Supervised exercise therapy for intermittent claudication: current status and future perspectives

Abstract

Intermittent claudication (IC) has a high prevalence in the older population and is closely associated with cardiovascular and cerebrovascular disease. High mortality rates are reported due to ongoing atherosclerotic disease. Because of these serious health risks, treatment of IC should address reduction of cardiovascular events (and related morbidity/mortality) and improvement of the poor health-related quality of life (QoL) and functional capacity. In several randomized clinical trials and systematic reviews, supervised exercise therapy (SET) is compared with non-supervised exercise, usual care, placebo, walking advice or vascular interventions. The current evidence supports SET as the primary treatment for IC. SET improves maximum walking distance and health-related QoL with a marginal risk of co-morbidity or mortality. This is also illustrated in contemporary international guidelines. Community-based SET appears to be at least as efficacious as programs provided in a clinical setting. In the Netherlands, a national integrated care network (ClaudicatioNet) providing specialized care for patients with IC is currently being implemented. Besides providing a standardized form of SET, the specialized physical therapists stimulate medication compliance and perform lifestyle coaching. Future research should focus on the influence of co-morbidities on prognosis and effect of SET outcome and the potential beneficial effects of SET combined with a vascular intervention.

Keywords

intermittent claudication cardiovascular risk management supervised exercise therapy ClaudicatioNet

Introduction

The atherosclerotic process of progressive narrowing and hardening of arteries can occur in every artery in the human body; however, it mainly affects the coronary, cerebral and peripheral arteries of the lower extremities.^1,2 Lower-extremity peripheral arterial occlusive disease (PAOD) has an estimated prevalence of between 1.6 and 4.5% in the general population and rises to 19.1% in the Dutch population, age 55 years and older.^3–6 The primary sites of involvement of PAOD are the femoral and popliteal arteries in 80–90%, the tibial and peroneal arteries in 40–50%, and the aorta and iliac arteries in 30%.⁷ The manifestation of PAOD ranges from no symptoms to tissue loss that eventually requires amputation of the affected limb. The majority of patients with PAOD have asymptomatic or atypical disease.²

Intermittent claudication (IC), the mildest symptomatic manifestation of PAOD, is prevalent in the general population of approximately 3% in patients aged 40, to 6% in patients aged 60 years. An even higher prevalence was found in the elderly.² In women, the incidence rates of IC are approximately 50% lower than in men.^8,9 In IC, progressive atherosclerotic narrowing results in decreased oxygen availability in the periphery of the buttocks and/or lower extremities. During exercise, the lack of oxygen causes an anaerobic state in which lactic acid and other metabolites are formed. This causes cramping or aching pain in the buttock, hip, thigh, calf, or in rare occasions, the foot, forcing the patient to pause. In rest, the oxygen debt can be redeemed and symptoms are relieved. However, when PAOD progresses, the pain becomes constant and the increasing oxygen debt can no longer be redeemed. This condition, called critical limb ischemia, can eventually progress to the final stage of tissue loss. Although amputation is the greatest fear for patients with IC, the prognosis of the affected limb is favorable. After a five-year follow-up period, 28.8% of all patients with IC still have claudication symptoms and only 1.6–4.1% need a limb amputation.^8,9

PAOD and IC are strong predictors for coinciding atherosclerotic disease and related mortality. The prevalence of cerebrovascular disease in patients with IC is about 25–50%.¹⁰ The 10-year mortality rate due to cardiovascular disease is 62% for men with PAOD compared with 17% in the population of men without PAOD. For women with PAOD, the 10-year mortality rate is 33% compared with 12% without PAOD.¹¹ In a subgroup of patients with severe and symptomatic PAOD, a 15-fold increase in mortality rate was found.¹¹

For IC, a five-year mortality rate of 19.2% is described, of which 70% is due to cardiovascular causes. Non-fatal cardiovascular events (e.g. myocardial infarction, stroke) in patients with IC are found in 29% at five years of follow-up.⁹ In comparison with patients with IC, subjects with asymptomatic PAOD appear to have the same increased risk of cardiovascular events and death.⁹ Nonetheless, for those afflicted, IC has a negative impact on walking ability and health-related quality of life (QoL).^12,13

Because of these serious health risks, treatment of IC (and PAOD in general) should address two important targets: reduction of cardiovascular events (and related morbidity and mortality) and improvement of the poor health-related QoL and functional capacity. To manage these targets, all patients with IC should receive a multicomponent therapy consisting of cardiovascular risk modifications including lifestyle coaching and supervised exercise therapy (SET). A (minimal) invasive vascular intervention should be performed only when indicated. Since there is no outcome measurement available that truly compares the benefit of different treatment strategies (i.e. SET versus vascular interventions versus a combination of both), clear criteria to identify patients who will benefit the most from a certain intervention are not available. Existing outcome measurements like walking distances, exercise tests, health-related QoL questionnaires and arterial patency each have their flaws and are not ideally suitable to compare the contribution of the different treatments to the ultimate goal of treatment: regaining physical activity.

