Supervised exercise therapy versus non-supervised exercise therapy for intermittent claudication

  • Review
  • Intervention

Authors

  • Hugo JP Fokkenrood,

    Corresponding author
    1. Catharina Hospital, Department of Vascular Surgery, Eindhoven, Netherlands
    2. Maastricht University, CAPHRI Research School, Department of Epidemiology, Maastricht, Netherlands
    • Hugo JP Fokkenrood, Department of Vascular Surgery, Catharina Hospital, Michelangelolaan 2, Eindhoven, 5623 EJ, Netherlands. h.fokkenrood@gmail.com.

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  • Bianca LW Bendermacher,

    1. Catharina Hospital, Department of Vascular Surgery, Eindhoven, Netherlands
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  • Gert Jan Lauret,

    1. Catharina Hospital, Department of Vascular Surgery, Eindhoven, Netherlands
    2. Maastricht University, CAPHRI Research School, Department of Epidemiology, Maastricht, Netherlands
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  • Edith M Willigendael,

    1. Alkmaar Medical Centre, Department of Surgery, Alkmaar, Netherlands
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  • Martin H Prins,

    1. Maastricht University, CAPHRI Research School, Department of Epidemiology, Maastricht, Netherlands
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  • Joep AW Teijink

    1. Catharina Hospital, Department of Vascular Surgery, Eindhoven, Netherlands
    2. Maastricht University, CAPHRI Research School, Department of Epidemiology, Maastricht, Netherlands
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Abstract

Background

Although supervised exercise therapy is considered to be of significant benefit for people with leg pain (peripheral arterial disease (PAD)), implementing supervised exercise programs (SETs) in daily practice has limitations. This is an update of a review first published in 2006.

Objectives

The main objective of this review was to provide an accurate overview of studies evaluating the effects of supervised versus non-supervised exercise therapy on maximal walking time or distance on a treadmill for people with intermittent claudication.

Search methods

For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched September 2012) and CENTRAL (2012, Issue 9). In addition, we handsearched the reference lists of relevant articles for additional trials. No restriction was applied to language of publication.

Selection criteria

Randomized clinical trials comparing supervised exercise programs with non-supervised exercise programs (defined as walking advice or a structural home-based exercise program) for people with intermittent claudication. Studies with control groups, which did not receive exercise or walking advice or received usual care (maintained normal physical activity), were excluded.

Data collection and analysis

Two review authors (HJPF and BLWB) independently selected trials and extracted data. Three review authors (HJPF, BLWB, and GJL) assessed trial quality, and this was confirmed by two other review authors (MHP and JAWT). For all continuous outcomes, we extracted the number of participants, the mean differences, and the standard deviation. The 36-Item Short Form Health Survey (SF-36) outcomes were extracted to assess quality of life. Effect sizes were calculated as the difference in treatment normalized with the standard deviation (standardized mean difference) using a fixed-effect model.

Main results

A total of 14 studies involving a total of 1002 male and female participants with PAD were included in this review. Follow-up ranged from six weeks to 12 months. In general, supervised exercise regimens consisted of three exercise sessions per week. All trials used a treadmill walking test as one of the outcome measures. The overall quality of the included trials was moderate to good, although some trials were small with respect to the number of participants, ranging from 20 to 304.

Supervised exercise therapy (SET) showed statistically significant improvement in maximal treadmill walking distance compared with non-supervised exercise therapy regimens, with an overall effect size of 0.69 (95% confidence interval (CI) 0.51 to 0.86) and 0.48 (95% CI 0.32 to 0.64) at three and six months, respectively. This translates to an increase in walking distance of approximately 180 meters that favored the supervised group. SET was still beneficial for maximal and pain-free walking distances at 12 months, but it did not have a significant effect on quality of life parameters.

Authors' conclusions

SET has statistically significant benefit on treadmill walking distance (maximal and pain-free) compared with non-supervised regimens. However, the clinical relevance of this has not been demonstrated definitively; additional studies are required that focus on quality of life or other disease-specific functional outcomes, such as walking behavior, patient satisfaction, costs, and long-term follow-up. Professionals in the vascular field should make SET available for all patients with intermittent claudication.

Plain language summary

Supervised exercise versus non-supervised exercise for people with leg pain while walking (intermittent claudication)

Some people experience a type of leg pain in the calf of one or both legs that occurs during walking and is relieved only by rest. This is called intermittent claudication (IC), and it is the main symptom of peripheral arterial disease (PAD). PAD is characterized by reduced flow of blood in the leg due to hardening of the arteries, or blood vessels. Exercise is considered to provide significant benefit for people with this type of leg pain. People need to walk at least three times a week by themselves, or they can participate in a formal, supervised exercise program that involves walking on a treadmill. This review found that people in a supervised program improved their walking ability to a greater extent than those following an unsupervised walking program. After three months, people who followed the supervised treadmill program could walk 180 meters farther than those who did unsupervised exercise. Before participating in the program, they had walked around 300 meters, with a pain-free distance of 200 meters, so this improvement is likely to help with independence. These conclusions are drawn from the findings of 14 trials in which participants with PAD had been assigned to either supervised or unsupervised exercise. Altogether, 1002 participants with a mean age of 67 years were included. The overall quality of the included trials was moderate to good, although each had enrolled only a small number of participants. The trials lasted from six weeks to twelve months. Keeping to an exercise program is important because it leads to decreased leg pain and the likelihood of improving general physical condition, but it is not yet clear if it also improves quality of life.

Background

Description of the condition

Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is defined as leg pain in the muscles of the lower extremities that occurs with exercise and is relieved by rest. PAD increases progressively with age, in particular after the age of 40. The relationship between PAD prevalence and age was illustrated by data from the 1999–2000 National Health and Nutrition Examination Survey (NHANES), an ongoing cross-sectional survey of the civilian, non-institutionalized population of the United States. The prevalence of PAD, defined as an ankle-brachial index (ABI; the ratio of blood pressure in the lower legs to blood pressure in the arms) < 0.90 in either leg, was 0.9% between the ages of 40 and 49, 2.5% between the ages of 50 and 59, 4.7% between the ages of 60 and 69, and 14.5% in those 70 years of age and older (Selvin 2004). These numbers indicate that PAD affects more than 5 million adults in the United States. International guidelines reveal 27 million affected individuals in North America and Europe (Norgren 2007).

Description of the intervention

The primary and most effective treatment for people with IC is exercise therapy (Stewart 2002), which was first suggested by Erb (Erb 1898). In 1966 the first randomized controlled trial (RCT) of exercise therapy in participants with PAD demonstrated an obvious improvement in treadmill walking ability (Larsen 1966). In a Cochrane systematic review of randomized clinical trials, Leng et al (Leng 2000) and later the updated version by Watson et al (Watson 2008) described an overall improvement in maximal walking time: mean difference (MD) 5.12 minutes (95% confidence interval (CI) 4.51 to 5.72) with an overall improvement in walking ability of approximately 50% to 200% associated with exercise therapy compared with no exercise therapy. However, the exercise programs included in this meta-analysis vary widely, ranging from physician recommended unsupervised walking in the community to a formal supervised exercise program involving walking on a treadmill.

How the intervention might work

Exercise training provides significant symptomatic benefit for patients with claudication; however, the exact mechanisms for this improvement remain unclear (Beckitt 2012). The mechanisms of response to exercise training have been reviewed previously and include improvement in walking efficiency, induction of vascular angiogenesis, inflammatory activation, increased exercise pain tolerance, endothelial and mitochondrial dysfunction, and metabolic adaptations within skeletal muscle (Gustafsson 2001; Hamburg 2011; Norgren 2007; Stewart 2008; Zwierska 2005). Further benefits of exercise therapy are seen in the reduction of cardiovascular risk factors such as hypercholesterolemia, hypertension, and diabetes mellitus. Exercise is therefore implemented in secondary prevention therapies in patients with coronary artery disease (Smith 2011). Given its clear benefits, the importance of exercise therapy is highlighted in contemporary international guidelines (Hirsch 2006; Norgren 2007). In daily practice, lack of specific individual guidance and the absence of uniform supervision appear to be important barriers to the initiation and continuation of exercise therapy (Bartelink 2004).

Why it is important to do this review

Before the release of the original version of this review in 2006, the prescription of exercise therapy consisted mostly of "go home and walk" advice by the general practitioner, sometimes accompanied by a brochure. After this review was published, more studies compared supervised exercise therapy with non-supervised exercise therapy. Although supervised exercise therapy proved effective in the treatment of PAD by increasing maximal or pain-free walking time or distance, exercise programs are not designed to change day-to-day walking behavior (Crowther 2008; McDermott 2009). Moreover, limitations continue to hinder implementation of supervised exercise programs in daily practice. Some describe the lack of a supervised setting to which patients can be referred to or a lack of knowledge among referring healthcare professionals; in other studies participants are not willing to persist with an exercise program to maintain the benefit (Fokkenrood 2012; Lauret 2012a; Makris 2012; Norgren 2007; Stewart 2008). Therefore debate continues about whether exercise should be offered under supervision. With disregard for all financial and organizational aspects, we believe it is important to provide an accurate systematic review of the effects of supervised exercise therapy in relation to non-supervised exercise on walking distance and quality of life.

Objectives

The main objective of this review was to provide an accurate overview of studies evaluating the effects of supervised versus non-supervised exercise therapy on maximal walking time or distance on a treadmill for people with intermittent claudication.

Methods

Criteria for considering studies for this review

Types of studies

Parallel-group RCTs comparing supervised exercise programs with non-supervised exercise programs, in participants with PAD, were included. Trials were included irrespective of whether an intention-to-treat analysis was carried out.

Types of participants

Adults (18 years and older) with intermittent claudication (Fontaine II/Rutherford 1 to 3) (Fontaine 1954 ; Rutherford 1997) due to atherosclerotic disease, diagnosed by questionnaire or clinically, who were considered for conservative treatment, were included. Studies of participants with asymptomatic lower limb atherosclerosis identified by testing were excluded.

Types of interventions

Supervised exercise programs

A supervised exercise program needed to consist of more than six consecutive weeks of training, with more than 50% of the exercise time spent on walking or training the lower limbs. Inclusion of trials was not limited by frequency or intensity of the exercise program.

Non-supervised exercise programs

Non-supervised exercise programs were defined as those in which control group members were advised to walk (with or without a predefined exercise scheme or logbook) or were treated according to a structural home-based exercise program (walk advice with regular contact and exercise support from medically trained personnel).

Studies with control groups, which did not receive exercise or walking advice or which received usual care (maintained normal physical activity), were excluded.

Types of outcome measures

Primary outcomes

The primary outcome measure was the effect on maximal treadmill walking distance or time. Outcomes had to be available at baseline.

Secondary outcomes

The following secondary outcome measures were also considered:

  • Painfree treadmill walking distance, or time;

  • Mortality;

  • Adherence to exercise program; and

  • Quality of life.

Search methods for identification of studies

No restriction on language of publication was applied.

Electronic searches

For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched September 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) 2012, Issue 9, part of The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, and AMED, and through handsearching of relevant journals. The full list of the databases, journals, and conference proceedings which have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com). 

Searching other resources

A handsearch of references lists of relevant studies was carried out.

Data collection and analysis

Selection of studies

Two review authors (HJPF and BLWB) independently selected trials for this review, whereas two other review authors (JAWT and MHP) confirmed the suitability of selected trials for inclusion in the review. Disagreements regarding inclusion/exclusion of selected trials were resolved by discussion.

Data extraction and management

Two review authors (HJPF and BLWB) independently extracted data using a standard data collection form. Data were entered into Review Manager (RevMan 2011). When necessary, additional information was sought for included trials.

For all continuous outcomes (ie, walking distance or walking time, adherence to exercise program, quality of life), we extracted the number of participants and the mean difference between treatment groups per follow up period with accompanying standard deviation for each treatment group, if available. We also recorded other details of the included trials, for example, the study setting, the statistical power, and the number of dropouts in each group. We contacted authors for missing information regarding their methods.

Trials that compared three or more different therapy programs - supervised and non-supervised therapy programs - with other kinds of programs, were included. From these trials, only participants treated by supervised or non-supervised exercise therapy were taken into account.

