exercise training for management of peripheral arterial

SYSTEMATIC REVIEW

Exercise Training for Management of Peripheral Arterial Disease:A Systematic Review and Meta-Analysis

Belinda J. Parmenter • Gudrun Dieberg •

Neil A. Smart

Published online: 18 September 2014

� Springer International Publishing Switzerland 2014

Abstract

Background Peripheral arterial disease (PAD), a chronic

condition with debilitating clinical sequelae, leads to

reduced walking activity and increased mortality risk.

Objective We sought to quantify expected benefits elic-

ited via exercise training in people with PAD and aimed to

clarify which prescriptions were optimal.

Data sources We conducted a systematic search (Pub-

Med, CINAHL, Cochrane controlled trials registry;

1966–31 July 2013).

Study selection We included randomized controlled trials

(RCTs) of exercise training versus usual medical care in

persons with PAD. Studies were assessed by two review-

ers, 41 of 57 (72 %) of RCTs met selection criteria.

Data extraction and synthesis Data extraction sheets

were used to record data and two reviewers cross-checked

data. Included study authors were asked for missing data.

Main outcomes and measures Primary outcome: change in

aerobic capacity (peak VO2). Secondary outcomes: ankle-

brachial index (ABI), flow-mediated dilatation, 6-minute

walk claudication distances (initial and absolute) and graded

treadmill (initial and absolute) distances. The primary

hypothesis was that peak VO2 would increase with exercise

training. Using sub-analyses, we also aimed to clarify what

types of exercise prescription would provide patients with

most benefit; hypotheses were developed a priori.

Results Exercise training produced significant peak VO2

improvements with mean difference (MD) 0.62 ml�kg-1�min-1 (95 % CI 0.47–0.77; p\ 0.00001); 6-minute walk ini-

tial claudication MD 52.7 m (95 % CI 24.7–80.6 m;

p = 0.0002); total walking distance MD 34.9 m (95 % CI

25.6–44.1 m; p\ 0.00001); graded treadmill initial claudica-

tion MD 68.8 m (95 % CI 54.4–83.2 m; p\0.00001); abso-

lute claudication distance MD 41.0 m (95 % CI 28.8–53.2 m;

p\0.00001)); but not ABI (p = 0.12) or flow mediated

dilatation (FMD) (p = 0.96). Sub-analyses of change in peak

VO2 after arm cranking showed a MD of 1.91 ml�kg-1�min-1

(95 % CI 1.28–2.54, p\0.00001). Sub-analysis of peak VO2

according to exercise trainingpain thresholds suggested thatno-to-

mild pain may be superior (MD 0.79 ml�kg-1�min-1 [95 % CI

0.45–1.14, p\0.00001]) to moderate-to-maximum training pain

(MD 0.49 ml�kg-1�min-1 [95 % CI 0.31–0.66, p\0.00001]).

Conclusions and relevance Exercise training improves

cardio-respiratory fitness, pain-free and total flat-ground

walking distances, as well as graded treadmill performance in

PAD. Exercise prescriptions for PAD may consider arm

cranking as well as lower limb exercise, possibly at short vig-

orous intensity intervals, but only to a threshold of mild pain.

Key Points

Exercise training improves pain-free and total

walking distance.

Exercise tomild–moderate pain mayyield optimal results.

Full recovery from pain before resuming effort may

be optimal.

Electronic supplementary material The online version of thisarticle (doi:10.1007/s40279-014-0261-z) contains supplementarymaterial, which is available to authorized users.

B. J. Parmenter

Faculty of Medicine, University of New South Wales, Sydney,

Australia

G. Dieberg � N. A. Smart (&)

Clinical Exercise Physiology, School of Science

and Technology, University of New England,

Armidale, NSW 2351, Australia

e-mail: [email protected]; [email protected]

123

Sports Med (2015) 45:231–244

DOI 10.1007/s40279-014-0261-z

http://dx.doi.org/10.1007/s40279-014-0261-z

1 Introduction

Peripheral arterial disease (PAD) is a chronic athero-

sclerotic/occlusive disease of the aorta and its branches

excluding coronary and cerebral arteries, commonly

affecting the arteries supplying the legs and feet. In most

people PAD is asymptomatic; however, others may expe-

rience pain at rest or with walking, thus limiting walking

ability and physical activity levels. Current prevalence of

PAD is 7.51 % amongst a cohort of 3 million participants

[1], estimated to affect between 12 and 15 % of patients

aged over 65 years in the United States alone [2]. It was

recently reported that the economic PAD burden is large,

since the current management of PAD is centred on

expensive vascular surgical interventions, with high rates

of recurring hospitalizations and repeat revascularization

procedures [3]. Recent US studies found that it costs about

5 % more to treat people with PAD than those with coro-

nary artery disease (CAD) [4] and PAD is often overlooked

in favor of CAD [5]. It is clear secondary prevention

strategies aimed at improving health outcomes and mor-

tality rates in PAD patients are needed.

