Exercise as a treatment option in peripheral arterial disease

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1 r e v i e w a rt icle Exercise as a treatment option in peripheral arterial disease Arno Schmidt-Trucksäss Division of Sports Medicine, Institute of Exercise and Health Sciences, University of Basel Abstract Peripheral arterial disease (PAD) is a chronic, progressive atherosclerotic process limiting the blood flow to the lower limbs which causes an imbalance between oxygen supply and metabolic needs during physical activity with typical claudication symptoms. One important aspect of treatment besides optimal reduction of underlying risk factors is exercise training. Exerciseinduced increase of blood flow in arteries leading to the working and inactive musculature causes an increase of shear stress as the main physiological mechanism for the improvement in pain-free and maximal walking distances. The dominant and best examined training mode with respect to walking ability in daily life is walking exercise with an increase of maximal walking distance by around 150%. Strength training has a marginal or no effect on walking distance, however it facilitates strength dependent daily tasks like stair climbing. Arm cranking seems to be an alternative to walking, gaining a similar increase in walking distance as walking, and patients with orthopaedic problems might especially benefit from upper limb exercise. Basically, exercise training in PAD is determined by frequency, duration and intensity. A baseline walking test on a treadmill or in the field is very much recommended in order to monitor training advances and to establish a training plan. Exercise training has to be structured systematically with individual adaptation of training load. A total of 2 3 sessions per week with a duration of min walking time per session seems to be enough to peak the increase in absolute walking distance. Supervised training has a clinical relevant advantage compared to non-supervised training with respect to an increase in walking distance. Drug treatment has to be combined with exercise training and is not a substitute for exercise. Interventional treatment is best accompanied by exercise training and is only associated with a higher increase in walking distance in a Funding / potential short time after treatment comcompeting interests: pared with exercise. No financial support and no other potential conflict Key words: physical activity; of interest relevant to this exercise therapy; peripheral artearticle were reported. rial disease; exercise training Introduction Peripheral arterial disease (PAD) is a chronic, progressive atherosclerotic process. In this disease, the blood flow to the lower limbs is reduced which causes an imbalance between oxygen supply and metabolic needs during physical activity. The oxygen deficit causes intermittent claudication. Typical symptoms are cramps, pain, weakness and feelings of tension in the depending musculature, predominantly in the calves, but also in the sole of the foot, upper leg and sometimes the gluteus. Usually, symptoms occur during fast walking and disappear when patients rest. PAD is categorised into four stages according to symptoms and blood flow reduction (table 1). The prevalence of PAD, defined as ankle-brachial index at rest <0.9 or patients with a history of peripheral vascular revascularisation and/or limb amputation and ABI values 0.9, is 18% in persons older than 65 years [1]. A steep increase is visible for men and women from age years (men 17.1%, women 11.5%) to 85 years (men 27.8%, women 39.2%) [1]. Diabetic patients have a fourfold relative risk increase for PAD than non-diabetic subjects [2]. The most prevalent risk factors in PAD beside physical inactivity are hypertension (78.8%), smoking (58.7%), dyslipoproteinaemia (57.2%) and diabetes mellitus type 2 (36.6%). Smokers are at highest risk to develop PAD (9.3 fold), followed by people with diabetes type 2 (4.4 fold), hypertension (3.3 fold) and dyslipoproteinaemia (2.7 fold) [3]. PAD patients suffer from different impairments in daily life. Some patients can only walk a few hundred meters without experiencing pain [4]. Thus, they are stuck in their homes, becoming more and more isolated Correspondence: Professor Arno Schmidt-Trucksäss, MD Division of Sports Medicine Institute of Exercise and Health Sciences University of Basel Birsstrasse 320B CH-4052 Basel Switzerland arno.schmidt-trucksaess[at]unibas.ch Cardiovascular Medicine 2012;15(3):

2 Strength training Recently, one randomised controlled trial with a reasonable sample size compared endurance and resistance exercise training [22]. After a 6 month training period, walking distances in a 6 minute walk test improved significantly, not only in the endurance trainand losing their social contacts. The increase in inactivity further negatively influences the atherosclerotic risk factor profile. The aim of all therapeutic options in PAD is to reduce the overall risk for cardiovascular events, to minimise or even stop the progression of atherosclerosis and to improve quality of life. Exercise is one substantial element. Details in medical treatment are given in the ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease [5]. Physiological basis of exercise therapy Physical inactivity itself is associated with a reduced blood flow and shear stress in the arteries leading