Assessment of risk of bias in included studies

Three review authors (HJPF, BLWB, and GJL) assessed and one review author (MHP) confirmed the methodological quality of the trials, primarily for adequacy of allocation concealment and follow-up. In trials that compared exercise programs with walking distance as the primary outcome, blinding of staff and participants is not possible and was therefore not considered.

We graded study quality in a table of risk of bias on the basis of a checklist of design components. This checklist comprised random sequence generation, allocation concealment, incomplete outcome data, and selective reporting. We achieved consensus by informal discussion. We summarized the adequacy of each category as "low", "unclear", or "high" risk according to the criteria provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Measures of treatment effect

We standardized reported data on walking time and distance to effect sizes to enable the calculation of an overall standardized mean difference (SMD). If standard errors (SEs) had been reported (and authors did not reply to our request to send unpublished data), we converted these to standard deviations. We used a fixed-effect model to obtain summary statistics for all types of outcome measures. When significant heterogeneity was found (P < 0.05), we calculated overall efficacy using random-effects models.

Unit of analysis issues

Only RCTs with follow-up of at least six weeks' duration were included in this review.

Dealing with missing data

We contacted the study authors to request any missing information. For each trial, we extracted the number of participants originally allocated to each treatment arm from the data, and we performed an intention-to-treat analysis.

Assessment of heterogeneity

We used both a Chi2 test and an I2 statistic to test for heterogeneity between trial results. We used the tests of heterogeneity at a significance level of alpha = 0.05 to examine whether observed variation in study results was compatible with the variation expected by chance alone. When possible, we pooled trial results by meta-analysis.

Assessment of reporting biases

We contacted authors to request missing data. To prevent language bias, we did not impose a language restriction. Funnel plots were used to identify potential publication bias.

Data synthesis

If data were available, we performed statistical analyses using the Review Manager software (RevMan 2011). We standardized reported data on walking time and distance to effect sizes to enable the calculation of an overall standardized mean difference. For this purpose, the difference in outcomes of each study was expressed in the standard deviation (SD) observed in the study (Altman 1991). For articles with non-parametric data, SDs were calculated by dividing the SD by 1.35, according to Chapter 7.7.3.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We calculated the standardized mean difference (SMD) using a fixed-effect model, as the results were presented on different scales (distance or time).

Subgroup analysis and investigation of heterogeneity

Potential heterogeneity in non-supervised exercise programs might exist as the result of differences in intervention components (ranging from structural "go home and walk" advice to a formal home-based exercise program). We performed a subgroup analysis by dividing non-supervised exercise programs into studies that treated participants with "go home and walk" advice and trials that used a home-based exercise program. Home-based exercise was defined as walking advice supplemented with some form of observation method (eg, exercise logs, telephone support, educational videos, step monitors) used by medically trained personnel. In studies that compared both non-supervised types with a supervised exercise program, the "shared" supervised group was split into two groups and included in two comparisons according to Chapter 16.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Sensitivity analysis

Individual study effects on the results were examined by removing each study one at a time to examine whether removing a particular study changed the results significantly. Studies with apparent risk of bias were excluded.

Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies; and Characteristics of ongoing studies.

Results of the search

For this update, a total of 240 potentially new studies were identified by the Cochrane Peripheral Vascular Diseases Group, and the handsearch yielded four potential studies for inclusion. After title and abstract evaluation, 48 articles on supervised exercise therapy in participants with PAD remained for full-text analysis. The eight included and 19 excluded (27 in total) clinical trials identified in the initial review of 2006 were re-evaluated.

Selection process

One review author (HJPF) obtained full-text copies of the 75 articles (48 new articles and 27 originally documented in the 2006 review) for further assessment. We (HJPF, BLWB, JAWT, MHP) excluded 53 articles of 53 studies (Characteristics of excluded studies) and included 20 articles based on 14 studies (Characteristics of included studies). In addition, we found one ongoing trial (two articles) with potentially usable outcome variables (Frans 2012).

Unpublished data

To avoid publication bias, we contacted six authors of included studies to obtain unpublished data for the assessment of secondary outcome variables. From four authors, we received additional data (Collins 2011; Nicolai 2010; Sanderson 2006; Treat-Jacobson 2009). We were unable to obtain appropriate or adequate data for two studies (Cheetham 2004; Gardner 2011).

Included studies

For this update, nine additional studies were included (Collins 2011; Gardner 2011; Gardner 2012; Hodges 2008; Nicolai 2010; Parr 2009; Sanderson 2006; Stewart 2008; Treat-Jacobson 2009), making a total of 14 included studies. Three of the eight studies (Degischer 2002; Nielsen 1975; Nielsen 1977) that were included in the previous version of this review were excluded in this update for the reasons given in Characteristics of excluded studies. The 14 included trials involved a total of 1002 participants; 589 received supervised exercise therapy (SET), and 413 received non-supervised exercise therapy. The trials were conducted in the United States (7), the UK (4), Australia (1), the Netherlands (1), and South Africa (1). Nine of the trials were relatively recent (2006 to 2012). Five trials were conducted from 1997 to 2005 and were reported in the original review.

Some of the included trials were small; seven included fewer than 30 participants (Hodges 2008; Kakkos 2005; Parr 2009; Regensteiner 1997; Sanderson 2006; Savage 2001; Treat-Jacobson 2009), and four others included fewer than 80 participants (Cheetham 2004; Gardner 2011; Patterson 1997; Stewart 2008). Three trials included more than 140 participants (Collins 2011; Gardner 2012; Nicolai 2010); the largest trial, which was conducted in the Netherlands, consisted of 304 participants and was the only multicenter-based study (Nicolai 2010). 

In three studies (Parr 2009; Sanderson 2006; Treat-Jacobson 2009), three different modes of exercise regimens were investigated. For this review, we used data from the supervised walking groups and the regular non-supervised groups only. One trial was designed to investigate the effects of home-based exercise, but participants were treated with a supervised session once a week (Collins 2011). Therefore this study was included in the supervised group. Another trial (Gardner 2011) investigated the effects of supervised exercise in a three-armed randomized study. In this trial, a control group with "go home and walk" advice was compared with a group given home-based or supervised-based exercise against a background of standard medical care. We (HJPF, BLWB, JAWT, MHP) decided to use the results of the non-supervised exercise groups ("go home and walk" advice and home-based exercise) separately in the subgroup analysis. The results of the supervised group therefore were equally split and were used as comparator.

Inclusion criteria

In six of the trials, in order to be eligible for inclusion, participants with intermittent claudication had to be stable for several months (Cheetham 2004; Kakkos 2005; Patterson 1997; Regensteiner 1997; Sanderson 2006; Stewart 2008). This criterion was not mentioned in the other trials. In all trials, both males and females were included (Characteristics of included studies), except for one trial, which included only male participants (Regensteiner 1997).

The mean age of participants in the SET and control groups was 65.3 years (range 57 to 69) and 66.3 (range 61 to 70), respectively. In the four trials that used age restrictions, participants had to be older than 18 years of age (Treat-Jacobson 2009), older than 40 years of age (Collins 2011), older than 50 years of age (Savage 2001), or between 50 and 75 years of age (Patterson 1997).

A diagnosis of PAD was an essential inclusion criterion in all trials. In one trial (Savage 2001), the diagnosis of intermittent claudication was based on a clinical history. In two other trials (Kakkos 2005; Parr 2009), participants were included when intermittent claudication was clinically determined and a peripheral arterial lesion was found on ultrasound or angiography, or both. The remaining trials (Cheetham 2004; Collins 2011; Gardner 2011; Gardner 2012; Hodges 2008; Nicolai 2010; Patterson 1997; Regensteiner 1997; Sanderson 2006; Stewart 2008; Treat-Jacobson 2009) used a low ankle-brachial index (ABI) or a drop in ankle pressure after exercise to determine the clinical diagnosis of PAD. Collins et al included participants with PAD and diabetes mellitus type 1 or 2 (medication use, diet control, or hyperglycemia) (Collins 2011).

Exclusion criteria

The exclusion criteria used by the included trials were variable. In general, ischemic rest pain, comorbid illness with limitations in an exercise therapy program, and recent vascular surgery or percutaneous transluminal angioplasty (PTA) were mentioned. In one study, smoking habits (Savage 2001), and, in another, the presence of diabetes mellitus (Regensteiner 1997) were exclusion criteria. Kakkos 2005 and Nicolai 2010 excluded participants with a maximal claudication distance greater than 300 or with a maximal claudication distance less than 50 meters and greater 500 meters, respectively. Two trials excluded cases in which the results of the treadmill test differed by more than 25% in terms of absolute claudication distance derived from three screening tests (Kakkos 2005; Treat-Jacobson 2009). Collins excluded participants without a phone (Collins 2011), and Sanderson 2006 did not include participants who lived farther than 50 km from the research center. Gardner et al excluded participants who used cilostazol or pentoxifylline or both (Gardner 2011; Gardner 2012).

Supervised exercise regimens

In general, the supervised exercise programs consisted of three exercise sessions a week for durations of six weeks (Parr 2009; Sanderson 2006), three months (Gardner 2011; Hodges 2008; Patterson 1997; Regensteiner 1997; Treat-Jacobson 2009), six months (Gardner 2012; Kakkos 2005), and 12 months (Nicolai 2010). However, in three trials (Cheetham 2004; Collins 2011; Stewart 2008), the supervised program was given as a weekly session during six months, a weekly session with phone call support during three months, and biweekly supervised therapy during three months, respectively.

Generally, a training session involved walking on a treadmill with varying intensity until moderate or intense pain occurred; this was followed by a short period of rest. Three studies (Cheetham 2004; Parr 2009; Patterson 1997) described an alternative training regimen with walking training as the dominant exercise but with additional exercises for lower limb strengthening. In one trial, treadmill exercises were not performed and exercises were described as based on training of the lower extremity, but unfortunately this was not specified further (Stewart 2008).

In all trials, the duration of each supervised exercise session varied between 30 and 70 minutes, except in Patterson 1997, in which a session lasted 20 to 40 minutes. Four trials with an initial supervised period of three months and an additional three months' unsupervised follow-up were included (Patterson 1997; Savage 2001; Stewart 2008; Treat-Jacobson 2009). Cheetham and Kakkos treated participants with six months of SET with an additional six months' unsupervised follow-up (Cheetham 2004; Kakkos 2005). The remaining trials did not have a follow-up period without supervised therapy. In two trials (Patterson 1997; Savage 2001), participants were additionally educated weekly or monthly about PAD, and Treat-Jacobson 2009 described all non-supervised exercises in reports.

Non-supervised exercise regimens

In ten trials, participants in the non-supervised exercise therapy groups were advised to walk (Cheetham 2004; Collins 2011 Gardner 2011; Gardner 2012; Hodges 2008; Kakkos 2005; Nicolai 2010; Parr 2009; Sanderson 2006; Stewart 2008). This walking advice was given once and predominantly consisted of walking at least three times weekly with walking intensity ranging between tolerance and intense pain. Besides receiving this advice, participants in four trials were treated with standard medical therapy (Cheetham 2004; Hodges 2008; Nicolai 2010; Sanderson 2006). Nicolai et al provided an additional brochure as well (Nicolai 2010). In five other trials, participants in the control group were treated with a home-based exercise program (Gardner 2011; Patterson 1997; Regensteiner 1997; Savage 2001; Treat-Jacobson 2009).

Outcome measurements

All trials used a treadmill walking test to measure the pain-free treadmill walking distance or time and the maximal treadmill walking distance or time. The treadmill tests used varied between trials and are reported in the table of Characteristics of included studies. Three trials used a fixed protocol (Cheetham 2004; Kakkos 2005; Stewart 2008), and the other eleven used a graded protocol. Seven of these studies (Collins 2011; Gardner 2011; Gardner 2012; Hodges 2008; Nicolai 2010; Parr 2009; Savage 2001) used the Gardner Skinner protocol (Gardner 1991). Data on the maximal treadmill walking distance of Cheetham (Cheetham 2004) were calculated on the basis of the P value, and it was assumed that the standard deviations of both groups were equal. Data from Patterson (Patterson 1997) were extracted from the accompanying figures.