In this paper, we aim to provide an up-to-date overview of the current literature regarding SET as an integrated part of the treatment for patients with IC. In addition, we will address some future perspectives and trends in the management of IC that are linked to this multicomponent strategy.

Current status

General management of IC

The development of IC is accelerated by the same cardiovascular risk factors as known for other expressions of atherosclerotic disease (i.e. coronary heart disease and cerebrovascular disease). Treatment of IC should therefore consist of a multicomponent therapy of cardiovascular risk modification (1), including lifestyle coaching (2) and symptomatic treatment (3). The first two components aim to prevent cardiovascular events (myocardial infarction, stroke) and related morbidity and mortality. Recommendations from numerous consensus documents, including the American College of Cardiology/American Heart Association (ACC/AHA) and Trans-Atlantic Inter-Society Consensus on Management of Peripheral Arterial Disease (TASC II) guidelines on PAOD, identify patients with PAOD as a high-risk population who require intensive risk factor modification.^1,2 The modifiable risk factors for atherosclerosis are smoking, hypertension, diabetes mellitus, hyperlipidemia and obesity.¹⁴

International guidelines support the aggressive treatment of high blood pressure in patients with PAOD.^15,16 In this high-risk group, the current recommendation is a goal of 140/90 mmHg, or even 130/80 mmHg if the patient also has diabetes or renal insufficiency. In PAOD, thiazides and angiotensin-converting enzyme inhibitors should be considered as initial blood-pressure-lowering drugs to reduce the risk of cardiovascular events. Beta-adrenergic blocking drugs have been discouraged in PAOD because of the possibility of worsening claudication symptoms. In a Cochrane review, there was no supporting evidence that beta-blockers adversely affect walking distance in people with IC.¹⁷ However, due to the lack of large published trials, beta-blockers should be used with caution, but are not contraindicated in PAOD.

Diabetes increases the risk of PAOD approximately three- to four-fold, and the risk of claudication two-fold. Diabetes is also associated with peripheral neuropathy, which could lead to an increased risk of foot ulcers and foot infections. In recent years, there has been much discussion about the optimal treatment strategy (aggressive or standard glucose-lowering therapy) of type 2 diabetes mellitus. In a meta-analysis, an intensive glucose-lowering regimen (glycated hemoglobin level below 6.0%) was compared with standard therapy (targeted a level of 7.0–7.9%) in type 2 diabetes mellitus. Overall, intensive therapy significantly reduced coronary events without a significant effect on events of stroke or all-cause mortality.¹⁸ However, aggressive control of blood glucose levels cannot be recommended after publication of the long-term results of intensive therapy. The results described a significantly reduced non-fatal myocardial infarction risk but an increased five-year all-cause mortality rate (hazard ratio 1.21; 95% CI 1.02–1.44) related with aggressive glucose lowering.¹⁹

In case of hyperlipidemia, dietary modification should be the initial intervention to control abnormal lipid levels. The Heart Protection Study demonstrated the benefits of cholesterol-lowering statin therapy in 6.748 patients with peripheral arterial disease (PAD) and 13.788 other high-risk participants, regardless of their presenting cholesterol levels.²⁰ Allocation to 40 mg simvastatin daily reduced the rate of the first major vascular events by about one-quarter, and that of peripheral vascular events by about one-sixth, with large absolute benefits seen in participants with PAD because of their high vascular risk. Consequently, according to this study, statin therapy should be considered for all patients with PAOD. In contrast, the older ACC/AHA guidelines recommend achieving a low-density lipoprotein (LDL) cholesterol level <2.59 mmol/L (<100 mg/dL) in all patients with PAOD. In patients with PAOD and a history of other vascular disease (i.e. coronary heart disease and cerebrovascular disease), it is reasonable to lower LDL cholesterol levels to 1.81 mmol/L (70 mg/dL).¹ Statins should be the primary lipid-lowering agents to lower LDL cholesterol levels.