to the working musculature. This causes a reduced production of nitric oxide (NO), the most potent anti-atherosclerotic mediator of the endothelial cell [6]. The arteries of immobilised limbs reduce their diameter and elasticity by around one third [7, 8]. Without physical activity, patients with claudication do not elicit the local acidosis needed for the depending limb to develop collateral vessels. In addition, under use of musculature causes hypotrophy of the skeletal musculature and concomitantly impaired stair climbing or adverse effects on similar tasks of daily living. This is associated with a decrease in body balance leading to a stronger disposition for falls. Thus, decreased anklebrachial index (ABI) is aligned with neurological motor deficits leading to decreased tandem stand time [9], 4 meter fast walking time [10] and steps walked per day [11]. Furthermore, the distance walked in 6 min walk test and usual day physical activity measured by accelerometry decreased with worsening ABI [9, 11]. The increase of shear stress caused by blood flow to the working musculature through stenotic arteries results in an increased production of NO. This can only take place if the arterial bed distal to the stenosis is not affected by multiple plaques, because this impairs the increase in blood flow during exercise. Local ischaemia induced by repetitive exercise bouts stimulates the growth of capillaries in the ischaemic tissue. The arterio-venous oxygen difference and movement economy is increased with exercise training. Endurance exercise decreases blood viscosity and improves haemorheologic properties [12]. Recent studies show an increase in walking distance in PAD patients not only following walking exercise but also by arm endurance training [13, 14]. The effect may be mediated at least in part by an increase of shear rate in the non-exercising limb as suggested by arm-crank exercise in healthy subjects [15]. Another mechanism for increased NO production may be the cyclic distension of the artery during exercise. This has been shown to improve endothelium-dependent dilation in senescent soleus arteries in animals in part by enhancing NO bio-availability [16]. However, as later shown, only endurance exercise is able to significantly increase walking distance and time, thus indicating that increase in shear stress is the main mechanism improving arterial functioning and blood flow to the lower limbs in patients with PAD. Exercise as therapy in PAD Endurance training The average walking velocity of PAD patients is around km/h. The aim of exercise training should be to increase this walking velocity to km/h, which is the habitual walking velocity of a healthy person. Systematic endurance training, in terms of walking, over 12 weeks increased maximal treadmill walking time by 5.12 min compared to placebo according to a recent Cochrane Review [17]. The improvement of maximal walking distance was an average of 150% compared to inactive controls ranging from 50% to 200%. Pain-free walking distance increased by an average of m and maximum walking distance by m. Improvements were visible up to two years [17]. Even current smokers doubled their pain free (+119%) and maximal walking distance (+82%), which is a strong argument for exercise training even in the presence of the most important risk factor [18]. No significant improve of ankle-brachial index [19] and blood flow [20] has been shown in any study with an average duration of 12 weeks. Recently, arm cranking exercise has been proven to be efficient in prolonging claudication distance and maximal walking distance in an incremental shuttle walking test by 51% and 29%, respectively, after 6 months. The results were not significantly different from leg cranking exercise. The control group did not show any significant change from baseline [13]. In another randomised controlled trial with arm-ergometric exercise, treadmill walking and the combination of both, pain free walking distance improved from baseline to 12 weeks by 82%, 54%, and 60% and maximal walking distance by 53%, 69%, and 68%, respectively [14]. Both randomised controlled trials provide evidence, in addition to a non-randomised study almost one decade ago [21], that upper body exercise associated improvement in walking can result from changes in systemic as well as local skeletal muscle and vascular adaptations, and may be considered as an alternative for patients who are not able to walk. Of course, since these results have not been reproduced in larger cohorts, walking exercise remains the gold standard in endurance training. Cardiovascular Medicine 2012;15(3):