Exercise capacity has recently been shown to be a strong

predictor of mortality in PAD [6] and it is well known that

exercise training improves walking ability in PAD [7–9].

Physical activity provides a protective effect against mor-

tality in persons with claudication from PAD [10]. How-

ever, the optimal exercise prescription for this cohort

remains debatable. Previous systematic reviews [7, 8, 11]

have provided evidence that various modes of exercise

training other than walking lead to various changes in

hemodynamic, walking, and functional/fitness outcomes.

In addition, Cochrane meta-analyses [9, 12] have reported

that exercise improves treadmill walking times and dis-

tances. Corridor-based functional performance measures

have been shown to correlate better with physical activity

during daily life when compared with treadmill measures

in persons with PAD [13]; however, to our knowledge,

there has been no meta-analysis on exercise and PAD that

has quantified the magnitude of change attributable to

exercise training for homogenous functional performance,

exercise capacity, and walking measurements in people

with PAD. In addition, the mechanisms by which exercise

improves walking in PAD remain unconfirmed, although it

has been speculated, among others, that the mechanisms

primarily center on pathophysiological adaptations within

the exercising musculature of the symptomatic leg [14].

We sought to therefore conduct an updated systematic

review, while also undertaking meta-analyses, with a par-

ticular focus on homogenous testing protocols and aerobic

capacity. The a priori aims were to quantify the magnitude

of change attributable to exercise training for aerobic

capacity, ankle-brachial index, flow-mediated dilatation,

homogenous treadmill walking protocols and 6-minute

walk distance in people with PAD. In addition, using sub-

analyses, we aimed to clarify what types of exercise pre-

scription would provide patients with the most benefit for

these outcomes, with the view to providing an optimal

exercise prescription to improve aerobic capacity, func-

tional walking outcomes, and overall physical activity

participation in PAD.

2 Methods

2.1 Search Strategy

Potential studies were identified by conducting a system-

atic search using PubMed, http://www.ncbi.nlm.nih.gov/

pubmed (1966 to 15 May 2014). The PubMed search

strategy can be seen in the electronic supplementary

material (ESM). CINAHL and the Cochrane controlled

trials registry were also searched (1966 to 15 May 2014).

The search strategy included key concepts of peripheral

arterial disease, intermittent claudication, lifestyle therapy,

physical training, and exercise training. These were com-

bined with a sensitive search strategy to identify random-

ized controlled trials (RCTs). Reference lists of papers

found were scrutinized for new references. All identified

papers were assessed independently by two reviewers (BP

and GP), a third reviewer (NS) was consulted to resolve

disputes. Searches of published papers were also conducted

until 15 May 2014. Study quality was assessed by using a

modified PEDro score [15]. As supervision has previously

been deemed an important component of an exercise pro-

gram for this population [16, 17], supervision was added to

the quality criteria score for a maximum score out of 11.

2.2 Inclusions

RCTs of exercise training programs of greater than

2 weeks program duration in people with PAD were

included. There were no language restrictions. Studies

were included if they had a control group that had been

placed on usual medical care, with or without exercise

advice.

2.3 Exclusions

Animal studies, review papers and non-randomized con-

trolled trials were excluded. Studies that did not have any

of the desired outcome measures or had participants

without diagnosed PAD in either exercise or control groups

were excluded. Several authors were contacted to provide

232 B. J. Parmenter et al.

123

http://www.ncbi.nlm.nih.gov/pubmed

http://www.ncbi.nlm.nih.gov/pubmed

missing data or to clarify if data was duplicated in multiple

publications. If a partial data set was deemed to have been

previously published, and this was confirmed by the cor-

responding author, the more complete data set was used in

these analyses. All but three authors provided required

data. Studies using interventions other than exercise or in

addition to exercise (e.g., electro-acupuncture, ultrasound,

surgery) were excluded.

2.4 Studies Included in the Review

Our initial search identified 16,606 manuscripts, examina-

tion of the latest editions of relevant journals yielded a

further 60 manuscripts. Out of 16,666 studies, 62 were

excluded at first inspection as duplicates and 16,520 were

removed after reading titles or abstracts, leaving 84 studies;

of these, 43 studies did not meet inclusion criteria. A total

of 41 studies were included in this analysis (see literature

search flow diagram Fig. S1 in the ESM).

