Physical training for intermittent claudication: a comparison of structured rehabilitation versus homebased

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1 Physical training for intermittent claudication: a comparison of structured rehabilitation versus homebased training Steve Degischer a, Karl-Heinz Labs a, Jacques Hochstrasser b, Markus Aschwanden a, Martin Tschoepl a and Kurt A Jaeger a Abstract: In a non-randomized, open-label study results after a structured institution-based peripheral arterial occlusive disease (PAD) rehabilitation program were compared with the results of training at home. Three groups were compared: group 1 (n = 19) PAD rehabilitation; group 2 (n = 19) PAD rehabilitation + clopidogrel 75 mg once daily; group 3 (n = 21) home-based training. The training period was 3 months for all groups, which was followed by a 3-month observation phase (without prescribed training). The rehabilitation program consisted of 3 training hours per week. Background variables, demographics, and baseline claudication distances were comparable between groups. After 3 months of training the absolute claudication distances (ACD) improved by 82.7%, 131.4%, and 5.4% for groups 1, 2 and 3. The initial claudication distances (ICD) changed by 163.8%, 200.6%, and 44.4%, respectively. All changes, except the ACD result for group 3, were statistically signi cant (p # 0.05). Structured training groups (1 and 2) performed signi cantly better than group 3 (p # 0.05). When results from groups 1 and 2 were pooled, ACDs changed from to m, D m [95% CI m]; p # ICDs improved from m to m, D m [95% CI m]; p # The difference between the pooled mean results of the structured training groups and the results of group 3 amounted to m [95% CI m] and m [95% CI m], for ACD and ICD, respectively. Structured, supervised PAD rehabilitation is a highly ef cacious treatment for intermittent claudication and may be regarded as the present gold standard among conservative treatment options. Key words: claudication; exercise; home-based training; peripheral arterial disease; structured training Introduction Lower extremity peripheral arterial occlusive disease (PAD) is a common disorder affecting 10 20% of an elderly Western population with an annual incidence of 6 8%. 1,2 More than 50% of patients with PAD are asymptomatic, 30 40% have intermittent claudication and only a few suffer from critical limb ischemia. 3 However, all PAD patients have a substantially elevated risk for cardiovascular events, which can be six times as high as in the general population. 4 8 These gures demonstrate not only the medical but also the socio-economic importance of this disease for Western societies. 8 Speci c treatment modalities for intermittent claudication include various forms of physical training, drug therapy, vascular surgery and catheter-based interventions. Although the ef cacy of structured, supervised rehabilitation programs for peripheral arterial occlusive disease (PAD) has been documented by several meta-analyses, the prescription of these programs is still hampered by the low numbers of centers offering this service. Home-based physical training provides a cheap alternative, if ef cacious, without requiring the infrastructure and the logistics of structured rehabilitation programs. However, since the results of single trials vary widely and no meta-analysis of published results is available, a nal conclusion on the clinical ef cacy of this training form is dif cult. There are only a few papers available on the direct comparison of structured rehabilitation and home-based training. This information, however, is essential when deciding on the appropriateness of running or setting up structured programs. Thus, it was the aim of this study to directly compare the results of these two training forms and to evaluate whether an improvement in physical capacity can be maintained over time. a Department of Angiology and b the Institute for Medical Physiotherapy, University of Basel Medical School, Basel, Switzerland Address for correspondence: Kurt A Jaeger, Department of Angiology, University of Basel Medical School, Petersgraben 4, CH-4031 Basel, Switzerland. Tel: ; Fax: ; kjaeger@uhbs.ch Ó Arnold 2002 Materials and methods Patient sample Consecutive outpatients suffering from intermittent claudication with subjective claudication distances between / x02vm432oa

