Guideline-directed medical therapy for HFrEF: sequencing strategies and barriers for life-saving drug therapy

Abstract

Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials have led to the introduction of four main drug classes into the 2021 ESC guideline, namely angiotensin-receptor neprilysin inhibitors/angiotensin-converting-enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. The life-saving effect of these therapies has been shown to be additive and becomes apparent within weeks, which is why maximally tolerated or target doses of all drug classes should be strived for as quickly as possible. Recent evidence, such as the STRONG-HF trial, demonstrated that rapid drug implementation and up-titration is superior to the traditional and more gradual step-by-step approach where valuable time is lost to up-titration. Accordingly, multiple rapid drug implementation and sequencing strategies have been proposed to significantly reduce the time needed for the titration process. Such strategies are urgently needed since previous large-scale registries have shown that guideline-directed medical therapy (GDMT) implementation is a challenge. This challenge is reflected by generally low adherence rates, which can be attributed to factors considering the patient, health care system, and local hospital/health care provider. This review of the four medication classes used to treat HFrEF seeks to present a thorough overview of the data supporting current GDMT, discuss the obstacles to GDMT implementation and up-titration, and identify multiple sequencing strategies that could improve GDMT adherence. Sequencing strategies for GDMT implementation. GDMT: guideline-directed medical therapy; ACEi: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ARNi: angiotensin receptor-neprilysin inhibitor; BB: beta-blocker; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose co-transporter 2 inhibitor.

Keywords: Guidelines; Implementation; Pharmacotherapy; Registry; Sequencing; Titration.

Fig. 1

Historical GDMT trials. GDMT, guideline-directed medical therapy; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose co-transporter 2 inhibitor

Fig. 2

Relative risk reduction of different pharmacological treatment combinations for heart failure. Reprinted from JACC heart failure, volume 10, issue 2, Tromp et al., a systematic review and network meta-analysis of pharmacological treatment of heart failure with reduced ejection fraction, pages 73–84, copyright 2023, with permission from Elsevier. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; CV, cardiovascular; H-ISDN, hydralazine-isosorbide dinitrate; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SGLT2i, sodium glucose cotransporter-2 inhibitors

Fig. 3

Barriers to GDMT implementation. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license. GDMT, guideline-directed medical therapy