The role of exercise training in peripheral arterial disease

Vascular Medicine 2007; 12: 351–358

The role of exercise training in peripheral arterial disease Richard V Milani and Carl J Lavie Abstract: Peripheral arterial disease (PAD) is currently a major health problem affecting 8–12 million Americans, 15–40% of whom will have intermittent claudication that can lead to substantial impairment in their ability to carry out normal daily activities as well as perform the recommended cardiovascular exercise. Supervised exercise training is an effective tool in the treatment of claudication and is currently a recommended first-line therapy for patients with this condition. In addition to improving pain-free walking distance and quality of life, supervised exercise training can improve many cardiovascular risk factors, possibly reducing the risk for subsequent myocardial infarction, stroke, and death. This paper will review the benefits of supervised exercise training in patients with PAD. Key words: claudication; exercise therapy; peripheral arterial disease; risk factors

Introduction Peripheral arterial disease (PAD) currently affects 8–12 million Americans and by the year 2050 it is expected to reach a prevalence of 19 million Americans.1 The most common underlying etiology, atherosclerosis, is a disease that impacts multiple territories, leaving PAD patients at high risk for subsequent coronary and cerebrovascular events including myocardial infarction, stroke, and death.1,2 The risk of developing PAD can be predicted by age and welldefined atherosclerotic risk factors including tobacco use, diabetes mellitus, hypertension, hypercholesterolemia, and hypertension. Although about half of all people with PAD are asymptomatic or have atypical symptoms, the most frequent symptom of mild to moderate PAD is intermittent claudication, defined as walking-induced pain, cramping, aching, tiredness, heaviness in one or both legs (most often calves) that does not go away with continued walking and is relieved with rest.3,4 Moreover, claudication can severely limit the performance of daily physical activities and often impairs the normal personal, social, and occupational functional capacity of these patients, thus representing a disability.5 Claudication currently afflicts 5% of Americans over 55 years of age and is present in 15–40% of patients with PAD.6,7

Department of Cardiovascular Disease, Ochsner Clinic Foundation, New Orleans, LA, USA Address for correspondence: Richard V Milani, Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA. Tel: ⫹1 504 842 5874; Fax: ⫹1 504 842 5875; E-mail: [email protected] © 2007 SAGE Publications Los Angeles, London, New Delhi and Singapore

Contemporary treatment of claudication is dichotomized into two major goals: (1) improve walking ability and functional status by reducing claudication symptoms and preserving limb viability; and (2) reduce the risk of cardiovascular events by treatment of the underlying systemic atherosclerosis. The first of these goals is directed at improving symptoms and consists of exercise training, pharmacotherapy (primarily cilostazol), and revascularization (surgical or percutaneous).8 Of these, supervised exercise training is currently recommended as first-line treatment and is the only one of these interventions that can additionally reduce concomitant cardiovascular risk. This review will focus on the benefits of exercise training in improving symptomatic claudication and its effect on cardiovascular risk.

Baseline assessment Hemodynamic assessment is an integral component in the initial evaluation of patients with PAD and the most commonly used measurement to diagnose and assess the hemodynamic severity of PAD is the ankle-to-arm ratio of systolic blood pressure (ankle–brachial index or ABI). The ABI has been validated against angiographic confirmation of PAD and found to be 95% sensitive and almost 100% specific.9 Measurements can be readily obtained with standard blood pressure cuffs and a hand-held Doppler device. An ABI below 0.90 indicates the presence of PAD with ratios of 0.70–0.90 suggesting mild PAD, 0.40–0.70 moderate PAD, ⬍0.40 severe PAD, and values ⬎ 1.3 likely due to non-compressible arteries. 10.1177/1358863x07083177

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The evaluation of walking ability in claudicants most commonly employs motorized treadmills programmed to provide less intense progressive workloads (i.e. the Gardner–Skinner, Hiatt, or Naughton protocols) than are commonly used in evaluating patients for coronary artery disease. The treadmill test should record the onset of leg symptoms, laterality, specific muscle groups involved, the presence of associated coronary ischemic symptoms and signs, and total walking time.8 Exercise should be stopped when mandated by symptoms or if objective measures of myocardial ischemia manifest. Another option, particularly in elderly patients, is the 6-minute walk test, which can serve as an alternative objective method of assessing walking endurance.10,11 From these walking assessments come two frequently used measures in reporting outcomes from interventions: maximum walking distance and time (or claudication distance and time) and pain-free walking distance and time (or initial claudication distance and time).12 Finally, health-related quality of life issues should be assessed using validated questionnaires. The two most commonly used instruments in the PAD population are the non-disease specific Medical Outcomes Study SF-36 and the disease-specific Walking Impairment Questionnaire (WIQ), both of which assess functional status in the community and have been independently validated in patients with PAD.13,14 Exercise training and its effects on claudication symptoms Peak oxygen consumption in patients with claudication is generally 50% of age-matched normal individuals, indicating a level of impairment similar to patients with New York Heart Association class III heart failure.12,15,16 Because of the limitations imposed by claudication symptoms, many patients develop progressive functional impairment due to superimposed deconditioning from restricting physical activities. Self-reported walking distance has been reported to decline at the rate of 8.4 meters per year.17 This leads to reduced muscle mass, and a lack of muscle strength and endurance, exacerbating their physical infirmity.18 This cycle of disability can lead to marked and progressive impairment over time such that many patients become housebound or dependent on others (Figure 1).19 Exercise training can be promoted in two formats: unsupervised home-based exercise and supervised hospital or clinic-based exercise training. Although home-based programs can generate several health benefits, the usefulness of unsupervised exercise programs is not well established as an effective initial treatment of claudication and significant symptomatic improvement in walking distance has not been Vascular Medicine 2007; 12: 351–358