2.5 Data Synthesis

Information on outcome measures was archived in a

database. The outcome measures were: aerobic capacity

(peak VO2), ankle brachial blood pressure index (ABI), calf

flow mediated dilatation (FMD), 6-minute walk distance

(6MWD) and initial claudication distance (6MW-ICD),

graded treadmill initial (GTrd-ICD) and absolute claudi-

cation distance (GTrd-ACD). Only studies reporting the

Gardner-Skinner treadmill protocol [18] and a treadmill

protocol of 3.2 km h-1 with 3.5 % increase in grade every

3 minutes [19–26] were considered to be homogenous and

included in treadmill outcomes. All studies using one of the

above protocols and reporting claudication times were

converted to distance for the purpose of this data synthesis.

The mean difference (MD) was calculated for the out-

come measures by subtracting baseline from post-inter-

vention values (e.g., peak VO2, using the formula

MD = post-mean – pre-mean). Standardized mean differ-

ence (SMD) calculated as percentage change from baseline

was used when different methods to establish the same

outcomes have been used (e.g., FMD). If studies reported

median and standard error, range or inter-quartile range,

then the median was substituted for the mean when sample

size exceeded 25 and measures of variability were con-

verted to standard deviation as per Hozo et al. [27].

2.6 Statistical Analysis

Meta-analyses were completed for continuous data by

using the change in the mean and standard deviation of

outcome measures. It is an accepted practice to only use

post-intervention data for meta-analysis but this method

assumes that random allocation of participants always

creates intervention groups matched at baseline for age,

disease severity, etc. Change in post-intervention mean was

calculated by subtracting baseline from post-intervention

values. Change in the standard deviation of post-interven-

tion outcomes was calculated by using Revman 5.0 (Nordic

Cochrane Centre, Denmark). Data required was (i) 95 %

confidence interval data for pre-/post-intervention change

for each group or, when this was unavailable, (ii) actual

p values for pre-/post-intervention change for each group

or, if only the level of statistical significance was available,

(iii) we used default p values (e.g., p \ 0.05 becomes

p = 0.049, p \ 0.01 becomes p = 0.0099 and p = not

significant becomes p = 0.05). A random effects inverse

variance was used with the effects measure of mean dif-

ference. Heterogeneity was quantified using the Cochrane

Q test [28]. Egger plots were provided to assess the risk of

publication bias (see ESM). We used a 5 % level of sig-

nificance and 95 % confidence intervals; figures were

produced using Revman 5.

2.7 Sub-Analyses

We conducted sub-analyses where sufficient numbers of

studies existed in sub-groups. These analyses were only

possible for peak VO2. We conducted four sub-analyses:

(i) vigorous (60 \ 85 % VO2 max; RPE [rate of perceived

exertion] 14–16) exercise training intensity versus light

(20 \ 40 % VO2 max; RPE 8–10) to moderate (40 \ 60 %

VO2 max; RPE 11–13) intensity as categorized according

to Norton et al. [29] for aerobic exercise and American

College of Sports Medicine (ACSM) guidelines for resis-

tance training intensity [30]; (ii) training according to level

of pain: no/mild onset of pain versus moderate to maxi-

mum pain as defined by individual studies; (iii) study

duration 12 weeks or less and 13–24 weeks; (iv) arm

cranking training.

3 Results

Forty-one studies [19–21, 23, 25, 26, 31–65] (50 inter-

vention groups) met the inclusion criteria for our analyses;

eight of these studies [20, 25, 32, 40, 49, 54, 56, 65] had

more than one intervention group, which were separated in

Forest plots. The total number of patients in our analyses

was 1,938, consisting of 1,115 exercise and 823 non-

exercising patients (see Table 1). Forty-three randomized

trials were excluded for various reasons (see Fig. S1 in the

ESM). Interval walking to moderate–maximum claudica-

tion pain was the most common prescription. Training was

often interval-based due to claudication pain and ranged

from 20 to 60 minutes in duration. Training frequency

Exercise Training for Peripheral Arterial Disease 233

123

Ta

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NR

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[59]

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Tis

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19

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[62,

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Tis

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No

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Yes

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Coll

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.,2

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60

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123

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ble

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123

ranged from 2 to 7 days per week. Most studies fully

supervised the intervention.

