Efficacy of optimal long-term management of multiple cardiovascular risk factors (CVD) on walking and quality of life in patients with peripheral artery disease (PAD): Protocol for randomized controlled trial

Abstract

Peripheral artery disease (PAD) is an understudied chronic illness most prevalent in elderly individuals. PAD patients experience substantial walking impairment due to symptoms of limb ischemia that significantly diminishes quality of life (QOL). Cardiovascular disease (CVD) morbidity and mortality is increased in this population because of aggressive atherosclerosis resulting from untreated CVD risk factors. Despite current national guidelines recommending intensive CVD risk factor management for PAD patients, untreated CVD risk factors are common. Interventions that bridge this gap are imperative. The Vascular Insufficiency – Goals for Optimal Risk Reduction (VIGOR²) study is a randomized controlled trial (RCT) that examines the effectiveness of a long-term multifactor CVD risk reduction program on walking and quality of life in patients with PAD. The purpose of this article is to provide a detailed description of the design and methods of VIGOR². Clinical Trial Registration – URL: http://clinicaltrials.gov/ct2/show/NCT00537225

Keywords

atherosclerosis cardiovascular disease chronic disease dietary modification elderly exercise peripheral artery disease

Introduction

Peripheral artery disease (PAD) affects 8–10 million Americans and is associated with increased cardiovascular disease (CVD) events and death.^1–3 Clinical presentation of PAD varies, but typically these individuals are elderly with multiple CVD risk factors including hypertension, diabetes, hyperlipidemia, smoking, obesity and physical inactivity due to limited walking ability resulting in poor quality of life (QOL).^4–6 Current treatment options for PAD patients focus on limb salvage, reducing CVD events and death, and improving walking or functional capacity.⁷ To attain these outcomes current clinical guidelines recommend aggressive CVD risk factor management inclusive of appropriate pharmacologic agents that have demonstrated efficacy in lowering CVD events including angiotensin-converting enzyme inhibitors (ACE-I), statins and antiplatelets. In conjunction with these agents, adoption of a healthy lifestyle with diet and exercise is recommended.^8–10 Despite these recommendations, disparities in treatment and outcomes have been reported for this patient population compared with that for individuals with coronary artery disease.^3,11,12

Background

Current treatment guidelines for PAD focus on optimal management of CVD risk factors.⁷ Current recommendations include medications for improving individual risk factors as well as incorporating lifestyle modification including healthy diet and exercise regimens. In addition, exercise or a supervised walking program is recommended to improve walking impairment in this population.^7,13 While reducing CVD risk factors is important for enhancing long-term outcomes such as CVD events and death, what is immediately meaningful to these patients’ quality of life is maintaining or improving physical function – specifically, walking. Our study focuses on examining the efficacy of patient-centered behavioral interventions to reduce CVD risk factors and their impact on improving walking ability. Walking was selected not only because of its clinical significance in this patient population, but also because of the known association between CVD risk factors and exercise. While the biological underpinnings for this association have not been conclusively demonstrated in PAD, there is evidence suggesting a relationship between CVD risk factors and endothelial function and the progression of atherosclerosis. Current studies show that CVD risk factors are associated with endothelial dysfunction and reduced nitric oxide (NO) bioavailability. This impairment is reversed with treatment. Additionally, there is a positive relationship between endothelial function, walking and CVD risk factors, including hypertension, diabetes, obesity, hyperlipidemia and PAD. Thus, while there is currently no direct evidence demonstrating that improving CVD risk factors alone (i.e. lowering blood pressure, lipids and glucose levels) enhances walking time, there is substantial evidence indicating a positive relationship between CVD risk factors, endothelial function and walking. Therefore, we propose that lowering CVD risk factors will improve vascular milieu, thereby restoring NO bioavailability that will translate into improved walking ability. This is further substantiated by the effect of exercise on improving a number of CVD risk factors.

Although evidence demonstrates the efficacy of pharmacological and non-pharmacological therapies for PAD, owing to the complexity of care regimens for multiple CVD risk factors and the age of this patient population, successful implementation and adherence to treatment recommendations are challenging. To address this issue, we incorporated a patient-centered behavioral intervention to address treatment adherence. For the purposes of our study, patient-centered care is defined according to the Institute of Medicine as ‘care that is respectful of and responsive to individual patient preferences, needs, and values’. We also expanded this to include patients as partners, involving them in planning their health care and encouraging them to take responsibility for their own health. Studies suggest that by using this approach, patients are more likely to adhere to medications, alter their diets and be more actively involved in their care.^14–20

Thus, the Vascular Insufficiency – Goals for Optimal Risk Reduction (VIGOR²) study is a randomized controlled trial (RCT) that examines the efficacy of a 24-month, patient-centered, behavioral intervention focusing on lifestyle modification emphasizing exercise and healthy diet to increase peak treadmill walking time and self-reported walking impairment compared to enhanced usual care in men and women with PAD. A secondary objective is to assess the program’s effects on quality of life as measured by the SF-36 (ClinicalTrials.gov Identifier: NCT00537225). The purpose of this article is to provide a description of the design and methods of VIGOR².

Theoretical foundation for behavioral intervention

The study intervention is based on three behavioral theoretical constructs: (1) the transtheoretical model recognizes an individual’s readiness for change or stages of change;²¹ (2) cognitive behavioral therapy (CBT) assists a motivated individual to initiate, adopt and maintain healthy behaviors²²; and (3) self-efficacy from social cognitive theory that emphasizes the human capacity for self-directed change through an individuals’ own motivation and behavior.²³ These theoretical constructs will be implemented by study case managers using motivational interviewing, a therapeutic approach to facilitate behavioral change.²⁴ Previous studies report the effectiveness of these approaches in facilitating behavior change in a variety of clinical settings.^22,25–29

The transtheoretical model describes change as occurring through a series of distinct stages (precontemplation, contemplation, preparation, action, maintenance) with interventions that are most appropriate and effective to facilitate change.²¹ Processes that facilitate an individual to move from early stages of change (precontemplation, contemplation and preparation) to action include cognitive, affective, and evaluative strategies. Specific CBT activities in the precontemplation phase include: raising consciousness (increasing awareness), dramatic relief (emotional arousal), and environmental reevaluation (social reappraisal). Self-reevaluation (self-reappraisal) and social liberation (environmental opportunities) are key strategies during the contemplation and preparation stages.^22,30 As an individual moves from preparation to action, CBT strategies include: commitment, conditioning, contingencies, environmental controls, and support.³¹ The action phase involves self-liberation (commitment). Once behavior is adopted for at least 6 months, maintenance strategies emphasize reinforcement management (rewarding mechanism), counter-conditioning (substituting), stimulus control (re-engineering), and helping relationships (social support reinforcement management).^21,32–34 Relapse prevention is emphasized throughout.³¹

