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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 date, no study has investigated therapeutic options for executive dysfunction. Recent evidence suggest 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 (ARB) block the type 1 but not type 2 whereas angiotensin converting enzyme inhibitors (ACEI) 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 HCTZ in hypertensives with early executive dysfunction.
The study design is fully described elsewhere.5 Subjects were recruited from the greater Boston area and were 60 years or older, have hypertension, and demonstrated evidence of executive dysfunction based on the executive clock draw test (CLOX1 <10). We excluded those with a Mini-Mental-State-Exam (MMSE)<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 HCTZ to achieve a blood pressure <140/90 mm Hg. Long acting nifedipine and long-acting metoprolol were added if goal blood pressure was not achieved. Cognitive assessments were repeated at 6 and 12 months and included Trail Making Test parts A and B (TMT), which assesses executive function; Hopkins Verbal Learning Test – Revised (HVLT), which assesses memory, and the Digit Span Test which assesses attention. Hebrew SeniorLife IRB approved the study a written informed consent was obtained. The study was registered in ClinicalTrials.gov (NCT00605072). 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 three groups and least square means adjusted for age and baseline MMSE were computed for each visit by treatment group.
Of the 63 eligible individuals screened, 53 stopped their antihypertensives and were randomized to lisinopril (n=18), candesartan (n=20), and HCTZ (n=15), 47 completed 6 months and 31 completed 12 months. Sample description is provided in an online e-Table. Blood pressure control levels were equivalent (lisinopril 91%, candesartan 100% and HCTZ 100%, p=0.40) and systolic blood pressure reductions were equivalent in all three groups (lisinopril mean reduction ± standard error:28±5 mm Hg; candesartan:27±5 mm Hg, and HCTZ:21±5 mm Hg; p=0.75). There were no differences in the reported adverse events between the three groups. After adjusting for age and baseline MMSE, those randomized to candesartan demonstrated the greatest improvement in TMT-B (p=0.008), the adjusted TMT, B-A which adjusts the test for motor speed (p=0.012) and the recognition portion of the HVLT (p=0.034). Figure 1
This study suggests that ARBs are associated with improvement in executive function in hypertensive older 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 antihypertensives have excluded those with existing cognitive impairment and have used the MMSE which is not sensitive to the domains related to frontal lobe dysfunction manifesting as executive dysfunction. Our findings further support observational data showing that use of ARB was associated with lower risk of dementia and AD compared to ACEI or other antihypertensives.6 The mechanisms of the potential superior ARB cognitive effects may be related to restoring proper central endothelial function, decreasing inflammation, and preventing neuronal degeneration through the selective non-inhibition 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 studies exploring the effects of ARB on cognitive impairment are needed.
Dr. Hajjar and the AVEC trial are supported by grant 1 K23 AG030057 from the National Institute on Aging. This work is also supported by P01-AG004390 and R37-AG025037 from the NIA to Dr. Lipsitz, the Irving and Edyth S. Usen and Family Chair in Geriatric Medicine at Hebrew SeniorLife, and the generous donation Hinda Marcus to the Cardiovascular Research Laboratory at Hebrew SeniorLife and Harvard Medical School.
Ihab Hajjar, Division of Geriatric, Hospital & General Internal Medicine, Department of Medicine, University of Southern California, Los Angeles, California.
Meaghan Hart, Institute for Aging Research, Hebrew Senior Life, Boston, Massachusetts.
Yu-Ling Chen, Alzheimer Disease Research Center and Department of Neurology, University of Southern California, Los Angeles, California.
Wendy Mack, Department of Biostatistics, University of Southern California, Los Angeles, California.
William Milberg, Department of Psychiatry, Harvard Medical School, Associate Director for Research, New England GRECC- Boston Division, VA Boston Healthcare, 150 S. Huntington Avenue, Boston, MA 02130.
Helena Chui, Department of Neurology, Raymond and Betty McCarron Chair in Neurology, Professor, University of Southern California, Los Angeles, California.
Lewis Lipsitz, Harvard School of Medicine, Co-Director, Institute for Aging Research, Hebrew SeniorLife, Chief of division of Gerontology, Beth Israel Deaconess Medical Centre, Boston, Massachusetts.