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Research Letters |

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

Ihab Hajjar, MD, MS; Meaghan Hart, BSc; Yu-Ling Chen, MS; Wendy Mack, PhD, MS; William Milberg, PhD; Helena Chui, MD; Lewis Lipsitz, MD
[+] Author Affiliations

Author Affiliations: Division of Geriatric, Hospital & General Internal Medicine, Department of Medicine (Dr Hajjar), Alzheimer Disease Research Center, Department of Neurology (Ms Chen), Department of Biostatistics (Dr Mack), and Department of Neurology, Raymond and Betty McCarron Chair in Neurology (Dr Chui), University of Southern California, Los Angeles; Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts (Ms Hart and Dr Lipsitz); Department of Psychiatry, Harvard Medical School, and New England Geriatric Research, Education and Clinical Center (GRECC), Boston Division, VA Boston Healthcare, Boston, Massachusetts (Dr Milberg); and Harvard School of Medicine and Division of Gerontology, Beth Israel Deaconess Medical Center, Boston (Dr Lipsitz).


Arch Intern Med. 2012;172(5):442-444. doi:10.1001/archinternmed.2011.1391.
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Published online

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).

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Significant changes in the adjusted least-square mean over study period in the 3 groups. A, Trail-Making Test (TMT), part B; B, Adjusted TMT (part A–part B); and C, Hopkins Verbal Learning Test–Revised (HVLT), recognition score. Least-square means were adjusted for age and baseline Mini-Mental State Examination. P values were obtained from the linear mixed model for the visit by group interaction parameter. V0-V1 indicates change from baseline to 6 months; V0-V2, change from baseline to 12 months; and V1-V2, change from 6 months to 12 months.

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.

Correspondence: Dr Hajjar, Department of Medicine, University of Southern California, 2020 Zonal Ave, IRD 320, Los Angeles, CA 90033 (ihajjar@usc.edu).

Author Contributions:Study concept and design: Hajjar, Milberg, and Lipsitz. Acquisition of data: Hajjar and Hart. Analysis and interpretation of data: Hajjar, Chen, Mack, Chui, and Lipsitz. Drafting of the manuscript: Hajjar, Mack, and Lipsitz. Critical revision of the manuscript for important intellectual content: Hajjar, Hart, Chen, Mack, Milberg, Chui, and Lipsitz. Statistical analysis: Hajjar, Chen, and Mack. Obtained funding: Hajjar and Lipsitz. Administrative, technical, and material support: Hajjar, Hart, and Lipsitz. Study supervision: Hajjar, and Mack, Milberg, Chui, Lipsitz.

Financial Disclosure: None reported.

Funding/Support: Dr Hajjar and the Antihypertensives and Vascular, Endothelial and Cognitive Function (AVEC) Trial are supported by grant 1 K23 AG030057 from the National Institute on Aging (NIA). This work is also supported by NIA grants P01-AG004390 and R37-AG025037 given to Dr Lipsitz, the Irving and Edyth S. Usen and Family Chair in Geriatric Medicine at Hebrew SeniorLife; National Institutes of Health/National Center for Research Resources grant UL1RR031986 for the University of Southern California Clinical Translational Science Institutions and Dr Mack; and the generous donation from Hinda Marcus to the Cardiovascular Research Laboratory at Hebrew SeniorLife.

