Vascular Disease Burden, Outcomes and Benefits with Empagliflozin in Heart Failure: Insights From the EMPEROR-Reduced Trial

Abstract

Presence of ischemic heart disease impacts prognosis in patients affected by heart failure and reduced ejection fraction (HFrEF). It is not well known how the extent of vascular disease impacts prognosis and response to therapy in this setting. In this post hoc analysis of the EMPEROR-Reduced trial, outcomes, and the effect of empagliflozin, were assessed in study participants according to the extent (none vs. mono [1] vs. poly [≥2] vascular bed) of vascular disease. Vascular disease was defined as investigator-reported coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease at baseline. Cox proportional-hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Incidence rates are presented per 100 person-years (py) of follow-up. Of the 3,730 study participants enrolled, 1324 (35.5%) had no, 1879 (50.4%) had mono, and 527 (14.1%) had poly-vascular disease. Participants with poly-vascular disease tended to be older, male, and with history of hypertension, diabetes, and smoking. In the placebo arm, a significant higher risk for cardiovascular death existed in those with poly-vascular disease (HR1.57, 95%CI 1.02, 2.44 compared to no vascular disease). In adjusted analysis, the benefit of empagliflozin on cardiovascular death or HF hospitalization, HF hospitalization, cardiovascular death, renal composite endpoint, estimated glomerular filtration slope changes, and health status scores, were seen across the three groups (interaction P>0.05 for all) but were attenuated in those with poly-vascular disease. Adverse events were higher in those with poly-vascular disease but there were no major differences noted between empagliflozin or placebo assignment in the three groups. In patients with HFrEF, the extent of vascular disease is associated with the risk for adverse cardiovascular outcomes. Empagliflozin offers cardiovascular and renal benefits in HFrEF across the extent of vascular disease, but this benefit is attenuated in those with poly-vascular disease.