Efficacy of ertugliflozin on hospitalisation for heart failure across the distribution of pre-trial ejection fraction: post hoc analyses of the VERTIS CV trial

Abstract Introduction There is controversy over whether SGLT2 inhibitors have efficacy in high-risk patients with heart failure (HF) and ejection fraction (EF) >60% with or without type 2 diabetes (T2D). The VERTIS CV trial studied a population of patients with T2D and atherosclerotic cardiovascular disease (ASCVD), 23% of whom had a history of HF. In VERTIS CV, ertugliflozin (ERTU) significantly reduced the risk of first and total hospitalisation for heart failure (HHF) vs placebo (PBO). Whether efficacy in the VERTIS CV population is consistent across the spectrum of pre-trial EF, particularly among those with EF >60%, is unknown. Purpose These post hoc analyses explored the effects of ERTU (5 mg; 15 mg) vs PBO on time to first and total HHF among patients in VERTIS CV across the spectrum of pre-trial EF. Methods As prospectively planned, the 2 ERTU dose groups were combined for all analyses vs PBO. Treatment effects of ERTU vs PBO on the risk of first and total HHF were analysed using adjusted Cox models for first and Andersen-Gill models for total (i.e., first + recurrent) events. Data on pre-trial EF were abstracted from the medical record at trial entry. Multiplicative interaction terms (EF × treatment arm) were used to determine if the efficacy of ERTU was modified by pre-trial EF. Results In VERTIS CV, 8246 patients were randomised to ERTU 5 or 15 mg or PBO (mean follow up 3.5 years). Overall, 5006 patients had pre-trial EF data available; 959 had EF ≤45%, 2860 had EF >45–60%, and 1187 had EF >60%. In the overall population, the event rate for first HHF was lower with ERTU vs PBO (hazard ratio [HR] 0.70; 95% CI 0.54–0.90). The findings were generally consistent across pre-trial EF (P-interaction = 0.26; Figure), including patients with pre-trial EF >60% (HR 0.72; 95% CI 0.34–1.55). In the overall population, event rate for total HHF was lower with ERTU vs PBO (HR 0.70; 95% CI 0.56–0.87). A significant interaction was observed between pre-trial EF and treatment arm for the risk of total HHF events (P-interaction = 0.02), with a greater magnitude of risk reduction in patients with a low pre-trial EF (≤45%; HR 0.39; 95% CI 0.26–0.57). However, the 95% CIs for the HR for total HHF for those with EF >45–60% and >60% nearly entirely or entirely contained the 95% CI of the overall population, respectively (Figure). Conclusion In the VERTIS CV trial of patients with T2D and ASCVD, the efficacy of ERTU in preventing first HHF was generally comparable across the spectrum of pre-trial EF. The trend for greater benefit at lower EF was statistically significant for total HHF events. Findings for patients with EF >45–60% and >60% appeared quantitively consistent with the overall findings for both first and total HHF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.