Trial Registration: clinicaltrials.gov Identifier: NCT00605072

Grigsby J, Kaye K, Shetterly SM, Baxter J, Morgenstern NE, Hamman RF. Prevalence of disorders of executive cognitive functioning among the elderly: findings from the San Luis Valley Health and Aging Study.  Neuroepidemiology. 2002;21(5):213-220
PubMed   |  Link to Article
Oveisgharan S, Hachinski V. Hypertension, executive dysfunction, and progression to dementia: the Canadian study of health and aging.  Arch Neurol. 2010;67(2):187-192
PubMed   |  Link to Article
Ciobica A, Bild W, Hritcu L, Haulica I. Brain renin-angiotensin system in cognitive function: pre-clinical findings and implications for prevention and treatment of dementia.  Acta Neurol Belg. 2009;109(3):171-180
PubMed
Horiuchi M, Mogi M, Iwai M. The angiotensin II type 2 receptor in the brain.  J Renin Angiotensin Aldosterone Syst. 2010;11(1):1-6
PubMed   |  Link to Article
Hajjar I, Hart M, Milberg W, Novak V, Lipsitz L. The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: role of the renin angiotensin system inhibition.  BMC Geriatr. 2009;9:48
PubMed   |  Link to Article
Kang HG, Mahoney DF, Hoenig H,  et al; Center for Integration of Medicine and Innovative Technology Working Group on Advanced Approaches to Physiologic Monitoring for the Aged.  In situ monitoring of health in older adults: technologies and issues.  J Am Geriatr Soc. 2010;58(8):1579-1586
PubMed   |  Link to Article
Rompe F, Artuc M, Hallberg A,  et al.  Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB.  Hypertension. 2010;55(4):924-931
PubMed   |  Link to Article
Ghiadoni L, Virdis A, Magagna A, Taddei S, Salvetti A. Effect of the angiotensin II type 1 receptor blocker candesartan on endothelial function in patients with essential hypertension.  Hypertension. 2000;35(1, pt 2):501-506
PubMed

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Significant changes in the adjusted least-square mean over study period in the 3 groups. A, Trail-Making Test (TMT), part B; B, Adjusted TMT (part A–part B); and C, Hopkins Verbal Learning Test–Revised (HVLT), recognition score. Least-square means were adjusted for age and baseline Mini-Mental State Examination. P values were obtained from the linear mixed model for the visit by group interaction parameter. V0-V1 indicates change from baseline to 6 months; V0-V2, change from baseline to 12 months; and V1-V2, change from 6 months to 12 months.

Tables

References

Grigsby J, Kaye K, Shetterly SM, Baxter J, Morgenstern NE, Hamman RF. Prevalence of disorders of executive cognitive functioning among the elderly: findings from the San Luis Valley Health and Aging Study.  Neuroepidemiology. 2002;21(5):213-220
PubMed   |  Link to Article
Oveisgharan S, Hachinski V. Hypertension, executive dysfunction, and progression to dementia: the Canadian study of health and aging.  Arch Neurol. 2010;67(2):187-192
PubMed   |  Link to Article
Ciobica A, Bild W, Hritcu L, Haulica I. Brain renin-angiotensin system in cognitive function: pre-clinical findings and implications for prevention and treatment of dementia.  Acta Neurol Belg. 2009;109(3):171-180
PubMed
Horiuchi M, Mogi M, Iwai M. The angiotensin II type 2 receptor in the brain.  J Renin Angiotensin Aldosterone Syst. 2010;11(1):1-6
PubMed   |  Link to Article
Hajjar I, Hart M, Milberg W, Novak V, Lipsitz L. The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: role of the renin angiotensin system inhibition.  BMC Geriatr. 2009;9:48
PubMed   |  Link to Article
Kang HG, Mahoney DF, Hoenig H,  et al; Center for Integration of Medicine and Innovative Technology Working Group on Advanced Approaches to Physiologic Monitoring for the Aged.  In situ monitoring of health in older adults: technologies and issues.  J Am Geriatr Soc. 2010;58(8):1579-1586
PubMed   |  Link to Article
Rompe F, Artuc M, Hallberg A,  et al.  Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB.  Hypertension. 2010;55(4):924-931
PubMed   |  Link to Article
Ghiadoni L, Virdis A, Magagna A, Taddei S, Salvetti A. Effect of the angiotensin II type 1 receptor blocker candesartan on endothelial function in patients with essential hypertension.  Hypertension. 2000;35(1, pt 2):501-506
PubMed

Correspondence

August 13, 2012
Chittaranjan Andrade, MD; Praveen Fernandes, MD
Arch Intern Med. 2012;172(15):1191-1192. doi:10.1001/archinternmed.2012.2091.
August 13, 2012
Ihab Hajjar, MD, MS; Wendy Mack, PhD, MS; Lewis Lipsitz, MD
Arch Intern Med. 2012;172(15):1191-1192. doi:10.1001/archinternmed.2012.3885.
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