–1.0%) at 240 days, and –4.8 days (–1.3%) at 360 days.
• By 360 days, the dapagliflozin group had lost fewer days due to any death than the placebo group (11.5 ± 1.0 vs. 14.9 ± 1.0 days; difference: –3.4 days; 95%CI: –6.3 to –0.5; P=0.021)—which was mostly explained by CV death (difference: –3.2 days; P=0.020)—and any hospitalization (4.0 ± 0.3 vs. 5.4 ± 0.3 days; difference: –1.4 days; 95%CI: –2.2 to –0.5; P=0.001).
• However, there was no significant difference in the number of days lost due to impaired well-being after adjustment for KCCQ-OSS (95.1 ± 1.4 vs. 96.6 ± 1.4 days; difference: –1.5 days; 95%CI: –5.3 to –2.4; P=0.45), nor after adjustment for any of the other measures of patient well-being.

Conclusion

During the first 360 days of the DAPA-HF trial, dapagliflozin reduced the total number of days of potential full health lost due to death, hospitalization, and impaired well-being in HFrEF patients compared with placebo. The difference in number of days lost with dapagliflozin versus placebo was largest for CV death (3.4 days), followed by any hospitalization (1.4 days). Overall, most days of potential full health were lost due to impaired well-being, although there was no significant difference between the treatment groups. The benefit of dapagliflozin increased proportionally over the follow-up period. The authors believe “the integrated endpoints used in this study give a much more holistic patient-centered assessment of any new treatment, reflecting also the health economic and societal perspective[,] than traditional trial endpoints.”

Find this article online at J Am Coll Cardiol.

References

1. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail 2001;7:176-82.
2. Neaton JD, Gray G, Zuckerman BD, Konstam MA. Key issues in end point selection for heart failure trials: composite end points. J Card Fail 2005;11:567-75.
3. Packer M. Development and Evolution of a Hierarchical Clinical Composite End Point for the Evaluation of Drugs and Devices for Acute and Chronic Heart Failure: A 20-Year Perspective. Circulation 2016;134:1664-1678.
4. McMurray JJV, Solomon SD, Inzucchi SE et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019;381:1995-2008.
5. McMurray JJV, DeMets DL, Inzucchi SE et al. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail 2019;21:665-675.
6. McMurray JJV, DeMets DL, Inzucchi SE et al. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail 2019;21:1402-1411.
7. Kosiborod MN, Jhund PS, Docherty KF et al. Effects of Dapagliflozin on Symptoms, Function, and Quality of Life in Patients With Heart Failure and Reduced Ejection Fraction: Results From the DAPA-HF Trial. Circulation 2020;141:90-99.