Foundational drugs for HFrEF: the growing evidence for a rapid sequencing strategy

In randomised, placebo- or active-controlled trials in patients with heart failure with reduced ejection fraction (HFrEF), each of the combination of a neprilysin inhibitor and an angiotensin-receptor blocker (i.e. sacubitril/valsartan), a beta blocker, a mineralocorticoidreceptor antagonist and a sodium-glucose co-transporter 2 (SGLT2) inhibitor have been shown to reduce morbidity and mortality, firmly establishing the role of these five agents, prescribed as four pills, as foundational therapy for HFrEF. Traditionally, the guideline-advocated strategy for the initiation of these therapies was based on the historical order in which the landmark clinical trials were performed, and the requirement to uptitrate each individual drug to the target dose (or maximally tolerated dose below this) prior to initiation of another therapy. This process could take six months or more to complete, during which time patients would not be taking one or more of these life-saving drugs. Recently an alternative, evidence-based, rapid three-step sequencing strategy has been proposed with the aim of establishing HFrEF patients on low-doses of all four foundational treatments within four weeks. This strategy is based on the premise that the benefits of each of these therapies are independent and additive to the others, the benefits are apparent at low doses early following initiation, and a specific ordering of therapies may increase likelihood of tolerance of others. This article will outline this novel rapid-sequencing strategy and provide an evidence-based framework to support its adoption into clinical practice.