Choosing the Optimal Antihypertensive for Brain Health: A Deep Dive into ARB vs. ACEI Initiation and Cognitive Trajectories

Prescribing a first-line antihypertensive medication is one of the most frequent clinical decisions made in primary care and cardiovascular medicine. While current guidelines frequently treat Angiotensin-II Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme Inhibitors (ACEIs) as interchangeable options for primary blood pressure management, a crucial clinical question remains: Do these two classes differ in their long-term impact on late-life cognitive health?

New Research

A landmark study published in Neurology Open Access by Andrews et al. addresses this clinical dilemma. By emulating a target randomized trial using data from the Systolic Blood Pressure Intervention Trial (SPRINT), the investigators evaluated the comparative effectiveness of initiating ARB-based versus ACEI-based regimens on long-term cognitive change.

Why It Matters

The Biological Mechanics of Neuroprotection

To understand why this study is vital for clinical practice, we must look beyond systemic hemodynamics. While lowering systemic blood pressure is a proven strategy to mitigate the risk of cognitive decline and dementia, emerging evidence suggests that certain antihypertensive classes may exert direct, blood-pressure-independent neuroprotective effects via the renin-angiotensin system (RAS).

The RAS Pathway Split

ARBs and ACEIs target distinct nodes of the RAS pathway, resulting in opposite downstream cellular environments in the central nervous system:

• The ARB Mechanism (AT1 Antagonism & AT2/AT4 Stimulation): ARBs selectively block angiotensin type 1 (AT1) receptors. This targeted blockade prevents the harmful effects of AT1 activation, such as vasoconstriction and cellular stress, while leaving circulating angiotensin II free to bind to open angiotensin type 2 (AT2) and type 4 (AT4) receptors. The upregulation and activation of AT2 and AT4 receptors have been associated with reduced oxidative stress, diminished neuroinflammation, and enhanced cerebral perfusion—pathways that directly safeguard cognitive reserves.
• The ACEI Mechanism (Upstream Inhibition): In contrast, ACEIs act upstream by blocking the conversion of angiotensin I to angiotensin II. While this successfully lowers blood pressure by reducing overall angiotensin II levels, it simultaneously curtails the activation of all downstream receptors. Consequently, ACEIs inadvertently shut down the potentially beneficial, neuroprotective signaling cascades mediated by the AT2 and AT4 pathways.

Addressing the Clinical Gap

Despite these compelling mechanistic differences, older adults in real-world clinical settings have historically been more likely to be initiated on an ACEI than on an ARB. Prior randomized controlled trials evaluating cognitive outcomes between these classes have been chronically limited by small sample sizes or inadequate follow-up periods. By generating Class II evidence through a rigorous target trial emulation framework, this study provides clinicians with much-needed data on the real-world cognitive consequences of these everyday prescribing choices.

Who It Affects

Patient Demographics and Distinct Subgroup Vulnerabilities

Understanding the exact cohort studied is essential for translating these findings to your patient panel. The investigators restricted their analytic sample to SPRINT participants who were new users of either ARB or ACEI therapy (initiated within 12 months of trial entry) and who demonstrated no baseline cognitive impairment or dementia.

The Baseline Analytic Cohort

Out of the broader SPRINT population, 1,597 participants met the strict eligibility criteria for this comparative analysis. Their collective baseline characteristics included:

• Treatment Breakdown: 579 (36%) initiated an ARB-based regimen, while 1,018 (64%) initiated an ACEI-based regimen.
• Age and Gender Distribution: The mean baseline age of the sample was 65 years (interquartile range: 59–74 years), and 36% (n = 570) were female.
• Race and Ethnicity: 64% (n = 1,022) identified as non-Hispanic White, 26% (n = 422) as non-Hispanic Black, 8% (n = 125) as Hispanic, and 2% (n = 28) as another race or ethnicity.
• Comorbidities and Health Metrics: At baseline, the cohort exhibited a median systolic blood pressure of 141.0 mm Hg, a median body mass index of 28.7 kg/m^2, a 17% prevalence of clinical cardiovascular disease, and a 19% prevalence of a history of depression.
• Concomitant Medications: Cardiovascular therapies were highly prevalent, including statins (33%), calcium channel blockers (34%), thiazide diuretics (49%), loop diuretics (4%), beta-blockers (31%), and alpha-1 blockers (4%).

Analytic Cohort (N = 1,597)

• ACEI Initiators: 64% (n = 1,018) – Primary Drug: lisinopril (99%)
• ARB Initiators: 36% (n = 579) – Primary Drugs: losartan (54%) | valsartan (44%)

Who Benefited Most?

In the primary, fully weighted intention-to-treat analysis, the overall difference in the rate of global cognitive decline between ARB and ACEI initiators was small and compatible with chance variation. However, the study uncovered notable heterogeneity of treatment effects across specific pre-specified subgroups.