2 110 S Degischer et al and 500 m were recruited. The diagnosis of PAD was established through the patient s history and a physical examination. The diagnosis was then con rmed by an ankle/brachial pressure index # 0.95 at rest. Stable intermittent claudication had to be present for $ 3 months. All patients had to be able to walk on a treadmill. Patients with orthopedic, cardiac, pulmonary or an other concomitant disease interfering with or preventing steady walking on a treadmill, patients with a pronounced peripheral neuropathy, patients with Buerger s disease, patients who had undergone vascular reconstruction within the last 3 months and patients with a consuming disease and a life expectancy, 2 years were excluded from the study. No patient was on vasoactive drugs for the treatment of PAD. Study design Non-randomized, open-label, parallel group comparison of structured, supervised PAD rehabilitation versus non-structured, home-based physical training. All patients were asked whether they would be prepared to participate in a rehabilitation program and were then allocated to three training groups. Group 1: institution-based PAD rehabilitation; group 2: institution-based rehabilitation + clopidogrel 75 mg once daily; group 3: daily home-based physical training. The rationale for forming two structured rehabilitation groups and for using clopidogrel was to gather some pilot data on the potential effects of the drug on walking capacity which could be useful for hypothesis generation. All patients were free to continue their medical care regimens if they did not interfere with the exclusion criteria. Patients in group 2 were taken off anti-aggregants other than clopidogrel. The total study duration was 6 months divided in a 3- month active training period and a 3-month follow-up period without recommended training. All patients underwent a full clinical and vascular examination at baseline and at 3 and 6 months. Compliance (pill-count) and safety of group 2 patients (clopidogrel) was evaluated on a weekly basis during the active training phase. Patients in group 3 were contacted by phone once weekly in order to offer advice in case training-related problems should occur; patients were requested to document the time and the duration of daily exercise in a logbook provided by the University of Basel. Clinical and vascular examinations The patients medical histories, including cardiovascular risk factors, concomitant diseases, present medical therapy, and previous vascular interventions, were assessed by questionnaire. The clinical examination focused on vital signs and the cardiovascular, pulmonary, musculoskeletal, and neurological systems. The vascular examination consisted of a full vascular status including pulse palpation and auscultation, multisegmental pulse volume recording, the assessment of bilateral peripheral pressures at rest and 1 min after exhaustive exercise on a treadmill, as well as duplex sonography of the entire peripheral vascular tree, to verify and to objectively document vascular lesions. Also, the post-exercise pressure recovery time was documented with the help of repeated measurements in 2-min intervals. In patients with non-compressible arterial walls, the toe pressures were used instead of the ankle pressures. The hemodynamic assessment was preceded by a resting period of $ 10 min with patients in a supine position. Outcome measures Primary study endpoint: change in absolute claudication distance (ACD) at 3 months. ACD, i.e. the walking distance until pain forced cessation of exercise, was assessed by a graded treadmill protocol with a xed speed of 2.0 mph (3.2 km/h) and a grade starting with 0%, which then was increased in 2% increments every 2 min (Woodway treadmill, Weil, Germany). Treadmill testing was discontinued after a grade of 20% and a distance m was reached. The baseline walking test was preceded by at least two treadmill familiarization periods; handrail support was only allowed for brief moments to maintain balance. Secondary study endpoints: change in initial claudication distance (ICD) at 3 months, i.e. walking distance until rst ischemic pain occurred, and change in ICD and ACD at 6 months, change in peripheral ankle or toe pressures, change in ankle/brachial or toe/brachial pressure indices (ABI, TBI), change in peripheral pressure recovery time. PAD rehabilitation training program (groups 1 and 2) The PAD rehabilitation program was performed as a joint program between the department of angiology and the institute for medical physiotherapy of the University of Basel. The program consisted of three 1-h training sessions per week. Each session was composed of a general 5-minute warm-up phase, several training periods on the treadmill, and a cool-down phase. Groups of two to four patients were trained together under the supervision of a physiotherapist or a vascular physician. The patients were requested to walk up to approximately 60% of their maximum walking capacity (60% ACD), as tested at baseline, and then to pause for at least 5 min or until the ischemic pain had disappeared. In order to coordinate the training between the participants of a training group, i.e. to warrant that all patients were walking and pausing in parallel, the treadmill settings were individually adjusted for