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April 1, 2026JAMA Cardiology
Time to Quadruple Therapy After Initial Diagnosis of Heart Failure With Reduced Ejection Fraction
Key result
Prescription copays were associated with an 8% lower rate of achieving quadruple therapy compared with no prescription copay (HR 0.92; 95% CI 0.87-0.96) among patients with incident HFrEF.
Why the study?
What is the time to quadruple therapy and what factors are associated with its achievement in patients with incident HFrEF?
Study Design
Type
Cohort (n=52,850)
Multicenter
Yes
Structured PICO
What is the time to quadruple therapy and what factors are associated with its achievement in patients with incident HFrEF?
P
Population
52,850 predominantly male veterans with incident HFrEF, followed for a median of 2.9 years to assess time to quadruple guideline-directed medical therapy.
E
Exposure
Assessment of demographic and socioeconomic factors (race/ethnicity, sex, copay status) and clinical characteristics on the achievement of quadruple guideline-directed medical therapy.
C
Comparator
Reference groups including White patients, males, and patients with no prescription copay.
O
Outcome
Achievement of quadruple therapy (concurrent use of evidence-based beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors) and time to quadruple therapy (TTQ).
Main Result
Hazard Ratio: 0.92 (95% CI 0.87–0.96)
In a large cohort of incident HFrEF patients, only 21.2% achieved quadruple guideline-directed medical therapy, with medication copays identified as a significant modifiable barrier to timely implementation.
Discussion
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“In HFrEF, the four medications clearly reduce all-cause mortality, are nonoverlapping and truly and fully additive, and their benefits are cumulative, incremental, and begin within days. Yet, when we look at their actual implementation in clinical practice, we've seen this slow and variable uptake.”
SJStephen J. GreeneCardiologist, Duke Clinical Research Institute
“We need to turn our thinking on its head about heart failure in clinical practice.”
“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start.”
Implication
Copays were associated with delayed quadruple therapy uptake in HFrEF; this cohort leaves open effective interventions to close the implementation gap.
Abstract
IMPORTANCE: Timely prescription of quadruple guideline-directed medical therapies (GDMTs) for patients with heart failure with reduced ejection fraction (HFrEF) is associated with improved morbidity and mortality, yet contemporary estimates of time to quadruple therapy (TTQ) and the factors associated with its achievement remain unknown. OBJECTIVE: To characterize TTQ and factors associated with TTQ in HFrEF. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study including patients with incident HFrEF from the Veterans Health Administration database during the January 1, 2020, to December 31, 2023, period. Study data were analyzed from November 2024 to December 2025. EXPOSURES: Primary factors included race and ethnicity, sex, and copay status (priority group). Secondary factors included clinical characteristics. MAIN OUTCOMES AND MEASURES: The main outcome included quadruple therapy according to pharmacy fill data-concurrent use of evidence-based β-blockers, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. TTQ was defined as the first date that all 4 medication classes overlapped, based on dispense date and days' supply. RESULTS: Among 52 850 patients with incident HFrEF (median [SD] age, 71.8 [11] years; 51 473 male [97%]; 10 791 Black [20%]; 2528 Hispanic [5%]; 35 867 White [68%]; 3664 other [7%]), 11 217 (21.2%) achieved quadruple therapy over a median (IQR) follow-up of 2.9 (1.9-3.9) years. The median (IQR) TTQ was 197 (49-528) days. After adjustment, Black patients (hazard ratio [HR], 1.22; 95% CI, 1.15-1.30), Hispanic patients (HR, 1.21; 95% CI, 1.09-1.33), and those from other racial or ethnic groups (HR, 1.11; 95% CI, 1.02-1.20) had higher rates of quadruple therapy than White patients. There was no difference in TTQ in females vs males (HR, 0.97; 95% CI, 0.86-1.09). Prescription copays (priority groups 2-8) were associated with an 8% lower rate of achieving quadruple therapy (HR, 0.92; 95% CI, 0.87-0.96) than no prescription copay (priority group 1). Rates of quadruple therapy were higher among veterans with an outpatient HFrEF diagnosis vs inpatient (22.2% vs 14.2%), with diabetes vs without diabetes (23.6% vs 19.3%), and without chronic kidney disease vs with chronic kidney disease (22.5% vs 18.1%). CONCLUSION AND RELEVANCE: Results of this cohort study suggest that opportunities exist to improve both the rate and timeliness of quadruple therapy as only 21.2% of patients with HFrEF achieved it, with a median follow-up of 2.9 years and TTQ of 6 months. Medication copays represent a modifiable barrier, providing a potential target for interventions to enhance TTQ.
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
Cite This Study
Jacobs et al. (2026) conducted a cohort in Heart failure with reduced ejection fraction (HFrEF) (n=52,850). Prescription copays vs. No prescription copay was evaluated on Achievement of quadruple therapy (concurrent use of β-blockers, RAS inhibitors, MRAs, and SGLT2 inhibitors) (HR 0.92, 95% CI 0.87-0.96). Prescription copays were associated with an 8% lower rate of achieving quadruple therapy compared with no prescription copay (HR 0.92; 95% CI 0.87-0.96) among patients with incident HFrEF.