The treatment of heart failure with reduced ejection fraction (HFrEF) involves implementing preventive measures, delaying disease progression, relieving symptoms and, above all, prolonging survival. The effectiveness of the drug arsenal for the management of HFrEF has been well established by several randomized clinical trials and is based on 4 foundational pillars of treatment: (1) β-blockers; (2) renin-angiotensin system inhibitors, including angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), and angiotensin receptor-neprilysin inhibitors (ARNIs); (3) sodium-glucose cotransporter 2 inhibitors (SGLT2is); and (4) mineralocorticoid receptor antagonists (MRAs).
The conventional pharmacological approach presented by HFrEF treatment guidelines recommends sequential prescribing of the 4 foundational drug classes in the order in which they were tested in classic clinical trials. – Based on a 5-step protocol, physicians are instructed to initiate treatment with an ACEi/ARB, followed by a β-blocker and then an MRA. In step 4, replacement of the ACEi/ARB with an ARNI is considered and, finally, an SGLT2i can be added ( ). This approach advises prescribers to titrate the dose of each drug to the target dose used in large-scale trials before initiating the next recommended drug class ( ). In 2021, however, a perspective article written by John McMurray and Milton Packer, authors of most of the main trials in the field in the last decade, pointed out a series of limitations in the conventional approach and proposed a new sequence of pharmacological treatment for ambulatory HFrEF based on 3 steps ( ). According to the new proposal, the conventional approach presents an algorithm based on the historical order of publication of the clinical trials, wrongly assuming that the most effective and well-tolerated drugs were developed first. Another point observed by the authors is that the conventional approach prioritizes the achievement of the target dose of a given drug before initiating treatment with the next one, which can delay the achievement of optimal medical therapy by more than 6 months. Indeed, if we look at participants in large-scale clinical trials and surveys, we will see that a substantial percentage of them were not receiving recommended medications. , Even in recently completed trials, a meaningful proportion was not being treated with an MRA or an ARNI. In addition, proper sequencing of foundational drugs can improve safety and tolerability, as medications such as ARNIs can reduce the risk of renal insufficiency associated with ACEis/ARBs and both ARNIs and SGLT2is can mitigate the risk of hyperkalemia associated with the use of MRAs.
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