Less than 25% of veterans with newly diagnosed heart failure with reduced ejection fraction achieved concurrent quadruple therapy during 2.9 years of median follow-up, with a median time to quadruple therapy of more than 6 months, according to a retrospective cohort study.
Investigators evaluated 52,850 adult patients with incident heart failure with reduced ejection fraction (HFrEF) in the Veterans Health Administration (VHA) from January 1, 2020, to December 31, 2023. Incident HFrEF was defined using an International Statistical Classification of Diseases and Related Health Problems, 10th Revision heart failure diagnosis code and a left ventricular ejection fraction of 40% or less, without a prior documented heart failure diagnosis dating back to 2016.
Quadruple guideline-directed medical therapy was defined using overlapping prescription dispensing records for concurrent use of an evidence-based beta-blocker, renin-angiotensin system inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter-2 (SGLT2) inhibitor, regardless of the dosage. The investigators used pharmacy fill data records and added a 14-day grace period to account for dose adjustments, stockpiling, and adherence.
The cohort had a median age of about 72 years and was 97% male. Overall, 68% were the patients were White, 20% were Black, 5% were Hispanic, and 7% were classified as other race or ethnicity. During follow-up, 21% (n = 11,217) of the patients achieved quadruple therapy.
Use of individual guideline-directed medical therapy classes varied. During follow-up, 78% of the patients had at least one prescription fill for an evidence-based beta-blocker, 79% for a renin-angiotensin system inhibitor, 38% for a mineralocorticoid receptor antagonist, and 46% for an SGLT2 inhibitor. Among the patients receiving a renin-angiotensin system inhibitor, 49% had at least one angiotensin receptor-neprilysin inhibitor fill.
Overall, the mortality rate was about 31% during the follow-up period, and 91% of those deaths occurred prior to quadruple therapy was achieved. In an accompanying editorial published in JAMA Cardiology, editorialists noted that patients were more likely to die during follow-up than to receive quadruple therapy.
Prescription copays were associated with lower rates of quadruple therapy. After adjustment, patients in VHA priority groups 2 through 8 had an 8% lower rate of achieving quadruple therapy compared with patients in priority group 1 who had no prescription copay. However, the editorial authors wrote that medication access barriers alone were unlikely to explain the low uptake, noting that fewer than 30% of patients without copays achieved quadruple therapy despite relatively low out-of-pocket costs within the VHA system.
Adjusted rates of quadruple therapy were higher among Black patients, Hispanic patients, and those who identified as other race and ethnicity compared with White patients. The investigators observed no statistically significant difference in the rates of quadruple therapy between female and male veterans.
Subgroup analyses showed quadruple therapy was numerically more common among patients diagnosed in the outpatient setting vs. inpatient setting (22% vs. 14%), those with diabetes vs. without diabetes (24% vs. 19%), and those without chronic kidney disease vs. with chronic kidney disease (23% vs. 18%).
The editorial authors noted that inpatient diagnosis was associated with an approximately 50% lower likelihood of achieving quadruple therapy within 6 months despite evidence supporting in-hospital initiation and postdischarge optimization of combination therapy.
In sensitivity analyses requiring an angiotensin receptor-neprilysin inhibitor as the renin-angiotensin system inhibitor component, 16% of patients achieved quadruple therapy. Among those diagnosed in 2023, 23% achieved quadruple therapy with a median time to quadruple therapy of 136 days.
“[L]ess than one quarter of veterans with HFrEF achieved quadruple therapy within 2.9 years, and the median [time to quadruple therapy] was 6 months,” wrote lead study author Joshua A. Jacobs, PharmD, PhD, of the Department of Internal Medicine in the Division of Cardiovascular Medicine at the Spencer Fox Eccles School of Medicine at the University of Utah, and colleagues.
The investigators cited several limitations, including the focus on medication class use rather than dose, the predominantly male VHA population, and possible undercapture of non-VHA prescriptions.
“[T]he speed of [guideline-directed medical therapy] initiation has received less attention,” despite persistently low rates of quadruple therapy, wrote lead editorial author Neil M. Kalwani, MD, MPP, of the Cardiology Section at the Medical Service of the VA Palo Alto Health Care System in California, and colleagues, according to the editorial authors.
The editorial authors suggested that time from diagnosis to quadruple therapy could serve as a performance measure for HFrEF care, while noting that additional measures accounting for medication dose intensity would still be needed.
“The prevailing practice of incremental, slow, and steady [guideline-directed medical therapy] treatment is misaligned with the high clinical risk these patients face,” the editorial authors added. “To approach HFrEF with the urgency it deserves, we must recognize the need for speed in treatment,” they concluded.
Full disclosures can be found in the published study, which was funded in part by the National Institute on Aging. Co–editorial author Jessica R. Golbus, MD, MS, reported grants from the Patient-Centered Outcomes Research Institute and the National Institutes of Health as well as salary support from Blue Cross and Blue Shield of Michigan outside the submitted work. Senior editorial author Stephen J. Greene, MD, reported personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Corcept, CSL Vifor, Cytokinetics, Idorsia, Lexicon, Lilly, Merck, Mineralys, Novartis, Novo Nordisk, Otsuka, PharmIN, Sanofi, scPharmaceticals, Sumitomo, Roche Diagnostics, Tricog Health, and Viatris outside the submitted work. No other disclosures were reported.
Source: JAMA Cardiology, Editorial