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Persons aged over 65 years account for over 75% of healthcare expenditures and deaths attributable to cardiovascular disease (CVD). Accordingly, reducing CVD risk among older adults is an important public health priority. Functional status, determined by measures of physical performance, is an important predictor of cardiovascular outcomes in older adults and declines more rapidly in seniors with hypertension. To date, physical exercise is the primary strategy for attenuating declines in functional status. Yet despite the general benefits of training, exercise alone appears to be insufficient for preventing this decline. Thus, alternative or adjuvant strategies are needed to preserve functional status among seniors with hypertension. Prior data suggest that angiotensin converting enzyme inhibitors (ACEi) may be efficacious in enhancing exercise-derived improvements in functional status yet this hypothesis has not been tested in a randomized controlled trial. The objective of this randomized, double-masked pilot trial is to gather preliminary efficacy and safety data necessary for conducting a full-scale trial to test this hypothesis. Sedentary men and women ≥ 65 years of age with functional limitations and hypertension are being recruited into this 24 week intervention study. Participants are randomly assigned to one of three conditions: (1) ACEi plus exercise training, (2) thiazide diuretic plus exercise training, or (3) AT1 receptor antagonist plus exercise training. The primary outcome is change in walking speed and secondary outcomes consist of other indices of CV risk including exercise capacity, body composition, as well as circulating indices of metabolism, inflammation and oxidative stress.
Cardiovascular disease (CVD) is the leading cause of death in the United States, and persons over 65 years of age account for over 80% of deaths attributable to CVD. CVD is also the second leading cause of disability among older adults, an important contributor to the loss of independence and subsequent institutionalization. As a consequence, older adults account for nearly three-quarters of health care expenditures related to CVD. Importantly, these expenditures are expected to increase dramatically in coming years as the number of older adults is expected to double to approximately 80 million in the next three decades. Thus the clinical and economic costs related to CVD are expected to increase dramatically in coming years. Consequently, the identification of interventions capable of reducing CVD risk among older adults is an important goal with dramatic public health implications.
Functional status, determined by measures of physical performance, is an important predictor of cardiovascular outcomes in older adults. Functionally-limited older adults, i.e. those with physical limitations which limit their ability to perform daily activities (e.g. low muscle strength, impaired gait), experience more cardiovascular events, have a higher risk of undergoing cardiac surgery and higher risk of cardiovascular-related death than higher-functioning peers.[5-10] Declines in self-paced walking speed, a recommended indicator of health and well-being among seniors,[11, 12] are also associated with incident stroke, adverse outcomes following cardiac surgery, as well as cardiovascular and all-cause mortality.[5, 10, 13] Compared to normotensive counterparts, older persons with hypertension experience accelerated declines in functional status.[14-17] Among older persons enrolled in the Charleston Heart Study, higher systolic blood pressure was associated with greater declines in functional outcomes and seniors with hypertension were at increased risk of developing new disability. Hypertension was also associated with accelerated declines in walking speed among seniors participating in the Cardiovascular Health and Three-City studies.[15, 17] Thus, older adults with hypertension represent a particularly high risk group for functional decline and associated cardiovascular events.
Accumulating evidence suggests that the choice of antihypertensive medication may play an important role in the rate of functional decline among older adults. Epidemiologic evidence from the Women's Health and Aging Study (WHAS) and the Systematic Assessment of Geriatric drug use via Epidemiology (SAGE) study indicated that, compared to non-users, seniors using angiotensin converting enzyme (ACE) inhibitors displayed attenuated declines in walking speed and limitations in Activities of Daily Living (ADL).[18, 19] However, the results of subsequent randomized controlled trials (RCTs) were mixed, with studies reporting that ACE inhibitors may [20, 21] or may not [22, 23] improve functional status. While it remains possible that the efficacy of ACE inhibitors as a therapeutic for physical function may vary by drug and/or patient population, recent evidence from our group suggests that the greatest benefit of ACEi may be observed when combined with regular physical exercise[24, 25] though a conflicting report exists. This study was designed to begin to test our central hypothesis among older adults with hypertension that – compared to other first-line antihypertensive therapies – ACE inhibitors improve functional status and other cardiovascular risk factors when combined with regular exercise. The objective of this randomized pilot trial is to refine and finalize elements critical to conducting a future, fully-powered randomized, controlled trial to definitively test our central hypothesis.