Seven trials (Cheetham 2004; Gardner 2011; Gardner 2012; Kakkos 2005; Parr 2009; Stewart 2008; Treat-Jacobson 2009) measured adherence to the exercise program by registering absence in the supervised groups. In the non-supervised groups, attendance was noted in three trials on the basis of self-reported logbooks (Cheetham 2004; Gardner 2011; Treat-Jacobson 2009).

Participant-reported outcomes were taken into account in nine trials (Cheetham 2004; Collins 2011; Gardner 2011; Gardner 2012; Kakkos 2005; Nicolai 2010; Patterson 1997; Regensteiner 1997; Savage 2001). The Medical Outcomes Study (MOS) Short Form (SF)-36 was used in seven trials (Cheetham 2004; Collins 2011; Gardner 2011; Kakkos 2005; Nicolai 2010; Patterson 1997; Savage 2001); the MOS SF-20 was used in the trial of Regensteiner (Regensteiner 1997). Additionally, the Walking Impairment Questionnaire (WIQ) was used in four trials (Gardner 2011; Gardner 2012; Kakkos 2005; Nicolai 2010), the Intermittent Claudication Questionnaire (ICQ) in one trial (Kakkos 2005), the Geriatric Depression Scale (GDS) in one trial (Collins 2011), and the Charing Cross Claudication Questionnaire (CCCQ) in one trial (Cheetham 2004).

Excluded studies

For this update, 34 additional studies were excluded (Ciuffetti 1994; Collins 2005; Crowther 2008; Dahllöf 1976; Degischer 2002; Fakhry 2011; Fowler 2002; Gardner 2005; Greenhalgh 2008; Grizzo 2011; Hobbs 2007; Krause 1974; Kruidenier 2011; Leicht 2011; Leon 2005; Manfredini 2008; McDermott 2009; Menêses 2011; Mika 2005; Mika 2006; Mika 2011; Murphy 2012; Nielsen 1975; Nielsen 1977; Ritti-Dias 2010; Saxton 2011; Schlager 2011; Schlager 2012; Spronk 2009; Tebbutt 2011; Tew 2009; Walker 2000; Wood 2006; Zwierska 2005). A summary of the excluded studies can be found in the table entitled Characteristics of excluded studies. Overall, 53 studies were excluded. Thirty-two studies compared SET with a non-exercising group or a group that maintained usual care with or without usual medical care. Seven trials (Ciuffetti 1994; Gardner 2005; Grizzo 2011; Krause 1974; Lepantalo 1991; Menêses 2011; Ritti-Dias 2010) compared SET with another kind of supervised therapy, and six studies compared SET with an invasive procedure (Gelin 2001; Kruidenier 2011; Murphy 2012; Spronk 2009; Taft 2001; Taft 2004). Four trials (Fowler 2002; Leon 2005; Manfredini 2008; Tebbutt 2011) compared home-based exercise therapy with walk advice. In another study (Tisi 1997), participants were treated with a 4-week SET program. Five trials (Degischer 2002; Fakhry 2011; Nielsen 1975; Nielsen 1977; Wind 2007) were excluded because they used a non-randomized study design. Three of these had been classified as included studies in the original review (Degischer 2002; Nielsen 1975; Nielsen 1977). However, because a greater number of eligible studies were available, we decided to include RCT designs only in the current update.

Ongoing studies

One trial (Frans 2012) was a description of a study protocol.

Risk of bias in included studies

See Figure 1; Figure 2.

Figure 1.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Sequence generation

Four studies did not detail the process of sequence generation (Patterson 1997; Regensteiner 1997; Savage 2001; Treat-Jacobson 2009). All others (Cheetham 2004; Collins 2011; Gardner 2011; Gardner 2012; Hodges 2008; Kakkos 2005; Nicolai 2010; Parr 2009; Sanderson 2006; Stewart 2008) described an adequate sequence generation.

Concealment of allocation

Five studies described adequate concealment of allocation, using sealed opaque envelopes or a computer program with or without block randomization (Gardner 2011; Gardner 2012; Nicolai 2010; Sanderson 2006; Stewart 2008). Allocation concealment was not detailed in the remaining nine studies (Cheetham 2004; Collins 2011; Hodges 2008; Kakkos 2005; Parr 2009; Patterson 1997; Regensteiner 1997; Savage 2001; Treat-Jacobson 2009).

Blinding

In trials that compared exercise programs with walking distance as the primary outcome, blinding of staff and participants is not possible and therefore was not considered. Two trials were judged to have a low risk of detection bias because a blinded analysis of the outcomes was performed (Cheetham 2004; Nicolai 2010).

Incomplete outcome data

All included studies reported results of predefined primary outcome variables. Nicolai et al reported additional outcome variables, which were not published (Nicolai 2010). However, through contact with the author, these unpublished data were obtained. Five trials reported an intention-to-treat analysis (Collins 2011; Gardner 2011; Gardner 2012; Kakkos 2005; Nicolai 2010), and six other trials reported no dropouts or had minimal loss to follow-up and therefore did not perform an intention-to-treat analysis (Cheetham 2004; Regensteiner 1997; Sanderson 2006; Savage 2001; Stewart 2008; Treat-Jacobson 2009). Overall, 159 participants were lost to follow-up (15.9%). Two trials were unclear in their attrition bias description (Parr 2009; Patterson 1997), and Hodges et al reported no details on attrition (Hodges 2008).

Selective reporting

Reporting bias was difficult to determine. No study protocols of trials were obtained. All included studies reported commonly used primary outcome parameters, so a low reporting bias was assumed for these outcomes. In one trial, we assessed a high risk of reporting bias (Cheetham 2004). In this study, quality of life was measured with Medical Outcomes Study Short Form 36; however, we could not obtain usable data from the figures. In another trial, reporting bias was just as unclear because quality of life was reported in a "Physical function score" only (Gardner 2011). Only one author replied with unpublished SF-36 data (Nicolai 2010).

Other potential sources of bias

To detect publication bias, we analyzed the two best represented outcome variables (maximal walking distance at three and six months) with the use of funnel plots (Figure 3; Figure 4). No asymmetrical plots were observed, leading to the conclusion that publication bias was minimal. Seven trials were judged to have an unclear risk of potential bias. The work of Collins 2011 was funded by the American Diabetes Association; however, no potential conflicts of interest relevant to this article were reported. Two studies by Gardner et al (Gardner 2011; Gardner 2012) could be influenced by participation bias. Participants in these trials were volunteers; therefore, they may represent those more interested in exercise. Four other trials reported data in interquartile range (IQR) format, which had to be recalculated; this could have led to potential bias (Kakkos 2005; Nicolai 2010; Patterson 1997; Stewart 2008). All other trials were judged to have low risk (Cheetham 2004; Hodges 2008; Parr 2009; Regensteiner 1997; Sanderson 2006; Savage 2001; Treat-Jacobson 2009).

Figure 3.

Funnel plot of comparison: 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, outcome: 1.2 Maximal treadmill walking distance after 3 months.

Figure 4.

Funnel plot of comparison: 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, outcome: 1.3 Maximal treadmill walking distance after 6 months.

Effects of interventions

Primary outcome

Maximal treadmill walking distance or time

Data on maximal treadmill walking distance after six weeks of exercise therapy were available in five trials (Gardner 2012; Hodges 2008; Kakkos 2005; Parr 2009; Sanderson 2006) with a total sample size of 234 participants. This outcome was repeated after three months in nine trials (n = 592) (Cheetham 2004; Gardner 2011; Hodges 2008; Nicolai 2010; Patterson 1997; Regensteiner 1997; Savage 2001; Stewart 2008; Treat-Jacobson 2009), after six months (n = 686) in nine trials (Cheetham 2004; Collins 2011; Gardner 2012; Kakkos 2005; Nicolai 2010; Patterson 1997; Savage 2001; Stewart 2008; Treat-Jacobson 2009), after nine months (n = 308) in two trials (Cheetham 2004; Nicolai 2010), and after 12 months (n = 321) in three trials (Cheetham 2004; Kakkos 2005; Nicolai 2010).

We calculated the effect estimates after standardization of mean differences. At six weeks, the maximal treadmill walking distance was increased with an overall effect size (ES) of 0.52 (95% confidence interval (CI) 0.24 to 0.81) when the fixed-effect model was used in favor of the SET group. At three months, the overall effect size increased to 0.69 (95% CI 0.51 to 0.86). This translates to a difference in favor of the supervised group of approximately 180 m in increased walking distance, corresponding with an approximately 35% to 40% difference in increase between the groups. At six months, this effect was maintained with an overall effect size of 0.48 (95% CI 0.32 to 0.64). In two trials in which the outcomes were repeated, the effect was present at nine months (ES 0.60, 95% CI 0.36 to 0.85) (Cheetham 2004; Nicolai 2010) and 12 months after exercise therapy (ES 0.61, 95% CI 0.37 to 0.84) (three trials: Cheetham 2004; Kakkos 2005; Nicolai 2010).

We performed a subgroup analysis at three months and six months of follow-up by splitting the non-supervised group into a walking advice group and a home-based exercise group. At three months, the difference favored the supervised group, with an ES of 0.76 (95% CI 0.56 to 0.96) and 0.50 (95% CI 0.17 to 0.83) for the walking advice group and the home-based group, respectively. No significant difference was found between the two subgroups (P = 0.19). At six months, the supervised exercise group was still in favor compared with both non-supervised groups. In addition, we found no significant differences between the two subgroups (P = 0.78).

At six weeks, non-significant heterogeneity was noted with an I2 of 27% (P = 0.24). At three months, moderate heterogeneity was observed (I2 = 43%; P = 0.07). Use of the random-effects model for the results after three months resulted in a similar overall effect size of 0.69 (95% CI 0.43 to 0.94), indicating that this heterogeneity is of non-importance. At six months, significant heterogeneity was seen (I2 = 71%; P = 0.0006). With a random-effects model, the effect size was increased from 0.48 to 0.58 (95% CI 0.24 to 0.91). This heterogeneity is likely due to the negative trial of Collins (Collins 2011). When a sensitivity analysis was performed by excluding this trial, a non-important heterogeneity was achieved (I2 = 25%; P = 0.23). At other time points, moderate heterogeneity was noted at nine months (I2 = 82%; P = 0.02) and at 12 months (I2 = 64%; P = 0.06).

Secondary outcomes

Pain-free treadmill walking distance or time

Data on pain-free treadmill walking distance after six weeks were available in four trials (Gardner 2012; Kakkos 2005; Parr 2009; Sanderson 2006) with a total sample size of 171. This outcome was repeated after three months in seven trials (n = 479) (Gardner 2011; Nicolai 2010; Patterson 1997; Regensteiner 1997; Savage 2001; Stewart 2008; Treat-Jacobson 2009), at six months in eight trials (n = 630) (Collins 2011; Gardner 2011; Kakkos 2005; Nicolai 2010; Patterson 1997; Savage 2001; Stewart 2008; Treat-Jacobson 2009), and at 12 months after exercise therapy in two trials (Kakkos 2005; Nicolai 2010) (n = 266).

We calculated the effect estimates after standardization of the mean differences. At six weeks, the pain-free treadmill walking distance was increased, with an overall effect size of 0.51 (95% CI 0.18 to 0.84), when the fixed-effect model was used in favor of the SET group. At three months, the overall effect size increased to 0.70 (95% CI 0.52 to 0.89). This translates to a difference in favor of the supervised group of approximately 150 m in increased pain-free walking distance. At six months and twelve months, this effect was maintained, with an overall effect size of 0.52 (95% CI 0.35 to 0.69) and 0.50 (95% CI 0.24 to 0.76), respectively.

We again performed a subgroup analysis in the non-supervised group at three months and six months of follow-up. At three months, the difference favored the supervised group, with an ES of 0.72 (95% CI 0.49 to 0.94) and 0.65 (95% CI 0.29 to 1.01) for the walking advice group and the home-based group, respectively. No significant differences were found between the two subgroups (P = 0.76). At six months of follow-up, the SET group was still in favor, with an ES of 0.45 (95% CI 0.27 to 0.63) and 1.04 (95% CI 0.54 to 1.53) compared with the walk advice group and the home-based exercise group, respectively. However, a significant difference (P = 0.03) between the non-supervised subgroups was found in favor of the home-based group.