CBT views health behavior as acquired and maintained through a complex set of behavioral, cognitive, and environmental factors.³⁵ CBT focuses on restructuring attitudes, beliefs and misconceptions; identifying potential barriers; and assisting individuals in developing strategies to overcome them. The cognitive-behavioral assumption of the intervention is that durable change occurs temporally through a series of distinct stages beginning with problem identification and proceeding through building commitment, increasing awareness, developing an action plan, evaluating the results, and working to maintain specific goals.^36–38 CBT strategies have been found to be effective across the lifespan, in a variety of health behaviors and with all stages of change.^39,40

Motivational interviewing is a dynamic, patient-centered approach to facilitate behavior change by assisting individuals to explore and resolve ambivalence to change and identify discrepancies between present behavior and goals.⁴¹ Motivation is defined as a situational state of readiness for change rather than a personality trait; thus, resistance or lack of motivation is amenable to change.^42–44 Motivational interviewing is a narrative process involving respectful discussions to explore an individual’s perceptions.^44,45 A key strategy in motivational interviewing is improving self-efficacy.

Self-efficacy (SE) is defined as an individual’s belief in their ability to successfully perform behaviors or take actions to achieve goals despite barriers and obstacles.⁴⁶ Specific to walking, self-efficacy theory suggests that an individual with high efficacy expectations will walk regularly and continue, despite barriers such as discomfort, compared to those with low efficacy expectations. In the VIGOR² study, self-efficacy will be assessed at the time behavioral goals are developed and used to assess an individual’s level of confidence in their ability to achieve goals and to develop effective strategies to overcome barriers.

Based on the behavioral constructs described above, key behavioral strategies used in the VIGOR² study intervention will include: (1) comprehensive assessment of CAD risk factors for goal-setting, monitoring progress and providing feedback; (2) matching intensity and prioritizing risk factor management with specific clinical needs; (3) recognizing behavioral interdependence of multiple risk factors; (4) explicit short and long-term goal-setting by patients, with guidance from care managers; (5) defining specific strategies for short-term goal attainment (including potential barriers and facilitators to goal attainment); (6) continuity and tracking of adherence to strategies and adjusting short-term goals as needed; (7) matching of patients with available and appropriate community resources; (8) focusing on patient adherence; and (9) engaging patients to be actively involved in their own care.

Materials/design

Study design

The study design is a randomized controlled trial (RCT) of 300 men and women aged 50 years and older who meet medical criteria. Following a baseline evaluation, subjects will be randomized into one of two groups: intervention (Int) or enhanced standard of care (ESC) for 24 months. Individuals in the intervention group will meet with one member of the care management team face to face or by telephone at minimum every 3 months or more frequently if needed. Individuals in the ESC group will receive limited contact with the care team at baseline, 12 months, and 24 months. These individuals will be invited to four group health education sessions a year. All subjects will be retained in their originally assigned condition for 24 months.

Ethics

Institutional review board approval was granted by the Committee on Human Research at the University of California, San Francisco (UCSF).

Study population and site

Inclusion criteria

Subjects eligible for this study include: (1) age 50 years or older with one or more CVD risk factors; (2) PAD secondary to atherosclerosis as documented by: (a) ankle–brachial index (ABI) < 0.90; (b) toe pressure < 70 mmHg in patients with diabetes; (c) ABI 1 minute after exercise at least 20% lower than index leg resting ABI; (3) capable of walking at least 50 feet (15.24 meters); and (4) difference of walking time between two consecutive (of four) baseline treadmill tests < 25%.

Exclusion criteria include: (1) active malignancy or tumor or other condition that would severely limit life expectancy; (2) any type of major surgery during the past 3 months (i.e. aortic or lower extremity artery surgery, angioplasty, or lumbar sympathectomy, leg amputation above the ankle); (3) residence in a long-term institutional setting; (4) psychiatric disorders with currently active manifestations; (5) uncontrolled metabolic disorders (renal failure, liver failure, thyrotoxicosis); (6) active symptoms suggestive of an acute coronary syndrome or decompensated heart failure; (7) lack of phone access (either by self or through neighbors/family members); (8) other specified circumstances incompatible with case management (i.e. plan to move away from area); (9) presence of another household member or first-degree relative already enrolled in the study; and (10) current enrollment in another clinical trial.

Recruitment

Three hundred men and women with PAD will be recruited using multiple strategies. The primary approach will be mass mailing to individuals over the age of 70 years by proximity to the medical facility. Other plans include: (1) advertising in local newspapers, health clinics, and senior centers; (2) sending letters and flyers to local primary care providers (PCP), vascular and cardiac surgery and cardiac rehabilitation services; and (3) providing free ABI screening at local community health fairs and senior centers.

Randomization procedures

After an individual is recruited and determined to be eligible, the participant will be randomized to one of two groups, stratified by sex. Prior to the randomization visit, project staff will contact the data manager who generates the treatment assignment. Confirmation of the treatment group assignment is then printed for the care manager containing the participant’s ID and group assignment. This algorithm tracks subject group assignment and ensures near-equal group sample size at all stages of randomization within each strata.

Study protocol

Individuals who are interested in the study will be asked to contact study staff via mail or telephone (PAD hotline). Individuals will be asked to undergo an initial telephone-screening questionnaire and those who meet inclusion criteria will be invited to a group or individual study information session. At this session, informed consent will be obtained by study staff in accordance with requirements of the Human Subjects Protection Committee, and ABI will be performed to determine eligibility (Figure 1).

Figure 1.

Algorithm for the management of CVD conditions and CV risk factors. All risk factors will be treated with lifestyle modification. The order of priority is smoking cessation, antiplatelet therapy, exercise, weight management, diet, and stress management. Depending on the individual’s CV risk factor profile, additional therapies will be implemented. These include diabetic teaching principles such as foot care and glucose lowering medications for diabetics. For hypertensive patients, blood pressure lowering medications will be prescribed. Dyslipidemia will be treated with lipid lowering medications such as statins. Monitoring will consist of laboratory analysis of risk factors as well as logs to assess weight, and BP measurement. Successful management will be determined by attainment of guideline goals. Interventions will be modified based on attainment of guideline goals. In the case of multiple comorbid conditions, recommendations and goals will be combined. (ACE-I, angiotensin-converting enzyme inhibitor; ADA, American Diabetes Association; ARB, angiotensin receptor blocker; ASA, aspirin; BB, beta-blocker; BP, blood pressure; CCB, calcium channel blockers; FBS, fasting blood sugar; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride.)

