Drug Layering in Heart Failure: Phenotype-Guided Initiation.

Abstract Medications with proven benefit in patients with heart failure with reduced ejection fraction are recommended, according to prospective large clinical trials, in the stable patient after careful up-titration in a strict sequential order. Although the relevance of careful clinical up-titration is unproven, there is evidence that after recompensation and shortly after hospital discharge, the rate of cardiovascular death and hospitalization is high. Clinical studies provided evidence that the onset of treatment effects is rapid, occurring within 28 days with most of these drugs used, and in some trials, early treatment after discharge or already started in the hospital has provided benefits. Therefore, early treatment without deferring it to the stable outpatient may be useful to reduce cardiac-related events further. This expert opinion proposes treatment layering according to individual patient phenotypes involving heart rate, blood pressure, impaired renal function, and electrolyte disturbances, as well as dedicated subgroups of patients with specific requirements for treatment initiation. This complements other approaches that suggest starting sequential treatment according to the size of treatment effects of drugs, specific cardiac diseases, and patient wishes. Patient phenotyping may guide personalized drug layering in heart failure with reduced ejection fraction that provides the best outcomes, whereas pragmatic clinical trials are warranted to scrutinize the effectiveness of these approaches.