No statistical heterogeneity was observed at six weeks (I2 = 0%; P = 0.45), at three months (I2 = 0%; P = 0.56), and at 12 months (I2 = 0%; P = 0.54). However, at six months, substantial heterogeneity was reported (I2 = 64%; P = 0.007). After a sensitivity analysis that excluded the negative trial of Collins (Collins 2011), we found an unimportant heterogeneity (I2 = 16%; P = 0.30).

Mortality

In five of the fourteen trials (Cheetham 2004; Kakkos 2005; Nicolai 2010; Patterson 1997; Stewart 2008), a total of thirteen participants died during the course of the study. In the trial of Patterson 1997, nothing is mentioned about the cause of death of the two participants who died during follow-up (both from the supervised group). Cheetham 2004 registered two deaths (one from each group), neither of which could be attributed to a vascular event. Kakkos (Kakkos 2005) described one death. This person died as the result of acute leg ischemia after undergoing an operation for bladder cancer. Nicolai et al mentioned three deceased people in the control group (coronary heart disease (n = 2), renal cell carcinoma (n = 1)) and four deaths in the supervised group (complication lower extremity bypass surgery (n = 1), lung carcinoma (n = 1), ruptured abdominal aortic aneurysm (n = 1), pancreatic cancer (n = 1)) (Nicolai 2010). One death occurred in the control group of Stewart (Stewart 2008). No deaths were reported in the remaining trials.

Adherence to exercise program

Five trials (Cheetham 2004; Gardner 2011; Gardner 2012; Parr 2009; Stewart 2008) studied adherence to exercise training. Cheetham 2004 simply asked participants whether they walked "less than three times", "three times", or "more than three times" a week. Twice as many participants in the SET group as in the non-supervised group claimed to be walking more than three times a week. Gardner 2011 provided participants with a step activity monitor, and they were instructed to wear it for each exercise session. Additionally, participants received an exercise logbook in which they were to record their walking sessions. Adherence to home-based exercise and supervised exercise was similar (82.5% vs 84.8% completion of exercise sessions, respectively). Unfortunately, no adherence data were available from the group that received walking advice at baseline only. The adherence ratio from the exercise group in Gardner 2012 did not differ greatly (74% completion) from that obtained in their earlier research, although a progressive decline in attendance was evident from the first two months to the final stage at six months (from 86% to 63%). Kakkos 2005, Parr 2009, and Stewart 2008 noted the attendance of the supervised group only (mean attendance: 60%, 80%, and 89%, respectively). Treat-Jacobson 2009 revealed an adherence of 100% in 61% of participants in the SET group, and 97% of participants completed at least 75% of the prescribed training. Conversely, 75% of control group participants reported participation in outside exercise at least three times a week.

Patient-reported outcomes (quality of life)

In this update, we calculated the effect estimates after standardization of mean differences in SF-36 outcomes after three and six months. The SF-36 was used in seven trials after three months (Cheetham 2004; Collins 2011; Gardner 2011; Kakkos 2005; Nicolai 2010; Patterson 1997; Savage 2001), and the MOS SF-20 in the trial of Regensteiner (Regensteiner 1997). However, Collins 2011 and Cheetham 2004 published SF-36 results as a change from baseline, but they were not usable. We contacted the study authors but were not able to obtain raw or unpublished data. Results of the physical function role were presented in five trials (Gardner 2011; Nicolai 2010; Patterson 1997; Regensteiner 1997; Savage 2001); both social function and the emotional role were noted in four trials (Nicolai 2010; Patterson 1997; Regensteiner 1997; Savage 2001); and the remaining roles were mentioned in three trials (Nicolai 2010; Patterson 1997; Savage 2001). The role "general health" showed significant improvement with supervised exercise (ES 0.30, 95% CI 0.05 to 0.55) only. The other roles showed a positive trend toward the intervention; however, these changes are not statistically significant. A subanalysis of non-supervised exercise programs could not be made because of the small number of studies.

SF-36 outcomes at six months were obtained in four trials (Kakkos 2005; Nicolai 2010; Patterson 1997; Savage 2001). Again, almost all roles showed a positive trend toward supervised exercise, except for the role of "pain", which revealed a significant positive change (ES 0.25, 95% CI 0.00 to 0.49). SF-36 outcomes at other time periods were not used because they could be obtained only from unpublished data of Nicolai 2010 and summary data of Kakkos 2005.

No statistical heterogeneity was noted in all quality of life analyses, except for the vitality role, at three months' follow-up (I2 = 79%; P = 0.008). Use of random-effects models resulted in a somewhat increased overall effect size from 0.05 to 0.30 (95% CI -0.43 to 1.03), indicating that no important heterogeneity was present.

Using the CCCQ, Cheetham 2004 reported a statistically significant difference between the two groups (P < 0.05) after nine months of exercise in favor of the SET group. Intragroup analyses of the WIQ and the ICQ showed less improvement or even reduction in the non-supervised group compared with an increase in score in the supervised group (Kakkos 2005; Regensteiner 1997). However, these changes were not compared between groups (Kakkos 2005; Regensteiner 1997).

Discussion

Summary of main results

Primary outcome

We included data from 14 randomized trials enrolling a total of 1002 participants. Statistically significant and clinically relevant differences in improvement in walking distance were consistently demonstrated in favor of SET compared with non-supervised exercise therapy regimens during the first year of treatment. A subanalysis was performed to investigate the influence of two types of non-supervised exercise regimens. No significant differences were found between "go home and walk" advice and a more structural home-based exercise program. Despite the variability of prescribed exercise training and treadmill walking tests used to measure the outcome, heterogeneity was present only for the results of the maximal treadmill walking distance after six months. This is likely a result of the negative trial of Collins (Collins 2011). Indeed removing this trial from the analysis resulted in the absence of statistical heterogeneity. In addition to chance alone, several factors could contribute to the observed heterogeneity. First, the supervised exercise regimen used by Collins was described as home-based exercise and consisted of once-a-week supervised training only, thereby reducing the intensity of supervision compared with the other trials, which trained three times a week or biweekly (Stewart 2008). Furthermore, in the trial of Collins (Collins 2011), all participants had diabetes mellitus.

Reported data on walking time and distance were standardized to allow calculation of the difference in increase between the two treatment groups. When the standardized data were translated back to walking distances, summary estimates of maximal treadmill walking distance showed a difference in increase of approximately 180 m in favor of the SET regimens over non-supervised therapy for three months. This difference was maintained at six, nine, and twelve months.

Secondary outcomes

In line with maximal walking distance, pain-free walking distance was more increased by supervised exercise than non-supervised exercise during the first year of treatment, with a maximal effect size of 0.76 (95% CI 0.57 to 0.95) at three months. This effect was maintained at six and twelve months. A significant difference was found in the subanalysis between "go home and walk" advice and a more structured home-based exercise program, probably as a result of the SET negative trial of Collins (Collins 2011). Furthermore, significant heterogeneity was found at six months. A sensitivity analysis excluding the trial of Collins (Collins 2011) resulted in non-important heterogeneity and no significant difference between the two non-supervised exercise types. No obvious results in mortality registration were obtained. Thirteen of the 1002 participants died, but none of these deaths were related to exercise therapy. Participant-related outcomes (SF-36) were not significantly different between the two exercise regimens. This could be explained by an underpowered analysis. We obtained complete SF-36 data from three studies (n = 245) at three months of follow-up (Nicolai 2010; Patterson 1997; Savage 2001) and from four trials at six months of follow-up (n = 258) (Kakkos 2005; Nicolai 2010; Parr 2009; Savage 2001). Five other studies did record SF-36 outcomes; however, we were not able to obtain the raw data. This could have led to a potential publication bias.

Overall completeness and applicability of evidence

Participants

Both inclusion and exclusion criteria were variable across studies, but they did not differ very widely from daily practice. Regensteiner 1997 included solely male participants, and Collins 2011 included participants with diabetes mellitus only.

Interventions

Most included studies were performed in hospital settings all over the world. One trial provided supervised exercise in part at the hospital and in part at home (Collins 2011). Another used community-based supervised exercise (Nicolai 2010). Kruidenier concluded that community-based SET appeared to be as effective as hospital-based SET, so it seems unlikely that these potential factors of heterogeneity limit the applicability of the results (Kruidenier 2009). In three trials, training sessions were complemented by strength training (Cheetham 2004; Parr 2009; Patterson 1997), and one trial was based on exercise therapy of the lower extremity without treadmill walking (Stewart 2008). There were no indications that these supervised sessions were less stringent than in the other studies. The effectiveness of different modes of exercise will be compared in another Cochrane review (Lauret 2012b). Six trials had a follow-up period without supervision. After a sensitivity analysis was performed by removing four trials with a non-supervised follow-up period (n = 350; Patterson 1997; Savage 2001; Stewart 2008; Treat-Jacobson 2009), effect size at six months did decrease slightly from 0.48 (95% CI 0.32 to 0.64) to 0.45 (95% CI 0.27 to 0.63). This suggests that exercise therapy with a period of supervision could have a prolonged effect on increasing walking distance and could be as effective as that described in trials with a full follow-up trajectory.

Comparator

This review compared supervised with non-supervised exercise therapy. We found that non-supervised regimens showed a lot of heterogeneity from simple walking advice at the start of treatment to a structured home-based exercise program with some form of remote "supervision". Therefore, we performed a subanalysis within the non-supervised exercise group, which was divided into a "go home and walk" advice group and a home-based exercise group. In one three-armed trial (Gardner 2011), the results of the control group and those of the home-based treated exercise group were compared with results of the supervised group by splitting the supervised group into two groups.

Outcomes

All trials used treadmill exercise to investigate the effectiveness of supervision. Only three trials used a fixed protocol. Furthermore, we used standardized mean differences to reduce potential heterogeneity caused by differences in treadmill testing. To reduce heterogeneity in secondary outcomes, we used SF-36 values only for participant-reported outcomes.

Applicability

To determine the clinical relevance of the ability to walk 180 m farther, one should realize that a mean maximal walking distance at baseline is approximately 300 m with an even shorter pain-free walking distance of approximately 200 m. Regular exercise, such as walking, has been shown to significantly reduce cardiovascular events (Izquierdo 2000; Wannamathee 2001). Because claudicants have high cardiovascular morbidity and mortality (30% mortality at five years) (Aquino 2001; Dormandy 1999; Hooi 2002), a habit of regular walking with increased exercise capacity could be of considerable importance. Results of our review reveal increased ability to perform on a treadmill. However, such an increase might not have any influence on walking behavior in daily life because some studies have found that supervised exercise does not affect day-to-day walking behavior (Crowther 2008; McDermott 2009).

Quality of the evidence

Unfortunately, the raw data from one study (Cheetham 2004) were not directly available and had to be derived by working backward from the reported P values. We assumed that the standard deviations of both groups were equal. Compared with other trials that reported equal standard deviations, this seemed reasonable. The data of Patterson (Patterson 1997) were extracted from the accompanying figures. Previously included non-randomized studies were excluded (Degischer 2002; Nielsen 1975; Nielsen 1977). Other detailed information of quality is presented in the Assessment of risk of bias in included studies. We noted two important limitations in the quality of the evidence. The nature of the interventions made participant blinding effectively impossible. In addition, participation bias may have influenced the results, in that enrollment in a study motivated participants to walk (Collins 2011).

Potential biases in the review process

Unfortunately, heterogeneity was noted in the non-supervised comparator group. We tried to minimize this by introducing a subgroup analysis. Furthermore, because of differences in inclusion and exclusion criteria, such as age or gender restrictions or the presence of diabetes mellitus and smoking behavior, generalization of the results of this meta-analysis could be a topic of discussion. Not all outcome data were available for inclusion. This potentially introduced bias into our review and may reflect publication bias. Therefore, we conducted a formal analysis of publication bias by using a funnel plot. It is suggested from this analysis that publication bias is not a matter of importance (Figure 3; Figure 4).

Agreements and disagreements with other studies or reviews

Several other systematic reviews have been performed that are in line with our findings. Watson et al suggested that exercise therapy should play an important part in the care of selected patients with intermittent claudication, to improve walking times and distances. Effects were demonstrated after three months of supervised exercise, although some programs lasted longer than one year (Watson 2008). Wind et al concluded that SET increases pain-free and absolute walking distances in participants with intermittent claudication as well (Wind 2007). A recent review of Fakhry et al. compared supervised exercise with no interventional observation. The authors concluded that supervised exercise yielded significant clinical benefit (Fakhry 2012).

