Exercise Training for Patients With Peripheral Artery Disease
Andrew W. Gardner, PhD
Exercise and Sports Cardiology Series
THE PHYSICIAN AND SPORTSMEDICINE - VOL 29 - NO.7 - JULY 2021
In Brief: Peripheral artery disease is a significant health concern among the elderly and will likely become more common. Nonsurgical management, such as modification of risk factors for atherosclerosis, can improve the health of asymptomatic patients and those with intermittent claudication. Exercise rehabilitation, with or without pharmacotherapy, is highly effective in improving health and ambulation in patients with intermittent claudication. Percutaneous transluminal angioplasty and arterial reconstruction may be required for more severely affected patients.
C ardiac diseases were the leading cause of death in 1990, and cerebrovascular diseases were the fourth (1), making atherosclerotic cardiovascular disease the most significant health problem in the United States. Atherosclerosis in the lower-extremity arteries, called peripheral artery disease (PAD), is also an important medical concern because of a high prevalence of concomitant coronary and cerebral artery disease (2), and because ischemic pain in the leg musculature (intermittent claudication) severely limits daily physical activities.
Most research on PAD derives from work done by vascular specialists, but contributions from exercise physiologists are growing, fueled by studies of exercise rehabilitation in affected patients. The synergy between vascular surgeons and exercise clinicians is important for clinical management of PAD because of the overlapping concerns of the disciplines. The primary goal for the vascular surgeon is to improve circulation and limb viability, whereas the primary concern of the exercise clinician is to regain function lost through years of physical inactivity from intermittent claudication.
Definitions and Classification
PAD occurs from lesions in the abdominal aorta and iliac, femoral, popliteal, and tibial arteries. Reduced blood flow distal to the arterial lesions occurs, ultimately hindering the ambulation and functional independence of affected patients. The hallmark clinical measure for detecting PAD is the ankle-brachial index (ABI), or the ratio of systolic blood pressure measured in the ankle to that in the arm (3). In patients with PAD, the reduction in leg blood flow results in a low ankle pressure and a low ABI.
The defined prevalence of PAD is highly dependent on the ABI cutpoint used to detect inadequate peripheral circulation. The definition of an abnormal ABI has ranged between less than 0.80 to less than 0.97 (4-7), with less than or equal to 0.90 accepted as the reference standard (8). The normal ABI is greater than or equal to 1.00, because systolic pressure increases as the pressure is measured farther from the central aorta. When an ABI of less than or equal to 0.90 is used as the definition of PAD, the prevalence of PAD is 16% in people older than 55 (8).
Classification. In the early stages of PAD development, reduced blood flow does not produce noticeable symptoms. This represents stage 1 or asymptomatic PAD, according to the Fontaine classification system (table 1: not shown) (9). As PAD progresses, ischemic pain in the leg muscles that occurs when patients walk is considered stage 2 (intermittent claudication). In more advanced stages, blood flow is reduced so much that pain is experienced even at rest (stage 3). Progression leads to ischemic leg ulcers and gangrene (stage 4). Patients with stage 3 or stage 4 disease have critical leg ischemia that endangers part or all of the limb. These patients are candidates for surgery or percutaneous revascularization procedures.
Exercise rehabilitation programs are indicated for patients with stage 1 and stage 2 PAD and for revascularized patients who have significant hemodynamic improvements but remain functionally dependent because of the extreme deconditioning that occurs with critical leg ischemia. These patients can benefit greatly from exercise rehabilitation, medication therapy, and atherosclerotic risk-factor reduction.
Evaluation of PAD Patients
The primary focus here is on the evaluation and treatment of patients with stage 1 and stage 2 PAD.
Claudication. The main effect of PAD on acute exercise is the development of claudication pain from insufficient blood flow to the leg muscles. Thus, claudication and peripheral hemodynamic measurements obtained from a treadmill test are the primary criteria to assess functional limitations and disease severity (10). The specific claudication variables that are measured include the distances (or times) to pain onset and to maximal pain. The most accepted variable is the ankle systolic blood pressure. Measurement is made before and after the treadmill test, and test values are used to calculate ABI.