consistently demonstrated with this format of exercise prescription.20 In contrast, the data supporting the efficacy of supervised exercise programs to alleviate claudication symptoms are impressive.21–24 Supervised exercise has been shown to improve maximal treadmill walking distance more effectively than pharmacotherapy with pentoxifylline and/or cilostazol (Figure 2).25,26 Exercise-induced improvements in walking ability enhance routine daily activities, quality of life and community-based functional capacity.27 A meta-analysis of 21 randomized and non-randomized trials of exercise training revealed that pain-free walking time improved an average of 180% and maximal walking time increased by 120%.21 A separate meta-analysis from the Cochrane Collaboration evaluating only randomized, controlled trials concluded that exercise improved maximal walking ability by an average of 150%.24 Improvements in walking ability were most often attained when each exercise session lasted longer than 30 minutes, sessions took place at least three times per week, when the exercise modality was walking to nearmaximal pain, and when the program lasted at least 6 months.8,21 A rigorous exercise-training program may be as beneficial as bypass surgery and more beneficial than angioplasty.28,29 As a result of these data, the recent ACC/AHA guidelines for management of patients with PAD advocate supervised exercise rehabilitation as a IA recommendation for the initial treatment of patients with intermittent claudication.8 As per these guidelines, exercise training should be performed for a minimum of 30–45 minutes, in sessions performed at least three times per week for a minimum duration of 12 weeks. The key elements of a successful exercisetraining program are listed in Table 1. The mechanisms by which exercise training yields improvements in walking ability remain speculative. Exercise training improves oxygen extraction and muscle carnitine metabolism in the leg.30,31 Following a program of exercise training, humans with heart failure will increase expression of vascular endothelial growth factor (VEGF) messenger RNA in skeletal muscle,32 and animal models reveal an increase in collateral development.33,34 Moreover, exercise increases levels of circulating endothelial progenitor cells (EPC), monocyte/macrophage-derived angiogenic cells, and reduces EPC apoptosis.35,36 In an animal model, exercise training induces neoangiogenesis.35 In spite of this data, human studies in PAD patients with improved walking ability following exercise training have not demonstrated increases in leg blood flow, suggesting other mechanisms for the large improvements observed following exercise training.19,28,37 Exercise training stimulates endothelial-dependent vasodilatation.38,39 By periodic exposure to repeated episodes of exercise-induced hyperemia, the increased blood flow augments vascular expression of nitric

Exercise training in PAD

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Figure 1 The cycle of disability and benefits of exercise training in PAD patients with claudication.

oxide and prostacyclin, thereby promoting vasodilatation.40 We and others have shown that exercise training improves hemorheology, thereby facilitating oxygen delivery to ischemic skeletal muscle.41–43 Although coronary patients demonstrate significant improvements in blood viscosity and tissue oxygen extraction following formal exercise training, these benefits may be even more applicable for patients with PAD. Walking efficiency is reduced in patients with claudication in that walking patterns change to favor stability over speed.19,44–46 As a result of this less efficient alteration in biomechanics, the oxygen cost of walking is increased. Following a program of exercise training, walking economy has been shown to improve in PAD patients and in patients with other chronic diseases, as evidenced by a decrease in oxygen consumption at submaximal workloads.12,47–49 Vascular Medicine 2007; 12: 351–358

Calf muscle strength and endurance has been shown to be improved following treadmill-walking training and this is associated with improved walking capacity.50 However, a separate investigation suggests that improvement in lower-limb muscle strength may not fully account for enhanced walking distance following exercise training. A recent study randomized PAD patients to a 24-week upper versus lower-limb aerobic exercise training program and compared them to a non-exercise control group.51 Claudication distance and maximum walking distance improved similarly in both training groups as well as higher levels of reported pain. This data would suggest that exercising patients could tolerate a higher level of cardiovascular stress and claudication pain, accounting for the improvements in walking performance following exercise training, and provides an alternative exercise (arm crank) for patients unable or unwilling to negotiate