Several plausible mechanisms might explain the beneficial results of SET over non-supervised regimens. A first explanation could be the fact that the exercise regimen of the SET group mainly consisted of treadmill walking, which involves a higher workload than level ground walking at "normal" speed as used by the non-supervised group (Degischer 2002). It is very difficult to measure the intensity of training, but it is generally assumed that home training cannot be considered to be performed with the same energy as training under supervision (Nielsen 1975). Second, a higher workload will lead to a larger positive effect of the general physical condition of the patient, possibly as the result of increased cardiovascular stress, providing a better stimulus for exercise-induced adaptations (Hamburg 2011). Furthermore, a supervised program could offer additional encouragement and motivation to patients resulting in a higher adherence rate, which can be explained in part by the Hawthorne effect as mentioned by Wind et al (Wind 2007). The Hawthorne effect describes the effect that the awareness of being under observation can alter the way a patient behaves or can positively influence the outcome. Nevertheless, when adherence is taken into account, and on the basis of the contrasting results between two trials (Cheetham 2004; Gardner 2011), nothing can be suggested about the influence of a supervised exercise regimen on adherence. However, adherence in a supervised exercise setting is effortlessly measurable during the session in contrast to adherence during home-based intervals or in home-based settings.

Authors' conclusions

Implications for practice

Supervised exercise therapy provides statistically significant benefits for treadmill walking distance when compared with non-supervised regimens. The clinical relevance of this difference requires additional studies with a focus on quality of life or other disease-specific functional outcomes, such as walking behavior, patient satisfaction, and costs. The results of this review are consistent with those of previously performed studies and meta-analyses. All indicate that SET is an effective treatment that should be available as part of the care of patients with intermittent claudication. However, the availability of SET in clinical practice is far from optimal (Lauret 2012a; Makris 2012; Nicolai 2010; Shalhoub 2009). Professionals in the vascular field are obliged to take action to make supervised exercise therapy that is community or hospital based available for all patients with intermittent claudication.

Implications for research

Research to optimize exercise program components (eg, duration, exercise intensity, different modes of exercise, endurance training vs interval training, implementation of lifestyle interventions) is needed. Future research should include people who have a more severe stage of PAD and other comorbidities, as this is more representative of the PAD population.

Most of the included studies in this review have focused on treadmill hospital-based exercise, although the effectiveness of community-based exercise programs is an interesting consideration for future research (Kruidenier 2009), particularly because some form of conservative treatment should be initiated before an invasive revascularization is performed (Hirsch 2006; Norgren 2007). Others have shown that access to a conservative supervised exercise program is low across Europe (UK: 36.4%; Germany: 46.7%; Greece: 10%) (Makris 2012). Research is needed to investigate the effects of community-based exercise programs on walking behavior, physical activity, and costs, and their long-term effects on morbidity, cardiovascular risk factors, and mortality (eg, the ClaudicatioNet concept, which was launched in The Netherlands; 100% SET access; Makris 2012). The concept aims to implement nationwide coverage of regional networks that provide quality care according to contemporary guidelines for patients with PAD (Fokkenrood 2012; Lauret 2012a).

Acknowledgements

We acknowledge the help and infrastructure provided by the Department of Vascular Surgery of the Catharina Hospital, in particular, Nicole Verhofstad, PhD, Pieter Broos, MD, and Saskia Houterman, epidemiologist. We acknowledge the help provided by Dr Marlene Stewart, Managing Editor, and Dr Karen Welch, Trials Search Co-ordinator, of the Cochrane Peripheral Vascular Diseases Group, and their support in updating this review.

Data and analyses

Download statistical data

Comparison 1. Walking distances: Supervised exercise therapy versus non-supervised exercise therapy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Maximal treadmill walking distance after 6 weeks5234Std. Mean Difference (IV, Fixed, 95% CI)0.52 [0.24, 0.81]
2 Maximal treadmill walking distance after 3 months9592Std. Mean Difference (IV, Fixed, 95% CI)0.69 [0.51, 0.86]
2.1 Walking advice5439Std. Mean Difference (IV, Fixed, 95% CI)0.76 [0.56, 0.96]
2.2 Home-based exercise5153Std. Mean Difference (IV, Fixed, 95% CI)0.50 [0.17, 0.83]
3 Maximal treadmill walking distance after 6 months9686Std. Mean Difference (IV, Fixed, 95% CI)0.48 [0.32, 0.64]
3.1 Walking advice6612Std. Mean Difference (IV, Fixed, 95% CI)0.46 [0.29, 0.63]
3.2 Home-based exercise374Std. Mean Difference (IV, Fixed, 95% CI)0.68 [0.20, 1.16]
4 Maximal treadmill walking distance after 9 months2308Std. Mean Difference (IV, Fixed, 95% CI)0.60 [0.36, 0.85]
5 Maximal treadmill walking distance after 12 months3321Std. Mean Difference (IV, Fixed, 95% CI)0.61 [0.37, 0.84]
6 Pain-free treadmill walking distance after 6 weeks4171Std. Mean Difference (IV, Fixed, 95% CI)0.51 [0.18, 0.84]
7 Pain-free treadmill walking distance after 3 months7508Std. Mean Difference (IV, Fixed, 95% CI)0.70 [0.52, 0.89]
7.1 Walking advice3355Std. Mean Difference (IV, Fixed, 95% CI)0.72 [0.49, 0.94]
7.2 Home-based exercise5153Std. Mean Difference (IV, Fixed, 95% CI)0.67 [0.33, 1.00]
8 Pain-free treadmill walking distance after 6 months8630Std. Mean Difference (IV, Fixed, 95% CI)0.52 [0.35, 0.69]
8.1 Walking advice5556Std. Mean Difference (IV, Fixed, 95% CI)0.45 [0.27, 0.63]
8.2 Home-based exercise374Std. Mean Difference (IV, Fixed, 95% CI)1.04 [0.54, 1.53]
9 Pain-free treadmill walking distance after 12 months2266Std. Mean Difference (IV, Fixed, 95% CI)0.50 [0.24, 0.76]
Analysis 1.1.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 1 Maximal treadmill walking distance after 6 weeks.

Analysis 1.2.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 2 Maximal treadmill walking distance after 3 months.

Analysis 1.3.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 3 Maximal treadmill walking distance after 6 months.

Analysis 1.4.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 4 Maximal treadmill walking distance after 9 months.

Analysis 1.5.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 5 Maximal treadmill walking distance after 12 months.

Analysis 1.6.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 6 Pain-free treadmill walking distance after 6 weeks.

Analysis 1.7.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 7 Pain-free treadmill walking distance after 3 months.

Analysis 1.8.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 8 Pain-free treadmill walking distance after 6 months.

Analysis 1.9.

Comparison 1 Walking distances: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 9 Pain-free treadmill walking distance after 12 months.

Comparison 2. Quality of life: Supervised exercise therapy versus non-supervised exercise therapy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Physical function role in Short Form 36 after 3 months5327Std. Mean Difference (IV, Fixed, 95% CI)0.06 [-0.16, 0.27]
2 Physical role in Short Form 36 after 3 months3245Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.28, 0.23]
3 Pain role in Short Form 36 after 3 months3245Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.07, 0.43]
4 General health role in Short Form 36 after 3 months3245Std. Mean Difference (IV, Fixed, 95% CI)0.30 [0.05, 0.55]
5 Vitality role in Short Form 36 after 3 months3245Std. Mean Difference (IV, Fixed, 95% CI)0.05 [-0.20, 0.31]
6 Social function role in Short Form 36 after 3 months4265Std. Mean Difference (IV, Fixed, 95% CI)0.17 [-0.08, 0.41]
7 Emotional role in Short Form 36 after 3 months4265Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.07, 0.42]
8 Mental health role in Short Form 36 after 3 months3245Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.07, 0.43]
9 Physical function role in Short Form 36 after 6 months4258Std. Mean Difference (IV, Fixed, 95% CI)0.24 [-0.01, 0.48]
10 Physical role in Short Form 36 after 6 months4258Std. Mean Difference (IV, Fixed, 95% CI)0.10 [-0.14, 0.35]
11 Pain role in Short Form 36 after 6 months4258Std. Mean Difference (IV, Fixed, 95% CI)0.25 [0.00, 0.49]
12 General health role in Short Form 36 after 6 months4258Std. Mean Difference (IV, Fixed, 95% CI)0.10 [-0.15, 0.34]
13 Vitality role in Short Form 36 after 6 months4258Std. Mean Difference (IV, Fixed, 95% CI)0.18 [-0.07, 0.43]
14 Social function role in Short Form 36 after 6 months4258Std. Mean Difference (IV, Fixed, 95% CI)0.08 [-0.17, 0.33]
15 Emotional role in Short Form 36 after 6 months4258Std. Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.29, 0.21]
16 Mental health role in Short Form 36 after 6 months4258Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-0.12, 0.38]
Analysis 2.1.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 1 Physical function role in Short Form 36 after 3 months.

Analysis 2.2.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 2 Physical role in Short Form 36 after 3 months.

Analysis 2.3.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 3 Pain role in Short Form 36 after 3 months.

Analysis 2.4.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 4 General health role in Short Form 36 after 3 months.

Analysis 2.5.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 5 Vitality role in Short Form 36 after 3 months.

Analysis 2.6.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 6 Social function role in Short Form 36 after 3 months.

Analysis 2.7.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 7 Emotional role in Short Form 36 after 3 months.

Analysis 2.8.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 8 Mental health role in Short Form 36 after 3 months.

Analysis 2.9.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 9 Physical function role in Short Form 36 after 6 months.

Analysis 2.10.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 10 Physical role in Short Form 36 after 6 months.

Analysis 2.11.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 11 Pain role in Short Form 36 after 6 months.

Analysis 2.12.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 12 General health role in Short Form 36 after 6 months.

Analysis 2.13.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 13 Vitality role in Short Form 36 after 6 months.

Analysis 2.14.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 14 Social function role in Short Form 36 after 6 months.

Analysis 2.15.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 15 Emotional role in Short Form 36 after 6 months.

Analysis 2.16.

Comparison 2 Quality of life: Supervised exercise therapy versus non-supervised exercise therapy, Outcome 16 Mental health role in Short Form 36 after 6 months.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Arteriosclerosis] this term only 893
#2 MeSH descriptor: [Arteriolosclerosis] this term only 0
#3 MeSH descriptor: [Arteriosclerosis Obliterans] this term only 71
#4 MeSH descriptor: [Atherosclerosis] this term only 377
#5 MeSH descriptor: [Arterial Occlusive Diseases] this term only 753
#6 MeSH descriptor: [Intermittent Claudication] this term only 708
#7 MeSH descriptor: [Ischemia] this term only 746
#8 MeSH descriptor: [Peripheral Vascular Diseases] explode all trees 2137
#9 atherosclero* or arteriosclero* or PVD or PAD or PADatherosclero* or arteriosclero* or PVD or PAD or PAD 16413
#10 (arter* or vascular or vein* or veno* or peripher*) near (occlus* or reocclus* or re-occlus* or steno* or obstruct* or lesio* or block* or harden* or stiffen*) 7845
#11 peripheral near/3 dis* 3147
#12 claudic* or IC 3311
#13 isch* or CLI 16581
#14 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 39856
#15 MeSH descriptor: [Exercise] explode all trees 8957
#16 MeSH descriptor: [Exercise Therapy] explode all trees 5384
#17 MeSH descriptor: [Physical Exertion] this term only 3150
#18 MeSH descriptor: [Sports] explode all trees 7301
#19 MeSH descriptor: [Exercise Movement Techniques] explode all trees 900
#20 MeSH descriptor: [Locomotion] explode all trees 3585
#21 MeSH descriptor: [Leisure Activities] this term only 157
#22 MeSH descriptor: [Fitness Centers] this term only 19
#23 MeSH descriptor: [Physical Exertion] this term only 3150
#24 (physical near/3 (exertion or endurance or therap* or conditioning or activit* or fitness)):ti,ab,kw 14648
#25 exercis* 37884
#26 (fitness near/3 (intervention* or protocol* or program* or therap* or activit* or regim* or centre* or center*)):ti,ab,kw 617
#27 activit* 58809
#28 (walk* or run* or treadmill or aerobic or swim* or danc*):ti,ab,kw 19240
#29 kinesiotherap*:ti,ab,kw 205
#30 ((endurance or aerobic or cardio*) near/3 (fitness or train* or intervention* or protoco* or program* or therap* or activit* or regim*)):ti,ab,kw 5983
#31 train* 30407
#32 #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 117506
#33 #14 and #32 7080 in Trials

What's new

DateEventDescription
4 February 2013New search has been performedSearches were rerun and the review updated. Nine additional studies included and 34 additional studies excluded
4 February 2013New citation required but conclusions have not changedSearches were rerun and the review updated. Nine additional studies included and 34 additional studies excluded. Risk of bias tables completed. Conclusions not changed. Two new authors joined the review team

History

Protocol first published: Issue 2, 2005
Review first published: Issue 2, 2006

DateEventDescription
26 September 2008AmendedConverted to new review format.
14 November 2006AmendedEdited to amend CDSR citations.

