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

doi:10.1016/j.jchf.2023.01.004

JACC: Heart Failure

Volume 11, Issue 5, May 2023, Pages 541-551

https://doi.org/10.1016/j.jchf.2023.01.004 Get rights and content

Abstract

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.

Central Illustration

Section snippets

Model overview

A 2-state Markov model (Supplemental Figure 1) was developed to compare a population of patients with HFrEF treated with the current standard of GDMT⁵ composed of ARN inhibitor, SGLT2 inhibitor, BB, and MRA (quadruple therapy) against historical regimens of BB, ACE inhibitor, and MRA (triple therapy) and BB and ACE inhibitor (double therapy). The population of patients in the model was predominantly New York Heart Association functional class II and III based on the patients enrolled in the

Results

The mean survival in the model for patients in the double therapy cohort was 8.12 years. The use of triple therapy added an additional 1.14 years. Treatment with quadruple therapy resulted in 2.87 and 1.73 additional years of life compared with double therapy and triple therapy, respectively (Table 2). At 10 years, survival rates were 50.0%, 40.3%, and 33.3% for the quadruple therapy, triple therapy, and double therapy cohorts, respectively (Figure 1).

The ICERs of quadruple therapy vs triple

Discussion

In this cost-effectiveness analysis, a model based on the clinical event reductions demonstrated in the pivotal randomized controlled trials for MRAs, ARN inhibitors, and SGLT2 inhibitors for HFrEF and extrapolated over a lifetime was used to investigate the economic value of quadruple therapy. This evaluation found for a U.S. HFrEF patient population with similar clinical characteristics to those enrolled in the PARADIGM-HF trial, treatment with quadruple therapy yielded therapy yielded the

Conclusions

At current pricing, the use of quadruple therapy with ARN inhibitors, BBs, MRAs, and SGLT2 inhibitors in patients with HFrEF was cost effective compared with triple therapy (ACE inhibitors, BBs, and MRAs) and double therapy (ACE inhibitors and BBs) with ICERs of $81,000 and $51,081, respectively. For patients with HFrEF, the optimization of a drug regimen to include all 4 pillars of GDMT results in substantially increased survival, fewer hospitalizations and urgent visits, and improved quality

Funding Support and Author Disclosures

Dr Fonarow has consulted for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Janssen, Medtronic, Merck, Novartis, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Cited by (12)

