Establishing Drug Therapy During Hospitalization
Gregg C. Fonarow, MD, Director Ahmanson-UCLA Cardiomyopathy Center, Co-director Preventative Cardiology Program, Eliot Corday Chair in Cardiovascular Medicine and Science, University of California, Los Angeles,
WASHINGTON, DC — In veteran patients with heart failure with reduced ejection fraction (HFrEF), using higher target doses of angiotensin-converting enzyme inhibitors (ACEIs) before discharge reduced the risks of death and kidney failure, according to a recent study.
The findings published in the Journal of Cardiac Failure examined whether target doses of ACEIs recommended in clinical guidelines had those effects in hospitalized patients with HFrEF, who have been less likely to receive target doses recommended in clinical guidelines due to hemodynamic instability and impaired kidney function. While previous studies have found that, in patients with relatively stable HFrEF, target-dose ACEIs, compared with below-target doses, reduced the risks of death and kidney failure, it has remained unclear whether these benefits extend to hospitalized patients, the investigators explained.
Gregg C. Fonarow, MD, a co-author of the study and director of the Ahmanson-UCLA Cardiomyopathy Center, co-director of the Preventative Cardiology Program and the Eliot Corday Chair in Cardiovascular Medicine and Science at the University of California, Los Angeles, noted the results directly counter the instinct for many clinicians to stay conservative with initiation and dosing of guideline directed medical therapies. In the patients where clinicians hesitate most, those recently decompensated, often with reduced kidney function, there are often concerns about safety, he said.
“The reassurance here is the safety profile: target dosing was not associated with any excess acute kidney injury (HR 1.10, non-significant), hyperkalemia (HR 1.05), hypotension (HR 1.23), or heart failure rehospitalization (HR 0.98), and spline analyses showed no evidence of harm at any point across the eGFR spectrum,” Fonarow explained. “That undercuts the reflexive caution, often extended from guideline language about ACE inhibitors in chronic kidney disease (CKD), that leads to under-dosing. The practical shift is toward standardized in-hospital and pre-discharge titration: order sets and pharmacist- or nurse-led optimization programs that make reaching target dose the default pathway. It’s worth stating plainly that this is observational, real-world evidence; yet it strengthens and operationalizes the guideline framework that has also been supported in randomized trial data from STRONG-HF.”
For Military Health Service and Indian Health Service clinicians, he told U.S. Medicine, “the transferable principle is that initiating and titrating to target dose before discharge is worthwhile and appears safe, with the caveat that these populations differ demographically from a nearly all-male veteran cohort.”
In this study, the lead researchers from the Washington, DC, VAMC, George Washington University and Georgetown University, all in DC, used data from the National DCVA-HF Registry to identify 15,152 patients aged 20 years or older with HFrEF (left ventricular ejection fraction less than or equal to 40%) who were hospitalized for acute decompensation and initiated on ACEIs before hospital discharge up to Dec. 31, 2018. The study included patients hospitalized from 2000 to 2018.
Of these patients, 3,143 (20.7%) received ACEIs in the target doses recommended in heart failure guidelines. The researchers calculated propensity scores for the receipt of target-dose for each of the 15,152 patients and used these scores to match 2,884 (91.8% of 3,143) target-dose patients to 2,884 below-target-dose patients. They then estimated hazard ratios for mortality and kidney failure associated with target-dose ACEIs.
The primary outcomes of the study were all-cause mortality and kidney failure. Information on death was obtained from the VA Death Ascertainment File. Patients with kidney failure at baseline were excluded. Kidney failure was defined as kidney transplantation or maintenance dialysis recorded in the U.S. Renal Data System (USRDS), or an estimated glomerular filtration rate (eGFR) less than 15 mL/min/1.73m² using the race‑free 2021 CKD‑EPI equation. The study baseline was defined as the time of new initiation of ACEIs.
Secondary outcomes of the study included hospitalizations due to heart failure, all-cause hospitalizations, and the combined outcome of kidney failure or death, and heart failure hospitalization or death. In addition, adverse outcomes included acute kidney injury (AKI), hyperkalemia and hypotension causing hospitalization or occurring during hospitalization for other reasons. All outcomes were established during a five-year follow-up period, starting from the date of new initiation of ACEIs and ending on Dec. 31, 2023, with death and kidney failure outcomes additionally assessed at one and two years to evaluate temporal changes in associations, according to the authors, who included representatives from the Uniformed Services University of the Health Sciences in Bethesda, MD; the Palo Alto, CA, VAMC; and the Providence, RI, VAMC, as well as other academic institutions.
