Victims of Success in Failure
Authors: Carolyn S.P. Lam, Javed Butler
Journal: Circulation (2020)

ultiple successful clinical trials have defined the medical treatment of heart failure (HF) with reduced ejection fraction (HFrEF).Trials in the past century established angiotensin-converting enzyme (ACE) inhibitors, βblockers, and mineralocorticoid receptor antagonists as the foundational therapies in HFrEF.The past decade brought more success with ivabradine, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan, the sodium glucose cotransporter-2 inhibitors dapagliflozin and empagliflozin, as well as the soluble guanylase cyclase stimulator vericiguat.This success has led to new challenges in clinical implementation, rising costs, and high pill burdens for patients with HFrEF, who are increasingly multimorbid and elderly.An analysis of the Get With The Guidelines-HF registry showed that to be compliant with HF guidelines, ≈50% patients hospitalized with HF needed to start at least 1 new HF-related medication and a quarter needed >1 by discharge; these figures did not include medications for other comorbidities or newer therapies (data limited to before 2013). 1 Although polypharmacy is challenging, it is still superior to not having treatment options or not prescribing the best available evidence-based treatment.In fact, the availability of multiple effective medical options represents important progress for treating patients with HFrEF.However, we need to acknowledge and provide guidance for clinicians faced with decisions about how best to prioritize and sequence multiple therapies.The traditional approach to HFrEF treatment sequencing has been informed by trials that assessed new therapies incremental to the established standard regimen at the time.For example, ACE inhibition was compared with vasodilators, and β-blockers were assessed on top of ACE inhibition.Thus, on the basis of trial protocol, 2 ARNI is currently recommended after ACE inhibition in some guidelines.Yet considering the early benefit with ARNI, are we justified in waiting before initiating the best therapy?Furthermore, the recent trials were conducted not sequentially but simultaneously and provide little opportunity to assess incremental benefit either among themselves or in combination with foundational therapy. 3,4Thus, the add-on incremental model of serial evidence generation in HFrEF is not relevant to recent trials, leaving unanswered the question of how sodium glucose cotransporter-2 inhibitors and soluble guanylase cyclase stimulators should be prioritized and sequenced on top of ARNI, β-blockers, and mineralocorticoid receptor antagonists.These issues are compounded when we consider the effect of any given therapy in specific subgroups of patients.Because one cannot reasonably expect a large outcomes-based randomized trial for every question and every subgroup, when is it reasonable to make clinical inferences from existing data?Despite robust evidence of superiority of ARNI compared with enalapril in the pivotal trial, 2 a call for additional evidence was pursued for new-onset HFrEF, patients naïve to ACE inhibitors, initiation in hospitalized settings, those with lower natriuretic peptide levels,