Effect of Antihypertensive Therapy on Cognitive Function in Early Executive Cognitive Impairment: A Double-blind Randomized Clinical Trial FREE

Approximately 50% of older hypertensive individuals have difficulties in executive function, the cognitive domain that controls complex tasks.¹ Hypertensive individuals with executive dysfunction have a high rate of conversion to dementia.² To our knowledge, to date, no study has investigated therapeutic options for executive dysfunction. Recent evidence suggests that the renin angiotensin system plays a central role in linking hypertension to cognitive function, offering new therapeutic options for cognitive protection.³ In the brain, angiotensin receptor blockers (ARBs) block the type 1 but not the type 2 receptor, whereas angiotensin-converting enzyme inhibitors (ACEIs) decrease activation of both receptors. Activating the type 2 receptor may provide cognitive protection.⁴ We therefore hypothesized that an ARB-based regimen would be superior to other antihypertensive regimens in cognitive protection, especially executive function, and conducted a 12-month double-blind randomized clinical trial comparing candesartan, lisinopril, and hydrochlorothiazide in hypertensive individuals with early executive dysfunction.

The study design is fully described elsewhere.⁵ Subjects were recruited from the greater Boston area, Massachusetts, and were 60 years or older, had hypertension (systolic blood pressure >140 mm Hg and diastolic blood pressure >90 mm Hg), and demonstrated evidence of executive dysfunction based on the executive clock draw test (CLOX1 score <10). We excluded those with a Mini-Mental State Examination (MMSE) score lower than 20 or those with a clinical diagnosis of dementia, diabetes mellitus, stroke, or congestive heart failure. Antihypertensive medications were tapered using a standard protocol described elsewhere.⁵ Randomization using a computer-generated random allocation sequence occurred after baseline data collection, and participants were seen every 2 weeks until their blood pressure was controlled (<140/90 mm Hg). Participants were treated with escalating doses of lisinopril, candesartan, or hydrochlorothiazide to achieve a blood pressure lower than 140/90 mm Hg. Long-acting nifedipine and long-acting metoprolol succinate were added if the goal blood pressure was not achieved. Cognitive assessments were repeated at 6 and 12 months and included Trail-Making Test (TMT) parts A and B, which assesses executive function; Hopkins Verbal Learning Test–Revised (HVLT), which assesses memory; and the Digit Span Test, which assesses attention. The Hebrew SeniorLife institutional review board approved the study, and written informed consent was obtained. An intention-to-treat analysis was performed, and linear mixed models for repeated measures were used to compare the progression of cognitive outcomes in the 3 groups. Least-square means adjusted for age and baseline MMSE score were computed for each visit by treatment group.

Of the 63 eligible individuals screened, 53 stopped their antihypertensive medications and were randomized to lisinopril (n = 18), candesartan (n = 20), or hydrochlorothiazide (n = 15); 47 completed 6 months, and 31 completed 12 months. A sample description is provided in the eTable. The number of subjects achieving blood pressure control were similar (lisinopril, 91%; candesartan, 100%; and hydrochlorothiazide, 100%; P = .40) and systolic blood pressure reductions were similar in all 3 groups (mean [SD] reduction was 28 [5] mm Hg for lisinopril, 27 [5] mm Hg for candesartan, and 21 [5] mm Hg for hydrochlorothiazide; P = .75). There were no differences in the reported adverse events between the 3 groups. After adjusting for age and baseline MMSE score, those randomized to candesartan demonstrated the greatest improvement in TMT part B (P = .008); the adjusted TMT (parts A and B), which adjusts the test for motor speed (P = .01); and the recognition portion of the HVLT (P = .03) (Figure).

This study suggests that ARBs are associated with improvement in executive function in older hypertensive adults with early executive cognitive impairment. To our knowledge, this is the first study to investigate the effect of antihypertensive therapy on executive function. Prior clinical trials that assessed cognitive outcomes of antihypertensive medications have excluded those with existing cognitive impairment and have used the MMSE, which is not sensitive to the domains related to frontal lobe executive dysfunction. Our findings further support observational data showing that ARB use is associated with lower risk of dementia and Alzheimer disease compared with the use of ACEIs or other antihypertensives.⁶ The mechanisms of the potential superior effects of ARBs on cognition may be related to restoring proper central endothelial function, decreasing inflammation, and preventing neuronal degeneration through the selective noninhibition of the type 2 angiotensin receptors in the brain.^4,7- 8 If confirmed in a larger trial, ARBs may be the optimal antihypertensive treatment for elderly patients with hypertension and cognitive impairment. Future large-scale studies exploring the effects of ARBs on cognitive impairment are needed.