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Table 1 Key elements of a therapeutic claudication exercise training program. Primary clinician role • Establish the PAD diagnosis using the ABI measurement or other objective vascular laboratory evaluations • Determine that claudication is the major symptom limiting exercise • Discuss risk/benefit of claudication therapeutic alternatives, including pharmacological, percutaneous, and surgical interventions • Initiate systemic atherosclerosis risk modification • Perform treadmill stress testing • Provide formal referral to a claudication exercise rehabilitation program Exercise guidelines for claudication • Warm-up and cool-down period of 5–10 minutes each Figure 2 Mean improvement in maximal walking distance following medical interventions in patients with claudication.

treadmill walking. Supporting this concept are reports utilizing alternative exercise programs including polestriding and high-intensity interval training, each yielding as good or greater improvements in walking performance than standard exercise methods.52,53 However, Gardner reported contrasting results in a randomized trial of high- and low-intensity exercise training, where similar improvements in walking performance were observed provided that a few additional minutes of walking is accomplished in the low-intensity group to elicit a similar volume of exercise.54 Patient enrollment into medically supervised exercise programs should mirror traditional cardiac rehabilitation and exercise training where supervised exercise can be carried out with electrocardiographic, heart rate, and blood pressure monitoring available. The typical program requires the performance of treadmill or track-based exercise for 45–60 minutes monitored by a nurse or exercise physiologist. Most commonly, treadmill exercise is employed and the initial workload is set to a speed and grade that elicit claudication symptoms within 3–5 minutes. Patients are asked to continue to exercise at this workload until they achieve moderate severity claudication, at which time the patient can rest briefly until symptoms resolve. The exercise–rest–exercise cycle is repeated throughout the exercise session. Over time, pain-free and maximal walking distance increase such that periodic adjustments in speed and grade are required by rehabilitation personnel in order to elicit claudication symptoms. Typical benefits of such a program include a greater than 100% improvement in maximal claudication, significant improvement in walking speed and distance, and improvements in physical function and vitality by questionnaire (SF-36).8,21,23,24,43,47 As patients augment their exercise capacity, rehabilitation Vascular Medicine 2007; 12: 351–358

Types of exercise • Treadmill and track walking are the most effective exercise for claudication • Resistance training has conferred benefit to individuals with other forms of cardiovascular disease, and its use, as tolerated, for general fitness is complementary to but not a substitute for walking Intensity • The initial workload of the treadmill is set to a speed and grade that elicit claudication symptoms within 3–5 minutes • Patients walk at this workload until they achieve claudication of moderate severity, which is then followed by a brief period of standing or sitting rest to permit symptoms to resolve Duration • The exercise–rest–exercise pattern should be repeated throughout the exercise session • The initial duration will usually include 35 minutes of intermittent walking and should be increased by 5 minutes each session until 50 minutes of intermittent walking can be accomplished Frequency • Treadmill or track walking three to five times per week Role of direct supervision • As patients improve their walking ability, the exercise workload should be increased by modifying the treadmill grade or speed (or both) to ensure that there is always the stimulus of claudication pain during the workout. • As patients increase their walking ability, there is the possibility that cardiac signs and symptoms may appear (e.g. dysrhythmia, angina, or ST-segment depression). These events should prompt physician re-evaluation. Reproduced from ref. 19. Copyright © 2002 Massachusetts Medical Society. All rights reserved.


personnel should continually evaluate patients for symptoms and signs of coronary ischemia as higher heart rates and blood pressures (double product) are achieved, thus increasing myocardial oxygen requirements. Exercise training and its effect on cardiovascular risk factors Sedentary behavior is one of the leading preventable causes of death, and an inverse relationship exists between volume of physical activity behavior and allcause mortality. Regular physical activity decreases the risk of multiple medical conditions including cardiovascular disease, type 2 diabetes, osteoporosis, depression, obesity, breast cancer, colon cancer, and falls in older adults.55 Although there are less data in patients with PAD, a graded relationship of decreasing CAD rates with increasing levels of activity is noted in the general population and in patients with established CAD.56 However, in a recent preliminary report from Japan, supervised exercise training has been reported to improve survival in patients with PAD. After a mean follow-up of 5.4 years, event-free survival was higher in those PAD patients completing supervised exercise training than in those who did not (80.5% versus 56.7%).57 Physical activity both prevents and treats many established atherosclerotic risk factors including elevated blood pressure, insulin resistance and glucose intolerance, elevated triglyceride concentrations, low levels of high-density lipoprotein cholesterol (HDL-C) concentrations, and obesity56 (Table 2). Furthermore, the prevalence of the metabolic syndrome (a constellation of obesity, glucose intolerance, reduced HDL-C, elevated triglycerides, and hypertension), which is associated with a marked increase in cardiovascular risk, can be dramatically reduced following exercise training.58 Moreover, other less established risk factors which can impact patients with PAD59 can be favorably improved by supervised exercise training including hs-CRP, homocysteine, blood rheology, autonomic function, depression, and psychosocial stress.42,60–64

