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Early in-hospital initiation and optimization of comprehensive disease-modifying pharmacotherapy in patients with heart failure with reduced ejection fraction: a time for the paradigm shift

Practical questions concerning the sequence, timing, initial doses, and subsequent titration strategies of foundational drugs constituting comprehensive disease-modifying therapy (CDMT) in patients with heart failure and reduced ejection fraction (HFrEF) remain unclear. Such therapy is also known as “quadruple” or “four pillars” therapy, and it consists of an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor-neprilysin inhibitor (ARNi), betablocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose co-transporter 2 (SGLT2) inhibitor. This pharmacologic armamentarium nowadays should represent a standard of care for HFrEF syndrome as these agents significantly curbed mortality and HF-related hospitalizations in randomized clinical trials. Similar to patients with acute myocardial infarction (AMI), patients with decompensated chronic or de novo HFrEF are at increased risk of sudden cardiac death (SCD) and readmission in the early post-discharge period – also known as the “vulnerable phase” [1]. For this reason, avoidance of unnecessary delays and rapid initiation of life-saving therapies are of paramount importance to mitigate syndrome progression and improve prognosis. In fact, according to the conceptual framework provided by Abdin and colleagues “time-to-treatment initiation” should be acknowledged as an important modifiable risk factor in HFrEF, and once this timeframe is narrowed, optimization of initiated treatments (meaning up-titration to target doses reached in pivotal trials or maximally tolerated doses) is crucial to gain most of clinical benefits [1]. Therefore, each HF hospitalization episode should be perceived as a teachable moment and opportunity to initiate, optimize, and/or switch life-saving therapies to improve post-discharge outcomes of patients with HFrEF [2].