Lifetime benefits of comprehensive medical therapy in heart failure with mildly reduced or preserved ejection fraction

Sodium–glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal 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. Here, 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 heart failure event by 31% in the overall population (hazard ratio 0.69; 95% confidence interval 0.59–0.81), 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% (hazard ratio 0.61; 95% confidence interval 0.48–0.77). 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 (2.0–5.2) or 4.9 (2.5–7.3) additional years free from cardiovascular death or a heart failure 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.