3 ing group but not in the strength training group (35.9 m / 12.4 m group difference between control and endurance/resistance training group, respectively). However, stair climbing significantly improved in the resistance group indicating a benefit for daily living in this respect. Exercise testing and prescription of exercise in PAD The basis for all recommendations to increase physical activity in patients with PAD is following a thorough physical examination including a cardiopulmonary stress test in order to prevent adverse cardiovascular events [5]. Of interest is that cycling exercise can induce 10 15% greater cardiopulmonary and metabolic responses in patients with PAD than treadmill exercise, and thus may be preferred when the aim of testing is to assess the overall capacity of the cardiovascular system [23]. However, this may not be the case in patients with high grade stenosis of the common iliac artery due to impaired blood flow to the gluteal musculature. Before starting an exercise-training programme, pain free and maximal walking distance should be assessed. This should be done on a treadmill and/or in a field test. An exercise test on the treadmill is usually done by a constant load test at 3.0 km/h and an incline of 12%. Parameters are pain free walking distance (until first onset of pain) and maximal walking distance. Pain free walking distance is classified as low at a walking distance <100 m, moderate between m and high between m. Above that a walking-through -phenomenon might happen caused by redistribution of blood flow due to collaterals. An ankle pressure <50 mm Hg at test cessation indicates claudication, which limits exercise performance. An ankle pressure >50 mm Hg at test cessation might indicate a pseudo-claudication due to other reasons like heart failure, chronic obstructive lung disease or most often spinal origin. Under field test conditions the pain free walking distance may be assessed using a simple walking test. At a walking speed of approximately 100 m/min (6 km/h, equivalent to two steps per second), the patient has to repeat the test three times with 5 minutes rest in between on a plain surface with a minimal length of 30 m. The pain free walking distance measured is the basis for exercise prescription. An intriguing alternative of assessing walking performance was based on a general positioning system (GPS) in order to assess maximal walking distance during a field test in a park [24]. Patients were given the advice to walk for 45 min at their usual walking speed including eventual rest periods due to leg pain. Patients were instructed to stop at maximal claudication in order to clearly determine maximal walking dis- tance in the GPS-based distance and speed profile. Maximal walking distance by GPS correlated highly with maximal walking distance on the treadmill (r = 0.81) which was higher than distance walked in the 6 minute walk test (r = 0.74) and much higher than a subjective estimate of walking ability by the patient (r = 0.51). Since patients get more and more used to newer electronic devices, this new type of walking test might be an upcoming possibility to monitor walking ability of patients in daily life in the future. An accelerometer may be even easier for monitoring physical activity in patients with PAD. Clear associations were shown for steps per day with ABI. Patients with a reduced ABI (0.63) compared to normal ABI (1.21) had nearly half of the steps per day (4737 ± 2712 steps/day) than healthy subjects (8672 ± 4235 steps/day) [25]. Due to low walking velocity in PAD, three-dimensional accelerometers should be recommended instead of two-dimensional accelerometers [26]. If combined with step goals per day, pedometers might significantly increase daily activity [27]. The mobility of the ankles, of the lower limb and the spine should be assessed before starting a training programme, because arthritis or deformities may mimic claudication or be a possible reason for pain during walking. Type, frequency, duration and intensity of exercise training Exercise training must be prescribed systematically. Training frequency should be 3 ( 6 ) /week and the duration of a training unit should be 30 min in the beginning and 60 min at the peak of the training programme. The training effect will disappear quickly if training is interrupted for more than one week. A recent study [28] compared 1, 2 and 3 or more training sessions per week in relation to the median change of absolute claudication distance in a randomised controlled trial. Two sessions per week were already shown to have the highest increase at 3 months (+273 m) and 12 months (+480 m) compared to one session (+205 m; +245 m) and three sessions (+245m; +425m), respectively. For the duration of training sessions per week, min/session revealed the highest increase in absolute claudication distance at 3 months (+270 m) and 12 months (+485 m) compared to one session (+230 m; +240 m) and three sessions (+290 m; +390 m), respectively. These results, although not confirmed by additional studies, would underline practice models with an average of 2 3 trainings sessions per week with a net exercise time of min per session. Overall, two different training regimens have proven to be efficient in daily training practise: interval and continuous training. Walking training at an intensity high enough to elicit symptoms associated with claudication seems to improve the pain free walking distance Cardiovascular Medicine 2012;15(3):

