Effect of initiating an ARB- versus ACEI-based regimen on dementia risk, a target trial emulation of 2.5 million US Veterans

Background: Hypertension is a modifiable risk factor for dementia, yet the comparative effectiveness of angiotensin receptor blockers (ARBs) versus angiotensin converting enzyme inhibitors (ACEIs) on dementia risk remains uncertain. Objective: To compare the risk of dementia and dementia-free death of ARB versus ACEI initiation among US Veterans with incident hypertension. Methods: We conducted a retrospective target trial emulation using a new-user, active-comparator design among Veterans with incident hypertension. We analyzed longitudinal electronic health records from 2,577,000 individuals who initiated ARBs or ACEIs between 1/1/2000-12/31/2017, with up to five years of follow-up. The exposure was initiation of an ARB-based versus ACEI-based antihypertensive regimen. Co-primary outcomes were dementia, identified using natural language processing of clinical notes, and dementia-free death. We used inverse probability of treatment weights based on 66 pretreatment covariates to estimate the cumulative incidence of the outcomes for each treatment group. Weighted risk ratios and absolute risk differences through five years were computed with bootstrapped 95% CIs. Secondary outcomes included all-cause death and a composite of dementia or death, evaluated using a weighted Kaplan-Meier approach. Results: Among 2,577,000 Veterans (mean age, 63 years; 4.5% female; 65% White; 15% Black), 10% initiated ARBs and 90% initiated ACEIs. Over five years of follow up, 6% developed dementia, 12% died without dementia, and 13% died overall. ARB initiation yielded consistently lower risk of dementia (risk ratio, 0.88; 95% CI, 0.83-0.93 at 6 months to 0.92; 95% CI, 0.90-0.94 at 5 years) and dementia-free death (risk ratio, 0.90; 95% CI, 0.86-0.96 at 6 months to 1.00; 95% CI, 0.98-1.01 at 5 years) than ACEI initiation. Effects on secondary outcomes were similar to those for primary outcomes. Greater protective dementia effects were observed in older and male Veterans and non-statin users, with similar effects on dementia-free death. Discussion: Among US Veterans with incident treated hypertension, initiation of ARB versus ACEI antihypertensive regimen conveyed a modestly lower risk of dementia. Given the high prevalence of hypertension, these modest effects may confer meaningful population-level benefits on brain health. Future research estimating per-protocol effects using a more generalizable population is needed to confirm our findings. Key words: antihypertensive medication, dementia, natural language processing, target trial emulation, Veteran