SGLT2i reduces specific causes of CV death in HF across wide LVEF spectrum
Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction: A Participant-Level Pooled Analysis of DAPA-HF and DELIVER
Literature - Desai AS, Jhund PS, Claggett BL, et al. - JAMA Cardiol. 2022 Dec 1;7(12):1227-1234. doi: 10.1001/jamacardio.2022.3736Introduction and methods
Background
Recently, dapagliflozin was shown to reduce the rate of the composite outcome of worsening HF events or CV death in 2 international RCTs, namely the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials [1-4]. However, the effect of dapagliflozin on specific causes of death has not been examined.
Aim of the study
In a pooled analysis of the DAPA-HF and DELIVER trials, the effect of dapagliflozin versus placebo on cause-specific CV and non-CV mortality in HFrEF, HFmrEF, and HFpEF patients was examined.
Methods
In this participant-level, pooled, prespecified secondary analysis, data from the DAPA-HF trial (LVEF ≤40%; n=4744) and the DELIVER trial (LVEF >40%; n=6263) were combined. Both trials had randomized patients with chronic HF, NYHA class II–IV symptoms, and elevated NT-proBNP levels to treatment with dapagliflozin 10 mg once daily or placebo. Median follow-up duration was 18.2 (DAPA-HF trial) or 27.6 months (DELIVER trial).
The authors assessed the mode of death (CV, non-CV, undetermined) and the specific causes of CV death (HF, sudden death, MI, stroke, other CV causes), as a whole and across different baseline LVEF categories (≤40%, 41%–49%, 50%–59%, ≥60%).
Outcome
The primary endpoint in both trials was time to the first occurrence of the composite outcome of adjudicated worsening HF events (i.e., hospitalization or urgent visits for HF) or CV death.
Main results
- Of the 11,007 patients in the pooled data set, there were 1628 deaths during follow-up. Of these deaths, 872 (53.5%) were attributed to CV causes, 487 (29.9%) to non-CV causes, and 269 (16.5%) to undetermined causes.
- Of the 872 CV deaths, 289 (33.1%; this was 17.8% of total deaths) were due to HF, 441 (50.6%; 27.1% of total deaths) were sudden, 69 (7.9%; 4.2% of total deaths) were due to stroke, 47 (5.4%; 2.9% of total deaths) were due to MI, and 26 (3.0%; 1.6% of total deaths) were due to other CV causes.
- The proportion of CV deaths was inversely related to LVEF (P<0.001), mainly due to higher proportions of HF-associated and sudden death in the lower LVEF categories.
- Conversely, the proportion of non-CV deaths was higher in patients with a higher LVEF (P<0.001). Still, 112/283 deaths (39.6%) among patients in the highest LVEF category (≥60%) were attributed to CV causes, mostly due to sudden death (19.1%), followed by death from progressive HF (12.7%).
- Treatment with dapagliflozin was associated with lower rates of CV death (3.9% vs. 4.5%; HR: 0.86; 95%CI: 0.75–0.98; P=0.02) and all-cause mortality (7.4% vs. 8.3%; HR: 0.90; 95%CI: 0.82–0.99; P=0.03) compared with placebo. This reduction in CV deaths was primarily driven by lower, albeit nonsignificant , rates of sudden death (1.9% vs. 2.3%; HR: 0.84; 95%CI: 0.70–1.01; P=0.07) and HF-associated death (1.3% vs. 1.5%; HR: 0.88; 95%CI: 0.70–1.11; P=0.30). There were only small, nonsignificant difference in rates of death from stroke or MI.
- There was no difference in rates of non-CV death between the dapagliflozin and placebo groups (2.4% vs. 2.3%; HR: 1.01; 95%CI: 0.84–1.20; P=0.94).
- The effect of dapagliflozin versus placebo on sudden death and HF-associated death was consistent across the entire LVEF spectrum (P for interaction between treatment assignment and LVEF was 0.49 and 0.71, respectively).
Conclusion
In a pooled analysis of the DAPA-HF and DELIVER trials, dapagliflozin reduced the risk of CV death and all-cause mortality in HF patients compared with placebo. The reduction in CV deaths with dapagliflozin was primarily due to lower, albeit nonsignificant, rates of sudden death and, to a lesser extent, death from progressive HF.
The authors believe these results support the consistent beneficial effects seen with dapagliflozin on CV mortality, regardless of LVEF. They also note that “[t]he higher proportionate contribution of non-CV death with rising EF may be partly responsible for the limited progress in reducing the burden of overall mortality in patients with HF and preserved EF using CV therapies.”
References
1. McMurray JJV, Solomon SD, Inzucchi SE, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303
2. 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
3. McMurray JJV, DeMets DL, Inzucchi SE, et al; DAPA-HF Committees and Investigators. A trial to evaluate the effect of the sodium-glucose cotransporter 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(5):665-675. doi:10.1002/ejhf.1432
4. Solomon SD, de Boer RA, DeMets D, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail. 2021;23(7):1217-1225. doi:10.1002/ejhf.2249
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