Contributions of authors

Dr Hugo JP Fokkenrood selected trials, assessed trial quality, extracted data, performed data analysis, and wrote the text of the review.

Dr Bianca LW Bendermacher selected trials, assessed trial quality, extracted data, and wrote the text of the review.

Dr Gert Jan Lauret revised text, helped with data analysis, and assessed trial quality.

Dr Edith M Willigendael revised text.

Professor Martin H Prins confirmed the suitability and quality of trials and helped with data analysis.

Professor Dr Joep AW Teijink revised text and confirmed the suitability of trials.

Declarations of interest

MP reports his institution has received funds for his Board membership of clinical studies and consultancy from Bayer, Boeringer Ingelheim, Daiichi Sankyo, Pfizer and ISIS Pharmaceuticals. These were not related to this review.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

    The PVD Group editorial base is supported by the Chief Scientist Office

  • National Institute for Health Research (NIHR), UK.

    The PVD Group editorial base is supported by a program grant from the NIHR

Differences between protocol and review

Because of the larger number of eligible studies, we decided to include RCT designs only in the current update, although in the previous review, controlled trials were included. Three studies (Degischer 2002; Nielsen 1975; Nielsen 1977) that had been included in the previous version were excluded.

The Rutherford classification is used increasingly to define PAD. Therefore, we decided to add this classification to our inclusion criteria.

Because of our extended quality of life assessment, we removed the secondary outcome "functional status".

We have rephrased the secondary outcome "compliance" to "adherence to exercise program" to avoid misunderstanding of the intended variable.

The methodological quality has been assessed using the risk of bias methodology described by Higgins 2011.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cheetham 2004

MethodsStudy design: randomized prospective controlled trial
Participants

Country: UK

Setting: regional center's vascular outpatient department

No of participants:

  • Baseline: exercise advice group (30), SET group (29);

  • 6 months' follow-up: exercise advice group (28), SET group (28); and

  • 12 months' follow-up: exercise advice group (28), SET group (27)

Age: mean 67 years (range 45 to 86 years); SET group mean 65 years; exercise advice group mean 70 years                                                                                                                                                                                              

Sex: 73% male; 27% female                                                                                   

PAD diagnosed by ABI in rest < 0.9 or fall in ankle pressure after exercise > 30 mmHg; positive Edinburgh claudication questionnaire; positive duplex ultrasound

Inclusion criteria: PAD; a minimum of 6 months' stable IC symptoms; able to walk > 300 m  

Exclusion criteria: severe IC warranting intervention; critical ischemia; significant comorbidity, preventing participation in an exercise program; vascular intervention within previous 2 years; received drugs within previous 6 months to improve symptoms

Interventions

Treatment: supervised ET in a group session weekly for 30 minutes combined with additional exercises. No treadmill walking. Information and the same advice given as in the control group

Control: non-supervised ET based on oral advice to walk 3 times weekly for 30 minutes to near maximal pain combined with additional exercises

Duration: 6 months

Folluw-up period: 6 months

Outcomes

Treadmill test: maximal walking distance (3.5 km/h, 12% slope)

Participant-reported outcomes: Short Form 36 and the Charing Cross Claudication Questionnaire, ABI at rest

Adherence: self-reported

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were allocated by predetermined computer code
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Personnel blinded to the group allocation compiled data." All measurements were made by vascular technologists blinded to the group allocation
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is reported

An ITT analysis was not described and is unclear. However, only 4 of 59 participants were excluded, reducing the likelihood of bias

The authors reported attrition in detail, also with respect to group assignments

The numbers for each intervention group were equal compared with total numbers of randomly assigned participants

Selective reporting (reporting bias)High riskAuthors measured quality of life with Medical Outcomes Study Short Form 36. However, only the role "Physical function score" was reported in the results section. All relevant primary outcomes were described but were calculated on the basis of the P value. Short Form 36 results were not usable
Other biasLow riskNo other forms of bias were detected

Collins 2011

MethodsStudy design: randomized controlled trial
Participants

Country: USA

Setting: participants recruited from vascular outpatient clinics; flyers distributed at health fairs, community centers, and churches

No. of participants:

  • Baseline: exercise advice group (73); SET group (72); and

  • 6 months' follow-up: exercise advice group (65); SET group (64)

Age: exercise advice group: 66.8 (± 10.1); SET group: 66.2 (± 10.2)        

Sex: exercise advice group: 73% male; SET group: 65% male                                       

PAD diagnosed by resting or postexercise ABI < 0.9, toe-brachial index < 0.7, or prior surgery for PAD with leg symptoms

Inclusion criteria:  PAD, age > 40, DM type 1 or 2, leg symptoms captured by San Diego Claudication Questionnaire

Exclusion criteria: participants without a phone, foot or lower leg amputation, critical leg ischemia, revascularization within 6 months before enrollment, significant coronary ischemia, life-threatening malignancy, and within the past year exercise tolerance limited by leg pain of non-vascular origin. Patients who indicated "no intention to start exercising in the next 6 months"

Interventions

Treatment: walk 1 day per week with instructor and walk 3 days per week on their own. Advice: 50 minutes each session, increase the number of steps by 50 each session. Biweekly phone call

Control: educational video about PAD; calendar to document glucose results, blood pressure, and lipid results. Twice-monthly phone calls

Duration: 6 months

Follow-up period: 6 months

Outcomes

Treadmill test: Gardner-Skinner protocol (2 mph on a 0% grade, increasing by 2% every 2 minutes)

Outcome: maximal treadmill walking distance, pain-free walking distance

Participant-reported outcomes: Short Form 36, depressive symptoms (GDS), self-efficacy (SEMCD), WIQ

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomly assigned in permuted blocks
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAuthors described trial as "single-blinded". However, this single-blinded character is not well described
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is reported

An ITT analysis is described

The authors reported attrition in detail also with respect to group assignments

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants

Selective reporting (reporting bias)Low riskIn the methods section, the use of several questionnaires is described. However, no results were reported on the self-efficacy and exercise behaviors questionnaires. These questionnaires are not frequently used in other included studies in this review. All relevant primary and secondary outcomes were described
Other biasUnclear risk"This work was funded by the American Diabetes Association. No potential conflicts of interest relevant to this article were reported"

Gardner 2011

MethodsStudy design: randomized controlled trial
Participants

Country: USA

Setting: Vascular Clinic referrals and newspaper advertisements

No. of participants:

  • Baseline: exercise advice group (39), home-based group (40), SET group (40); and

  • 3 months' follow-up: exercise advice group (30), home-based group (29), SET group (33)

Age: exercise advice group: 65 (± 10) years; home-based group 65 (± 11); SET group: 66 (± 12)        

Sex: exercise advice group: 54% male; home-based group: 45% male; SET group: 45% male

PAD diagnosed by: ABI < 0.90 at rest or ABI < 0.73 after exercise

Inclusion criteria: PAD patients

Exclusion criteria: absence of PAD, inability to obtain an ABI because of noncompressible arteries, asymptomatic PAD during treadmill test, use of cilostazol, exercise tolerance limited by factors other than leg pain, active cancer, renal disease, liver disease

Interventions

Treatment: 3 months, 3 d/wk at a speed of 2 mph. 15 minutes at first 2 weeks increased by 5 minutes biweekly until 40 minutes. Grade equal to 40% of final workload from the baseline treadmill test

Control: encouraged to walk more. No risk factor management or educational programming was provided

Home-based: 3 months, 3 d/wk at a self-selected space, 20 minutes at first 2 weeks increased by 5 minutes biweekly until 45 minutes. Step activity monitor on right ankle, logbook

Duration: 3 months

Follow-up period: none

Outcomes

Treadmill test: Gardner-Skinner protocol (2 mph on a 0% grade, increasing by 2% every 2 minutes)

Outcome: pain-free distance (COT), maximal walking distance, Peak O2 uptake (by calculation),

ambulatory activity monitoring

Participant-reported outcomes: Short Form 36, WIQ, Baltimore Activity Scale

NotesResults of home-based group and control group were pooled and used as non-supervised control group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlocked randomisation with computer program
Allocation concealment (selection bias)Low risk"Study personnel were allowed access to the allocation list only after subject eligibility was determined and baseline data were completed"
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is reported; however, it is not specified

An ITT analysis and a per-protocol analysis are described, as is a comparison to check differences between dropout patterns across groups

The authors did not report attrition

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants

Selective reporting (reporting bias)Unclear riskAuthors measured quality of life with Medical Outcomes Study Short Form 36. However, only the role "Physical function score" was noted in the results section of the study report. All relevant primary outcomes were described
Other biasUnclear risk

Participation bias: Participants who participated in this trial were volunteers and therefore may represent those more interested in exercise

This work was funded by the National Institute of Aging

Gardner 2012

MethodsStudy design: randomized controlled trial
Participants

Country: USA

Setting: outpatient vascular surgery clinics

No. of participants:

  • Baseline: exercise advice group (36); SET group (106); and

  • 6 months' follow-up: exercise advice group (36); SET group (80)

Age: exercise advice group: 68 (± 8) years; SET group: 68 (± 8)

Sex: exercise advice group: 86% male; SET group: 83% male

PAD diagnosed by ABI < 0.9 at rest or 20% decrease in ABI after exercise

Inclusion criteria: history of IC, ambulation during a graded treadmill test limited by claudication, PAD

Exclusion criteria: absence of PAD, asymptomatic PAD, rest pain, inability to obtain an ABI (noncompressible arteries), use of cilostazol and pentoxifylline, exercise tolerance limited by any disease other than PAD, non-adherence with baseline testing, uncontrolled hypertension, uncontrolled diabetes, active cancer, renal insufficiency, abnormal liver function

Interventions

Treatment: 6 months, 3 d/wk, supervised with physiologists and nurses

Control: walking advice at baseline (no risk factor management, no lifestyle advice)

Duration: 6 months

Follow-up period: none

Outcomes

Treadmill test: Gardner-Skinner protocol (2 mph on a 0% grade, increasing by 2% every 2 minutes)

Outcome: maximal walking distance, pain-free walking distance, daily physical activity, peak VO2/ischemic window, calf blood flow, and 6 minute walking test

Participant-reported outcomes: WIQ

NotesOutcomes at 4 months were not used
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number program with blocking
Allocation concealment (selection bias)Low risk"Study personnel were allowed access to the allocation list only after subject eligibility was determined and baseline data were completed"
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. "Study personnel were allowed to the allocation list only after patient eligibility was determined and baseline data were completed"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is reported

An ITT analysis is described

The authors did report attrition

A 3:1 ratio was used to allocate participants to the intervention group or the control group

Selective reporting (reporting bias)Low riskAll relevant primary outcomes were described
Other biasUnclear risk

Participation bias: Participants who participated in this trial were volunteers and therefore may represent those more interested in exercise.