Eligible subjects will then be scheduled for a baseline evaluation at the General Clinical Research Center (GCRC) at UCSF or the Cardiology Clinic at Mt Zion Hospital to undergo a medical history and physical examination, height and weight measurements, blood pressure evaluation, and repeat resting ABI. Individuals who are eligible will perform an exercise treadmill test to determine peak walking time (PWT) and also a 1-minute post-exercise ABI. Those individuals who continue to be eligible will then enter a 2–4-week run-in period that will be used to minimize differences in exercise test performance due to learning effects. In order to qualify for randomization, a difference of < 25% between two consecutive treadmill tests must be achieved by the participant. Two treadmill tests will be performed on two separate days at least 24 hours apart but no more than 2 weeks apart. A third or fourth test may be required to qualify based on treadmill criteria.

A maximum of 30 days will be allowed for the run-in period to account for missed and rescheduled appointments. Study participants will also have completed self-administered questionnaires during this time. After all baseline assessments are completed, participants will be randomized to one of two groups: care management intervention (Int) or enhanced standard care (ESC) for 24 months. Testing will be repeated at 12 months (study midpoint) and 24 months (at conclusion of the study intervention).

Design elements of the intervention program

Guideline-based program goals

The delivery of care by team managers will be guided by evidence-based guidelines/goals for management of CAD risk factors, including cholesterol,⁴⁷ hypertension,⁴⁸ physical activity,⁴⁹ diabetes mellitus,⁵⁰ obesity,⁵¹ smoking cessation⁵² and secondary CAD prevention (Table 1).

Table 1.

CVD risk reduction strategies for individuals with CVD and other vascular diseases

Risk factor	Recommendation	Guideline
Smoking	Goal: Complete cessation. No exposure to environmental tobacco smoke. Intervention: Stop smoking counseling and program referral. Use of pharmacological therapies as indicated.	AHA, NHLBI, CDC, NCI
Antiplatelet therapy	Goal: Antiplatelet therapy. Intervention: Aspirin 81 mg daily or other antiplatelet (clopidogrel 75 mg daily) is recommended unless contraindicated.	AHA, ACC
Lipid management	Goal: LDL < 100 mg/dl (or < 70 mg/dl if there are other uncontrolled risk factors). Secondary goals: If triglycerides > 200 mg/dl use non-HDL as a secondary goal: non-HDL < 130 mg/dl. Other targets: Triglycerides < 150 mg/dl; HDL > 40 mg/dl in men and > 50 mg/dl in women. Intervention: Nutrition and weight control, increased physical activity, medical therapies.	AHA. NHLBI, ACC
BP control	Goal: < 120/80 mmHg. Intervention: Sodium restriction, increased physical activity, weight control, stress management, medical therapies (ACE-inhibitors, beta-blockers unless contraindicated).	AHA, NHLBI, ACC, ADA
Diabetes	Goal: Normal fasting plasma glucose (< 110 mg/dl) and HgbA1c (< 7%) [ideally < 6%]. Intervention: Nutrition and weight control, increased physical activity, medical therapies.	ADA, NHLBI
Weight management	Goal: Achieve and maintain desirable weight (BMI 18.5–24.9 kg/m²). Intervention: Calorie restrictions/portion control; decreased saturated fats and trans-fatty acids; carbohydrate and glucose control; increased intake of fruits and vegetables and whole grains.	AHA, ADA, NHLBI, CDC
Stress management	Goal: Improve emotional well-being. Intervention: Life Skills program
Nutrition	Goal: An overall healthy eating pattern.Intervention: Reduced intake of saturated fats and trans-fatty acids; carbohydrate and glucose control; increased intake of fruits, vegetables and whole grains.	AHA, ADA, NHLBI
Physical activity	Goal: Increase moderate intensity activity:Intervention: Accumulate ≥ 50 minutes of pain-free walking on ≥ 5 days/week. Walking prescription consists of pain-free walking speed and bout. Progression of walking distance will be performed by maintaining pain-free walking speed with slow increase in walking duration to 50–60 minutes. Once the duration is met, speed will be increased and duration decreased to pain-free bout and slowly progressed to 50–60 minutes. This is anticipated to occur over a period of 4–6 months.	AHA, NHLBI, ACSM/CDC

ACC, American College of Cardiology; ACSM, American College of Sports Medicine; ADA, American Diabetes Association; AHA, American Heart Association; CDC, Centers for Disease Control; NCI, National Cancer Institute; NHLBI, National Heart, Lung, Blood Institute.

Based on ref. ⁵³

The cornerstone of the intervention is lifestyle modification (exercise and diet) as a partial, but critical, means of achieving CVD prevention goals. Home-based, patient-centered risk reduction is the core of the intervention. Subjects partnering with care managers will develop individualized, longitudinal strategies to achieve CVD risk factor reduction. The emphasis of intervention is long-term adherence to lifestyle modification and traditional medications. Medications, an important adjunct to lifestyle changes, will be provided by the participant’s PCP. Continuous monitoring of lifestyle change and adherence will be performed by care managers via telephone, email, and during clinic visits by review of adherence logs, pedometers and change in risk factor status. Behavioral interventions will be monitored and intensified as short-term goals are attained by study participants. In addition to counseling, participants will be referred to low-cost or free community services if deemed appropriate and consistent with study goals (i.e. smoking cessation programs, exercise classes, weight loss programs, nutrition education, etc).