Tests. The primary objective of a treadmill test for PAD patients is to obtain reliable measures of (1) the rate of claudication pain development, (2) the peripheral hemodynamic responses to exercise, and (3) the presence of coexisting coronary heart disease. The test should be progressive, with gradual increments in grade. A test with small increases in exercise intensity allows the walking distances of claudication patients to be stratified according to disease severity. Highly reliable treadmill protocols for PAD patients use a constant walking speed of 2 mph at 0% grade, with gradual increases in grade of either 2.0% every 2 minutes or 3.5% every 3 minutes (11,12). In these patients, the typical distance to onset of pain is about 170 m and to maximal pain about 360 m (13).
These protocols may be especially helpful when the diagnosis of PAD is in doubt or when the contribution of PAD to walking impairment is not clear. Typically these patients have ABIs that drop at least 0.15 units from the resting baseline value immediately following the treadmill test (11). Serial measurements of ABI following exercise should be done for 5 to 15 minutes to establish the time course of recovery to the resting baseline value. Gas exchange measures during the treadmill test show that PAD patients with intermittent claudication have peak oxygen consumption values from 12 to 15 mL/kg/min (14), or about 50% of that of age-matched controls. Favorable changes following successful interventions such as exercise rehabilitation, medication therapy, or surgery should include greater walking distances to the onset of claudication pain and to maximal pain, an increase in peak oxygen consumption, and possibly a blunted decline in ABI and a faster return to the resting ABI.
Quantification. Claudication distances and ABI are the most common measurements obtained in patients with intermittent claudication because they are specifically related to vascular insufficiency. However, measures that are more generally related to overall physical function may provide additional and insightful information regarding the functional independence of PAD patients. Since the typical profile of a patient with PAD is that of an elderly person with chronic ambulatory disability, the decline in physical functioning with aging may be accelerated by extreme deconditioning from the disease. Consequently, performance on a 6-minute walk test as well as measures of gait, walking economy (ie, efficiency), balance, flexibility, and lower-extremity strength may be worse in patients with PAD than in age-matched controls and should improve after a program of exercise rehabilitation. However, little information is available on these measures among the PAD population (15-17).
Other measures. In addition to the laboratory tests of physical function, assessment of patient-perceived ambulatory function should be measured. Ambulatory function should be assessed with the Walking Impairment Questionnaire (18), and health-related quality of life measured with the Medical Outcomes Survey Short-Form 36-item questionnaire (19). These questionnaires are becoming the standard devices to quantify the impact of intermittent claudication on performing activities of daily living.
In addition to these questionnaires, monitoring the physical activity levels of patients in community settings provides a more accurate assessment of the daily limitations imposed by intermittent claudication. Free-living daily physical activity can be measured with an accelerometer that quantifies movement over an extended period while the patient is awake. The device reveals that daily physical activity is approximately 33% lower in patients with PAD than in those of similar age without PAD. Activity decreases in claudication patients whose disease worsens (20). Thus, PAD patients with intermittent claudication are at the extreme low end of the physical activity spectrum.
Exercise Rehabilitation Programs
Significant improvements in claudication pain occur following exercise rehabilitation.
Meta-analysis. A meta-analysis (21) of exercise rehabilitation studies (22-42) demonstrates that the average distance walked to onset of claudication increased 179% from 126 + 57 m (mean + standard deviation) to 351 + 189 m following rehabilitation, and the average distance walked to maximal claudication pain increased 122% from 326 + 148 m to 723 + 592 m.
Mechanisms. Numerous mechanisms have been proposed to explain the improvement in walking distance following exercise rehabilitation, including increased blood flow to the exercising leg due to a greater collateral network (23,32,41,43), more favorable redistribution of blood flow (42,44), greater use of oxygen (45) due to higher levels of oxidative enzymes (26), improved hemorheologic properties of the blood (22), decreased reliance upon anaerobic metabolism (40,45), and greater walking efficiency (46,47). It may be that rather than a single mechanism, several contributions are responsible for the gains. Improvements in psychosocial attitude from accomplishments achieved during exercise rehabilitation may further enhance this effect.