The 5,768 matched patients — 99% men and 36% African American — had a mean age of 66 years old, left ventricular ejection fraction (LVEF) 26% and eGFR 76 mL/min/1.73 m². Patients in the two dose groups were balanced on 76 baseline characteristics.
The study found that among patients with HFrEF hospitalized for heart failure and initiated on ACEIs before discharge, target‑dose therapy was associated with a significant post‑discharge survival advantage and a lower risk of kidney failure or death, without an increased risk of kidney failure, AKI or other adverse events. In addition, patients who received target doses had a significantly lower five‑year risk of death.
While the association between target‑dose ACEIs and kidney failure didn’t reach statistical significance in the hospitalized cohort; still, the absolute and relative risk reductions were similar to those observed in previous research with a much larger veteran cohort with HFrEF, which included the hospitalized veterans, the researchers pointed out.
In the five-year follow-up period, the investigators found that all‑cause mortality occurred in 56.1% of below‑target‑dose patients and 52.6% of target‑dose patients. Kidney failure occurred in 4.2% and 3.6%, respectively. Target‑dose ACEIs were associated with a 9% lower risk of death. The hazard ratio for kidney failure was 0.83, and the hazard ratio for the composite endpoint of kidney failure or death was 0.90, study authors concluded.
The researchers said their findings suggested the renal safety profile of target-dose ACEIs extends to hospitalized patients initiated on therapy before discharge because the dosage wasn’t associated with higher rates of hospitalization or medication-related adverse events.
Fonarow, an American Heart Association volunteer who helped establish the Get With The Guidelines Heart Failure program,
explained the study predates the ARNI [angiotensin receptor/neprilysin inhibitor] (sacubitril/valsartan) era and excluded ARNI initiators. It discussed ACE inhibitors specifically, which remain the most commonly prescribed renin-angiotensin inhibitor and the recommended option for patients who can’t take or can’t access an ARNI.
According to current evidence and guidelines, clinicians should be prioritizing the use of ARNI over ACEI or ARBs [angiotensin II receptor blockers], he noted, adding that the durable lesson is broader than any single drug and is to: Get patients to target-dose, guideline-directed therapy before they leave the hospital, and don’t let real or feared renal and hemodynamic concerns become the reason to under treat.
The most actionable message of the study is to treat hospitalization for heart failure as a key opportunity to reach target dose, not merely to start a drug, Fonarow added.
Only about one in five patients in this cohort (20.7%) were actually discharged on a target-dose ACE inhibitor, so the implementation gap is large. He advised that the study also contains a striking adherence finding that explains why the inpatient window matters: whatever dose category patients left the hospital on tended to persist. Approximately, three-quarters stayed in their starting category at one year, and only 10% of below-target starters were ever up-titrated, he pointed out.
“In other words, if you discharge a patient with heart failure at below target doses, they will most likely stay below target indefinitely,” Fonarow said. “Clinicians can use these findings to further justify up-titration during the hospitalization, when blood pressure and renal function allow, and documenting a concrete titration plan with early post-discharge labs and follow-up, rather than deferring to an outpatient process that, in practice, rarely completes.”
Limitations of the study include potential unmeasured confounding, the absence of cystatin C and a predominantly male cohort that limits extrapolation to women, Fonarow explained.
Fonarow suggested the deeper significance of the study might be as much about systems as specific drugs or doses: the persistence of discharge dosing shows that heart failure hospitalization is where the trajectory gets set, which is a strong argument for building guideline-directed medical therapy optimization into the in-hospital and discharge process itself.
- Arundel C, Raman VK, Zhang S, Sheriff HM, et. al. Inpatient Initiation of Target-Dose ACE Inhibitors and Lower Risk of Death or Kidney Failure in Veterans With HFrEF: Results From the National DCVA-HF Registry. J Card Fail. 2026 Aug 21:S1071-9164(26)00498-7. doi: 10.1016/j.cardfail.2026.08.007. Epub ahead of print. PMID: 42628680.