The study is a three-arm randomized, double-masked pilot trial among older, hypertensive men and women with functional limitations. All participants are assigned to participate in a structured exercise intervention while also being randomly assigned to one of three first-line antihypertensive medications for blood pressure management at target pressures of < 140 mm Hg (systolic) and < 90 mm Hg (diastolic). Study medications are ACE inhibitor perindopril, the AT1 receptor antagonist losartan, and the thiazide diuretic hydrochlorothiazide. Participants are followed for a period of 24 weeks to evaluate changes in study outcomes indicative of functional status and cardiovascular risk. Study assessments are conducted by blinded research staff during clinic visits at baseline, as well as 2-, 8-, 16-, and 24-weeks post-randomization (Figure 1). Randomization and dispensing of study medications are conducted by an academic health center investigational pharmacy. Participant safety is overseen by a comprehensive study team – including the principal investigator, study cardiologist, study geriatrician, study staff, and an appointed Data and Safety Monitoring Board. The study is registered at www.clinicaltrials.gov prior to participant recruitment (NCT01891513) and all participants provide written informed consent based on documents approved by a university Institutional Review Board.
The study team is recruiting up to 72 (n = 24/group) functionally-limited older men and women with hypertension. Eligible participants are community-dwelling persons ≥ 65 years of age with a sedentary lifestyle, objective signs of functional limitations, as well as untreated hypertension or known uncomplicated hypertension. Persons with a primary indication for ACE inhibitor use, congestive heart failure (CHF), or coronary heart disease (CAD) are excluded. Persons with a known hypersensitivity to ACE inhibitors, with absolute contraindication(s) to exercise training according to American College of Sports Medicine guidelines (e.g. unstable angina, uncontrolled cardiac dysrhythmias causing symptoms or hemodynamic compromise, symptomatic severe aortic stenosis, uncontrolled symptomatic heart failure) or with other medical conditions precluding safe participation are excluded. Participants are being recruited from Alachua County, FL and surrounding areas using multiple recruitment strategies including mass mailings (i.e. postcards), flyers and local media (i.e. newspaper) advertisements, clinic referrals, and existing research registries. Incentive for participation is provided at the completion of each assessment visit in the form of gift cards (value = 30 USD) for the time and effort required for participation.
Interested individuals initially complete a telephone pre-screening prior to an in-person screening visit. Following the provision of informed consent, initial screening procedures include a review of medical history and medication use, a physical exam including blood pressure and measurement and performance of an electrocardiogram (ECG), the Community Health Activities Model Program for Seniors (CHAMPS) physical activity questionnaire to ensure participants are sedentary (≤ 150 minutes moderate-intensity physical activity/week), the Mini-mental State Exam to ensure participants have normal cognitive function (MMSE ≥ 24), as well as the 400 m walk test and Short Physical Performance Battery (walking speed < 1.2 m/sec or SPPB ≤ 10) as evidence of functional limitations. Participants also provide a urine specimen and a fasted blood sample to evaluate study entry criteria related to kidney and liver function.
If all study entry criteria are met, participants return to the clinic for baseline assessments prior to randomization. Block randomization, stratified by gender, is used to assign subjects to intervention arms (1:1:1 ratio) to ensure approximately equal accrual to each intervention group throughout the study. The randomization scheme was performed by an independent biostatistician using a random number generator program specifically designed for this purpose (Mersenne-Twister) and sent directly to the study pharmacy. Treatment is assigned by the study pharmacy according to the randomization list in order that prescription requests are received by pharmacy. The executed randomization scheme is maintained in the study pharmacy concealed to investigators and study staff until the completion of the study. At the end of the study, the study team will be provided with a full executed copy of the randomization schedule. Each study drug is provided in identical capsules and packaging. Because study medications may have opposing effects on circulating mineral concentrations, any potentially abnormal clinical chemistry result is communicated directly from the study coordinator to the study physician(s) to prevent unmasking of the PI.
The primary outcome of interest for the study will be the change in usual-pace walking speed, measured over a 4 m course. Secondary outcomes include exercise capacity, total body fat mass and fat-free mass, as well as circulating indices of cardiovascular risk. Extended details on the definition and measurement of primary and secondary outcomes are provided below. A timetable of events is also provided (Table 1) to indicate study visits at which each outcome is assessed.
A decline in one's usual-pace walking speed is associated with increased risk of numerous cardiovascular outcomes among older adults[5, 6, 8, 10] and has been proposed as a simple, cost-effective cardiovascular screening tool. Participants are instructed to stand with both feet touching the starting line and to start walking after a specific verbal command. Timing begins when the command is given, and the time needed to complete the entire distance is recorded. The test is performed twice and the faster of two walks is used. The reliability of the 4 m walk test is excellent – with an intraclass correlation coefficient (ICC) above 0.9.