Behavioral intervention

The skills required for adopting and maintaining lifestyle changes will be supported by the use of behavioral strategies that have been shown to be effective in CVD risk factor modification in a number of clinical settings.^22,25–29 Fundamental principles of the intervention include individualized, tailored feedback based on cardiac risk assessment, goal-setting, self-monitoring, developing action plans, social support and rewards. At baseline, all subjects will be given a comprehensive cardiac risk assessment summarizing their individual CVD risk factors (including lipid profile, blood pressure, glycosylated hemoglobin levels, current medication regimen) compared with national guideline recommendations. These results will provide the basis for a dialogue between care managers and study participants on strategies to optimize treatment and lower risk factors. In the case of multiple risk factors, priorities for treatment will be identified by the care manager and discussed with the participant. The priorities will be based on importance for overall risk and the subject’s ability, interest and willingness to work on reducing the risk factor. In the case where medication management is inadequate, the care management team member will contact the PCP to recommend medication changes (in accord with national guidelines and recent evidence) to improve CVD risk factors. During this intensive discussion, short and long-term goals will be established and a realistic action plan will be developed by the care manager and the participant. The care manager will carefully craft goals so that they are small and achievable in a 1–2-week timeframe with actions that are very specific. The goal is to achieve success in a short period of time to improve the individual’s self-efficacy or confidence levels. If a participant’s goals are not behavioral in nature, too broad, long term or not achievable, further discussion will ensue to identify a more appropriate goal. An example of a general goal is lowering low-density lipoprotein (LDL) levels. In this instance, the care manager will discuss specific behaviors that will likely contribute to lowering LDL (i.e. walking) and set appropriate actions and goals for a 1–2-week period. The level of specificity for action plans will include time of day, days per week and route for the planned walk, including places to stop and the support of family or friends if appropriate. Other discussion items will include preparation for walking (i.e. type of shoes, safety issues and symptom awareness). Once goals are identified and an action plan is established, the individual will be asked to rank the level of confidence in their ability to accomplish this goal. If the score is low, the care manager will discuss barriers and strategies that would improve the individual’s confidence in being able to perform the behaviors as stated in the plan. If needed, goals and actions will be revised accordingly. Action plans will focus on one or two attainable goals. Importantly, as goals are accomplished (in 1–2-week intervals), new goals will be set with appropriate action plans to ensure that the participant is continuously working toward achieving longer-term risk reduction goals. To maximize participant commitment to the intervention, care manager–subject action plans will represent a concise summary of mutually agreed-upon goals and actions. Because of the emphasis on behavior change and progression during the first year of the intervention, frequent contact is anticipated between the individual and care managers via telephone and face-to-face channels.

Initial counseling visit

The initial in-depth care management visit will occur within 1–15 days after randomization. The visit is described in detail above. Subjects in the ESC group will receive appropriate educational materials with a follow-up contact within 3 months.

Medical risk factor management and monitoring care

The care manager under the supervision of the investigator and in collaboration with the subject’s PCP will be responsible for management and for monitoring the clinical and behavioral records of subjects in the intervention group. Healthcare providers will be contacted after each visit and provided with any relevant new clinical information obtained during the visit with recommendations (if appropriate) for optimizing medication management. This information will also be provided to participants with instructions for the patient to follow-up with their PCP if needed.

Strategies or tools to promote adherence to the intervention

Care managers will also have a ‘toolbox’ containing a variety of ‘tools’ to use in the event of relapse (i.e. weight gain, smoking relapse, discontinuation of exercise or consumption of a high-fat or high-calorie diet). The ‘toolbox’ concept was developed in the Diabetes Prevention Program Trial and was highly successful in achieving behavior change to diet and exercise in diabetic patients.⁵⁴ The ‘toolbox’ will contain strategies or ‘tools’ for promoting adherence to the intervention, and will be grouped into two types: reinforcers (tools that support adherence or success) or roblem-solving tools (used to identify alternative strategies or work to resolve barriers).⁴⁰ Tools will be used as a preventative strategy, with initial signs of problems or after long periods of lapse. Strategies may not be specific to one behavior and may be used for multiple behaviors if appropriate. Problem-solving tools include those that are specific to a problem (i.e. attendance at clinic visits, self-monitoring of diet, exercise, medications or weight). The care manager will decide which strategies in the toolbox are appropriate and the duration of implementation. Tools will be tailored to the individual so that reinforcers and problem-solving tools address specific individual barriers. Cost and time will be considered when selecting a tool, beginning with the least expensive and progressing to more intensive, expensive tools. The underlying principles for the toolbox include the following. (1) Creativity and responsiveness to the unique needs of the participants to increase adherence; (2) adherence to the intervention is important, but retention in the study is foremost⁵⁵ (the goal is 100% adherence but is translated as participants doing as much as they possibly can while remaining in the study); and (3) rewards will be individualized and structured to reinforce steps and to maintain long-term adherence. The process for monitoring and supporting adherence will be refined throughout the trial.

Examples of ‘tools’ for maintaining walking include: DVDs or videos for seniors; books on exercise and increasing physical activity; diaries; music CDs; walking distance competitions; and involving the participant’s significant other, family member or friend in walking. The ‘tools’ for maintaining diet goals include: specific meal plans tailored to the individual’s taste/preferences/lifestyle; dietary self-monitoring; purchasing cook books or food scales; cooking classes; and food shopping trips with the case manager to learn appropriate food choices, food substitutions and how to read food labels.

Other strategies to maximize adherence include regularly scheduled telephone calls (progressing from weekly to biweekly, monthly and bimonthly) and scheduled visits. The frequency of contact will be gradually decreased if it does not adversely affect maintenance. Intervention subjects will be asked to keep daily diet and exercise logs for the first 3 months after randomization, then for 2 weeks every 6 months. Pedometers will be used to provide motivational feedback to increase walking distance and as a means to track adherence. Dietary adherence will be assessed by the food frequency questionnaire and random 3-day food diaries. Newsletters and educational materials, recipes, and birthday cards will be regularly sent to retain interest and participation in the study.

Enhanced standard of care group

Subjects in the ESC group will meet with the care manager at baseline, 12 months, and 24 months for 30–45 minutes to discuss the individual’s risk factor profile and recommendations for lifestyle modifications and to set preliminary goals and develop action plans. These subjects will receive standard patient education brochures developed by the American Heart Association (AHA), American Diabetes Association (ADA), National Heart, Lung, and Blood Institute (NHLBI) on diet, exercise, weight loss, smoking cessation and stress reduction. Study participants will be instructed to continue to receive their health care, including CVD risk factor reduction, from their existing medical providers, consisting of a PCP and medical specialists when indicated. The care for these patients is considered ‘enhanced’ since both the patients and their physicians will be provided with (a) relevant study laboratory tests (BP, lipids, hemoglobin A1c, fasting blood sugar, treadmill test results and ABI) following the baseline, 12-month, and 24-month evaluation visits; and (b) recommendations for clinical management to meet current guideline goals. Guidelines will include the NCEP Adult Treatment Panel III,⁵⁵ Joint National Committee (JNC) VII on the treatment of hypertension⁴⁸ and the ADA guidelines for the treatment of diabetes.⁵⁰ Implementation of these guidelines on a patient-by-patient basis will be left to the discretion of the PCP. Subjects will also receive minimal telephone contact (approximately every 3 months) by project staff to update contact information, monitor the occurrence of medical events and maintain interest and participation in the study. Subjects will also be invited to participate in educational group sessions three times per year, presented by care managers on general health topics such as a healthy diet, exercise, diabetes, and weight management. ESC will consist of a combination of limited care management contact, telephone calls and group sessions as an adjunct to routine care from their PCP. Our goal is to ensure that the patients assigned to ESC have an opportunity to receive the best possible care using the existing healthcare delivery system.⁵⁶