Blood homocysteine levels are positively associated with cardiovascular disease, but it is uncertain as to whether the association is causal. Studies investigating the effects of folic acid supplementation on major vascular events in patients with peripheral arterial disease are lacking. However, in a randomized clinical trial (RCT), including 12.064 survivors of myocardial infarction, long-term reductions in blood homocysteine levels with folic acid and vitamin B₁₂ supplementation did not lead to a reduction of cardiovascular events and therefore seems not indicated.²¹

Antiplatelet therapy reduces major vascular events (vascular death, non-fatal myocardial infarction and non-fatal stroke) in patients with PAOD by 23%.²² Therefore, all symptomatic patients with or without a history of other cardiovascular disease should be prescribed long-term antiplatelet therapy. Unfortunately, adherence to cardiovascular medication is fairly low.²³ Self-reported consistent use (reported on ≥2 consecutive follow-up surveys and then through death, withdrawal or study end) of cardiovascular medication was analyzed using the Duke Databank for Cardiovascular Disease in patients with coronary artery disease, with or without heart failure.²⁴ In 2002, consistent use was reported: for aspirin, 71%; beta-blockers, 46%; lipid-lowering therapy, 44%; aspirin and beta-blockers, 36%; and all three, 21%. Because of these findings, the assessment of medication compliance should be incorporated into the standard care for patients with PAOD.

Medication compliance as part of an SET program leans toward lifestyle coaching. Lifestyle coaching is the second component of the multicomponent therapy for IC and forms an essential part of cardiovascular risk modification. In general, the existence and potential value of lifestyle coaching programs are well known. However, in most cases, lifestyle coaching forms no part of standard care for patients with PAOD. Essential topics of lifestyle coaching are smoking cessation, dietary advice, weight control and stimulation of physical activity. Smoking is considered the single most important modifiable risk factor for the development of PAOD. Smokers have a risk of PAOD that is four times that of non-smokers and experience onset of symptoms almost one decade earlier.^25–27 However, patients who are able to quit smoking are less likely to develop critical limb ischemia and have improved survival.²⁸

Patients who are moderately overweight (body mass index 25–30) or who are obese (body mass index >30) should receive counseling for weight reduction by means of dietary advice and stimulation of physical activity. Dietary advice should address the need for a negative caloric balance with carbohydrate restriction and reduction of calorie intake. The level of physical activity should be assessed and compared with the global recommendations on physical activity for health, composed by the World Health Organization.²⁹ All adults should do at least 150 minutes or moderate-intensity aerobic physical activity (usually a 5 or 6 on a scale of 0–10 of personal capacity) or 75 minutes of vigorous-intensity aerobic physical activity (usually a 7 or 8 on a scale of 0–10 of personal capacity) throughout the week.

The third and last component addresses the poor health-related QoL in patients with IC. Patients with IC have a considerably poorer health status, functional capacity and health-related QoL compared with individuals without PAOD.^12,13 Treatments used to improve these impairments are pharmacological treatment, (supervised) exercise therapy and invasive forms of treatment (e.g. percutaneous and surgical vascular interventions). The latter are occasionally used as first-line treatment.

Pharmacological treatment for relief of claudication symptoms typically involves drugs other than those used for risk reduction. Cilostazol is currently the most effective drug for IC.³⁰ Approved by the Food and Drug Adminstration in 1999, the primary action of cilostazol is to inhibit phosphodiesterase type 3, which results in vasodilation and inhibition of platelet aggregation, arterial thromboses and vascular smooth muscle proliferation. A three- to six-month course of cilostazol is a possible first-line pharmacotherapy for the relief of claudication symptoms, as evidence shows both an improved walking distance and a QoL.³⁰ Naftidrofuryl can also be considered. In a meta-analysis, naftidrofuryl showed a clinically meaningful improvement in pain-free and maximum walking distance in patients with IC.³¹ It is a 5-hydroxytryptamine type 2 antagonist and may improve muscle metabolism, and reduce erythrocyte and platelet aggregation. Approval of cilostazol or naftidrofuryl for IC is, however, limited to certain countries.

Exercise therapy

Exercise therapy is the first suggested therapy for patients with IC. In 1898, Wilhelm Erb,³² a German neurologist, described the successful results of exercise therapy for a patient with IC. The first RCT was performed by Larsen and Lassen in 1966.³³ In this study, seven patients treated with exercise therapy were compared with a control group of seven patients who were given ‘medical treatment’ in the form of lactose tablets. For the group treated with exercise, a significant increase in maximum walking time was seen, whereas the patients in the control group did not improve.