Data at 2 months' follow-up are used in this review in the analysis of 6 week results. This could have introduced a bias

Hodges 2008

MethodsStudy design: randomized controlled trial
Participants

Country: UK

Setting: outpatient vascular surgery clinics

No. of participants:

  • Baseline: exercise advice group (14), SET group (14); and

  • 6 months' follow-up: exercise advice group (14), SET group (14)

Mean age: 68 (± 8) years

Sex: unknown

PAD diagnosed by ABI < 0.9 at rest and Edinburgh Walking Questionnaire

Inclusion criteria: PAD patients

Exclusion criteria: inability to complete familiarization test, poorly controlled hypertension and diabetes, severe CAD (angina at rest), valvular heart disease, COPD

Interventions

Treatment: 12 weeks, twice weekly, 75% of the initial grade achieved during the exercise test, walk until 30 minutes. Walking advice

Control: Walking advice + normal treatment

Duration: 3 months

Follow-up period: none

Outcomes

Treadmill test: 3.2 km/h; 0% grade, increasing by 2% every 2 minutes

Outcome: maximal walking time, cardiac function (VO2, heart rate, cardiac output, respiratory exchange ratio)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA computerized random numbers table was used
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
High risk

Allocation of excluded participants is not reported

An ITT analysis is not described

The authors did not report attrition

Selective reporting (reporting bias)Low riskAll relevant primary outcomes were described
Other biasLow riskNo other forms of bias were detected

Kakkos 2005

MethodsStudy design: randomized controlled trial
Participants

Country: UK

Setting: participants recruited from vascular outpatient clinics

No. of participants:

  • Baseline: exercise advice group (9), SET group (12);

  • 6 months' follow-up: exercise advice group (9), SET (6); and

  • 12 months' follow-up: exercise advice group (9), SET group (4)

Age: exercise advice group: 66 (± 10.5) years; SET group: 69 (± 11.8) years

Sex: exercise advice group: 89% male; SET group: 92% male

PAD diagnosed by duplex, angiography

Inclusion criteria: stable IC for longer than 6 months; superficial femoral artery stenosis ≥ 6 cm in length on duplex and/or angiogram

Exclusion criteria: previous angioplasty or arterial surgery to the symptomatic leg; MI within previous 6 months; inability to manage treadmill examination or training; psychiatric illness or other reason making follow-up difficult; ischemic rest pain; gangrene or ischemic ulceration; severe peripheral neuropathy, ABI > 0.9; non-compressible calf arteries; iliac occlusions or stenoses amenable to surgery or angioplasty; limited exercise capacity caused by symptoms of angina; congestive heart failure; COPD; disease of the spinal column; venous disease; neurological disease; mental illness; arthritis; maximal walking distance > 300 m or < 50 m; > 25% difference in absolute claudication distance over three tests at different times

Interventions

Treatment: supervised ET 3 hours weekly. Treadmill walking up to moderate pain

Control: non-supervised ET based on oral advice to walk daily as much as possible to near maximal pain, for a period of at least 45 minutes

Duration: 6 months

Folluw-up period: 6 months

Outcomes

Treadmill test: (3.5 km/h, 10% slope)

Outcome: pain-free walking distance, maximal walking distance, ABI at rest, hyperemic calf arterial inflow at rest

Participant-reported outcomes: Short Form 36, WIQ, and Intermittent Claudication Questionnaire

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA blind block "telephone" randomization procedure by means of computer
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is reported

An ITT analysis is described

The authors did report attrition and specified this per group

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants. Results of only four participants were used for the supervised group. The non-supervised group consisted of nine participants

Selective reporting (reporting bias)Low riskAll relevant primary and secondary outcomes were described; however, Short Form 36 outcomes were registered in a format that was not usable
Other biasUnclear riskStandard deviations were calculated by dividing the interquartile range by 1.35. This could have introduced bias

Nicolai 2010

MethodsStudy design: randomized controlled trial
Participants

Country: the Netherlands

Setting: outpatient vascular surgery clinics

No. of participants:

  • Baseline: exercise advice group (102), SET group (202); and

  • 12 months' follow-up: exercise advice group (83), SET group (169)

Age: exercise advice group: 66.9 (± 8.6) years; SET group: 65.9 (± 9.7) years

Sex: exercise advice group: 55.9% male; SET group: 66.4% male

PAD diagnosed by ABI < 0.9

Inclusion criteria: PAD, absolute claudication distance < 500 m

Exclusion criteria: previous SET program, previous peripheral vascular intervention, insufficient comment of Dutch language, NYHA class III or IV, lower limb amputation, psychiatric instability, serious comorbidity that might limit physical training (CAD, COPD)

Interventions

Treatment: walking advice similar to control group, SET according to the guidelines of the Royal Dutch Society for Physical Therapy (2 to 3 sessions of 30 minutes weekly)

Control: walking advice and a brochure (walk 3 sessions a day, during each session three times to maximum pain level)

Duration: 12 months

Follow-up period: none

Outcomes

Treadmill test: 3.2 km/h; 0% grade, increasing by 2% every 2 minutes, max inclination 10% and 1600 meters

Outcome: maximal walking distance, functional claudication distance

Participant-reported outcome: WIQ, Quality of Life, Short Form 36

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomization
Allocation concealment (selection bias)Low riskRandomization by telephone. Numbers were generated by computer
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The study personnel who administered the treadmill tests and collected the questionnaires were blinded for previous outcomes and group assignment"
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is not reported, probably because of the multicenter design of this trial

"A modified intention-to-treat" principle was used. The analysis included all data from patients who were randomized and completed the treadmill assessment for quantifying walking distance after 12 months of treatment. Patients who transferred to another group or patients who stopped the intervention but performed the treadmill assessment were analyzed in their original group. The analysis excluded patients who dropped out 12 months of follow-up"

The authors did report attrition and specified this per treatment group

A 2:1 ratio was used to allocate participants to the intervention group or the control group

Selective reporting (reporting bias)Low riskThis trial was designed as a three-armed study: an exercise advice group, a supervised exercise group and a supervised exercise group with feedback; however, because 30% of the participants reported non-use of a physical activity monitor, the trial authors decided to analyze the supervised exercise group and the supervised exercise group with feedback together. We believe that this finding did not influence the outcome of this meta-analysis. All primary and secondary outcome values were described
Other biasUnclear riskACD/ICD results from the SET group consist of a SET group and a SET with feedback group combined, although SF-36 outcomes were obtained only from the supervised group without feedback. FCD values were used as ICD outcomes. Standard deviations were calculated by dividing IQR by 1.35

Parr 2009

MethodsStudy design: randomized controlled trial
Participants

Country: South Africa

Setting: outpatient vascular surgery clinics

No. of participants:

  • Baseline: exercise advice group (10), SET group (10); and

  • 6 weeks' follow-up: exercise advice group (8), SET group (8)

Age: exercise advice group: 62 (± 10) years; SET group: 57 (± 14) years

Sex: exercise advice group: 65% male; SET group: 63% male

PAD diagnosed by medical history and duplex flow Doppler

Inclusion criteria: PAD patients

Exclusion criteria: rest pain, exercise tolerance limited by medical conditions other than PAD or COPD

Interventions

Treatment: 6 weeks, 3 times a week 45 minutes

Control: walking advice at baseline

Duration: 6 weeks

Follow-up period: none

Outcomes

Treadmill test: 3.2 km/h; 0% grade, increasing by 2% every 2 minutes

Outcome: pain-free walking distance, maximal walking distance, peak VO2, respiratory exchange ratio, 6 minute walking test, ABI

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was decided by participants while drawing an intervention group name
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Allocation of excluded participants is not reported

An ITT analysis is not described

The authors did report attrition but did not specify this per group

The numbers for each intervention group were equal compared with total numbers of randomly assigned participants

Selective reporting (reporting bias)Low riskAll relevant primary outcomes were described
Other biasLow riskNo other forms of bias were detected

Patterson 1997

MethodsStudy design: randomized controlled trial
Participants

Country: United States

Setting: hospital and home

No. of participants:

  • Baseline: exercise advice group (28), SET group (27);

  • 3 months' follow-up: exercise advice group (25), SET (23); and

  • 6 months' follow-up: exercise advice group (19), SET group (19)

Age: exercise advice group: 70.3 (± 8.6) years; SET group: 67.9 (± 7.5) years

Sex: exercise advice group: 46.4% male; SET group: 59.3% male

PAD diagnosed by 3 months stable IC; ABI < 0.9 at rest or a drop in ankle pressure > 15 mmHg

Inclusion criteria: PAD, participants between 50 and 75 years of age; IC symptoms > 3 months

Exclusion criteria: ischemic rest pain, tissue loss, comorbid illness with limitations in an ET program, exercise-related ischemia at a cardiac stress test

Interventions

Treatment: supervised ET 3 times per week during 1 hour. Weekly lectures about PAD

Control: advice to walk ≥ 3 times weekly up to tolerance, for a period of 20 to 40 minutes. Weekly lectures about PAD

Duration: 3 months

Follow-up: 3 months

Outcomes

Treadmill test: 1 mph, 5% slope increasing up to 2.5 mph, 10% slope in four stages

Outcome: pain-free walking time and maximal walking time

Participant-reported outcome: Short Form 36

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomization is not described
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Allocation of excluded participants is reported, however is not specified

An ITT analysis is not described

The authors did report attrition and specified this per group

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants

Selective reporting (reporting bias)Low riskAll relevant primary and secondary outcomes were described
Other biasUnclear riskWalking distance data were extracted from the figures. This could have introduced bias

Regensteiner 1997

MethodsStudy design: randomized controlled trial
Participants

Country: United States

Setting: hospital and home

No. of participants: SET group 10; control group 10

Age: control group: 64 (± 7) years; SET group: 64 (± 7) years

Sex: males (based on inclusion of veterans only)

PAD diagnosed by ABI < 0.94 at rest, decreasing to < 0.73 after exercise

Inclusion criteria: PAD patients, > 3 months stable IC

Exclusion criteria: rest pain; ischemic ulceration or gangrene; unable to walk on treadmill at 2 mph; limited exercise capacity due to comorbidity; DM; prior vascular intervention < 1 year

Interventions

Treatment: supervised ET 3 times weekly up to moderate pain, with an increasing period of time from 35 to 55 minutes

Control: advice to walk at least 3 times weekly at as rapid a rate as possible over an increasing period of time (35 to 55 minutes). Additional phone contact weekly for support

Duration: 3 months

Follow-up: 3 months

Outcomes

Treadmill test: 2 mph, 0% slope, with a subsequent 3.5% increase in slope every 3 minutes

Outcome: pain-free walking time and maximal walking time, ABI at rest

Participant-reported outcome: Short Form 20

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomization is not described
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is not reported

An ITT analysis is not described; however, no dropout was reported

The authors did not report attrition because they had no dropouts

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants

Selective reporting (reporting bias)Low riskAll primary and secondary outcome values were described
Other biasLow riskShort Form 20 physical role values were used to analyze the physical role of Short Form 36. This could introduce bias

Sanderson 2006

Methods

Study design: unblinded, randomized controlled trial

Method of randomization: blocked randomization (male diabetic, male nondiabetic, female diabetic, female nondiabetic) with the use of closed envelopes

Participants

Country: Australia

Setting: outpatient vascular surgery clinics

No. of participants:

  • Baseline: control group (14), SET group (13); and

  • 6 weeks' follow-up: exercise advice (14), SET group (13)

Age: control group: 61 (± 10) years; SET group: 62 (± 6) years

Sex: control group: 57% male; SET group: 61% male

PAD diagnosed by ABI < 0.9

Inclusion criteria: PAD patients, IC complaints > 1 year

Exclusion criteria: live > 50 km from the research centre, did not respond to the invitation, unable to participate for personal reasons, reduced cardiac function (other medical conditions for which exercise testing was contraindicated), rest pain, recently undergone surgery

Interventions

Treatment: best medical treatment, 3 times a week SET 

Control: walking advice at baseline with best medical treatment

Duration: 6 weeks

Follow-up: none

Outcomes

Treadmill test: 2.7 km/h, 0% grade first 5 minutes, 2% every 3 minutes

Outcome: changes in walking and cycling performance, physiological responses (heart rate, VO2, RER)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlocked randomization (male diabetic patient, male nondiabetic patient, female diabetic patient, female nondiabetic patient)
Allocation concealment (selection bias)Low riskRandomization with the use of closed envelopes
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is reported

An ITT analysis is not described; however, no dropout is reported

The authors did not report attrition because they had no dropouts

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants

Selective reporting (reporting bias)Low riskAll primary outcomes were described
Other biasLow riskNo other forms of bias were detected

