The Antihypertensives and Vascular, Endothelial and Cognitive Function Trial

Study Overview
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Brief Summary
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The purpose of this study is to examine the effects of blood pressure medications on cognition and blood flow in hypertensive elderly patients with cognitive impairment. The hypothesis is that treatment with an angiotensin receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEI) will be associated with a slower rate of further cognitive decline, improved cerebral blood flow and its regulation, and preserved physical function as compared to treatment with a diuretic (HCTZ), independent of blood pressure level.

Detailed Description
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There is mounting evidence that hypertension, which affects more than 65% of the US elderly population, accelerates cognitive decline and increases the risk of functional disability among older individuals. Hypertension is also associated with cerebral blood flow reduction and dysregulation which contribute to further cognitive and functional impairment. Drugs that inhibit angiotensin II (ACEI and ARB) are commonly used antihypertensives and may have a protective effect on cognitive function, cerebral blood flow and physical function compared to other antihypertensives such as hydrochlorothiazide (HCTZ). A total of 100 individuals will be recruited for this pilot 3-arm randomized study to investigate the effects of: (i) 12 months treatment with candesartan (ARB) compared to hydrochlorothiazide (HCTZ) and (ii) 12 months treatment with lisinopril (ACEI) compared to HCTZ and (iii) to estimate the effect size difference between lisinopril and losartan on cognition, cerebral blood flow regulation, and functional measures in a sample of elderly hypertensive individuals with objective evidence of cognitive impairment.

Official Title
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The Antihypertensives and Vascular, Endothelial and Cognitive Function Trial (AVEC Trial)

Conditions
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Cognitive Impairment, Hypertension, Aging

Intervention / Treatment
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* Drug: candesartan
* Drug: lisinopril
* Drug: hydrochlorothiazide
* Drug: nifedipine, long acting
* Drug: metoprolol, long-acting


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 60 years or older Hypertension Cognitive criteria: score either 10 or less out of 15 for the executive clock draw test 1 (CLOX1) or less than or equal to 1 standard deviation from the corresponding age specific mean on the immediate memory subtest Exclusion Criteria: Intolerance to ACEI or ARB History of congestive heart failure History of diabetes mellitus History of stroke (less than 6 months)

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Candesartan<br>Angiotensin Receptor Blocker | Drug: candesartan<br>* orally 8 mg increased to 16 mg then 32 mg to achieve target blood pressure of 140/90, then daily for 12 months<br>* Other names: Atacand;Drug: nifedipine, long acting<br>* If needed to achieve target blood pressure of 140/90, added to ARB or ACEI at 30 mg increased to 60 mg and 90 mg in 2 week increments<br>* Other names: Procardia XL;Drug: metoprolol, long-acting<br>* If needed to achieve target blood pressure of 140/90, added to ARB or ACEI at 12.5 mg increased to 25 mg and 50 mg<br>* Other names: Lopressor, Toprol XL;|
| Experimental: Lisinopril<br>Angiotensin-Converting Enzyme (ACE) Inhibitor | Drug: lisinopril<br>* orally 10 mg increased to 20 mg then 40 mg to achieve target blood pressure of 140/90, then daily for 12 months<br>* Other names: Prinivil;Drug: nifedipine, long acting<br>* If needed to achieve target blood pressure of 140/90, added to ARB or ACEI at 30 mg increased to 60 mg and 90 mg in 2 week increments<br>* Other names: Procardia XL;Drug: metoprolol, long-acting<br>* If needed to achieve target blood pressure of 140/90, added to ARB or ACEI at 12.5 mg increased to 25 mg and 50 mg<br>* Other names: Lopressor, Toprol XL;|
| Active Comparator: HCTZ<br>Hydrochlorothiazide (diuretic) | Drug: hydrochlorothiazide<br>* orally 12.5 mg increased to 25 mg to achieve target blood pressure of 140/90, then daily for 12 months<br>* Other names: HCTZ, multiple brand names;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Assessment: Trail Making Test Part B | This test requires the connection of sequentially numbered circles (A), and the connection of circles marked by numbers and letters in alternating sequence (B). This test is considered a benchmark of executive function. The test score is the time required to complete the task in seconds. | Baseline-12 months | 
| Cognitive Assessment: Hopkins Verbal Learning- Immediate Recall | This is a 12-item list learning test in which individuals are presented three learning and recall trials followed by a delayed recall and 24 item recognition test. The HVLT-R has been identified as an ideal memory measure for elderly patients, and appropriate reliability and validity have been shown in older individuals. The test score is the number of correct answers in the delayed recall ( score range 0-12) | Baseline-12 months | 
| Cognitive Assessment: Forward Digit Span Test | This test consists of series of digits of increasing length, some of which are recited as presented, and some of which are to be recited in reversed order. The forward digit span score ranges from 0 (ie cannot repeat two digits) to 8 ( participant can repeat up to 8 digits) | Baseline-12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure Outcome: Systolic BP | Blood pressure was measured as follows: the participant was in the sitting position, rested for 5 minutes, no caffeine or smoking 2 hours prior to measurement, using appropriate cuff size (covering 60% of upper arm length and 80% of arm circumference), correct cuff placement (1-2 inches above brachial pulse on bare arm), and the bell of the stethoscope. The systolic blood pressure was defined as the pressure corresponding to the first korotkoff sounds (K1) and the diastolic as the pressure corresponding to the last korotkoff sound (K5). Blood pressure was measured in both arms and recorded | Baseline-12 months | 
| Blood Flow Velocity, Sitting | This reports the change in the least square mean from baseline to 12 months, adjusted for age | Baseline-12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive disorders, angiotensin receptor blockers