(P150) 1-YEAR COMPARISON OF QUADRUPLE THERAPY SEQUENCING STRATEGIES FOR HEART FAILURE WITH REDUCED EJECTION FRACTION USING AN INDIVIDUAL-BASED STATE-TRANSITION MICRO-SIMULATION MODEL

Background: Pharmacotherapy consisting of “quadruple therapy” (an angiotensin receptor blocker-neprilysin inhibitor [ARNI]), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose co-transporter 2 inhibitor [SGLT2I]) is the cornerstone of management of heart failure (HF) with reduced ejection fraction (HFrEF). International clinical practice guidelines unanimously recommend quadruple therapy, yet none has proposed a specific order of initiation and titration (or “sequencing strategy”) of these agents. We modeled the 1-year efficacy and harms of proposed HFrEF quadruple therapy sequencing strategies using a microsimulation model.

METHODS AND RESULTS: We conducted an individual-based state-transition microsimulation modeling study to compare the 1-year cumulative incidence of death, total HF hospitalization, and adverse events (bradycardia, hyperkalemia, hypotension, and renal impairment) with six different HFrEF pharmacotherapy sequencing strategies (emulating 2 different traditional strategies, 2 two-drug combinations, a cluster-based approach, and four-drug simultaneous strategy), each with two versions (weekly or biweekly medication adjustments), applied to treatment-naïve outpatients with HFrEF. We modeled death as an incidence at 1 year. We modeled total HF hospitalization (first and recurrent events) and adverse events (bradycardia, hyperkalemia, hypotension, and renal impairment) as incidence rates per 100 patient-yearsAt 1 year, an estimated 15.5% died without treatment compared to 6.9% with the traditional sequence adjusted biweekly, and 5.2-6.3% with other sequencing strategies. Similarly, the HF hospitalization rate decreased from 32.8 per 100 patient-years with no treatment to 11.1 per 100 patient-years traditional sequencing adjusted biweekly, and 6.9-9 per 100 patient-years with other strategies. The incidence rates of medication-related adverse events per 100 patient-years were: hypotension (5.8-6.9), renal impairment (4.6-6.0), bradycardia (2.9-3.2), and hyperkalemia (approximately 0.5).

Conclusion: For treatment-naïve outpatients with HFrEF, pharmacotherapy sequencing strategies that started 2 to 4 medications on initial encounter reduced the risk of death and hospitalization at 1 year compared to a traditional sequencing strategy, and weekly medication adjustments outperformed biweekly adjustments, with diminishing returns with greater number of medications started in the first week. These findings can inform clinicians and policymakers in the development of HFrEF medication optimization programs with sequencing strategy protocols that fit the local practical context.