each patient once in a week with the goal of reaching 60% ACD within approximately 7 10 min. Furthermore, to warrant that identical muscle groups were exercised in all patients, the individual adjustment of the grade was limited to a range of 8 12%; thus, the goal to reach 60% ACD within the given time limit was mainly achieved through varying the walking speed. Non-structured training program (group 3) Patients participating in the non-structured, home-based training program were intensively informed at baseline about PAD and atherosclerotic risk, the importance of a risk factor modi cation, and the presently known results and the expected advantages of physical training. The patients were advised to walk for at least 1 h each day on an outdoor track, wearing rm footware. As in groups 1 and 2, the patients of group 3 were advised to walk until 60% of the maximum claudication pain occurred, then to stop and to pause until total disappearance of claudication pain before resuming the training. Statistics The objective for this study was to describe the maximum possible improvement in the primary endpoint. Because of the objective a per protocol (PP) rather than an intention-

3 Physical training for intermittent claudication 111 to-treat analysis was used; the PP population being de ned as those patients who completed the 3-month active training period. The Wilcoxon signed rank test was used for the description of the intra-group changes of the claudication distances. Inter-group differences were analysed by using the Mann Whitney test. Groups were compared by using the Kruskal Wallis test and Fisher s exact test. Regression modeling and ANCOVA or MANCOVA statistics were used to study the effect of patient characteristics on the study outcome. Effect sizes (ES) were calculated following the equation: ES * (post-test distance - pretest distance)/sd. The variance of the change score was not taken from the data but calculated based on an assumed correlation of 0.5 between pre-training and post-training values. 1 8 This approach is classically applied when calculating ES for published results reporting mean pre-treatment and post-treatment data, but no individual patient data; thus, the variance of the change score is unknown and must be estimated. This approach was used by Gardner and Poehlman 1 1 for a meta-analysis. It was intended to compare the ES of this study with ES as published by Gardner. Since the estimation of the SD of the change score and its direct calculation from the data leads to different ES, the estimation method was used in this analysis. Ethical and legal aspects The study protocol was reviewed and approved by the Institutional Review Board of the University of Basel Medical School (Ethisches Komitte beider Basel). Written informed consent was obtained from all patients before inclusion into the study. Prior to this, all patients were fully informed about the clinical trial, the procedures and the risks. All patients were free to discontinue their study participation at any time. Results General In total, 69 patients were enrolled but 10 patients (group 1: n = 7; group 2: n = 1; group 3: n = 2) did not complete the 3-month training phase for the following reasons: concomitantly existing coronary heart disease limiting exercise tolerance (n = 3: one patient from each group); deterioration of PAD (n = 1; group 1); development of a venous ulcer (n = 1; group 1); patient s wish (n = 2; group 1); and three patients died, one from an acute myocardial infarction unrelated to training (group 1), one from pulmonary embolism (group 3), and one from a previous unknown malignancy (group 1). Thus, the PP population consisted of 59 patients (group 1: n = 19; group 2: n = 19; group 3: n = 21). Data from all 59 patients were also available for the follow-up visit at 6 months. The background characteristics of the patient sample are summarized in Table 1. No signi cant differences were seen between the three groups regarding demographic data, the risk factor pattern, and PAD characteristics except for the ABI at rest (group 2 vs group 3); this difference, however, was not considered clinically relevant for the purpose of this trial. The low prevalence of diabetes mellitus is explained by the exclusion criterion diabetic neuropathy. Compliance to physical training Group 1 Two patients missed $ 6 (out of 36) training sessions; after intense discussions these patients discontinued the trial on own wish and were not considered for the analysis (see above). Four patients (21.0%) missed, 6 training sessions for various personal reasons. Group 2 None of the patients missed $ 6 training sessions; seven patients (36.8%) missed, 6 training sessions for various personal reasons. Group 3 The analysis of compliance was based on logbook entries and the weekly telephone interviews. No patient