Exercise capacity is assessed using 6-min walk test, a safe and reliable test of aerobic endurance in older persons and those with cardiovascular conditions.[34, 35] This test has strong reproducibility, with intra-subject coefficients of variation averaging < 10%, and has a modest correlation with peak VO2. Participants are asked to walk as far and fast as possible for 6-min on a 100 ft course, and the total distance walked is recorded. Participants are allowed to use their customary walking aids during the test and to rest if required.
Body composition is measured using dual x-ray absorptiometry (DEXA). Fat mass and fat-free mass (FFM) are assessed using a fan-bean densitometer (Hologic; Bedford, MA). Body composition analysis is performed in lower and upper body compartments using Lunar software. Values of fat-free mass are calculated after removing mass due to bone mineral content (BMC) using the equation, (FFM+BMC)-BMC=FFM.
In addition to measurement of clinical safety parameters, fasting blood samples (serum or plasma as appropriate) are evaluated for blood lipids, glucose, and hemoglobin A(1c) levels. Samples will also be assayed for prominent markers of inflammation (TNF-α, IL-6, VCAM-1, E-selectin) and oxidative stress, including oxidized LDL and myeloperoxidase (MPO) using previously-utilized, commercially-available ELISA kits.
Eligible participants are randomly assigned to one of three study antihypertensive medications (perindopril, losartan, or HCTZ). Participants assigned to perindopril are given an initial dose of 4 mg/day for two weeks after which, no adverse reactions are observed, the dose is increased to 8 mg/day. If the 4 mg/day dose is not tolerated due to issues such as hypotension, cough, or hyperkalemia, the participant is given the lower tolerated dose. The same general scheme will be utilized for the losartan group (dose titrated from 50 mg/day to 100 mg/day) and the HCTZ group (12.5 mg/day to 25 mg/day). Per protocol, doses may also be adjusted by the study cardiologist to safely control blood pressure in the target range. Study drugs are prepared by the study investigational pharmacy and dispensed upon provision of the requisite information including a copy of the signed informed consent form. The tablets of active drugs are loaded into identical opaque gelatin capsules with methylcellulose and participants are instructed not to tamper with or disassemble the capsules. All unused study drug is returned to the investigational pharmacy for tracking purposes.
In addition to taking the study drug, all participants participate in structured, exercise intervention involving both center-based and home-based components. During the first 12 weeks, participants are asked to participate in center-based, multi-modal exercise intervention on three days/week and also to engage in 30 minutes of home-based walking on two additional days. During the latter 12 weeks, center-based sessions are reduced to twice-weekly and home-based walking increased to three days/week. This intervention was designed to meet the exercise and physical activity guidelines for older adults established by the American College of Sports Medicine (ACSM) and American Heart Association[37-39] as well as the Physical Activity Guidelines for Americans established by the Department of Health and Human Services and ACSM's exercise guidelines for persons with hypertension.
Each center-based session begins with a brief warm-up followed by 30 minutes of moderate-intensity walking. Coupled with home-based walking, this program was designed to achieve a total of 150 min/week of endurance activity according to the established guidelines. Flexibility and balance exercises are performed at the end of the session to promote cool-down. After 12 weeks, upper- and lower-body resistance exercises are added to the center-based sessions. Initiation of resistance training during the second half of the trial will provide an opportunity to investigate any potential differences in the influences of aerobic and anaerobic (i.e. resistance training) exercise on study outcomes.
According to ACSM/AHA guidelines, exercise intensity is monitored using a subjective 0-10 scale for physical exertion (Borg CR10 scale). For endurance activity, participants are initially instructed to walk at a moderate intensity, equivalent to a 5-6 on the CR10 scale. They are encouraged to, as possible, incorporate brief periods of vigorous walking (7-8 on CR10 scale) with a target goal of achieving at least 10 minutes of vigorous walking per session. Participants wear a hear rate monitor (Polar FT2, Lake Success, NY) to measure pulse during center-based walking sessions to promote safety and to help to guide participants with gauging the accuracy of their subjective ratings. Participants are encouraged to perform home-based walking at a moderate intensity throughout the duration of the study based on the CR10 scale.
