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

Abstract

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.

Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden)

“…Whether optimal doses of RASi and beta‐blockers might be needed to consider treatment with ARNI and SGLT2i, this might lead to a strong delay or even prevent the use of these life‐saving medications. The increased risk of HHF and all‐cause death in the post‐HHF phase shown in our and previous analyses, 47 together with our results highlighting higher event rates in patients receiving ACEi vs. beta‐blockers vs. MRA vs. ARNI reflecting sequential GDMT initiation based on HF disease progression, highlight the need for improved and more time‐sensitive treatment optimization 48,49 . These findings have important implications for clinical practice, particularly in primary care, where many patients might not receive life‐saving treatments due to the limited resources and time needed for the currently used sequential approach.…”

“…Our data highlights the urgent need for simplified guidelines and more rapid GDMT sequencing, but also the need for HF drugs that are well-tolerated, safe and without need for titration in order to ensure compliance to prescribed therapy. 48,49…”

Approaches to the therapy of heart failure with reduced ejection fraction. Resolution of an online meeting of the Volga Federal District experts

“…Позиция британских специалистов, опубликованная от имени Европейского общества кардиологии, основана на доказательствах последовательности базисных препаратов при ХСНнФВ [10]. Результаты крупномасштабных рандомизированных контролируемых клинических исследований (РКИ) показывают, что (1) эффективность каждого основного препарата не зависит от лечения другими препаратами;…”

“…Лечение АМР может ухудшить функцию почек и вызвать гиперкалиемию. Следовательно, перед назначением АМР целесообразно начать лечение ингибитором неприлизина и иНГК2, поскольку эти 2 класса могут ослаблять действие АМР на ухудшение азотемии и повышение уровня К + в сыворотке крови и, таким образом, увеличивать вероятность того, что пациенты смогут продолжить длительное лечение АМР [10].…”

June 2021 at a glance: focus on epidemiology, biomarkers and medical treatment

“…A strategy of rapid sequencing of evidence-based treatment was also proposed to optimize medical treatment. 26…”