The data revealed that ARB initiation was associated with statistically slower mean rates of cognitive decline compared to ACEI initiation among three distinct patient groups:

1. Men: ARB initiators experienced an annual change in global cognition that was 0.08 points slower (95% CI, 0.01 to 0.15) compared to their ACEI counterparts.
2. Patients Younger Than 75 Years: Younger older adults initiating an ARB saw an annual cognitive trajectory that was 0.08 points slower (95% CI, 0.01 to 0.14) than those on an ACEI.
3. Patients Randomized to Intensive BP Control: Among individuals assigned to SPRINT’s intensive systolic blood pressure target (<120 mm Hg), ARB initiators exhibited a 0.09 point per year slower decline (95% CI, 0.002 to 0.16) than ACEI initiators.

What Changes

Clinical Practice and Methodological Implications

The insights from this research do not demand an immediate, sweeping re-prescription of all hypertensive regimens, but they do change how clinicians should conceptualize long-term treatment selection and the interpretation of future trial data.

The Shift in Cognitive Trajectories

While the primary objective difference between the two drug classes fell within the margin of chance variation over the four-year follow-up period, the underlying qualitative trajectories within each arm are telling. Over the course of follow-up, ACEI initiators experienced a steady, absolute mean cognitive decline of 0.03 points per year on the Montreal Cognitive Assessment (MoCA) (95% CI, -0.09 to 0.02). Conversely, ARB initiators experienced an absolute mean cognitive gain of 0.03 points per year (95% CI, -0.04 to 0.09).

This divergence, resulting in a net annual primary difference of 0.06 points favoring ARBs (95% CI, -0.01 to 0.12), suggests a subtle but consistent trend toward cognitive preservation. This trend was further mirrored in secondary testing parameters, including the Logical Memory Form I and II subtests and the Digit Symbol Coding Test.

Nuances to Keep in Mind

Clinicians must evaluate these results alongside several specific parameters of the SPRINT cohort:

• Class-Specific Drug Domain: The overwhelming majority of patients in this analysis were prescribed a limited selection of agents. Approximately 98% of the ARB cohort received either losartan (54%) or valsartan (44%), while 99% of the ACEI cohort received lisinopril. The findings are highly reflective of these specific medications rather than an equal distribution across all class variations, which is an important detail given that blood-brain barrier permeability varies significantly between individual agents.
• The Intensive Arm Interaction: The benefit of ARBs was more pronounced in the intensive blood pressure-lowering arm. This implies that when pushing patients toward stricter systolic targets (< 120 mmHg), choosing an ARB may offer synergistic, or at least better-preserved, neurovascular outcomes compared to an ACEI.

Key Methodological Strengths and Limitations

Evaluating the validity of clinical trials is crucial before altering management protocols. This study stands out for emulating a target randomized trial protocol, which helps eliminate common observational pitfalls such as immortal time bias.

Statistical Adjustments

To mimic baseline randomization at “time zero,” the investigators utilized stabilized inverse probability of treatment weighting (IPTW). This statistical adjustment successfully balanced a rich array of baseline variables across the groups, achieving excellent covariate balance with all absolute standardized mean differences (SMDs) falling below 0.10. The models adjusted for everything from age, education, and baseline MoCA scores to specific antihypertensive counts and systemic metabolic lab values.

Core Vulnerabilities

Despite its rigorous design, several key limitations must guide our interpretation:

• Unmeasured Genetic and Biomarker Confounders: The data lacked information regarding participants’ apolipoprotein E (APOE) gene status and baseline brain amyloid burden. Because APOE ε4 and amyloid accumulation are deeply tied to cognitive decline, any hidden imbalance in these factors between the groups could introduce unmeasured confounding.
• MCI Subtype Data: The study lacked adjudicated data on baseline mild cognitive impairment (MCI) subtypes, such as amnestic versus nonamnestic MCI, limiting the ability to track how these baseline variations affect a patient’s progression toward dementia.
• Sensitivity of Long-Term Monitoring: Global cognitive changes were measured using MoCA scores. While MoCA is an excellent screening tool for identifying impairment, its sensitivity in tracking fine, longitudinal changes over time is a subject of ongoing debate in neurocognitive research. Furthermore, a four-year follow-up window in a cohort in which half the individuals were under 65 may simply be too brief to observe wide variations in cognitive decline.

Clinical Summary

For the practicing physician, physician assistant, or nurse practitioner, this target trial emulation provides compelling evidence when deciding between two major antihypertensive classes.

While it stops short of supporting a mandatory therapeutic switch for currently stable patients, it provides a strong clinical rationale for favoring ARB initiation over ACEI initiation when launching new therapy in older adults with hypertension—particularly for men, individuals under 75, and those targeted for intensive systolic blood pressure control. It balances the theoretical benefits of neuroinflammation containment and cerebral perfusion optimization with practical, real-world data.

As we await definitive, long-term pragmatic randomized trials designed to track cognitive outcomes over decades rather than years, selecting an ARB-based regimen stands out as a proactive, brain-conscious approach to standard hypertension management.

References

1. Andrews RM, Addo DK, Marcum ZA, et al. Initiation of ARB- vs ACEI-Based Antihypertensive Medication Regimens and Differences in Rates of Cognitive Decline: An Analysis of SPRINT. Neurol Open Access. 2025;1(3):e000011. doi:10.1212/WN9.0000000000000011