Savage 2001

MethodsStudy design: unblinded, randomized controlled trial
Participants

Country: United States

Setting: hospital and home

No. of participants:

  • Baseline: exercise advice group (10), SET group (11);

  • 3 months' follow-up: exercise advice group (10), SET (11); and

  • 6 months' follow-up: exercise advice group (10) SET group (11)

Age: exercise advice group: 66.1 (± 8.9) years; SET group: 66.4 (± 9.1) years

Sex: exercise group: 70% male; SET group: 73% male

PAD diagnosed by clinical diagnosis of CI

Inclusion criteria: SVS/ISCS grade I or Category 1, 2, or 3

Exclusion criteria: unstable cardiopulmonary disease; severe lower extremity arthritis; tobacco use; weight > 40 kg above ideal; renal insufficiency; use of beta-blocking drugs; use of pentoxifylline or cilostazol < 8 weeks of entry; functioning lower-extremity bypass; severe cognitive impairment

Interventions

Treatment: supervised ET 3 times weekly up to intense pain with an increasing period of time from 15 to 40 minutes

Control: advice to walk 3 times weekly up to intense pain with an increasing period of time from 15 to 40 minutes. Monthly contact by phone

Duration: 3 months

Follow-up: 3 months

Outcomes

Treadmill test: 2 mph, 0% slope, with a subsequent 2% increase in slope every 2 minutes
Outcome: pain-free walking distance, maximal walking distance, ABI at rest, peak VO2

Participant-reported outcome: Short Form 36

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomization is not described
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is not reported

An ITT analysis is not described; however, no dropout is reported

The authors did not report attrition because they did not have any dropouts

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants

Selective reporting (reporting bias)Low riskAll primary and secondary outcomes were described
Other biasLow riskNo other forms of bias were detected

Stewart 2008

MethodsStudy design: randomized controlled trial
Participants

Country: UK

Setting: hospital vascular surgery clinic

No. of participants:

  • Baseline: exercise advice group (30), SET group (30);

  • 3 months' follow-up: exercise advice group (28), SET (28); and

  • 6 months' follow-up: exercise advice group (24), SET group (27)

Age: exercise advice group: 68 (± 9) years; SET group: 68 (± 8) years

Sex: exercise advice group: 73% male; SET group: 67% male

PAD diagnosed by ABI < 0.9

Inclusion criteria: PAD, history of exercise-induced calf or buttock pain, no revascularization procedure

Exclusion criteria: comorbidity that limited exercise, recent onset (< 3 months), recent revascularization (3 months), recent myocardial infarction (< 3 months)    

Interventions

Treatment: twice-weekly 1 hour class with a maximum exercise time of 40 minutes with 10 minute warm-up and cool-down periods. Exercises were mainly based on calf muscle and could be continued at home without the need for specialized equipment

Control: walking advice at baseline

Duration: 3 months

Follow-up: 3 months

OutcomesTreadmill test: constant load (2.5 km/h, 10% grade)
Outcome: change in walking distance, ABI, heart rate, and blood pressure; lactate change
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The randomization sequence was generated by an independent investigator and concealed in sealed envelopes"
Allocation concealment (selection bias)Low risk"Treatment allocation was revealed following completion of all baseline investigations"
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded for provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is reported

An ITT analysis is not described; however, no dropout is reported

The authors did report attrition and specified this per group

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants

Selective reporting (reporting bias)Low riskAll primary outcomes were described
Other biasUnclear riskNo treadmill exercises were included. However, provided exercises were mainly based on the calf muscles; therefore, this trial is included in this review. Standard deviations were calculated by dividing IQR by 1.35

Treat-Jacobson 2009

  1. a

    ABI: ankle-brachial index
    ACD: absolute claudication distance
    COPD: chronic obstructive pulmonary disease
    DM: diabetes mellitus
    ET: exercise therapy
    FCD: functional claudication distance
    IC: intermittent claudication
    ICD: initial claudication distance
    IQR: interquartile range
    ITT: intention-to-treat-analysis
    m: metre
    MI: myocardial infarction
    min: minute
    PAD: peripheral arterial disease
    SET: supervised exercise therapy
    SVS/ISCS: Society for Vascular Surgery/International Society for Cardiovascular Surgery
    WIQ: walking impairment questionnaire

    ≥ greater than or equal to
    ≤ less than or equal to

MethodsStudy design: randomized controlled trial
Participants

Country: USA

Setting: hospital vascular surgery clinic

No. of participants:

  • Baseline: exercise advice group (8), SET group (13);

  • 3 months' follow-up: exercise advice group (8), SET group (11); and

  • 6 months' follow-up: exercise advice group (6), SET group (9)

Age: exercise advice group: 70 (± 7.8) years; SET group: 63 (± 11.5) years

Sex: exercise group: 88% male; SET group: 60% male

PAD diagnosed by: ABI < 0.90 or 10% decrease in postexercise ABI

Inclusion criteria: PAD, > 18 years; lifestyle-limiting claudication, able to perform a treadmill test at 2 mph; willing to participate

Exclusion criteria: contraindications to exercise training (uncontrolled hypertension), ischemic leg pain, leg or foot ulcerations, gangrene, recent MI (< 6 months); unstable CAD, lower extremity revascularization (< 3 months), > 25% variation in MWD after three treadmill tests

Interventions

Treatment: 3 times weekly, 3 months, 70 minutes, 5 minutes warm-up and cool-down, treadmill walking (2 mph, 0% grade). Grade and speed were progressively increased                

Control: written instructions on how to exercise, once each week monitoring of heart rate and blood pressure, adverse events and encouragement

Duration: 3 months

Follow-up: 3 months

Outcomes

Treadmill test: 2 mph and 0% grade for 3 minutes, 3.5% every 3 minutes until 10.5%. Until this stage, speed increased by 0.5 mph every 3 minutes

Outcome: maximal and pain-free walking distance, peak VO2

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomization is unclear
Allocation concealment (selection bias)Unclear riskConcealment of allocation is not explained
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded to provided treatment. This is inherent to study design
Blinding of outcome assessment (detection bias)
All outcomes
High risk"Data were entered by study personnel"
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Allocation of excluded participants is reported

An ITT analysis is not described. Six of 21 participants were lost to follow-up

The authors did report attrition and specified this per group

The numbers for each intervention group were equal compared with the total numbers of randomly assigned participants

Selective reporting (reporting bias)Low riskAll relevant primary outcomes were described
Other biasLow riskNo other forms of bias were detected

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    BMT: best medical treatment
    ET: exercise therapy
    IC: intermittent claudication
    PAD: peripheral arterial disease

Arosio 1999This trial compared ET with treatment with iloprost.
Arosio 2001This trial compared supervised ET with treatment with iloprost. There was no control group with non-supervised ET.
Ciuffetti 1994This trial compared supervised ET with the use of pentoxifylline.
Collins 2003This trial compared polestriding exercise with polestriding combined with vitamin E; with vitamin E without exercise; and with placebo without exercise.
Collins 2005This trial compared supervised ET with a non-exercising control group.
Crowther 2008This trial compared supervised ET with a non-exercising control group (controls treated with standard medical therapy).
Dahllöf 1976This trial compared supervised ET with the use of a placebo drug without ET.
Degischer 2002In the previous version of this review this trial was included. However it is not a randomized controlled trial. Therefore in this updated version it is excluded.
Fakhry 2011Non randomized trial.
Fowler 2002This trial compared home-based ET with a non-exercising control group (maintained their usual level of activity).
Gardner 2001This trial compared supervised exercise rehabilitation with no exercise.
Gardner 2002This trial compared supervised exercise rehabilitation with no exercise.
Gardner 2005This trial compared supervised walking therapy with different intensities.
Gelin 2001This trial compared supervised ET with invasive treatment and observation. There was no control group with non-supervised ET.
Gibellini 2000This trial compared supervised ET with a non-exercising control group.
Greenhalgh 2008This trial compared supervised ET with a non-exercising control group (controls treated with standard medical therapy).
Grizzo 2011This trial compared supervised walking therapy with supervised strength training.
Hiatt 1990This trial compared supervised ET with a group which maintained their usual level of exercise.
Hiatt 1994This trial compared supervised ET with strength training and a group which maintained their usual level of exercise.
Hobbs 2007This trial compared best medical therapy (BMT) with supervised exercise, BMT plus cilostazol, BMT plus supervised exercise plus cilostazol.
Jansen 1991This trial compared supervised ET with no exercise.
Krause 1974This trial compared supervised ET with supervised ET with different treatment periods.
Kruidenier 2011This trial compared supervised ET with exercise therapy after vascular interventions.
Langbein 2002This trial compared polestriding exercise with no exercise.
Larsen 1966This trial compared supervised ET with the use of a placebo drug without ET.
Leicht 2011This trial compared supervised ET with a non-exercising control group (controls treated with standard medical therapy).
Leon 2005This trial compared home-based ET with a non-exercising control group (maintained their usual level of activity).
Lepantalo 1991This trial compared supervised ET with supervised ET combined with a placebo drug.
Manfredini 2008This trial compared home-based ET with home-based ET with different treatment protocols.
McDermott 2004This trial compared supervised ET with no exercise. Participants were diagnosed with PAD but had no symptoms of IC.
McDermott 2009This trial compared supervised treadmill and strength training with a non-exercising control group (nutritional information sessions, no change in behavior).
Menêses 2011This trial compared supervised strength training with supervised walking training.
Mika 2005This trial compared supervised ET with a non-exercising control group (controls maintained their usual level of activity).
Mika 2006This trial compared supervised ET with a non-exercising control group.
Mika 2011This trial compared supervised ET with a non-exercising control group (controls maintained their usual level of physical activity).
Murphy 2012This trial compared supervised ET with an invasive procedure.
Nawaz 2001This trial compared supervised lower-limb exercise training with supervised upper-limb exercise training, and with non-supervised ET. Participants were randomized to either the lower-limb or the upper-limb training. The participants of the control group were not randomized, but run parallel with the two intervention groups.
Nielsen 1975In the previous version of this review this trial was included. However it is a non randomized trial.
Nielsen 1977In the previous version of this review this trial was included. However it is a non randomized trial.
Ritti-Dias 2010This trial compared supervised strength training with supervised ET.
Saxton 2011This trial compared supervised ET with a non-exercising control group.
Schlager 2011This trial compared supervised ET with a non-exercising control group (best medical treatment).
Schlager 2012This trial compared supervised ET with a non-exercising control group (best medical treatment).
Spronk 2009This trial compared supervised ET with an invasive procedure.
Taft 2001This trial compared supervised ET with invasive therapy and with no exercise training.
Taft 2004This trial compared supervised ET with invasive therapy and with no exercise training.
Tebbutt 2011This trial compared home-based ET with or without the addition of a plantar flexion device.
Tew 2009This trial compared supervised arm-crank exercise (no treadmill) with a non-exercising control group.
Tisi 1997This trial compared supervised ET with a non-supervised group. However the supervised group was treated with 4 weeks exercise treatment only.
Tsai 2002This trial compared supervised ET with no exercise training.
Walker 2000This trial compared supervised arm or leg cranking (no treadmill) with a non-exercising control group.
Wood 2006This trial compared supervised ET with a non-exercising control group (controls maintained their usual level of activity).
Zwierska 2005This trial compared supervised arm or leg cranking (no treadmill) with a non-exercising control group.

Characteristics of ongoing studies [ordered by study ID]

Frans 2012

  1. a

    PTA: percutaneous transluminal angioplasty
    SET: supervised exercise therapy

Trial name or titleSUPERvised exercise therapy or immediate PTA for intermittent claudication in patients with an iliac artery obstruction
MethodsTo compare the (cost-) effectiveness of initial PTA versus initial SET in patients with disabling IC due to an iliac artery obstruction
Participants400 consecutive participants with IC
InterventionsSupervised exercise therapy (SET) or percutaneous transluminal angioplasty (PTA; with additional stent placement on indication)
OutcomesPrimary outcomes are maximum walking distance and health-related quality of life measured using the disease-specific VascuQol instrument after 1 year. Secondary outcomes are pain-free walking distance, functional status, generic quality of life, complications related to each of the interventions, additional interventions, treatment failures, and costs (cost-effectiveness and cost-utility) after 1 year
Starting date2012
Contact informationAcademic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
Notes 

Ancillary