omitted the training for $ 14 days of the active training period; ve patients (23.8%) were non-compliant for. 7 days but # 14 days; seven patients (33.3%) were non-compliant for # 7 days during the training period of 3 months. Claudication distances The development of the claudication distances over time is given in Table 2. At baseline both ICDs and ACDs were comparable between the three groups. ACD results At 3 months the ACD (the primary endpoint) signi cantly increased for the two PAD rehabilitation groups but remained statistically unchanged for home-based training (Table 2). The percentage improvement amounted to 82.7%, 131.4% and 5.4% for groups 1, 2, and 3, respectively. At 6 months the ACDs declined numerically but were statistically not different from the 3-month values. Results for groups 1 and 2 were still signi cantly different from baseline values. Between groups (i.e. between groups 1 and 2) there was no statistical difference, either at 3 or at 6 months. However, both structured training groups performed signi cantly better than group 3 (group 1 vs 3, p = 0.04; group 2 vs 3, p = 0.003; at 6 months). ICD results At 3 months the ICDs increased signi cantly in all three training groups (Table 2). The percentage change amounted to 163.8%, 200.6% and 44.4% for groups 1, 2, and 3. At 6 months the ICDs decreased numerically for groups 1 and 2, but increased slightly for group 3. At 6 months the results of all three groups were still signi cantly superior to baseline values but not different from the 3 months results (Table 2). The between-group comparison revealed no statistical differences regarding the results of groups 1 and 2, but both performed signi cantly better than group 3 (group 1 vs 3, p = 0.02/0.05; group 2 vs 3, p = 0.01/0.02 at 3 months/6 months, respectively). Pooled analysis Tables 1 and 2 show that there were no statistically signi - cant differences between both structured rehabilitation groups regarding their background characteristics and demographic data. Also, despite some numerical differ-

4 112 S Degischer et al Table 1 Demographics of the patient sample. x Supervised Supervised training training + Home clopidogrel training Total 2 Number of patients ns Gender males ns females ns Age (years) mean (± SD) 69.2 ± ± ± ± 9.7 ns range Weight (kg) mean weight (± SD) 73.2 ± ± ± ± 14.8 ns weight range mean BMI (± SD) 26.0 ± ± ± ± 3.9 ns BMI range Risk factors hypertension ns diabetes mellitus ns hyperlipidemia ns current smoker ns non-current smoker ns Super cial femoral artery ns lesions (%) ABI at rest mean (± SD) 0.55 ± ± ± ± 0.11 p = 0.04 a range Ankle pressure drop after exercise mean (± SD) (mmhg) 53.3 ± ± ± ± 18.9 ns range (mmhg) Pressure recovery time after exercise mean (± SD) (s) 685 ± ± ± ± 346 ns range (s) a Mann Whitney test group 2 vs 3. Table 2 Development of claudication distances over time. Baseline 3 months 6 months Group 1 ACD (± SD) ± ± 439.8* ± 397.2* ICD (± SD) ± ± 361.6* ± 280.4* Group 2 ACD (± SD) ± ± 479.3* ± 430.0* ICD (± SD) ± ± 293.9* ± 248.3* Group 3 ACD (± SD) ± ± ± ICD (± SD) ± ± 134.3* ± 140.5* *p < 0.05 (vs baseline). ICDs and ACDs given in meters. ACD, absolute claudication distance; ICD, initial claudication distance. ences, the development of the claudication distances over time were not statistically different between groups 1 and 2. Given these facts it was justi ed to pool the data from groups 1 and 2 in order to improve the generalizability of this study. The results are summarized in Table 3. A 3-month structured, supervised PAD rehabilitation program led to a change in ACD of m within the 95% con dence limits of m. For ICD the change score at 3 months was m [95% CI m]. These changes were equivalent to an improvement in claudication distances of 108% (ACD) and 182% (ICD). When the pooled data from groups 1 and 2 were compared with group 3, the difference of the 3-month mean improvement amounted to m

5 Physical training for intermittent claudication 113 Table 3 Pooled results from groups 1 and 2. Statistical comparison of 3-month (6-month) data versus baseline values. Baseline 3 months 6 months ACD (± SD) ± ± * ± * ICD (± SD) ± ± * ± * *p < 0.05 (vs baseline). Data given in meters. ACD, absolute claudication distance; ICD, initial claudication distance. [95% CI m] for ACD and m [95% CI m] for ICD, respectively. Effect sizes Effect sizes amounted to (ACD) and (ICD) for the pooled results of structured training and 0.53 (ACD) and 3.68 (ICD) for home-based training. Result categorization The 3-month change scores from the pooled groups 1 and 2 (rehabilitation group) and from group 3 (patients training at home) were categorized into no change or deterioration and improvements < 50%, 50 99%, $ 100%, and $ 200%. Results are given in Figures 1a and 1b. If response to training were de ned by an improvement of the ICD $ 