Nowadays, exercise therapy for patients with IC is extensively studied. In a Cochrane review by Watson et al.,²⁴ exercise therapy was compared with usual care or placebo on data of functional capacity outcome measurements. A total of 22 trials met the inclusion criteria involving a total of 1200 participants with IC. In conclusion, compared with placebo and usual care, exercise therapy significantly improved maximal walking time with a mean difference of 5.12 minutes (95% confidence interval 4.51–5.72) and an improved maximum walking distance of 113.2 m (range 95.0–131.4). Exercise therapy also showed a positive effect on the reduction of cardiovascular risk factors including hypercholesterolemia, hypertension and diabetes mellitus.³⁴

The most common exercise therapy prescription consists of a single oral advice, usually without supervision or follow-up. The adherence of patients given an oral exercise advice appears to be low. Co-morbidity, lack of (specific) advice, fear, and lack of discipline and supervision are barriers to actually perform regular walking exercise.³⁵ For these reasons, the importance of supervision was recognized.

Supervised exercise therapy

SET entails adequate coaching by a physical therapist (PT) or other exercise specialist (e.g. exercise physiologist, exercise therapist, specialized cardiovascular nurse) and aims to increase maximal walking distance, physical activity and health-related QoL. The most effective programs employ treadmill walking that is of sufficient intensity to bring on claudication symptoms. Supervised exercise is continued as tolerated over the course of a 30–60-minute session. Exercise sessions are typically conducted three times a week for three months.² A Cochrane review by Bendermacher et al.³⁶ compared SET with non-supervised exercise programs for patients with IC. SET showed statistically significant and clinically relevant differences in improvement of maximal walking distance compared with non-SET regimens, with an overall effect size of 0.58 (95% confidence interval 0.31–0.85) at three months. This translates into an improvement of approximately 150 m of maximum walking distance in favor of the supervised group. However, additional studies on QoL appear to be needed to definitely demonstrate clinical effectiveness.

In a number of RCTs, SET is compared with endovascular revascularization or surgical reconstruction. Spronk et al.³⁷ compared functional capacity and health-related QoL in patients with IC during a 12-month follow-up after endovascular revascularization or hospital-based SET. The results demonstrate that after 12 months, patients with IC benefited equally from either endovascular revascularization or hospital-based SET. Improvement is, however, more instantly following revascularization. In another RCT, Creasy et al. found a progressive and significant improvement in walking distance for patients treated with exercise therapy. For the group treated with endovascular revascularization, a non-significant increase in walking distance was found after three months followed by a steady deterioration until 12 months of follow-up.³⁸ Only one study compared SET to surgical reconstruction.³⁹ In both groups, walking distance improved but no significant difference was found.

To evaluate the complementary effects of angioplasty with SET, Mazari et al. randomized claudicants with angioplasty-suitable femoropopliteal lesions to SET, angioplasty or angioplasty + SET. All the groups demonstrated significant clinical and QoL improvements, but the angioplasty + SET group produced a much greater improvement in clinical outcome measures than angioplasty or SET alone, without a significant QoL improvement.⁴⁰ Also, in the MIMIC trial, patients with femoropopliteal and aortoiliac arterial disease were randomized to receive either PTA or no PTA against a background of supervised exercise and best medical therapy. The maximum walking distance was 38% greater in the PTA group for the femoropopliteal trial (95% CI 1–90; P = 0.04) and 78% greater in the PTA group for the aortoiliac trial (95% CI 0–216; P = 0.05). No benefits were found for health-related QoL.⁴¹

Few studies consider the long-term (>12 months) effects of SET. Gardner et al.⁴² tried to determine whether improvements in physical function after six months of SET could be sustained over a subsequent 12 months in older patients with IC. They concluded that improvements in maximum walking distance and physical activity level, after six months of exercise training, are prolonged for an additional 12 months using a less intense exercise maintenance program. Ratliff et al.⁴³ reported a three-year follow-up of 212 patients with IC who initially were treated with SET, with an exercise program of two sessions a week for 10 weeks. Their results show that the maximum walking distance seen at 12 weeks is still present at three years. Based on this limited experience, it appears that SET has long-term benefits for patients with IC.

In the majority of all reviewed studies on SET, an outpatient hospital setting was offered. This approach seems appropriate in trials, but has several limitations in daily clinical practice. First, the capacity of an exercise therapy program in an outpatient clinic is limited and not sufficient to provide SET for all patients with IC. Second, attending a hospital three times a week comes with considerable transportation costs and is time-consuming for the individual patient. For this reason, implementation of a community-based SET program was instigated.⁴⁴ The first results of a cohort study of patients treated with community-based SET resulted in a highly statistically significant improvement in maximum walking distance (on a treadmill) after three and six months.⁴⁵ The authors concluded that comparison of these results with historical studies on hospital-based SET should be done with caution due to the variability in the prescribed exercise regimens and the treadmill walking tests used. However, SET in a community-based setting seemed to be at least as efficacious as the programs provided in a clinical setting, but with a higher capacity.

In the ExitPAD trial, a multicenter RCT, Nicolai et al.⁴⁶ compared exercise therapy in the form of a ‘go home and walk’ advice (WA) with community-based SET for patients with IC. SET appeared to be significantly more effective than WA in improving maximum walking distance and health-related QoL. The data from the ExitPAD trial were also used to assess the cost-effectiveness of SET versus WA.⁴⁷ For community-based SET, the incremental cost-effectiveness ratio for cost per quality-adjusted life years (QALY) was €28.693. At a willingness-to-pay threshold of €40.000 per QALY, SET seemed a cost-effective therapeutic option for patients with IC. Based on this evidence, (community-based) SET programs should be made available for all patients with IC, as stated in several national and international guidelines.^1,2,48,49

Future perspectives

Although SET is considered the best evidence-based therapy for all patients with IC, general practitioners, vascular surgeons or vascular specialists do not always have the disposal of (community-based) PTs or exercise therapists with specific knowledge of IC or exercise training. Also, not all PTs have sufficient experience with this specific patient category. Patients suffer from a variety of co-morbidities and modifiable lifestyle factors, potentially generating suboptimal results. Unfortunately, too many examples of PTs treating patients with IC with massages and other alternative, non-evidence-based treatments exist. For this reason, Nicolai et al.⁴⁶ extensively trained all participating community-based PTs before they were allowed to participate in the ExitPAD trial.

To standardize treatment and assure quality of PTs in the Netherlands, the Royal Dutch Society for Physical Therapy developed 20 evidence-based guidelines. This includes the guideline ‘Intermittent claudication’ published in 2003.⁵⁰ Assessing guideline adherence was performed for the guideline ‘Lower back pain’. Bekkering⁵¹ showed an adherence to the low-back pain guideline for Dutch PTs in only 30% of the patients. When PTs had undergone an active implementation strategy, adherence increased by 12%. For the guideline ‘Intermittent claudication’, no studies on guideline adherence have been performed. It seems, however, likely that guideline adherence in general is suboptimal. Therefore, the assignment of quality indicators is in our view necessary. For example, in Parkinson's disease, guideline recommendations were transformed into quality indicators and incorporated into a questionnaire.⁵² This questionnaire was sent to 41 expert PTs and 286 general PTs. The score of the expert panel (35.1, SD 4.2) was significantly higher compared with those of the general PTs (22.2, SD 7.7). The results emphasize that quality-improving interventions are needed as guideline adherence is suboptimal.

In the ideal situation, all patients with IC should receive an evidence-based standardized form of SET by an exercise specialist. Owing to lack of capacity, hospital-based exercise therapy should be reserved for cases with severe (cardiac) co-morbidity. For this reason, the ClaudicatioNet concept was launched in the Netherlands, in January 2011. ClaudicatioNet is a concept of an integrated care network between PTs, vascular surgeons and general practitioners. ClaudicatioNet aims to implement nationwide coverage of regional networks for SET and lifestyle interventions by PTs. Participating PTs are required to comply with a progressive set of quality standards over a period of 3–4 years. These efforts should result in a transparent, high-quality care network as evaluated by objective quality indicators. For example, data on maximal walking ability, QoL, co-morbidities, lifestyle parameters and cardiovascular risk factors will be recorded in a national database. PTs also need to obtain a set number of continuous medical education points on topics linked to PAOD.

In our opinion, regular medication compliance should be performed four times a year as part of this standard SET program. If deviations of prescribed medication are noted by the exercise specialist, the patient's general practitioner and/or medical specialist should be notified. We hypothesized that due to the frequent (2–3 times a week) contact of patients with their PTs, as part of a SET program, it is more likely that patients will truly report non-adherence. However, this is not yet substantiated.

Current and future research on SET focuses on the influence of specific co-morbidities on prognosis and effect of SET outcome, besides the additional value of SET combined with a percutaneous vascular intervention (PVI).

Currently, in the Netherlands, two multicenter RCTs are including patients to evaluate the effectiveness and cost-effectiveness of SET. The ERASE trial compares SET with a PVI complementary to SET.⁵³ The optimal treatment strategy for IC due to an iliac artery obstruction will be determined in the SUPER-trial.⁵⁴ The SUPER-trial compares SET and deferred PVI in case of SET failure to an immediate PVI. Results have to be awaited and interpreted in view of the limited experience in SET among the participating PTs.

In the USA, another large multicenter RCT is being conducted. In approximately 25 centers, 252 patients will be followed over a period of 18 months.⁵⁵ The treatment arms are: (1) optimal medical care (OMC); (2) OMC and primary stent placement; (3) OMC and SET; and (4) combined stenting with SET and OMC. In this so-called CLEVER trial, the researchers aim to find the optimal treatment strategy for IC for the endpoints maximal walking duration and health-related QoL. In these trials, no usage of the future possibilities aimed for in ClaudicatioNet will be measured (i.e. lifestyle coaching, smoking cessation strategies, concurrent use of concomitant co-morbidity guidelines like chronic obstructive pulmonary disease, etc.). However, currently it is the best SET we have and results are eagerly awaited.

Although there is little evidence yet, SET could also be effective for patients with critical limb ischemia as an adjuvant to a revascularization procedure. Kruidenier et al.⁵⁶ performed an RCT to investigate the effects of SET after a PVI for patients with all stages of PAOD, mainly IC. They found that SET following PVI was more effective in increasing maximum walking distance than PVI alone. Badger et al.⁵⁷ evaluated the efficacy of an exercise program after arterial bypass surgery for short-distance IC or critical ischemia. SET resulted for this group in an increased maximum walking distance of 175% compared with 4% for the group with usual care. These studies indicate that SET is a useful adjunct after PVI or lower-limb bypass surgery. Further research should confirm the clinical effectiveness of SET after vascular intervention for the subgroup of patients with critical limb ischemia.

Conclusion

Multicomponent treatment of IC should address two important targets: reduction of cardiovascular events (and related morbidity and mortality) and improvement of the poor health-related QoL and functional capacity. Based on current evidence, SET appears to be the primary and most effective intervention for patients with IC. With the implementation of ClaudicatioNet in The Netherlands, a nationwide integrated care network of specialized PTs enables the delivery of a multicomponent therapy to all patients with IC. Current and future research focuses on the influence of specific co-morbidities on prognosis and effect of SET outcome and the potential beneficial effects of SET combined with (minimally) invasive vascular interventions.

Members of the ClaudicatioNet Study Group (in alphabetical order)

BL Bendermacher, F Brooijmans, RA de Bie, HJM Hendriks, B Honing, S Kleinveld, LM Kruidenier, GJ Lauret, SP Nicolaï, MH Prins, EV Rouwet, T Schambergen, S Spronk, JAW Teijink, E Troe, HCW van Dalen, S van de Voort, EM Willigendael, J Wolters.

Conflicts of interest: None.

References

Hirsch

, Haskal

, Hertzer

, ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463–e654

Norgren

, Hiatt

, Dormandy

, Nehler

, Harris

, Fowkes

. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45(Suppl. S):S5–67

Fowkes

, Housley

, Cawood

, Macintyre

, Ruckley

, Prescott

. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 1991;20:384–92

Murabito

, Evans

, Nieto

, Larson

, Levy

, Wilson

. Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study. Am Heart J 2002;143:961–5

Hooij

, Stoffers

, Kester

, Rinskens

, Kaiser

. Risk factors and cardiovascular diseases associated with asymptomatic peripheral arterial occlusive disease. The Limburg PAOD Study. Scand J Prim Health Care 1998;16:177–82

Meijer

, Hoes

, Rutgers

, Bots

, Hofman

, Grobbee

. Peripheral arterial disease in the elderly: The Rotterdam Study. Arterioscler Thromb Vasc Biol 1998;18:185–92

Fauci

. Harrison's Principles of Internal Medicine. 2nd edn. New York: McGraw-Hill, 1998

Kannel

, McGee

. Update on some epidemiologic features of intermittent claudication: the Framingham Study. J Am Geriatr Soc 1985;33:13–8

Leng

, Lee

, Fowkes

, Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996;25:1172–81

10.

Criqui

. Systemic atherosclerosis risk and the mandate for intervention in atherosclerotic peripheral arterial disease. Am J Cardiol 2001;88:43J–7J

11.

Criqui

, Langer

, Fronek

, Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381–6

12.

Regensteiner

, Hiatt

, Coll

, The impact of peripheral arterial disease on health-related quality of life in the Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) Program. Vasc Med 2008;13:15–24

13.

Dumville

, Lee

, Smith

, Fowkes

. The health-related quality of life of people with peripheral arterial disease in the community: the Edinburgh Artery Study. Br J Gen Pract 2004;54:826–31

14.

Dormandy

, Heeck

, Vig

. Predictors of early disease in the lower limbs. Semin Vasc Surg 1999;12:109–17

15.

Chobanian

, Bakris

, Black

, Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206–52

16.

Bonny

, Lacombe

, Yitemben

, The 2007 ESH/ESC guidelines for the management of arterial hypertension. J Hypertens 2008;26:825–6

17.

Paravastu

, Mendonca

, da Silva

. Beta blockers for peripheral arterial disease. Eur J Vasc Endovasc Surg 2009;38:66–70

18.

Ray

, Seshasai

, Wijesuriya

, Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009;373:1765–72

19.

Gerstein

, Miller

, Genuth

, Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:818–28

20.

Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007;45:645–54

21.

Armitage

, Bowman

, Clarke

, Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 2010;303:2486–94

22.

Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86

23.

Newby

, LaPointe

, Chen

, Long-term adherence to evidence-based secondary prevention therapies in coronary artery disease. Circulation 2006;113:203–12

24.

Watson

, Ellis

, Leng

. Exercise for intermittent claudication. Cochrane Database Syst Rev 2008;(4):CD000990

25.

Kannel

, Shurtleff

. The Framingham Study. Cigarettes and the development of intermittent claudication. Geriatrics 1973;28:61–8

26.

Powell

, Edwards

, Worrell

, Franks

, Greenhalgh

, Poulter

. Risk factors associated with the development of peripheral arterial disease in smokers: a case-control study. Atherosclerosis 1997;129:41–8

27.

Selvin

, Hirsch

. Contemporary risk factor control and walking dysfunction in individuals with peripheral arterial disease: NHANES 1999–2004. Atherosclerosis 2008;201:425–33

28.

Jonason

, Bergstrom

. Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand 1987;221:253–60

29.

WHO Press World Health Organization. Global Recommendations on Physical Activity for Health. Geneva: World Health Organization, 2010

30.

Thompson

, Zimet

, Forbes

, Zhang

. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol 2002;90:1314–9

31.

, Vander

, Lehert

, Van

. Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data. BMJ 2009;338:b603

32.

Erb

. About intermittent walking and nerve disturbances due to vascular disease. Deutsch Z Nervenheilk 1898;13:1–76

33.

Larsen

, Lassen

. Effect of daily muscular exercise in patients with intermittent claudication. Lancet 1966;2:1093–6

34.

Shephard

, Balady

. Exercise as cardiovascular therapy. Circulation 1999;99:963–72

35.

Bartelink

, Stoffers

, Biesheuvel

, Hoes

. Walking exercise in patients with intermittent claudication. Experience in routine clinical practice. Br J Gen Pract 2004;54:196–200

36.

Bendermacher

, Willigendael

, Teijink

, Prins

. Supervised exercise therapy versus non-supervised exercise therapy for intermittent claudication. Cochrane Database Syst Rev 2006;(2):CD005263

37.

Spronk

, Bosch

, den Hoed

, Veen

, Pattynama

, Hunink

. Intermittent claudication: clinical effectiveness of endovascular revascularization versus supervised hospital-based exercise training – randomized controlled trial. Radiology 2009;250:586–95

38.

Creasy

, McMillan

, Fletcher

, Collin

, Morris

. Is percutaneous transluminal angioplasty better than exercise for claudication? Preliminary results from a prospective randomised trial. Eur J Vasc Surg 1990;4:135–40

39.

Lundgren

, Dahllof

, Lundholm

, Schersten

, Volkmann

. Intermittent claudication – surgical reconstruction or physical training? A prospective randomized trial of treatment efficiency. Ann Surg 1989;209:346–55

40.