Resistance training is performed using standard isotonic resistance training equipment (Life Fitness, Schiller Park, IL). Resistance exercise is intended to be performed between moderate (5-6) and vigorous (7-8) intensity throughout the intervention, according to guidelines. Participants perform both lower- and upper-body exercises with the primary emphasis being on the lower extremity. Exercises vary by session and include leg press, leg extension, leg curl, chest press, overhead press, arm curls, and calf flexion. Participants perform two sets of each exercise and are encouraged to perform between 8-10 repetitions per set. Participants initially perform exercises at 75% of their 1 repetition maximum (1RM). The load for a given exercise is increased by 10% for the next session when participants perform ≥ 12 repetitions on both sets. Study staff track participant exercise volume to promote goal-setting and encourage progression.
To aid adherence to the pharmacologic intervention, study medication is provided in blister packs labeled with the day of the week. These packs serve as a “pillbox” equivalent and aid the participant in remembering if they took their dose. Participants are asked to bring their blister packs to study visits, from which a pill count is made. This method of pill counting is a validated method of compliance tracking. Participants with poor adherence (e.g. < 70%) are provided behavioral counseling on improved adherence strategies. Collection of this data will also allow for inclusion of adherence data in analysis models.
Attendance to the exercise intervention sessions is carefully documented and missed sessions are monitored. Bi-weekly study meetings enable staff and investigators to discuss potential problems and solutions to participation barriers. Adherence to the home-based intervention is tracked weekly by the use of written logs to record home-based exercise activity. Interventionists provide frequent instruction regarding the importance of proper completion of the logs. Home log completion rates are reviewed frequently to determine if behavioral counseling strategies are warranted to improve adherence. Home-based physical activity will also be measured objectively using wearable physical activity monitors (Body Media, Pittsburgh, PA) for one week following each assessment visit.
Numerous safety procedures are in place to ensure participant safety. For instance, interest individuals are advised during the telephone pre-screening to consult with their primary care physician prior to participation. Potential adverse events for study related activities and interventions are explained to each participant by trained study personnel during the informed consent process. Participants are encouraged to notify study staff immediately if they have any adverse experiences that could be related to the study drug or their blood pressure management. The dose titration and physician monitoring of blood pressure and clinical chemistries are in place to minimize adverse responses to the study drugs. Abnormal symptoms or vital signs detected during intervention visits are discussed with the study physician(s) in real time, who dictate the appropriate course of action. If study treatments according to the scheduled protocol do not manage hypertension safely, the study cardiologist has full discretion to manage the antihypertensive regimen to ensure safety. Notably, communication with the participant's physician is an important component of maintaining safety for the trial. Upon enrollment, participants are provided with a laminated “wallet-card” which provides details about the study for communication with their primary care physician. The study teams also provides written communication to the participant's primary care physician upon initial enrollment in the trial, as well as of all changes in medication prescription during their participation in the trial (e.g. drug initiation, dose escalation, study withdrawal/close-out). For per protocol changes, physicians are informed that participants are being moved to “Perindopril (dose), Losartan (dose), or HCTZ (dose)” to maintain blinding. For off-protocol changes, they are informed of the actual drug and dose utilized.
Participants are also provided a home blood pressure monitor and encouraged to conduct daily blood pressure monitoring. The provided home BP monitor meets the standards of the British Society of Hypertension and the Association for the Advancement of the Medical Instrumentation. Participants are instructed to take their home BP twice daily, on rising from bed and before retiring and to report any SBP > 180 or < 90 mmHg or DBP > 100 or < 60 mmHg to the study coordinator immediately. Blood pressure is also monitored at each assessment visit in the clinic. Participants are withdrawn from the pharmacologic intervention at the discretion of the study cardiologist for any DBP > 100 mmHg or SBP > 180 mmHg, and will be automatically removed from intervention for any weekly average home BP above these thresholds. The cardiologist may decide to withdraw treatment from subjects with slightly lower BP levels than these cut points, but for whom there is any medically-relevant concern that would preclude continued participation. Withdrawn or completed participants are returned to their standard antihypertensive therapy under the supervision of their physician or referred for care.
The primary statistical analyses will estimate an intention to treat effect, the causal effect of being randomized to the treatment arm. Pattern mixture models will be used to determine the relative effect of the intervention on study outcomes in the presence of attrition. Differences in mean outcome measures between intervention groups will be estimated with visit number and intervention group in the model. Hypothesis tests for intervention effects at assessment visits will be performed using contrasts of the 8, 16, and 24 week intervention means. Overall comparisons between groups for the outcome measure across follow-up visits will be obtained using a contrast to compare average effects. Sensitivity analyses will be performed to account for potentially non-ignorable missing data due to dropout as well as the possible impact of other potentially influential factors. Caution will be taken in the interpretation of hypothesis tests as power is limited and the relatively small sample size may create an imbalance in pre-randomization covariates. This sample size will, however, provide for nominal estimation (using a 95% confidence interval) of the mean changes in dependent variables within each arms of the study which will facilitate planning of a larger, fully-powered trial.
Functional status is a key clinical indicator of cardiovascular risk in the elderly as seniors with compromised function (e.g. impaired gait) experience more cardiovascular events, have a higher risk of undergoing cardiac surgery and higher risk of cardiovascular-related death than higher-functioning peers.[5-10] Compared to normotensive counterparts, older persons with hypertension experience accelerated functional declines.[14-17] Physical exercise is currently the standard intervention for improving functional status among older adults. However, despite the global benefits of exercise, many individuals do not experience significant improvements in functional status[25, 48] – potentially limiting the cardiovascular benefits of exercise among older persons. Consequently, alternative or adjuvant strategies are needed optimize the functional benefits of exercise training for older adults at highest risk of functional decline, including those with hypertension.
Our long-term goal is to develop interventions that optimize the efficacy of exercise as a strategy to reduce cardiovascular risk among older adults with hypertension. The present report provides a summary of an ongoing pilot study designed to provide preliminary evidence necessary to design a trial to test the hypothesis that when combined with regular exercise, ACE inhibitors are superior to other first-line antihypertensive therapies for improving functional status and other cardiovascular risk factors among older adults with hypertension.
We previously reported – using retrospective analyses of a multi-site trial of exercise for older adults – that older adults who took ACE inhibitors had greater exercise-derived improvements in functional status than non-users. Improvements in functional measures observed in response to exercise were driven largely by persons using ACE inhibitors – despite the fact that this group accounted for approximately one quarter of the study population. Indeed, persons not using ACE inhibitors displayed relatively poor functional adaptations to exercise. These findings were in line with evidence from aged rats indicating that combining exercise with systemic ACE inhibition improved exercise tolerance significantly more than exercise alone.[24, 50] Biologic rationale for such as potential interaction stems from evidence that some therapeutic effects of ACE inhibitors may be mediated by mechanisms that are independent of blood pressure regulation. For instance, prior work from members of our group has demonstrated effects of ACE inhibitors in endocrine signaling, regulation to tissue-specific oxidative stress and inflammation, and in the regulation of body composition.[51-53] Clinically, several large-scale trials have reported – compared to other antihypertensive drug classes – beneficial effects of ACE inhibitors on cardiovascular outcomes that are unrelated to differences in blood pressure.[54-58] This evidence suggests that, compared to other antihypertensive medications, ACE inhibitors may have beneficial effects on the functional status and overall cardiovascular risk of older adults with hypertension when utilized in conjunction with exercise. Such a finding, if confirmed in a fully-powered randomized trial, would have critical implications for the prescription of antihypertensive medications for managing the blood pressure of older adults.
In addition to gathering preliminary data, a key objective of the trial is also to refine the study protocol and procedures prior to conducting a fully-powered trial. For instance, a key aspect of the pilot study is to identify the most appropriate type of exercise to utilize (i.e. aerobic vs. resistance) for a fully-powered trial. Our prior findings utilized multimodal (i.e. aerobic and resistance combined) exercise, but evidence exists to suggest that the biological pathways influenced by and physiologic effects of ACE inhibitors and AT1 receptor antagonists are not identical (reviewed in) – making it important to evaluate the influence of exercise modalities which stress differing energetic systems. Additionally it should be noted that the study protocol may be modified during the trial to optimize study procedures (recruitment, safety, etc) based upon information obtained during the course of the trial. Due to these factors and other limitations (e.g. relatively small sample size; single site design), it will be important not to over-interpret the results of this pilot study.
Still, the study will provide critical data necessary for designing a fully-powered trial which could have important health implications for a prevalent and clinically-relevant population. The study described here will provide important feasibility and early efficacy data regarding the benefits of physical exercise, in combination with each of three first-line antihypertensive medications, on clinically-relevant cardiovascular risk factors among older adults with hypertension. These data will inform the efficient and definitive full-scale trial to determine if, compared to other first-line therapies, ACE inhibitors potentiate the beneficial effects of exercise on these risk factors. If our hypothesis is correct, the findings could provide evidence suggesting the need to augment standard practice for prescribing both antihypertensive medication and physical exercise among hypertensive older adults.
We would like to thank all study participants and staff devoting their time and effort to the study. The study is funded by a grant from the American Heart Association (13SDG17080033) with support from the University of Florida Claude D. Pepper Older Americans Independence Center (2P30AG028740).
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