100%, the response rate from PAD rehabilitation would be 63% in comparison with 29% from home-based training. No change or even deterioration was found in 3% of the rehabilitation patients but in 29% of home trainers. Figure 1 (a) Proportional ACD response rates after 3 months of supervised or home-based training; (b) proportional ICD response rates after 3 months of supervised or home-based training. The contribution of the original groups 1 and 2 to the results of the pooled rehabilitation group was similar for each category, except for the category ACD improvement > 200%, where all but one patient came from the original group 2. Responder de nition With the help of multiple regression models and ANCOVA and MANCOVA statistics it was intended to predict training response using the clinical information, the information on training compliance, and all sets of background variables available. There was no usable relationship between any of the independent variables and outcome. Ankle pressure, ABI, and pressure recovery time after exercise did not change over time. Safety aspects Patients in group 2 received clopidogrel (Plavix Ò ) for 6 months. In two patients the drug was discontinued; in one because of pruritus (week 13), and in another one because of blood on stools (week 24). All adverse events disappeared after the discontinuation of the drug. Four patients (21%) stopped taking the drug temporarily for less than 10 days for various reasons but not because of clearly or potentially related adverse events. Clopidogrel was well tolerated by all remaining patients. Discussion In agreement with the literature this study demonstrates that supervised physical training led to a highly signi cant and clinically relevant improvement of PAD patients functional capacities, whereas the results from home-based training did not meet the expectations. The value of structured PAD rehabilitation programs As shown by Gardner and Poehlman, 1 1 the magnitude of training effects depends on variables such as the training frequency and intensity, the overall duration of the training program, and the endpoint to which the patients walk before pausing. Since these variables vary between programs published to date, the results vary accordingly. If effect sizes are used as summary measures of a training response, they range between approximately 3.5 and 10.5 for training effects on ICD and 3.5 and 13.5 for ACD. 1 1 In this study the active training duration was relatively short (3 months), the intensity moderate (3 h per week), and the patients stopped exercising when they reached approximately 60% of the maximum pain intensity, rather than walking to the absolute claudication distance. Still, the effect sizes were 15.1 and 17.7 for ACD and ICD and thus superior to those published in the literature. A potential explanation for the excellent results would be that training was performed exclusively on treadmills, with training intensities ranging between 3.9 and 5.8 metabolic equivalents (METs). The question of whether or not it may be useful to force the patients towards ACD before pausing is answered contradictorily. From the results of multiple regression analyses, Gardner and Poehlman conclude that the claudication pain endpoint may be one of the most important parameters (the further patients walk towards

6 114 S Degischer et al ACD, the better the training result may be) 1 1 ; on the other hand, there is evidence that walking too far into ischemia may lead to neutrophil activation and endothelial damage. 1 9 Further trials are required to nally answer this question. In a clinical trial setting a highly standardized method such as treadmill testing is required to assess a patient s exercise capacity. However, since treadmill workloads are higher than workloads required for level ground walking at normal pace, treadmill results underestimate the absolute bene t a patient will have from vascular rehabilitation. If the change scores resulting from our program were translated (MET-normalized) 2 0 into walking under daily life conditions (de ned as level ground walking at 2 mph = 3.2 km/h), the training-related improvements of ICD and ACD were m and m rather than 318 m and 533 m (Table 3), clearly underlining the clinical relevance of this study s results. The major drawbacks with PAD rehabilitation programs are the still limited number of centers offering this service and the high level of self-responsibility and motivation requested from the patients. As shown by de la Haye et al, 2 1 approximately half of those patients who theoretically qualify for a rehabilitation program would not take advantage of it for logistic and motivational reasons. On the other hand, as shown by this trial, those who agree to the program clearly bene t in terms of a training-related improvement in mobility. There is evidence from the literature that with a discontinuation of active training the walking capacity may again decline. 