Cost-Effectiveness of Comprehensive Quadruple Therapy for Heart Failure With Reduced Ejection Fraction

JACC Heart Fail. 2023 May;11(5):541-551. doi: 10.1016/j.jchf.2023.01.004. Epub 2023 Mar 1.


Background: Heart failure with reduced ejection fraction (HFrEF) is one of the most costly and deadly chronic disease states. The cost effectiveness of a comprehensive quadruple therapy regimen for HFrEF has not been studied.

Objectives: The authors sought to determine the cost-effectiveness of quadruple therapy comprised of beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium glucose cotransporter-2 inhibitors vs regimens composed of only beta-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists (triple therapy), and angiotensin-converting enzyme inhibitors and beta-blockers (double therapy).

Methods: Using a 2-state Markov model, the authors performed a cost-effectiveness study using simulated populations of 1,000 patients with HFrEF based on the participants in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial and compared them by treatment strategy (quadruple therapy vs triple and double therapy) from a United States health care system perspective. The authors also performed 10,000 probabilistic simulations.

Results: Treatment with quadruple therapy resulted in an increase of 1.73 and 2.87 life-years compared with triple therapy and double therapy, respectively, and an increase in quality-adjusted life-years of 1.12 and 1.85 years, respectively. The incremental cost-effectiveness ratios of quadruple therapy vs triple therapy and double therapy were $81,000 and $51,081, respectively. In 91.7% and 99.9% of probabilistic simulations quadruple therapy had an incremental cost-effectiveness ratio of <$150,000 compared with triple therapy and double therapy, respectively.

Conclusions: At current pricing, the use of quadruple therapy in patients with HFrEF was cost effective compared with triple therapy and double therapy. These findings highlight the need for improved access and optimal implementation of comprehensive quadruple therapy in eligible patients with HFrEF.

Keywords: Markov model; cost-effectiveness analysis; guideline-directed medical therapy; heart failure with reduced ejection fraction; high-value care; incremental cost effectiveness ratio.

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use
  • Angiotensin Receptor Antagonists / pharmacology
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Cost-Benefit Analysis
  • Heart Failure* / drug therapy
  • Humans
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Stroke Volume
  • United States
  • Ventricular Dysfunction, Left*


  • Mineralocorticoid Receptor Antagonists
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Adrenergic beta-Antagonists