Perspective:

For treatment of HFrEF, which agent should be initiated first and how rapidly should medications be titrated remains hotly debated. More recently, there has been an increased endorsement of accelerated approaches including simultaneous initiation of multiple classes together. In this study, the authors model various approaches and the overarching finding is that minimizing the time taken to achieve target doses of all four agents for HFrEF leads to lower risk for all-cause and CV death and HF hospitalization. While various combinations were modeled, it is difficult to draw interpretations on which combination is the best given the fact that these results are modeled off clinical trials and these regimens assume that one agent is maximally up-titrated prior to initiating the next class. Furthermore, initiating multiple agents in real-world practice comes with increased risk for adverse events such as hyperkalemia, renal injury, and hypotension. Regardless, these data support that rapid initiation and up-titration of GDMT for HFrEF leads to the best outcomes. In particular, upfront use of ARNI when feasible helps shorten time to achieve medication optimization.