Monitoring fidelity of intervention

The treatment fidelity plan for this study will be based on the comprehensive model described by the behavioral change consortium.^57–59 Five areas of monitoring will include: (1) study design; (2) training providers; (3) delivery of treatment; (4) receipt of treatment; and (5) enactment of treatment skills.⁶⁰

Adverse events

Adverse events will be regularly assessed at each visit and during telephone contacts. All events whether elicited by the study staff or reported by the subject at clinic visits or via telephone contact will be recorded. Additionally, all participants will be asked to contact study staff in the case of hospitalization, emergency room visits or any unexpected medical event.

Measurement (Table 2)

Primary and secondary outcomes will be assessed at baseline, 12 months, and 24 months. All biological tests will be performed in the morning and performance testing will be scheduled at the same time of day for baseline, 12 months, and 24 months to control for circadian variation.^61,62 The primary study outcome is walking time as measured by PWT during exercise treadmill test and self-reported walking impairment. Quality of life as measured by SF-36 is the secondary outcome of interest. Process variables will be measured every 3 months in the intervention group and include lipid levels for individuals who are hyperlipidemic, blood pressure for hypertensive participants, hemoglobin A1c for diabetics, weight for overweight and obese individuals, and smoking cessation for current smokers. These interim CVD risk markers will provide feedback to study participants, their clinicians, and the study team. These measures will be used to assess and monitor progress toward attainment of lowering risk factors.

Table 2.

Study procedures

Phase	Run in				Baseline	Intervention / ESC
	V1	V2	V3	V4	Baseline	12 mo	24 mo
Procedure
Informed consent, medical history, physical exam, ABI	×
Walking distance
Treadmill exercise test (PWT)	×	×	a	b		×	×
Walking Impairment Questionnaire (WIQ)					×	×	×
Quality of life questionnaire
SF-36					×	×	×
Risk factor assessment (process variables)
Diabetes (glycemic control [HgbA1c], fasting glucose, insulin)					×	×	×
Hypercholesterolemia (TC, LDL, VLDL, HDL, TG)					×	×	×
Hypertension (BP, antihypertensive use with medication list)					×	×	×
Physical activity (pedometer)					×	×	×
Smoking status (self-report)					×	×	×
Overweight/obesity (height/weight = BMI; abdominal hip circumference)					×	×	×
Dietary management (FFQ)					×	×	×
Antiplatelet use (aspirin/antiplatelet with medication records)					×	×	×
Behavioral questionnaires (SE, readiness for change scale)					×	×	×

Third run-in treadmill may be needed to qualify; ^bfourth run-in treadmill may be needed to qualify.

ABI, ankle–brachial index; BMI, body mass index; BP, blood pressure; HDL, high-density lipoprotein; FFQ, food frequency questionnaire; HgbA1c, hemoglobin A1c; LDL, low-density lipoprotein; mo, month; PWT, peak walking time; SE, self-efficacy; TC, total cholesterol; TG, triglyceride; V, visit; VLDL, very low-density lipoprotein.

1. Peak walking time (PWT) is the primary outcome and will be measured at baseline, 12 months, and 24 months. PWT is defined as the point of termination or maximum time walked during an exercise treadmill test (ETT). PWT from two consecutive run-in visits will be used to determine whether a patient qualified for randomization into the study. The PWT from each of the two consecutive run-in visits must be within 25% of the greater time. To minimize variability, the mean of two ETTs will be used to determine baseline PWT. A ramp exercise protocol is administered to determine PWT. This protocol identifies an individual’s maximal walking speed within the first 2 minutes of the test. This speed is then held constant as workload is increased every 2 minutes by 2% increases in grade. Incremental exercise testing was selected for this study because it has been shown to be more reliable than constant-load testing in patients with PAD.⁶³ Blood pressure and a 12-lead electrocardiogram will be monitored: (1) prior to testing after 2 minutes standing and 5 minutes supine rest; (2) continuously during the ETT and recorded during the last 30 seconds of each exercise stage; and (3) during a supine recovery period after exercise is terminated until both parameters return to baseline levels. ETT will be conducted by an exercise physiologist and the study investigator using standardized verbal encouragement. At baseline, the ETT will be used to determine the extent of walking limitation.⁶⁴ At 12 and 24 months, ETT will be used to assess the efficacy of the intervention.

2. Walking impairment will be assessed by the self-reported Walking Impairment Questionnaire (WIQ) developed to evaluate the efficacy of interventions on community-based walking ability in PAD patients. Walking distance and speed are quantified with the WIQ. Changes in these scores are moderately (r = 0.49, p < 0.05) associated with change in graded exercise performance.⁶⁵

3. Quality of life is the secondary outcome of interest measured using the SF-36 questionnaire. The SF-36 has been extensively administered to a variety of populations including PAD patients. Internal reliability ranges from r = 0.76 to r = 0.94.

Statistical analysis

All variables will be summarized by appropriate descriptive statistics at each time point. The intervention group will be compared to the ESC group for homogeneity on demographic and baseline clinical variables via the chi-squared test or Student’s t-test (depending on the type of variable). Through stratified randomization, these variables are anticipated to be comparable in both groups. Data analyses are planned to compare those who did and did not drop from the study to determine if there was a differential bias. All analyses will be based on intention to treat (all participants randomized will be analyzed based upon their assigned group). The significance level will be preset at 0.05 and two-tailed tests will be performed.

To analyze both 12 and 24-month data, we will first consider the repeated measures analysis of variance (ANOVA) approach. To address dropouts, we will use the mixed models for longitudinal outcomes approach which provide unbiased estimates of the effects of covariates for data that are randomly missing.⁶⁶ Specifically, we will employ well-established methods such as the general linear mixed-effects models⁶⁷ and the generalized estimating equations (GEE) approach for marginal models. We will use a mixed model approach, accounting for within-subject correlation to model PWT, WIQ and quality of life, to compare their improvements over time between the two intervention groups, and to identify predictors of the outcomes. Random intercepts and slopes will be used to model the subject-specific improvement in the outcome measures and to accommodate the correlation structure.