To address the peripheral hemodynamic mechanism, several studies have assessed calf blood flow and ABI both before and after a program of exercise. On average, blood flow in the calf under resting and maximal conditions increases by approximately 19% (26-29,33,35-37,42,45,48-51), and ABI increases by approximately 7% (30,34-37,40,43,44,50-52) following exercise rehabilitation.
Only a few studies have examined the change in redistribution of peripheral blood flow, blood viscosity, leg arteriovenous oxygen difference, concentration of oxidative enzymes, and efficiency of walking. Consequently, the changes in these variables following exercise rehabilitation are not well established in patients with PAD. Since the magnitude of increases in calf blood flow (19%) and ABI (7%) are much smaller than the increases in the walking distances to onset (179%) and to maximal (122%) claudication pain (21), differences must be due to either small changes in peripheral blood flow that yield exponential improvements in claudication symptoms or other mechanisms that also contribute to the improved walking distances.
Exercise Program Components and Claudication
Although these studies show substantial increases in walking distances, they also reveal considerable variability. For example, the increased distance to onset of pain ranges from 72% to 746%, and the increased distance to maximal pain ranges from 61% to 739% (21). Differences in the components of exercise programs (eg, intensity, duration, and frequency of sessions) may largely account for widely divergent responses. Although these exercise programs are generally effective in treating intermittent claudication, none assessed different components to determine an optimal exercise rehabilitation program.
Meta-analysis. Because no experimental study can systematically examine the effects of all exercise rehabilitation program components in claudication pain, meta-analysis can help identify the most important components for optimizing exercise distances (21). Six components were examined in this meta-analysis: (1) frequency of exercise (sessions per week), (2) duration of exercise (minutes per session), (3) mode of exercise (walking vs combination of exercises), (4) length of the program (weeks), (5) claudication pain endpoint used in the program (onset vs near-maximal pain), and (6) level of supervision (supervised vs supervised plus home-based exercise). All components, except for the level of supervision, had a significant effect on the change in distance to onset of claudication. Programs that had patients exercise to near-maximal claudication pain were more effective than programs in which patients exercised only to onset of pain (figure 1). Furthermore, exercise programs consisting of long duration, high frequency, long program length (figure 2), and walking as the only mode of exercise (figure 3) were more effective than exercise programs consisting of short duration, low frequency, short program length, and combined exercise modes. The addition of supplementary home exercise to that performed in a supervised setting did not result in additional ambulatory benefit.
Of the five components that had an effect on the change in the claudication distances, only three had an independent effect when multivariate analyses were performed: walking to near-maximal claudication pain during training, long program length, and using walking as the sole training modality. The combination of these factors accounted for nearly 90% of the variance in the increase in the postexercise rehabilitation walking distances. Although the duration and frequency of exercise sessions are not independent predictors of the change in claudication pain times, patients should walk for at least 30 minutes per session and for at least three sessions a week, levels shown to be more beneficial than low-duration and low-frequency programs.
Recommendations. The appropriate exercise intensity for training could not be determined because no study has addressed this issue. The common misconception is that walking beyond pain onset to near-maximal pain represents an increase in intensity when, in fact, it merely represents an increase in duration. The rate of work performed while walking, regardless of the duration, is the important consideration when evaluating exercise intensity. Since heart rate is commonly used as a measure in adjusting the intensity of exercise, a conservative recommendation for claudication patients beginning rehabilitation is to walk at an appropriate speed and grade on a treadmill to elicit an intensity of approximately 50% of heart rate reserve, and to gradually increase the intensity to 70% to 80% by program's end. Exercise recommendations for patients with PAD are summarized in table 2.
Other Therapies for PAD Patients
Several different therapeutic modalities are available for PAD patients in addition to exercise rehabilitation.
Drugs. Pharmacologic therapy for intermittent claudication in the United States is limited to pentoxifylline and cilostazol.
Pentoxifylline, which exerts a hemorheologic effect by improving the flexibility of red blood cell membranes and by reducing platelet aggregation, was first studied in the United States in 120212 (53). Pentoxifylline significantly increased the distance to onset of claudication pain and the distance to maximal pain after 24 weeks of treatment compared with placebo (45% and 32% vs 23% and 20%). Although this initial study demonstrated the efficacy of pentoxifylline, the drug's usefulness in treating intermittent claudication has been questioned (54).