2 2,2 3 In this context it is interesting to note that the 3-month results could be maintained over time, although training was not of cially recommended for the observation phase of this trial. However, since the activity level of the patients was not objecti ed for this period of time, the explanation for this nding remains speculative. Value of non-structured, home-based training Since no meta-analysis on the overall response to homebased physical training is available, results from single studies are more dif cult to generalize. The motivation of the individual patient seems to be key to a potential success. This study clearly indicates that the maximum effect (in individual patients) does not differ between training forms. However, the response rates differ substantially with twothirds of patients improving their ICD by $ 100% with a structured training, but only one-third with training at home. Additionally, nearly all patients came forward with some kind of response to rehabilitation, whereas about 30% showed no response or even deterioration with home-based training. In agreement with the above, ICD effect sizes in this trial dropped from 17.7 to 3.7 with structured and home-based training, respectively. The difference between the results of structured rehabilitation and home-based training may be potentially explained as an effect of non-randomization and existing confounding factors. There were no differences regarding baseline patient characteristics or the compliance to the training program, and statistical analysis did not give evidence that differences in training frequency might explain the variance. However, from the fact that exercise training was documented in a logbook it does not automatically follow that the training was performed with a high motivation or that home training intensity was appropriate. The fact that individual home training patients achieved an outcome comparable to that of supervised rehabilitation together with the fact that response could not be predicted through any patient characteristic would support the idea that a difference in motivation may indeed be the explanation for the differences in results. The proof of this hypothesis, however, would include the use of psychometric testing, which was out of the scope of this study. The use of clopidogrel Clopidogrel was used as a potent platelet inhibitor in approximately one-third of patients. The drug was well tolerated and safe in this high-risk population. An effect on morbidity and mortality, as suggested by the results of previous large-scale trials, 2 4 may only be seen at long-term follow-up. It was interesting to note that the majority of patients, showing best ACD responses (> 200% improvement) were those exposed to clopidogrel. The patient sample was far too small to draw any conclusions on the effects of clopidogrel on the claudication distance. However, further efforts seem to be justi ed to explore the potential of clopidogrel on the walking capacity of PAD patients. Limitations and strengths of the study There are two major limitations related to the design of this study. First, the patients were open to choose the treatment arm, rather than being randomized. Although all background variables were similarly distributed between the groups, a selection bias cannot be fully excluded. Secondly, since all patients who decided on a structured rehabilitation were fully aware about all problems and obligations but still accepted this choice, a positive selection must be postulated (Horton effect). The strengths of this study include the fact that the training form and the test methodology were strictly standardized and that this study is one of the largest trials on the comparison of structured and non-structured physical training available at present. In addition, this trial represents one of the few studies reporting results not only after training but also after a follow-up period. Conclusions Appropriate structured, supervised PAD rehabilitation programs will lead to a statistically signi cant and clinically relevant improvement in physical ability with a response rate of approximately 60%. The option of PAD rehabilitation is hampered by lacking facilities and the high level of self-responsibility and engagement required from the patients. The overall results and the response rates from homebased training are less satisfactory. Although in individual patients the improvement in walking capacity may be similar to what can be expected from PAD rehabilitation, lack of or inappropriate motivation of the patients seems to be a key problem. Acknowledgement The authors gratefully acknowledge a non-restricted educational grant from Sano -Synthelabo Switzerland to support this study.