Discussion

Summary

PAD is a systemic manifestation of atherosclerosis that is most prevalent in elderly people and those with CVD risk factors, including hypercholesterolemia, hypertension, obesity, diabetes and physical inactivity. Patients with PAD often report walking impairment due to symptoms of limb ischemia resulting in poor quality of life. Current national guidelines recommend intensive CVD risk factor management for PAD patients, including lifestyle modification and medications. Our study will examine the impact of a 24-month, patient-centered, behavioral, multiple CVD risk reduction program targeting exercise and diet on walking and quality of life in elderly patients with PAD.

Significance of the study and contribution to knowledge development

This study will be one of the first to examine the efficacy of a long-term, patient-centered, behavioral intervention to improve walking in elderly PAD patients. The foundation of the behavioral intervention is lifestyle modification; specifically, exercise and diet as the cornerstone of risk reduction. In addition, project staff will work with the participant’s primary care or specialty practice provider to optimize the medical treatment of chronic disease conditions in accordance with national guidelines, including diabetes, hypertension, and hypercholesterolemia.

One of the unique aspects of our study is the implementation of a patient-centered approach to focus and prioritize the treatment of multiple CVD risk factors and maximize adherence to our study program. While patient-centered interventions have demonstrated efficacy in patients with diabetes and more recently in improving hypercholesterolemia in PAD patients,⁶⁸ our study will be one of the first that we are aware of, that is patient-centered, includes long-term follow-up, and manages multiple CVD risk factors in elderly patients with PAD.^68–70

In a recent study, McDermott et al. (2011)⁶⁸ reported that a telephone counseling intervention successfully increased patient activation as demonstrated by a patient’s ability to request more intensive lipid-lowering treatment. This resulted in markedly lower LDL levels in the activated group. Our study, in contrast to McDermott et al., will be longer in duration, 24 months versus 12 months, includes a variety of approaches to risk factor reduction such as face-to-face counseling, telephone calls and email, and monitoring and management of other CVD risk factors including hypertension, diabetes, smoking cessation and weight management. Our study is also unique in incorporating the principle of collaboration and partnership, including shared decision-making with study participants. Study staff and participants will work together on developing plans for care, including the use of short and long-term goals and action items and incorporating behavioral strategies to achieve progress. While both studies include process biological markers, our study will incorporate modification of goals and action items to tackle other CVD risk factors as appropriate.

The duration of our study will also allow care managers to successively intervene on multiple CVD risk factors in this patient population. For example, initially the highest priority for one study participant may be to lower glucose levels by improving medication adherence. Other less urgent but equally important concerns for this patient may include management of hypertension, hypercholesterolemia and obesity, all of which will be addressed over the study period.

The significance of using a patient-centered approach is the collaborative environment created between the study staff and participants as clinical problems and solutions are discussed and prioritized. It considers the participant’s state of readiness for change and self-efficacy for making those changes. Our approach will also be based on communication between the study participant and the staff in identifying barriers and practicing strategies to ensure successful behavior change. Problem-solving techniques will be supported and shared. The study staff will provide guidance in setting realistic and achievable goals that are modified according to whether goals are met.

Participants will learn new self-management skills and strategies as well as communication skills. The study staff will facilitate the exchange of information with the participant’s healthcare provider. Prior to a clinic visit, study participants will be coached on questions to ask their providers regarding medication changes, information about laboratory tests, referrals, and consultations. We hypothesize that close follow-up with study staff will encourage study participants to be more actively involved in their care and ultimately reduce CVD risk factors.

Our approach differs from the usual risk factor management and case management approach because it requires active engagement by the participant. The study intervention will be tailored to the needs and interests of the participant while considering priorities for the study. While this approach is unique, it has several limitations. The first is the time required to train providers in the skills needed to deliver a patient-centered behavioral intervention. Motivational interviewing skills require additional training and practice as well as a shift in the normal approach to clinical care and patient interactions. Second, individuals who are unfamiliar with the patient-centered model of care may be reluctant to actively engage in decision-making and self-management, requiring additional coaching and staff time. Finally, the clinical interactions in our study may require a longer period of time than might be allotted during a usual office visit and currently may not be reimbursed by third party payers, limiting portability of the intervention into clinical settings. We hypothesize that the increased interactions between study staff and participants will contribute significantly to improvement in CVD risk factors and change in lifestyle required to increase walking performance. To address this concern, the study intervention was delivered by a multidisciplinary team (nurse, exercise physiologist, registered dietician) who in a team or teamlet model patient care environment may be able to implement the proposed intervention.

Another important aspect of this study is the interaction between study staff and the participant’s primary care providers and specialists. All test results will be provided to the participant’s primary care providers and specialists. The longitudinal nature of the study and the many diagnostic tests that will be performed for monitoring risk factor reduction (i.e. lipid panels,⁷¹ inflammatory markers, exercise tests, and ABIs) lend themselves to repeated interactions, follow-up, and opportunities to reinforce the importance of aggressive treatment and options to reduce CVD risk factors. These interactions may lead to increased awareness of PAD management and more active medical and surgical intervention in our study population. We anticipate that the intervention group will receive more attention by their providers since clinical data will be sent to providers and follow-up will be provided to the intervention group.

The cornerstone of the study intervention is optimal medication management and lifestyle modification; specifically, a home-based supervised walking program and a healthy diet. At the time the study was funded, there was little evidence that home-based walking would improve walking ability. Most evidence pointed to supervised exercise programs such as cardiac rehabilitation programs. A recent study has shown that home-based walking was as effective as supervised exercise in patients with intermittent claudication.⁷² Our trial will provide further evidence for supervised home-based walking in conjunction with other CVD risk reduction strategies to improve walking time in patients with PAD. It is possible that behavioral factors such as improving depression, enhanced self-efficacy for walking, social support and increased self-management skills will contribute to increased walking ability and quality of life. Although not measured in this study, adherence to a walking program may also improve muscle strength and balance. With increased walking ability, quality of life is enhanced in this patient population.

Additional limitations of study/design/methods

In addition to the constraints attributed to the intervention described above, other limitations include the use of pedometers and self-report for walking and 3-day diet recall for dietary adherence. Previous studies suggest that exercise self-report tends to over-estimate activity and underestimate dietary intake.^73–77 Additionally, medication adherence is self-reported as is dosage of medications. Every attempt will be made to verify prescribed medications by having study participants bring in their medication bottles at clinic visits and obtaining medical health records. Other limitations include the use of exercise treadmill testing to assess walking impairment. PWT is a subjective endpoint and although standardized instructions and encouragement will be provided for all study participants, PWT is influenced by an individual’s level of effort and can also be influenced by pain tolerance. Our study is also limited to those who are English speaking or have a reasonable command of the English language.

Conclusion

This study will be an important first step in examining the efficacy of patient-centered, behavior change strategies targeting multiple CVD risk factors; specifically, exercise and dietary habits as a means to improve walking ability and quality of life in elderly PAD patients.

Footnotes

Acknowledgements

The investigators wish to thank all the individuals and their families who participated in this study. We would also like to thank the staff of the UCSF Moffitt and Mt Zion CTSI centers and the staff of the Mt Zion Cardiology Laboratory.

This publication was made possible by grant numbers 5RO1NR9197, 3RO1NR009197-04S1, 3RO1NR009197-04S2, and 3RO1NR009 197-04S3 from September 2005 to 31 March 2011; the UCSF School of Nursing Intramural Fund; a UCSF Academic Senate Grant; and a Society of Vascular Nursing Research Grant.

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

Roger

Lloyd-Jones

. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 2011; 123: e18–e209.

Lloyd-Jones

Adams

Brown

. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 2010; 121: e46–e215.

Hirsch

Murphy

Lovell

. Gaps in public knowledge of peripheral arterial disease: the first national PAD public awareness survey. Circulation 2007; 116: 2086–2094.

Garg

Liu

Tian

. Physical activity during daily life and functional decline in peripheral arterial disease. Circulation 2009; 119: 251–260.

Gardner

Montgomery

Killewich

. Natural history of physical function in older men with intermittent claudication. J Vasc Surg 2004; 40: 73–78.

Guidon

McGee

. Exercise-based interventions and health-related quality of life in intermittent claudication: a 20-year (1989–2008) review. Eur J Cardiovasc Prev Rehabil 2010; 17: 140–154.

Olin

Sealove

. Peripheral artery disease: current insight into the disease and its diagnosis and management. Mayo Clin Proc 2010; 85: 678–692.

McDermott

McCarthy

. Intermittent claudication. The natural history. Surg Clin North Am 1995; 75: 581–591.

Creager

. Medical management of peripheral arterial disease. Cardiol Rev 2001; 9: 238–245.

10.

Norgren

Hiatt

Dormandy

. The next 10 years in the management of peripheral artery disease: perspectives from the ‘PAD 2009’ Conference. Eur J Vasc Endovasc Surg 2010; 40: 375–380.

11.

McDermott

Hahn

Greenland

. Atherosclerotic risk factor reduction in peripheral arterial disease: results of a national physician survey. J Gen Intern Med 2002; 17: 895–904.

12.

McDermott

Mandapat

Moates

. Knowledge and attitudes regarding cardiovascular disease risk and prevention in patients with coronary or peripheral arterial disease. Arch Intern Med 2003; 163: 2157–2162.

13.

Parmenter

Raymond

Dinnen

Singh

. A systematic review of randomized controlled trials: walking versus alternative exercise prescription as treatment for intermittent claudication. Atherosclerosis 2011; 218: 1–12.

14.

Cooper

Roter

Carson

. A randomized trial to improve patient-centered care and hypertension control in underserved primary care patients. J Gen Intern Med 2011; 26: 1297–1304.

15.

Roter

Hall

. Communication and adherence: moving from prediction to understanding. Med Care 2009; 47: 823–825.

16.

Cooper

Roter

Bone

. A randomized controlled trial of interventions to enhance patient–physician partnership, patient adherence and high blood pressure control among ethnic minorities and poor persons: study protocol NCT00123045. Implement Sci 2009; 4: 7.

17.

Roter

. Patient-centered communication. BMJ 2004; 328: E303–304.

18.

Cooper

Roter

Johnson

Ford

Steinwachs

Powe

. Patient-centered communication, ratings of care, and concordance of patient and physician race. Ann Intern Med 2003; 139: 907–915.

19.

Roter

. The medical visit context of treatment decision-making and the therapeutic relationship. Health Expect 2000; 3: 17–25.

20.

Roter

Hall

Merisca

Nordstrom

Cretin

Svarstad

. Effectiveness of interventions to improve patient compliance: a meta-analysis. Med Care 1998; 36: 1138–1161.

21.

Prochaska

Levesque

. A transtheoretical approach to changing organizations. Adm Policy Ment Health 2001; 28: 247–261.

22.

Saarmann

Daugherty

Riegel

. Patient teaching to promote behavioral change. Nurs Outlook 2000; 48: 281–287.

23.

Bandura

. Health promotion by social cognitive means. Health Educ Behav 2004; 31: 143–164.

24.

Rollnick

. Behaviour change in practice: targeting individuals. Int J Obes Relat Metab Disord 1996; 20 suppl 1: S22–26.

25.

Van Sluijs

van Poppel

van Mechelen

. Stage-based lifestyle interventions in primary care: are they effective? Am J Prev Med 2004; 26: 330–343.

26.

Whitlock

Orleans

Pender

Allan

. Evaluating primary care behavioral counseling interventions: an evidence-based approach. Am J Prev Med 2002; 22: 267–284.

27.

Strecher

Wang

Derry

Wildenhaus

Johnson

. Tailored interventions for multiple risk behaviors. Health Educ Res 2002; 17: 619–626.

28.

Goldstein

Whitlock

DePue

. Multiple behavioral risk factor interventions in primary care. Summary of research evidence. Am J Prev Med 2004; 27(2 suppl): 61–79.

29.

Pronk

Peek

Goldstein

. Addressing multiple behavioral risk factors in primary care. A synthesis of current knowledge and stakeholder dialogue sessions. Am J Prev Med 2004; 27(2 suppl): 4–17.

30.

Prochaska

DiClemente

Velicer

Ginpil

Norcross

. Predicting change in smoking status for self-changers. Addict Behav 1985; 10: 395–406.

31.

Prochaska

Redding

Evers

. The transtheoretical model and stages of change. In: Glanz

Rimer

Lewis

(eds) Health behavior and health education. San Francisco, CA: John Wiley and Sons, 2002, p.99–120.

32.

Marcus

Pinto

Simkin

Audrain

Taylor

. Application of theoretical models to exercise behavior among employed women. Am J Health Promot 1994; 9: 49–55.

33.

Prochaska

Velicer

Rossi

. Stages of change and decisional balance for 12 problem behaviors. Health Psychol 1994; 13: 39–46.

34.

Prochaska

DiClemente

. Self change processes, self efficacy and decisional balance across five stages of smoking cessation. Prog Clin Biol Res 1984; 156: 131–140.

