Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction

Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor-neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and a sodium-glucose co-transporter 2 (SGLT2) inhibitor. However, the conventional approach to the implementation is based on a historically-driven sequence that is not strongly evidence-based, typically requires ≥6 months, and frequently leads to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2-4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease-of-use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over up-titration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated three-step approach, which consists of the simultaneous initiation of a beta-blocker and an SGLT2 inhibitor, followed 1-2 weeks later by the initiation of sacubitril/valsartan, and 1-2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be re-ordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence-based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction.