Lifetime Benefits of Comprehensive Medical Therapy in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

Abstract

Sodium glucose co-transporter-2 inhibitors (SGLT2i) and the non-steroidal mineralocorticoid receptor antagonist (nsMRA) finerenone have each been shown to individually improve heart failure events among patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Moreover, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan has been shown to improve outcomes in patients with HFmrEF/HFpEF with a left ventricular ejection fraction (LVEF) below normal (<60%). However, the expected benefits of the combined use of these agents with long-term administration are not well defined. In this cross-trial analysis of DELIVER, FINEARTS-HF, and PARAGON-HF, combined use of SGLT2i and nsMRA therapies was estimated to reduce the risk of cardiovascular death or first worsening HF event by 31% in the overall population (HR 0.69; 95% CI 0.59 to 0.81), while combined use of SGLT2i, nsMRA, and ARNI therapies was estimated to reduce risk by 39% in patients with HFmrEF/HFpEF and an LVEF<60% (HR 0.61; 95% CI 0.48 to 0.77). With long-term use, combined SGLT2i and nsMRA therapies in a 65-year-old patient with HFmrEF/HFpEF, or combined SGLT2i, nsMRA, and ARNI therapies in a 65-year-old patient with an LVEF<60%, were projected to afford 3.6 (2.0 to 5.2) or 4.9 (2.6 to 7.3) additional years free from cardiovascular death or a HF event, respectively. Combined therapy was estimated to result in meaningful gains in event-free survival across a broad age range from 55 to 85 years. Among patients with HFmrEF and HFpEF, the potential aggregated long-term treatment effects of early combination medical therapy with SGLT2i and nsMRA (and ARNI in selected individuals) are projected to be substantial.