35.

Bandura

. Social foundations of thought and action. Inglewood Cliffs, NJ: Prentice-Hall, 1986.

36.

Marcus

Forsyth

. The challenge of behavior change. Med Health R I 1997; 80: 300–302.

37.

Marcus

Rakowski

Rossi

. Assessing motivational readiness and decision making for exercise. Health Psychol 1992; 11: 257–261.

38.

Marcus

Simkin

. The transtheoretical model: applications to exercise behavior. Med Sci Sports Exerc 1994; 26: 1400–1404.

39.

Dishman

. Compliance/adherence in health-related exercise. Health Psychol 1982; 1: 237–267.

40.

DPP. The Diabetes Prevention Program (DPP). Diabetes Care 2002; 25: 2165–2171.

41.

Rollnick

Miller

. What is motivational interviewing? Behav Cogn Psychother 1995; 23: 325–334.

42.

Britt

Hudson

Blampied

. Motivational interviewing in health settings: a review. Patient Educ Couns 2004; 53: 147–155.

43.

Miller

. Motivational interviewing with problem drinkers. Behav Psychother 1983; 11: 147–172.

44.

Miller

Sanchez

. Motivating young adults for treatment and lifestyle change. In: Howard

Nathan

(eds) Alcohol use and misuse by young adults. Notre Dame, IN: University of Notre Dame Press, 1994, p.55–81.

45.

Miller

Rollnick

. Motivational interviewing: preparing people to change behaviour. New York: Guilford Press, 1991.

46.

Bandura

. Self-efficacy: toward a unifying theory of behavioral change. Psychol Rev 1977; 84: 191–215.

47.

NCEP. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497.

48.

Chobanian

Bakris

Black

. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–2572.

49.

Pate

Pratt

Blair

. Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 1995; 273: 402–407.

50.

Regensteiner

Ware

Jr McCarthy

. Effect of cilostazol on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease: meta-analysis of six randomized controlled trials. J Am Geriatr Soc 2002; 50: 1939–1946.

51.

National Heart, Lung, and Blood Institute in cooperation with The National Institute of Diabetes and Digestive and Kidney Diseases. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. NIH Publication 98-4083. Bethesda, MD: NHLBI, September 1998.

52.

Development of clinical guideline for smoking prevention and cessation with Centers for Disease Control—AHCPR. Fed Regist 1992; 57: 59,353–59,355.

53.

Hirsch

Haskal

Hertzer

. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006; 113: e463–654.

54.

Adler

Turner

. The diabetes prevention program. Diabetes Care 1999; 22: 543–545.

55.

Diabetes Prevention Program (DPP) Research Group. The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care 2002; 25: 2165–2171.

56.

Avery

Gardner

Palmer

. Vulvectomy. Am J Nurs 1974; 74: 453–455.

57.

Ory

Jordan

Bazzarre

. The Behavior Change Consortium: setting the stage for a new century of health behavior-change research. Health Educ Res 2002; 17: 500–511.

58.

Moher

Schulz

Altman

. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001; 357: 1191–1194.

59.

Resnick

Inguito

Orwig

. Treatment fidelity in behavior change research: a case example. Nurs Res 2005; 54: 139–143.

60.

Bellg

Borrelli

Resnick

. Enhancing treatment fidelity in health behavior change studies: best practices and recommendations from the NIH Behavior Change Consortium. Health Psychol 2004; 23: 443–451.

61.

Kanabrocki

Murray

Hermida

. Circadian variation in oxidative stress markers in healthy and type II diabetic men. Chronobiol Int 2002; 19: 423–439.

62.

Antonicelli

Testa

Bonfigli

. Relationship between lipoprotein(a) levels, oxidative stress, and blood pressure levels in patients with essential hypertension. Clin Exp Med 2001; 1: 145–150.

63.

Gardner

Skinner

Cantwell

Smith

. Progressive vs single-stage treadmill tests for evaluation of claudication. Med Sci Sports Exerc 1991; 23: 402–408.

64.

Haskell

Durstine

. Coronary heart disease. In: Skinner

(ed.) Exercise testing and exercise prescription for special cases. Philadelphia, PA: Lea & Febiger, 1993, p.251–274.

65.

Regensteiner

Steiner

Panzer

Hiatt

. Evaluation of walking impairment by questionnaire in patients with peripheral arterial disease. J Vasc Med Biol 1990; 2: 142–152.

66.

Little

RJA

Rubin

. Statistical analysis with missing data. New York: Wiley, 1987.

67.

Verbeke

Molenberghs

. Linear mixed models for longitudinal data. New York: Springer-Verlag, 2000.

68.

McDermott

Reed

Greenland

. Activating peripheral arterial disease patients to reduce cholesterol: a randomized trial. Am J Med 2011; 124: 557–565.

69.

Naik

Palmer

Petersen

. Comparative effectiveness of goal setting in diabetes mellitus group clinics: randomized clinical trial. Arch Intern Med 2011; 171: 453–459.

70.

Carter

Nunlee-Bland

Callender

. A patient-centric, provider-assisted diabetes telehealth self-management intervention for urban minorities. Perpect Health Inf Manag 2011; 8: 1b.

71.

Gardner

Parker

Montgomery

Scott

Blevins

. Efficacy of quantified home-based exercise and supervised exercise in patients with intermittent claudication. Circulation 2011; 123: 491–498.

72.

Gardner

Montgomery

Flinn

Katzel

. The effect of exercise intensity on the response to exercise rehabilitation in patients with intermittent claudication. J Vasc Surg 2005; 42: 702–709.

73.

Zeller

Ramseier

Teagtmeyer

Battegay

. Patients’ self-reported adherence to cardiovascular medication using electronic monitors as comparators. Hypertens Res 2008; 31: 2037–2043.

74.

Garber

Nau

Erickson

Aikens

Lawrence

. The concordance of self-report with other measures of medication adherence: a summary of the literature. Med Care 2004; 42: 649–652.

75.

Patterson

Saquib

Natarajan

. Improvement in self-reported physical health predicts longer survival among women with a history of breast cancer. Breast Cancer Res Treat 2011; 127: 541–547.

76.

Natarajan

Fan

. Measurement error of dietary self-report in intervention trials. Am J Epidemiol 2010; 172: 819–827.

77.

Luke

Dugas

Durazo-Arvizu

Cao

Cooper

. Assessing physical activity and its relationship to cardiovascular risk factors: NHANES 2003–2006. BMC Public Health 2011; 11: 387.