Addressing the Limitations of Quadruple Therapy in HFrEF, With Stephen Greene, MD

Despite promising results in clinical trials, quadruple therapies are not sufficient for reducing the severe risk of mortality and hospital readmission for older patients with heart failure with reduced ejection fraction (HFrEF).1

Quadruple therapy for HFrEF is generally comprised of angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i) – this combination is strongly recommended to reduce mortality and hospitalization risk. Previous research has indicated a 73% reduction in mortality risk; however, the residual risk of patients with HFrEF in contemporary practice despite quadruple therapy has not been examined.2

“Even though quadruple therapy lowers the relative risk substantially, it does not make the absolute risk low,” Stephen Greene, MD, associate professor of medicine and cardiology at the Duke Clinical Research Institute and lead investigator on this study, told HCPLive in an exclusive interview. “There’s this absolute risk persistence even when you achieve that major relative risk reduction with quad therapy. So, I think that, while quad therapy is our fundamental goal, in a lot of respects, we can’t necessarily breathe a sigh of relief that our patients are all of a sudden going to be okay.”

Greene and colleagues collected data from the GWTG-HF registry, identifying patients ≥65 years discharged from a hospitalization for HF with EF of ≤40% between July 2021 and December 2023. For patients with multiple hospitalizations, the first hospitalization was used for analysis. Patients were excluded if they had a history of dialysis, heart transplant, or left ventricular assist device, were discharged to hospice care, left against medical advice, or transferred to another acute care facility.1

The primary outcomes of the study were mortality, HF hospitalization, mortality or HF hospitalization, and per-patient health care expenditure as determined by Medicare Part A and B inpatient and outpatient costs in 2023 US dollars. Mortality and hospitalization outcomes were assessed as time to first event, and mortality risk was also evaluated as median survival in years.1

A total of 20,651 patients hospitalized for HFrEF and medically eligible for quadruple therapy were enrolled in the study. Of these patients, only 1490 (7.2%) were prescribed quadruple medical therapy with angiotensin receptor-neprilysin inhibitor (ARNI) at discharge, and 2438 (11.8%) were prescribed quadruple therapy including angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or ARNI at discharge.1

Rates of discharge prescription of ARNI quadruple therapy were substantially variant across the 532 hospitals included in the study (median OR, 2.04; 95% CI, 1.89-2.24). Of the 1490 patients prescribed ARNI quadruple therapy at discharge, the median age was 74 years (interquartile range [IQR], 69-80). Median EF was 26% (IQR, 20-33%).1

Over a 12-month follow-up period, patients receiving ARNI quadruple therapy exhibited a cumulative incidence of 19.3% (95% CI, 17.3-21.4%) for all-cause mortality, 26% (95% CI, 23.6-28.5%) for HF hospitalization, 37.1% (95% CI, 34.4-39.8%) for mortality or HF hospitalization, and 54.5% (95% CI, 51.6-57.2%) for all-cause hospitalization. Median survival ranged from 7.4 years in patients aged 65-69 years to 3.1 years for patients aged 85-89 years.1

Among the patients prescribed ARNI quadruple therapy, 408 (27.4%) were hospitalized with new-onset HFrEF, 1071 (71.9%) were hospitalized for worsening HFrEF, and 11 (0.7%) had unknown prior HF status. When comparing this against new-onset FHrEF prescribed quadruple therapy at discharge, Greene and colleagues found that patients with worsening HFrEF prescribed quadruple therapy at discharge had higher cumulative incidences across hospitalization and mortality outcomes.1

“I would argue that, for an eligible patient to not receive HFrEF medicine, that decision has the same gravity as a cancer patient saying they’re not going to take chemotherapy,” Greene said. “Patients and clinicians would take decisions over chemotherapy very, very seriously. We need to take it just as seriously when we’re discussing whether to start GDMT in a HFrEF patient.”

Editor’s Note: Greene reports disclosures with Amgen, AstraZeneca, Novartis, Corcept Therapeutics, Idorsia, Boehringer Ingelheim, and others.

References

1. Greene SJ, Xu H, Chiswell K, et al. One-year outcomes in patients hospitalized for heart failure with reduced ejection fraction prescribed quadruple medical therapy at discharge. JAMA Cardiology. Published online January 28, 2026. doi:10.1001/jamacardio.2025.5339

2. Bassi NS, Ziaeian B, Yancy CW, Fonarow GC. Association of optimal implementation of sodium-glucose cotransporter 2 inhibitor therapy with outcome for patients with heart failure.JAMA Cardiol. 2020;5(8):948-951. doi:10.1001/jamacardio.2020.0898