4 better (+350 m) than walking at an intensity below this limit (+105 m) [29]. Interval training may challenge the adaptive response to a higher degree than continuous training. However, patients are more compliant in the continuous mode training, because they usually try to avoid pain during exercise training. Thus, it might be appropriate to offer both options as shown in table 2. Treadmill walking programmes can be determined based on the test results. For example, 300 m pain free walking distance in constant load test at 3 km/h speed and 12% incline is equivalent to 5 km/h speed at 9% incline, assuming 2 km/h speed is equivalent to 3% incline. Exercise training should be held at 80% of the intensity in a treadmill test. At the onset of pain caused by claudication the patient should rest for 3 5 minutes. Then training should be continued in the same sequence until minutes duration is reached. If the patient does not experience any claudication pain within the first 10 min, treadmill incline can be increased by 1.5% until a 10% incline is reached. An incline above 10% is not tolerated very well by most patients. As an alternative, the treadmill speed can be increased incrementally by 0.5 km/h up to a maximum Table 1 Fontaine stages I to IV in PAD. I II IIa IIb III IV Symptom free Intermittent claudication Pain free walking distance >200 m Pain free walking distance <200 m Pain at rest Necrosis (gangrene) Table 2 Comparison of walking training in interval and continuous mode. Training mode Interval Continuous Aims Increase of maximal walking distance Increase of maximal walking distance Type Walking Walking Duration Start with 30 min, aim for 60 min Start with 30 min, aim for 60 min Frequency 3 ( 5) per week 3 ( 5) per week Intensity Remarks Above ischaemic threshold into claudication pain Compliance might be lower due to pain but is probably more efficient in increasing maximal walking distance. Accompanying stabilisation of trunk and leg musculature and increase in ankle flexibility is recommended. Postural control is important. Around 80% of velocity leading to claudication pain Accompanying stabilisation of trunk and leg musculature and increase in ankle flexibility is recommended. Postural control is important. speed of 6 km/h which is the usual peak walking speed in elderly people. For arm cranking exercise a typical training regimen may be as follows (adapted from [14]): total duration: 24 weeks, frequency: 2 3 /week, interval training with 2 minutes exercise at 50 U/min and 2 minutes rest in between, accumulating a total of 30 min exercise at a total training duration of 60 minutes. Increase every 2 3 weeks until 5 minutes exercise and 1 minute rest (total exercising time 50 minutes within 1 h training); initial intensity equivalent to 10 Watts under the individual maximum; adjustment every 3 weeks to changes in individual maximum. An absolute contraindication for walking exercise in PAD patients is claudication pain at rest with an ankle pressure of <50 mm Hg. Upper body exercise might be an option for these subjects. Supervised versus non-supervised training Supervised training programmes have a significant and clinically relevant better outcome with respect to maximal walking distance in patients with intermittent claudication. This is the result of a recent Cochrane review [30]. A total of 8 randomised controlled trials were included with more than 50% of the training session spent in a supervised exercise therapy programme at an average frequency of three training sessions per week. With a total of 319 men and women involved in mainly small trials of 20 to 59 participants, the advantage of supervised training reached 150 m in maximal walking distance compared to non-supervised after three months of training. The baseline pain free walking distance was 200 m and the maximal walking distance was around 300 m meaning that the increase had a clear benefit in daily live. This is a strong argument for employing professional expertise in the initial training phase. Secondary aims of training are gait control, improved flexibility of the lower limbs and strengthening of the trunk musculature. Moreover, training in a group increases the patient compliance to adhere to their exercise training. The positive results of a walking programme seen in PAD are clouded by the fact that roughly 30% of all patients are only able to participate in walking programmes. Frequent neurological and orthopaedic problems hamper participation or make it impossible. Thus, a good alternative to walking training seems to be the earlier mentioned arm cranking exercise. Exercise versus interventional therapy Comparison of exercise training with surgical re-canalisation does not show significant differences in maximal walking time (plus 150% compared to plus 173%) after months. The improvement was greatest in the combined group (plus 263%). Only the surgery Cardiovascular Medicine 2012;15(3):

5 Patients with diabetes have to control serum glucose levels directly before, 15 and 30 min after the beginning of exercise and 30 min post exercise in order to monitor a possible exercise-induced decrease in blood glucose levels. Several patients with diabetes experience reduced skin sensibility (diabetic neuropathy) and inspection of the feet before and after every training session helps to avoid skin ulcers as the healing process in diabetic patients is attenuated compared to non-diabetics. However, the inspection of the feet is recommended as a routine in all patients before and after the training session. After percutaneous transluminal intervention, the increased performance during walking exercise might cause higher demands on the myocardium and thus higher myocardial oxygen consumption. Since patients with PAD have coexistent coronary artery disease in 62 90% [40], relevant stenosis of coronary arteries might be present. Consequently, every patient with PAD should undergo an exercise ECG after intervention to exclude any significant coronary stenosis. In conclusion, exercise, especially walking exercise, has proven