Mazari

, Gulati

, Rahman

, Early outcomes from a randomized, controlled trial of supervised exercise, angioplasty, and combined therapy in intermittent claudication. Ann Vasc Surg 2010;24:69–79

41.

Greenhalgh

, Belch

, Brown

, The adjuvant benefit of angioplasty in patients with mild to moderate intermittent claudication (MIMIC) managed by supervised exercise, smoking cessation advice and best medical therapy: results from two randomised trials for stenotic femoropopliteal and aortoiliac arterial disease. Eur J Vasc Endovasc Surg 2008;36:680–8

42.

Gardner

, Katzel

, Sorkin

, Goldberg

. Effects of long-term exercise rehabilitation on claudication distances in patients with peripheral arterial disease: a randomized controlled trial. J Cardiopulm Rehabil 2002;22:192–8

43.

Ratliff

, Puttick

, Libertiny

, Hicks

, Earby

, Richards

. Supervised exercise training for intermittent claudication: lasting benefit at three years. Eur J Vasc Endovasc Surg 2007;34:322–6

44.

Willigendael

, Bendermacher

, van der Berg

, The development and implementation of a regional network of physiotherapists for exercise therapy in patients with peripheral arterial disease, a preliminary report. BMC Health Serv Res 2005;5:49

45.

Bendermacher

, Willigendael

, Nicolai

, Supervised exercise therapy for intermittent claudication in a community-based setting is as effective as clinic-based. J Vasc Surg 2007;45:1192–6

46.

Nicolai

, Teijink

, Prins

. Multicenter randomized clinical trial of supervised exercise therapy with or without feedback versus walking advice for intermittent claudication. J Vasc Surg 2010;52:348–55

47.

van Asselt

, Nicolai

, Joore

, Prins

, Teijink

. Cost-effectiveness of exercise therapy in patients with intermittent claudication: supervised exercise therapy versus a ‘go home and walk’ advice. Eur J Vasc Endovasc Surg 2011;41:97–103

48.

Vahl

, Reekers

. The guideline ‘Diagnosis and treatment of peripheral artery disease of the lower extremities' of The Netherlands Surgical Society. Ned Tijdschr Geneeskd 2005;149:1670–4

49.

Bartelink

, Stoffers

HEJH

, Boutens

, Hooij

, Kaiser

, Boomsma

. Guideline peripheral arterial disease from the Dutch General Practioners Society. Huisarts Wet 2003;46:848–58

50.

Hendriks

HJM

, Bekkering

, Van Ettekoven

, Brandsma

, van der Wees

, De Bie

. Development and implementation of national practice guidelines: a prospect for continuous quality improvement in physiotherapy: introduction to the method of guideline development. Physiotherapy 2000;86:535–47

51.

Bekkering

. Physiotherapy Guidelines for Low Back Pain. Development, Implementation and Evaluation. Academic thesis. Amsterdam: Vrije Universiteit, 2004

52.

Nijkrake

, Keus

, Ewalds

, Quality indicators for physiotherapy in Parkinson's disease. Eur J Phys Rehabil Med 2009;45:239–45

53.

Nederlands Trial Register. Amsterdam: Academic Medical Center (The Netherlands). 2004 Oct 26. Spronk S. Cost-effectiveness of treatment strategies for intermittent claudication: a multicenter randomized controlled trial. Identifier NTR2249. 2010. See http://www.trialregister.nl (last checked 28 October 2011)

54.

Nederlands Trial Register. Amsterdam: Academic Medical Center (The Netherlands). 2004 Oct 26. Koelemay MJW. SUPERvised exercise therapy or immediate PTA for intermittent claudication in patients with an iliac artery obstruction: a randomized controlled trial. SUPER study. Identifier NTR2776. 2011. See http://www.trialregister.nl (last checked 28 October 2011)

55.

Murphy

, Hirsch

, Ricotta

, The claudication: exercise vs. endoluminal revascularization (CLEVER) study: rationale and methods. J Vasc Surg 2008;47:1356–63

56.

Kruidenier

, Nicolai

, Rouwet

, Peters

, Prins

, Teijink

. Additional supervised exercise therapy after a percutaneous intervention for peripheral arterial disease: a randomised clinical trial. J Vasc Interv Radiol 2011;22:961–8

57.

Badger

, Soong

, O'Donnell

, Boreham

, McGuigan

. Benefits of a supervised exercise program after lower limb bypass surgery. Vasc Endovasc Surg 2007;41:27–32