Comparison of Quadruple Therapy Sequencing Strategies for Heart Failure With Reduced Ejection Fraction

Background Guidelines unanimously recommend quadruple therapy for patients with heart failure with reduced ejection fraction (HFrEF), yet direct comparative evidence is lacking to recommend a specific order of initiating and titrating these agents (or “sequencing strategy”). In the absence of randomized evidence, we aimed to compare the 1‐year efficacy and harms of proposed HFrEF quadruple therapy sequencing strategies using a microsimulation model. Methods We conducted a microsimulation study to compare 6 different HFrEF medication sequencing strategies (emulating the range of conventional, 2‐drug, and rapid or simultaneous strategies), each with 2 versions (twice‐weekly/weekly medication adjustments), applied to treatment‐naïve outpatients with HFrEF. We modeled death; total heart failure hospitalization (including recurrent events); the composite of death or first heart failure hospitalization; and adverse drug events (bradycardia, hyperkalemia, hypotension, and renal impairment) at 1 year. Results At 1 year, an estimated 15.3 per 100 patients died without treatment compared with 6.9 per 100 patients with the conventional sequence adjusted biweekly, and 5.2 to 6.4 per 100 patients with other sequencing strategies. The incidence of heart failure hospitalization decreased from 31.5 per 100 patients without treatment to 11.4 per 100 patients with conventional sequencing adjusted biweekly, and 7.3 to 9.4 per 100 patients with other strategies. The cumulative incidence of total adverse drug events per 100 patients was 14.2 to 16.0 across sequencing strategies. Conclusions For treatment‐naïve outpatients with HFrEF, sequencing strategies that started 2 to 4 medications on the first visit, followed by titration biweekly or weekly, were associated with lower risk of death and heart failure hospitalization, and similar risk of treatment‐related adverse events, at 1 year compared with conventional sequencing.