Perspective:

Trials examining efficacy of pharmacological therapy in HFrEF have been staggered and performed over a span of several decades. In the last decade, three new agents have shown a survival benefit in this population: MRA, ARNI, and SGLT-2 inhibitors. However, their additive effect when compared to conventional therapy has not been examined. This cross-trial study provides estimates of benefit of a combination therapy with ARNI, beta-blocker, MRA, and SGLT-2 inhibitors when compared to decades old conventional therapy for HFrEF. Apart from a large reduction in cardiovascular death and HF rehospitalization, the survival benefit seen was largest in younger individuals.

Important limitations to note include limited generalizability due to use of trial data which may not apply to real-world cohorts and overestimation of benefit, as the authors assumed an additive effect of each agent. However, incidence of adverse effects and cost implications of these agents were not reported. ARNI and SGLT-2 inhibitors are currently not generic and thus, associated with significant cost burden. Hence, individual patient-level risk-benefit discussions with patients should be considered. An additional concern is medication adherence, as new HFrEF therapy will now include at the least four different medications. A polypill may pave the way for the future.