7 Physical training for intermittent claudication 115 References 1 Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a de ned population. Circulation 1985; 71: Kannel WB, McGee DL. Update on some epidemiological features on intermittent claudication: The Framingham Study. J Am Geriatr Soc 1985; 33: Hiatt WR. Current and future drug therapies for claudication. Vasc Med 1997; 2: Criqui MH, Langer RD, Fronek A et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: Sikkink CJ, van Asten WN, van t Hof MA, van Langen H, van der Vliet JA. Decreased ankle/brachial indices in relation to morbidity and mortality in patients with peripheral arterial disease. Vasc Med 1997; 2: Criqui MH, Denenberg JO. The generalized nature of atherosclerosis: how peripheral arterial disease may predict adverse events from coronary artery disease. Vasc Med 1998; 3: Brandsma JW, Robeer BG, van den Heuvel S, Smit B, Wittens CH, Oostendorp RA. The effect of exercises on walking distance of patients with intermittent claudication: a study of randomized clinical trials. Phys Ther 1998; 78: Coffman JD. Intermittent claudication: not so benign. Am Heart J 1986; 112: Girolami B, Bernardi E, Prins MH et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: a meta-analysis. Arch Intern Med 1999; 159: Cachovan M. Methoden und Resultate eines kontrollierten Gehtrainings bei Patienten mit peripherer arterieller Verschlusskrankheit. Z Arztl Fortbild Qualitatssich 1999; 93: Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA 1995; 274: Ernst E, Fialka V. A review of the clinical effectiveness of exercise therapy for intermittent claudication. Arch Intern Med 1993; 153: Radack K, Wyderski RJ. Conservative management of intermittent claudication. Ann Intern Med 1990; 113: Regensteiner JG, Meyer TJ, Krupski WC, Cranford LS, Hiatt WR. Hospital vs home-based exercise rehabilitation for patients with peripheral arterial occlusive disease. Angiology 1997; 48: Neilsen SL, Larsen B, Prahl M et al. Hospital-traening contra hjemmetraening af patienter med claudicatio intermittens. Ugesk Laeger 1977; 139: Jonason TI, Ringqvist A, Oman-Rydberg A. Home-training of patients with intermittent claudication. Scand J Rehabil Med 1981; 13: Larsen OA, Lassen NA. Effect of daily muscular exercise in patients with intermittent claudication. Lancet 1966; ii: Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 1992; 45: Nawaz S, Walker RD, Wilkinson CH, Saxton JM, Pockley AG, Woo RF. The in ammatory response to upper and lower limb exercise and the effects of exercise training in patients with claudication. J Vasc Surg 2001; 33: Degischer S, Labs KH, Aschwanden M, Tschöpl M, Jaeger KA. Reproducibility of constant-load treadmill testing with various treadmill protocols and predictability of treadmill test results in patients with intermittent claudication. J Vasc Surg 2002; 36: De la Haye R, Diehm C, Blume J et al. Eine epidemiologische Untersuchung zur Einsetzbarkeit und zu den Grenzen der physikalischen Therapie/Bewegungstherapie bei der arteriellen Verschlusskrankheit im Stadium II nach Fontaine. VASA 1992; 38 (suppl): Weidinger P, Bachl N. Fünf Jahre Wiener Erfahrungen mit ambulanten Claudicatio Gruppen. In: Diehm C, Gerlach HE (eds). Bewegungstherapie bei peripheren arteriellen Durchblutungsstörungen. Munich: Zuckschwerdt, 1987: Weidinger P. Ergebnisse eines Langzeit-Gehtrainings bei arteriellen gefässkranken Patienten. In: Denk H (ed). Arterielle Durchblutungsstörungen der unteren Extremitäten: Grenzzonen der Therapieentscheidung. Bad Oeynhausen: TM Verlag, 1982: CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: