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Target Versus Below-Target Dose ACE Inhibitors in U.S. Veterans with HFpEF: Differential Outcomes by CKD Status
Frederick Lu1,2, Amiya A Ahmed3, Sijian Zhang1
1Center for Data Science and Outcomes Research, Veterans Affairs Medical Center, Washington, DC; 50 Irving St. NW, Washington, DC 20422, USA.
European Journal of Heart Failure
|July 30, 2026
Summary
Target-dose angiotensin-converting enzyme inhibitors (ACEIs) reduced kidney failure risk in heart failure with preserved ejection fraction (HFpEF) patients, especially those with chronic kidney disease (CKD). However, target-dose ACEIs increased HF hospitalization risk without affecting mortality.
Area of Science:
- Cardiology
- Nephrology
- Pharmacology
Background:
- Angiotensin-converting enzyme inhibitors (ACEIs) are linked to better outcomes in heart failure with reduced ejection fraction (HFrEF).
- The role of target-dose ACEIs in heart failure with preserved ejection fraction (HFpEF) remains less understood.
- Understanding ACEI dosing effects in HFpEF is crucial for optimizing patient care.
Purpose of the Study:
- To investigate the association between target-dose ACEIs and outcomes in patients with HFpEF.
- To compare the effects of target-dose versus below-target-dose ACEIs on mortality, kidney failure (KF), and HF hospitalization.
- To examine these associations specifically in HFpEF patients with chronic kidney disease (CKD).
Main Methods:
- A retrospective cohort study of 96,473 Veterans with HFpEF initiated on ACEIs between 2000-2018.
- Propensity score matching was used to create a balanced cohort of 61,160 patients (30,580 on target-dose ACEIs).
- Outcomes assessed included 5-year all-cause mortality, incident KF, and HF hospitalization.
Main Results:
- Target-dose ACEIs were associated with a lower risk of KF (HR, 0.89) but a higher risk of HF hospitalization (HR, 1.08) compared to below-target doses; no difference in mortality was observed.
- In the subgroup with CKD, target-dose ACEIs showed a significantly lower risk of KF (HR, 0.82) and mortality (HR, 0.93).
- These associations differed significantly between patients with and without CKD (interaction p<0.001).
Conclusions:
- In HFpEF, target-dose ACEIs are linked to reduced KF risk and increased HF hospitalization risk, with no impact on mortality.
- The benefits of target-dose ACEIs, particularly for KF and mortality, were more pronounced in HFpEF patients with CKD.
- These findings highlight the need for phenotype-specific treatment strategies in HFpEF.
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