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. Note: Participants with a documented history of hypersensitivity to ACE inhibitors will be randomized 1:1 to one of the two other study drugs. 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

• 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 outside normal reference range
• 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