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Abstract

Introduction: Heart failure with reduced ejection fraction (HFrEF) is a debilitating condition that can be managed with pharmacotherapy, consisting of an angiotensin receptor- neprilysin inhibitor (ARNI), a beta-blocker (BB), a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose cotransporter-2 inhibitor (SGLT2I). However, the optimal process of initiating and titrating these medications, known as sequencing strategy, is widely debated. Methods and Results: A scoping review was conducted to identify ambulatory sequencing strategies for treatment-naïve, de novo HFrEF patients, revealing a trend in the selection of attributes from the identified strategies, with a focus on expediting the initiation of quadruple therapy. Two attributes were found to heavily influence this trend: the number of medications initiated during the first visit and whether to prioritize initiation or titration. Based on these attributes, we developed a framework to classify sequencing strategies into 3 strategy types, and proposed 2 profiles to represent each type. A benefit-harm and cost-utility analysis was performed using an individual-based state-transition microsimulation model, where each profile was modeled in 2 versions with medication adjustment made fortnightly (a) or weekly (b). Probabilistic analysis of 10,000 trials and 1,000 samples with a willingness-to-pay threshold of $50,000/QALY were conducted, along with one-way sensitivity analysis, and 2 scenario analyses. The analysis demonstrated that the incremental cost-effectiveness among the different strategies is minimal, favoring more intensive strategies after considering benefits, harms and costs. In the base scenario, “simultaneous” sequencing strategy with fortnightly adjustment (Profile 6a) was most likely to be cost-effective. However, in the scenario where sub-target doses were assumed to be ineffective, strategies involved weekly adjustment were more likely to be optimal compared to fortnightly adjustment. In the scenario where medication adjustments were stopped after 3 months, “traditional” sequencing strategy with fortnightly adjustment (Profile 1a) failed to achieve quadruple therapy, resulting in substantially fewer benefits. Conclusions: There was a noticeable trend towards prioritizing the speed of sequencing HFrEF quadruple therapy in the literature. However, this analysis revealed that the incremental cost-effectiveness among the different strategies was marginal. The key factor determining optimal outcomes was the successful establishment of patients on quadruple therapy within a reasonable timeframe.