Pharmacotherapy sequencing strategies for patients with heart failure with reduced ejection fraction: a cost–utility analysis

<h3>Background</h3> Standard pharmacotherapy for patients with heart failure with reduced ejection fraction (HFrEF) comprises “quadruple therapy” with a renin–angiotensin system inhibitor, a β-blocker, a mineralocorticoid receptor antagonist, and a sodium–glucose cotransporter-2 inhibitor. Randomized controlled trials evaluating different sequencing strategies for initiating and titrating these medications are lacking. We sought to compare costs for various HFrEF quadruple therapy sequencing strategies. <h3>Methods</h3> We used an individual-based state-transition microsimulation model to compare cost utility for 12 sequencing strategies with either weekly or biweekly medication adjustments for treatment-naive patients with HFrEF. We conducted a probabilistic analysis with a lifetime horizon from the public-payer perspective, along with a deterministic sensitivity analysis and 2 scenario analyses. We estimated costs, quality-adjusted life years (QALYs), incremental net monetary benefit (NMB) at a willingness-to-pay threshold of $50 000/QALY, and incremental cost-effectiveness ratios (ICERs) of each strategy versus the conventional approach. <h3>Results</h3> Over a lifetime, the 12 strategies resulted in costs ranging from $76 440 to $79 338, QALYs ranging from 9.55 to 9.72, and incremental NMB ranging from $2233 to $6529. Compared with the conventional sequencing strategy of starting and titrating biweekly 1 medication at a time, other strategies had ICERs ranging from $11 175 to $22 492. The simultaneous initiation of all 4 medications with subsequent biweekly adjustment had the highest probability of being the most cost-effective strategy at the specified willingness-to-pay threshold. <h3>Interpretation</h3> Simultaneous initiation of the 4 standard HFrEF medications with biweekly adjustment provided the highest cost utility compared with other strategies. Systems of care are needed to enable rapid initiation and sustained use of HFrEF medications.