Cilostazol is a new medication with vasodilatory and antiplatelet activity (55). Cilostazol produced significant increases in the distances to claudication onset and to maximal claudication pain compared with placebo (40% and 42% vs 1% and -14%) (56). These studies (55,56) suggest that pharmacologic intervention may be used to treat intermittent claudication in a large percentage of most patients. However, exercise rehabilitation results in greater increases in walking distances of patients who are capable and motivated to walk on a regular basis compared with those who only take the drug. The potential synergy between cilostazol and exercise has not been studied.
Revascularization. Another treatment option for patients with intermittent claudication is revascularization. Percutaneous transluminal angioplasty (PTA) is suitable for patients whose limb arterial anatomy is favorable (57). Direct comparison between PTA and exercise rehabilitation for PAD patients revealed that PTA could increase patients' walking distances. Three months after PTA, the distances to onset and to maximal claudication pain increased by more than 100%, but these gains had diminished to approximately 60% at 1 year follow-up (57).
In contrast, the exercise group had gradual improvements throughout the study. The distance to onset of claudication pain increased by more than 300% by the end of the year, and the distance to maximal pain increased by more than 400%. In patients with more severe intermittent claudication who underwent arterial reconstruction, the distances to pain onset increased by 376% and to maximal claudication pain by 173% at 1-year follow-up (51). Patients who exercised during the 1-year study increased these distances by 179% and 151%, though arterial reconstruction patients who did exercise rehabilitation had the greatest improvements: Their walking distances to these points increased by 699% and 263%.
These studies suggest that exercise is superior to PTA for increasing walking distances in patients with mild-to-moderate claudication, and that exercise rehabilitation provides an additive effect to arterial reconstruction for increasing walking distances in patients with severe claudication.
After a 10-year effort, a landmark change recently occurred in the field of PAD rehabilitation with the creation of a new current procedural terminology (CPT) code (93668). Although Medicare has not yet approved reimbursement for PAD rehabilitation, the creation of the CPT code will likely change the medical approach for patients with intermittent claudication by recognizing exercise as a primary therapeutic modality. Indeed, an internal medicine approach of combining pharmacotherapy with exercise rehabilitation is rapidly replacing revascularization as the standard of care for this population.
What Remains to Be Done
PAD is a significant health concern among the elderly and will likely increase as the population ages. Nonsurgical management, including risk modification and exercise rehabilitation, can improve patients' ability to walk, though more seriously affected patients will require revascularization. Current evaluation of interventions has relied on laboratory measures such as distance walked and maximal pain during a treadmill test. Improved walking ability has not yet clearly been shown to translate into an overall increase in physical activity and enhanced quality of life. Future research should target functional outcomes such as submaximal exercise performance, walking economy, balance, flexibility, and lower-extremity strength because these measures may be better assessments of everyday functioning in geriatric populations. Until these measures are obtained, the full benefit of exercise rehabilitation for patients with PAD is likely to be underestimated.
Dr Gardner is supported by grants from the National Institute on Aging (NIA, K01-AG-00657, RO1-AG16685), by a Claude D. Pepper Older American Independence Center (OAIC) from NIA (P60-AG12583), and the Geriatric, Research, Education, and Clinical Center from the Veterans Affairs Administration.
This article was adapted from the recently published book: Thompson PD (ed): Exercise and Sports Cardiology, New York City, McGraw-Hill Medical Publishing, 2021 (to order: 1-800-262-4729 [ISBN:0-07-134773-9]).
Dr Gardner is associate professor in the department of medicine, division of geriatrics, at the University of Maryland and the Geriatric Research, Education, and Clinical Center at the Veterans Affairs Medical Center, both in Baltimore. Address correspondence to Andrew W. Gardner, PhD, Baltimore VA Medical Center, Geriatrics Service, GRECC (18), 10 N Greene St, Baltimore, MD 21201-1524; e-mail to [email protected].
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