Abstract 15872: Development and External Validation of a De Novo Simulation Model to Inform Implementation Strategies for Guideline-Directed Medical Therapy of Heart Failure With Reduced Ejection Fraction

Introduction Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) includes four medication classes and improves survival. However, uptake and adherence to GDMT remain low. Simulation models to project long-term benefits can inform ongoing trials of GDMT implementation strategies (such as a polypill). As such, we sought to develop and validate a mathematical model of HFrEF and GDMT treatment.

Methods We developed a state-transition, Markov model to simulate hospitalizations, urgent care visits, and cardiovascular and non-cardiovascular death among patients with HFrEF on 0, 2, 3, and 4 GDMT drugs. Input parameters were derived from trials, epidemiologic cohorts, national surveys, and published literature. External validation compared model-projected all-cause mortality with data from the Seattle-HF model and three major HFrEF trials (eplerenone in EMPHASIS-HF, sacubitril/valsartan in PARADIGM-HF, and dapagliflozin in DAPA-HF). Goodness-of-fit was assessed by root-mean-square-error (RMSE), with RMSE ≤ 5.0 considered to be a good fit.

Results In external validation, the model accurately replicated 5-year survival curves from the Seattle-HF model among treatment-naïve patients age 65 years (RMSE 1.9), 75 years (RMSE 1.2), and 85 years (RMSE 1.9). Model projections demonstrated good fit among individuals on various combinations of GDMT, with RMSE 0.6-2.8 across all combinations tested (Figure). For a 65-year-old with HFrEF, our model projected a mean survival of 6.3 years without GDMT, increased by 2.5 years on 2-drug, 3.4 years on 3-drug, and 4.7 years on 4-drug GDMT.

Conclusion Our model replicated survival outcomes with GDMT in HFrEF and demonstrated improved survival associated with more classes of GDMT. Future work will project the long-term health and economic impacts of implementation strategies to improve GDMT uptake and adherence, incorporating healthcare costs and quality-of-life measures.