The Effect of Using a Remote Patient Management Platform in Optimizing Guideline-Directed Medical Therapy in Heart Failure Patients: A Randomized Controlled Trial
2024, JACC: Heart Failure
Guideline-directed medical therapy (GDMT) remains underutilized in patients with heart failure with reduced ejection fraction, leading to morbidity and mortality.
The Medly Titrate (Use of Telemonitoring to Facilitate Heart Failure Mediation Titration) study was an open-label, randomized controlled trial to determine whether remote medication titration for patients with heart failure with reduced ejection fraction was more effective than usual care (UC).
In this study, 108 patients were randomized to remote GDMT titration through the Medly heart failure program (n = 56) vs UC (n = 52). The primary outcome was the proportion of patients completing GDMT titration at 6 months. Secondary outcomes included the number of clinic visits and time required to achieve titration, patient health outcomes, and health care utilization, including urgent clinic/emergency department visits and hospitalization.
At 6 months, GDMT titration was completed in 82.1% (95% CI: 71.2%-90.8%) of patients in the intervention arm vs 53.8% in UC (95% CI: 41.1%-67.7%; P = 0.001). Remote titration required fewer in-person (1.62 ± 1.09 vs 2.42 ± 1.65; P = 0.004) and virtual clinic visits (0.50 ± 1.08 vs 1.29 ± 1.86; P = 0.009) to complete titration. Median time to optimization was shorter with remote titration (3.42 months [Q1-Q3: 2.99-4.04 months] vs 5.47 months [Q1-Q3: 4.14-7.33 months]; P < 0.001). The number of urgent clinic/emergency department visits (incidence rate ratio of remote vs control groups: 0.90 [95% CI: 0.53-1.56]; P = 0.70) were similar between groups, with a reduction in all-cause hospitalization with remote titration (incidence rate ratio: 0.55 [95% CI: 0.31-0.97]; P = 0.042).
Remote titration of GDMT in heart failure with reduced ejection fraction was effective, safe, feasible, and increased the proportion of patients achieving target doses, in a shorter period of time with no excess adverse events compared with UC. (Use of Telemonitoring to Facilitate Heart Failure Mediation Titration [Medly Titrate]; NCT04205513)
Outcomes with guideline-directed medical therapy and cardiac implantable electronic device therapies for patients with heart failure with reduced ejection fraction
2024, Heart Rhythm O2
Limited real-world evidence exists for outcomes with contemporary guideline-directed medical therapy (GDMT) or GDMT with implantable cardioverter-defibrillator (ICD)/cardiac resynchronization therapy defibrillator (CRT-D) therapy for patients with heart failure with reduced ejection fraction (HFrEF) and left ventricular ejection fraction (LVEF) ≤35%.
The present study aimed to assess survival associated with GDMT or GDMT with ICD/CRT-D therapy.
This retrospective observational study included real-world de-identified data from January 1, 2016, to December 19, 2023, from 24 U.S. institutions per participating institutional agreements (egnite Database; egnite, Inc.). Patients with a diagnosis of HFrEF and an echocardiographic study documenting LVEF ≤35% were included for analysis.
Of 43,591 patients with eligible index event of LVEF ≤35%, prescription history through ≥1 year preindex, and no ICD/CRT-D therapy preindex, mean ± standard deviation age at index was 71.2 ± 13.2 years; 14,805 (34.0%) patients were female. At 24 months, an estimated 99.1% (95% confidence interval [CI] 99.0%–99.2%), 89.9% (95% CI 89.7%–90.1%), 54.8% (95% CI 54.4%–55.2%), and 17.2% (95% CI 16.9%–17.5%), had ≥1, 2, 3, or all 4 GDMT classes prescribed, respectively; an estimated 15.7% (95% CI 15.3%–16.1%) had device placement. Of those without a device, by 24 months, an estimated 45.1% (95% CI 44.4%–45.7%) had a documented LVEF >35%. Counts of GDMT classes prescribed as well as ICD/CRT-D device therapy were associated with lower mortality risk in this population, even after adjustment for patient age, sex, and comorbidities.
Both GDMT classes prescribed and device therapy were independently associated with lower mortality risk, even in the presence of more GDMT options for this more contemporary population.
The economics of heart failure care
2024, Progress in Cardiovascular Diseases
Heart failure (HF) poses a significant economic burden in the US, with costs projected to reach $70 billion by 2030. Cost-effectiveness analyses play a pivotal role in assessing the economic value of HF therapies. In this review, we overview the cost-effectiveness of HF therapies and discuss ways to improve patient access. Based on current costs, guideline directed medical therapies for HF with reduced ejection fraction provide high economic value except for sodium-glucose cotransporter-2 inhibitors, which provide intermediate economic value. Combining therapy with the four pillars of medical therapy also has intermediate economic value, with incremental cost-effectiveness ratios ranging from $73,000 to $98,500/ quality adjusted life-years. High economic value procedures include cardiac resynchronization devices, implantable cardioverter-defibrillators, and coronary artery bypass surgery. In contrast, advanced HF therapies have previously demonstrated intermediate to low economic value, but newer data appear more favorable. Given the affordability challenges of HF therapies, additional efforts are needed to ensure optimal care for patients. The recent Inflation Reduction Act contains provisions to reform policy pertaining to drug price negotiation and out-of-pocket spending, as well as measures to increase access to existing programs, including the Medicare low-income subsidy. On a patient level, it is also important to encourage patient and physician awareness and discussions surrounding medical costs. Overall, a broad approach to improving available therapies and access to care is needed to reduce the growing clinical and economic morbidity of HF.
Health equity in heart failure
2024, Progress in Cardiovascular Diseases
The treatment of heart failure (HF) with reduced ejection fraction (HFrEF) has substantially developed over the past decades. More than ever before, the application of appropriate evidence-based medical therapy for HFrEF is associated with remarkable improvements in survival, noteworthy increases in quality of life, and a marked reduction in symptomatic HF sufficient to warrant hospitalization. These enhanced clinical outcomes are driven by the “four pillars” of HF therapy: 1) evidence-based beta blockers, 2) Renin-angiotensin-aldosterone system inhibitors (angiotensin-converting enzyme inhibitors /angiotensin II receptor blockers or angiotensin receptor-neprilysin inhibitors, 3) mineralocorticoid receptor antagonists, and most recently, 4) sodium-glucose cotransporter-2 inhibitors. Despite robust evidence from well-conducted randomized clinical trials, guideline-directed medical therapies with established cardiovascular benefits remain significantly underutilized in clinical practice, particularly among under-represented minority populations. This phenomenon has led to class 1 level recommendations from the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guidelines to address HF disparities among vulnerable populations as follows. In this article, we highlight the difference between health equality and health equity and discuss the need to address equity in the treatment of heart failure, ensuring that the impressive progress made in the treatment of HFrEF is equally beneficial to all individuals. We discuss strategies to reduce and ultimately eliminate disparities in the determinants of health that particularly affect marginalized groups, including the socioeconomic determinants and racism as a threat to public health. Finally, we discuss and propose a combination of the four pillars of ethics with the four pillars of GDMT to optimize and personalize treatment of all patients with HFrEF, to achieve true equity in the treatment of HF.
The Value of Comprehensive Guideline-Directed Therapy for Heart Failure With Reduced Ejection Fraction
2023, JACC: Heart Failure
Cost-Effectiveness of New Quadruple Therapy Compared with Standard Treatment for Patients with Heart Failure in China
2024, Journal of Cardiovascular Pharmacology

View all citing articles on Scopus

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

Abstract

Background

Objectives

Methods

Results

Conclusions

Central Illustration

Section snippets

Model overview

Results

Discussion

Conclusions

Funding Support and Author Disclosures

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol HF

Lancet

J Am Coll Cardiol HF

J Am Coll Cardiol

J Am Coll Cardiol

EClinicalMedicine

Int J Cardiol

Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association

Circ Heart Fail

Epidemiology and risk profile of heart failure

Nat Rev Cardiol

Quadruple medical therapy for heart failure

J Am Coll Cardiol

Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure-optimizing therapy with the need for speed

JAMA Cardiol

Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction

JAMA Cardiol

Cost-effectiveness of dapagliflozin for the treatment of heart failure with reduced ejection fraction

JAMA Network Open

Cost-effectiveness of sacubitril-valsartan in patients with heart failure with reduced ejection fraction

Ann Intern Med

Cost-effectiveness of dapagliflozin for treatment of patients with heart failure with reduced ejection fraction

JAMA Cardiol

Angiotensin-neprilysin inhibition versus enalapril in heart failure

N Engl J Med

Eplerenone in patients with systolic heart failure and mild symptoms

N Engl J Med

Dapagliflozin in patients with heart failure and reduced ejection fraction

N Engl J Med

Estimating the long-term treatment benefits of sacubitril-valsartan

N Engl J Med

Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)

Eur J Heart Fail

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