ACES - ACE Inhibitors Combined With Exercise for Seniors With Hypertension

The purpose of this project is to conduct a randomized, controlled trial (RCT) to determine
if choice of antihypertensive medication influences changes in functional status and other
cardiovascular risk factors among older persons with hypertension. Functional status,
determined by measures of physical performance, is an important predictor of cardiovascular
outcomes in older adults. Seniors with compromised function experience more CV events, have a
higher risk of undergoing cardiac surgery and higher risk of CVD-related death than
higher-functioning peers. Seniors with hypertension experience accelerated declines in
function, and presently physical exercise is the primary strategy for preventing this
decline. However, functional responses to exercise are highly variable and appear to be
influenced by the type of antihypertensive medication(s) utilized to control blood pressure.
Preliminary evidence suggests that, compared to other first-line antihypertensive agents,
angiotensin converting enzyme (ACE) inhibitors enhance exercise-derived improvements in
functional status among hypertensive seniors. This RCT will test this hypothesis. Sedentary
men and women > 60 years of age with functional limitations and hypertension will be
recruited from two sites to participate in a longitudinal intervention study. Participants
will be randomly assigned to one of three first-line antihypertensive agents: (1) the ACE
inhibitor perindopril, (2) AT1 receptor antagonist losartan, or (3) the thiazide diuretic
hydrochlorothiazide. All participants will also participate in a structured aerobic exercise
intervention. The primary aim is to determine if, compared to losartan and HCTZ, perindopril
improves self-paced gait speed. The secondary aim is to determine the relative effect of
perindopril on a) exercise capacity, b) body mass and composition, and c) circulating indices
of cardiovascular risk. This study is expected to differentiate beneficial effects of three
FDA-approved antihypertensive medications on an emerging cardiovascular risk factor in a
clinically-relevant population. Thus the study has important implications for expeditiously
influencing clinical practice guidelines in the prescription of antihypertensive drugs to
millions of Americans.

Inclusion Criteria:

- Age 60 years and older

- Hypertension - untreated (SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg) or treated

- > 290 seconds needed to complete long-distance corridor walk test

- Sedentary lifestyle, defined as <150 min/wk of moderate physical activity

- Willingness to participate in all study procedures, including allowing study team to
communicate with primary care physician regarding changes in antihypertensive
treatment

Exclusion Criteria:

- Resistant hypertension, defined as BP > 140/90, despite the use of three or more
anti-hypertensive drugs

- SBP > 180 mm Hg or DBP > 110 mm Hg

- Chronic kidney disease

- Serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women

- Serum potassium >5.0 mEq/L

- Urinary protein > 1 on dipstick

- Abnormal liver enzymes (AST, ALT, or alkaline phosphatase > 2.5 times the upper limit
of normal)

- Severe cardiac disease, including NYHA Class III or IV congestive heart failure,
clinically significant aortic stenosis, history of cardiac arrest, use of a cardiac
defibrillator, or uncontrolled angina

- Acute myocardial infarction identified by ECG

- Significant cognitive impairment, defined as a known diagnosis of dementia or a
Mini-Mental State Examination exam score < 24;

- Simultaneous participation in another intervention trial

- Known hypersensitivity to ACE inhibitors (exclusion only to perindopril arm; will be
randomized among other two interventions)

- Any other condition that would preclude participating based upon judgement of PI or
study clinician team