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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Cognitive Impairment; Aging
• Intervention / Treatment: Drug: candesartan; Drug: nifedipine, long acting; Drug: metoprolol, long-acting; Drug: lisinopril; Drug: hydrochlorothiazide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
  • Massachusetts
    • Boston, Massachusetts, United States, 02131
      • Hebrew SeniorLife

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Candesartan; Angiotensin Receptor Blocker	Drug: candesartan; orally 8 mg increased to 16 mg then 32 mg to achieve target blood pressure of 140/90, then daily for 12 months; Other Names: Atacand; Drug: nifedipine, long acting; 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; Other Names: Procardia XL; Drug: metoprolol, long-acting; 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; Other Names: Lopressor, Toprol XL
Experimental: Lisinopril; Angiotensin-Converting Enzyme (ACE) Inhibitor	Drug: nifedipine, long acting; 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; Other Names: Procardia XL; Drug: metoprolol, long-acting; 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; Other Names: Lopressor, Toprol XL; Drug: lisinopril; orally 10 mg increased to 20 mg then 40 mg to achieve target blood pressure of 140/90, then daily for 12 months; Other Names: Prinivil
Active Comparator: HCTZ; Hydrochlorothiazide (diuretic)	Drug: hydrochlorothiazide; orally 12.5 mg increased to 25 mg to achieve target blood pressure of 140/90, then daily for 12 months; Other Names: HCTZ, multiple brand names

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Southern California
• Collaborators: National Institute on Aging (NIA); Hebrew SeniorLife
• Investigators: Principal Investigator: Ihab Hajjar, MD, University of Southern California

Publications and helpful links

General Publications

• Lipsitz LA, Gagnon M, Vyas M, Iloputaife I, Kiely DK, Sorond F, Serrador J, Cheng DM, Babikian V, Cupples LA. Antihypertensive therapy increases cerebral blood flow and carotid distensibility in hypertensive elderly subjects. Hypertension. 2005 Feb;45(2):216-21. doi: 10.1161/01.HYP.0000153094.09615.11. Epub 2005 Jan 17.
• 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 Nov 18;9:48. doi: 10.1186/1471-2318-9-48.
• Hajjar I, Hart M, Chen YL, Mack W, Milberg W, Chui H, Lipsitz L. Effect of antihypertensive therapy on cognitive function in early executive cognitive impairment: a double-blind randomized clinical trial. Arch Intern Med. 2012 Mar 12;172(5):442-4. doi: 10.1001/archinternmed.2011.1391. No abstract available.
• Hajjar I, Hart M, Chen YL, Mack W, Novak V, C Chui H, Lipsitz L. Antihypertensive therapy and cerebral hemodynamics in executive mild cognitive impairment: results of a pilot randomized clinical trial. J Am Geriatr Soc. 2013 Feb;61(2):194-201. doi: 10.1111/jgs.12100. Epub 2013 Jan 25.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: January 11, 2008
• First Submitted That Met QC Criteria: January 17, 2008
• First Posted (Estimate): January 30, 2008

Study Record Updates

• Last Update Posted (Estimate): February 15, 2013
• Last Update Submitted That Met QC Criteria: January 14, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: cognitive disorders; angiotensin receptor blockers
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Protease Inhibitors; Protective Agents; Natriuretic Agents; Cardiotonic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Reproductive Control Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Tocolytic Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Sodium Chloride Symporter Inhibitors; Hydrochlorothiazide; Metoprolol; Nifedipine; Candesartan; Lisinopril
• Other Study ID Numbers: IA0127; K23AG030057 (U.S. NIH Grant/Contract)