to be an inherent part of the treatment regimen in patients with PAD with an increase of maximal walking distance by around 150%. Strength traingroup showed an improvement in ankle-arm index. Two patients of the exercise group had to undergo surgical treatment because of severe ischaemia [31]. However, this single randomised controlled trial does not justify surgical re-canalisation in intermittent claudication because the risk by far outweighs the benefits. In contrast to the relative benign character of lower limb ischaemia, the risks associated with surgery in patients with peripheral arterial occlusive disease clearly favours other treatment options [32]. Angioplasty seems to be attractive in patients with PAD because of its immediate treatment effect on walking ability. Thus, patients undergoing angioplasty had a stronger increase in walking ability shortly after treatment, but tendentiously higher rates of intermittent claudication in the contralateral limb after 6 and 12 months [33]. This recent randomised controlled trial showed a remarkable increase in pain free walking distance at 12 months compared to baseline in the endovascular revascularisation group (82 m to 806 m) and exercise group (104 m to 943 m), with no significant difference between groups [33]. Another study showed slightly higher maximal walking time post angioplasty up to 6 months after intervention compared to the exercise group consistent with the above named study. However, at 12 months post intervention a progressive reduction of maximal walking distance was observed in patients undergoing angioplasty. Due to an increase of maximal walking time in the exercise group up to 12 months, maximal walking time in walking group was significantly higher in the exercise group than in the angioplasty group at this time point [34]. The long term patients with intermittent claudication treated with angioplasty had a lower pain-free walking distance after six years than patients with exercise treatment [34, 35]. In another randomised controlled trial comparing angioplasty with exercise training, only the invasive therapy group significantly improved maximum walking distance on the treadmill from 274 ± 172 m to 344 ± 169 m, while the exercise group did not (258 ± 142 to 247 ± 111 m). However, the compliance was low in the exercise group (49% after 1 year) [36] which might explain non-respondents. Thus, discrepancies still exist among study results. The CLEVER trial (Claudication: Exercise versus Endoluminal Revascularisation) was designed to compare medical therapy, stenting, and exercise training in patients with claudication and aortoiliac obstructive disease [37]. The six month outcome showed that supervised progressive intermittent claudication walking exercise three times weekly was superior in treadmill walking performance to stent revascularisation. However, patient-reported quality of life was better for stent revascularisation than for exercise, which again might be an argument for pain-free walking exercise. However, this assumption is rather speculative and warrants further study. Overall, the benefits of an increased walking distance can be seen in daily life. There are no reports about severe cardiovascular events during exercise training in PAD patients. Exercise versus medical treatment Due to the high risk factor burden in patients with PAD, multiple drug treatment regimens are very common in patients with PAD. The combination of aspirin and exercise has been shown to be superior to each treatment option alone with respect to maximum walking distance [38]. However, nearly every patient has anti-platelet therapy as a standard therapy, mostly aspirin. Aspirin alone has only a marginal effect far away from the potential of exercise therapy. Thus, aspirin cannot be assumed as a substitute for exercise therapy. In addition, current clinical practice guidelines suggest that cilostazol improves treadmill walking performance by approximately 40% to 60% and statin medication may also improve treadmill walking performance in patients with PAD [5]. In one study walking training was compared with administration of pentoxyphyllin. After 13 weeks of treatment the maximum walking time improved by 62% in the exercise group and by 88% in the pentoxyphyllin group [39]. The improvements seen by exercise training were far below the average seen in more structured exercise training groups. Pitfalls of exercise training Cardiovascular Medicine 2012;15(3):

6 ing has a marginal or no effect on walking distance. Arm cranking may turn out to be an alternative to walking in patients unable or less able to walk because of orthopaedic problems. At least in the beginning, exercise training should be implemented in a structured and supervised programme with a frequency of 2 3 times per week and duration of 45 to 60 min per session to accomplish a clinically relevant improvement of walking distance and quality of life. Based on a lecture at the annual meeting of the Swiss Society of Cardiology, Swiss Society of Sports Medicine, Swiss Society of Paediatric Cardiology, Swiss Society of Thoracic and Cardiovascular Surgery and the Swiss Society of Hypertension; June 8 10, References 1 Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis. 2004;172(1): Marso SP, Hiatt WR. Peripheral arterial disease in patients with diabetes. 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