Table 2 Benefits of exercise training in cardiovascular risk reduction. Improvement in exercise capacity Improvement in lipids (primarily HDL-cholesterol and triglycerides) Reduction in obesity indices Reduction in blood pressure Reduction in inflammation (hs-CRP) Improvement in autonomic function Improvement in blood rheology Improvement in insulin resistance/glucose intolerance Reduction in depression and psychosocial stress Vascular Medicine 2007; 12: 351–358

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Finally, perhaps the strongest cardiovascular risk factor is a low functional capacity, and we and others have demonstrated marked improvements in overall exercise capacity in many different subgroups including elderly people, women and obese patients.65–68 An additional benefit of a comprehensive program of exercise training is that it provides a framework for complimentary non-pharmacologic interventions that can assist the patient towards achieving better health. Such interventions include nutritional counseling with dietary recommendations, smoking cessation, stress management, and educational classes on PAD, cardiovascular risk factors and healthy behaviors.65,69 These interventions can be provided in group sessions, and can improve adherence to therapy as well as assist in reducing claudication symptoms and cardiovascular outcomes. Diabetics as a unique population It is estimated that more than 20% of the PAD population carries the diagnosis of diabetes mellitus.70,71 Although the beneficial effects of exercise training on weight reduction and insulin resistance have been well described, it is particularly important to avoid hypoglycemia during a program of sustained exercise training.72 For example, the potential for hypoglycemia in type 2 diabetes is increased by the use of sulfonylureas, insulin secretagogues, or insulin injections and so doses of these oral hypoglycemic agents or insulin are often reduced during exercise training to prevent hypoglycemia, since exercise increases sensitivity to insulin.72 Therefore, a relatively important role of the rehabilitation staff is to assist the patients and primary care physicians with the monitoring and treatment of glucose levels in patients with diabetes. Patients should also be taught techniques of self-monitoring for both blood pressure and glucose levels, as such surveillance has led to significant alterations in dose of medications.73 A major concern during exercise, particularly higher intensity or when prolonged, is to avoid hypoglycemia.74 If the pre-exercise finger stick blood sugar is below 90–100 mg/dl, a source of simple carbohydrate, such as one fruit or starch exchange or two to three glucose tablets containing 4 or 5 g of glucose each, should be administered before starting exercise.72 Insulin should be administered preferably in abdominal sites and not in sites used for exercise. In addition to the finger stick glucose monitoring, the exercise area should have glucose tablets or gels to administer to patients during exercise, and glucagon emergency kits containing 1 g glucagon if severe symptoms make it impossible for oral glucose administration. If hypoglycemic episodes are frequent, significant reductions in medications are needed. Likewise, for patients who exercise in evening exercise classes, occasionally nocturnal hypoglycemia can be problematic, necessitating

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reductions in evening medications, taking an extra source of complex carbohydrate at night, or occasionally changing exercise sessions to earlier in the day. Although hyperglycemia is usually not as important a problem in exercise programs as hypoglycemia, poor glucose control can occasionally lead to severe hyperglycemia in type 2 diabetes. Many patients with long-standing diabetes have complications, including peripheral neuropathy, retinopathy, nephropathy, and autonomic neuropathy. Patients with peripheral neuropathy may have painful burning, tingling, and numbness in the feet or foot ulcers. In these situations, self-examination of the feet before and after exercise is imperative, and shockabsorbing shoes with ample room for the distal foot are needed.72,74 Impediments to success Despite the efficacy of exercise training, it is currently underutilized in clinical practice. The major problem preventing more widespread use of supervised exercise training has been a lack of coverage by medical insurance. Recently however, a new current procedural terminology (CPT) code was created for exercise rehabilitation for patients with claudication (93668); however, the Centers for Medicare & Medicaid Services (CMS) has not at this time provided reimbursement for this code. Other barriers to participating in a supervised exercise program include transportation and time issues for patients. Moreover, exercise training does require a motivated patient who will maintain exercise post-training on a continuous basis over time, or the benefits will be lost. Available data analyzing the implementation of unsupervised exercise in patients with PAD are not encouraging. In The Netherlands, regular walking exercise programs were not followed by almost 50% of patients with intermittent claudication.75–77 Conclusions Supervised exercise training for PAD patients with claudication has been consistently effective in improving maximal walking distance and pain-free walking distance and is currently regarded as first-line therapy for these patients. Other complementary benefits of this therapy may include a reduction in many cardiovascular risk factors. References 1

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