3.1 Peak VO2

Baseline peak VO2 was 15.30 ± 2.38 ml�kg-1�min-1. A

small peak VO2 improvement was observed in exercise

training participants versus control (19 studies, 26 inter-

vention groups; MD 0.62 ml�kg-1�min-1 [95 % CI

0.47–0.77, p \ 0.00001]), Fig. 1; this equates to about

0.04–0.05 l�min-1. Only two [19, 20] of 15 studies that

used interval treadmill walking showed more than 15 %

improvement in peak VO2 with walking.

Sub-analysis of peak VO2 according to exercise training

intensity suggested that vigorous intensity training (six

studies, ten intervention groups; MD 1.42 ml�kg-1�min-1

[95 % CI 1.04–1.80, p \ 0.00001]; see Fig. S2 in the ESM)

was superior to moderate intensity training (five studies;

MD 0.43 ml�kg-1�min-1 [95 % CI 0.01–0.85], p = 0.05;

see Fig. S3 in the ESM), noting that 95 % CIs do not

overlap. These MDs equated to approximately 0.1–0.12

and 0.03–0.04 l�min-1, respectively. There was sufficient

study data to conduct a sub-analysis of arm cranking (three

studies, five intervention groups; MD 1.91 ml�kg-1�min-1

[95% CI 1.28–2.54, p \ 0.00001]; see Fig. S4 in the ESM);

this MD equates to approximately 0.14–0.15 l�min-1.


pain thresholds reported no to mild pain (six studies, seven

intervention groups; MD 0.79 ml�kg-1�min-1 [95 % CI

0.45–1.14, p \ 0.00001]; see Fig. S5 in the ESM);

moderate to maximum training pain produced similar

results: (12 studies, 14 intervention groups; MD

0.49 ml�kg-1�min-1 [95 % CI 0.31–0.66, p \ 0.00001];

see Fig. S6 in the ESM). These MDs equate to about

0.06–0.07 and 0.03–0.04 l�min-1, respectively, noting that

95 % CIs do overlap.


duration of 12 weeks or fewer (12 studies, 18 intervention

groups; MD 0.94 ml�kg-1�min-1 [95 % CI 0.68–1.21,

p \ 0.00001]; see Fig. S7in the ESM) was superior to

study duration of 13–24 weeks (four studies, five inter-

vention groups; MD 2.16 ml�kg-1�min-1 [95 % CI

1.25–3.08, p \ 0.00001]; see Fig. S8 in the ESM); these

MDs equate to 0.07–0.08 and 0.15–0.17 l�min-1, respec-

tively, noting that 95 % CIs do not overlap.

3.2 Six-Minute Walk—Intermittent Claudication

Distance (6MW-ICD)

Analysis of 6MW-ICD showed significant improvements

with exercise versus control (four studies, five intervention

groups; MD 52.7 m [95 % CI 24.7–80.6 m, p = 0.0002];

see Fig. S9 in the ESM). The larger increases ([100 m) in

onset of claudication distance were seen with moderate-to-

high [52] and high intensity [54] progressive resistance

training.

3.3 Six-Minute Walk Distance (6MWD)

Total 6MWD showed significant improvements with

exercise versus control (eight studies, ten intervention

groups; MD 34.9 m [95 % CI 25.6–44.1 m,

p \ 0.00001]; Fig. 2). The larger clinically significant

increases ([50 m) in 6MWD were seen with supervised

treadmill walking (53.8 m) and moderate-to-high (108 m)

[52] and high intensity (69.8 m) [54] progressive resis-

tance training.

3.4 Graded Treadmill—Intermittent Claudication

Distance (ICD)

Graded treadmill-ICD significantly improved with exercise

versus control (18 studies, 24 intervention groups; MD

68.8 m [95 % CI 54.4–83.2 m, p \ 0.00001]; Fig. 3).

Significant improvements were seen across a variety of

exercise modes. The largest improvements ([200 m) were

seen with supervised walking to moderate/maximum pain.

3.5 Graded Treadmill—Absolute Claudication

Distance (ACD)

Graded treadmill-ACD significantly improved with exer-

cise versus control; (22 studies, 28 intervention groups;

MD 41.0 m [95 % CI 28.8–53.2 m, p \ 0.00001]; Fig. 4).

The largest improvements ([300 m) were seen with

supervised walking to varied levels of claudication pain.

3.6 Ankle Brachial Blood Pressure Index (ABI)

No change in ABI was observed in exercise training par-

ticipants versus control (MD 0.00 [95 % CI 0.00–0.01,

p = 0.12]; see Fig. S10 in the ESM).

3.7 Flow Mediated Dilatation (FMD)

FMD in the calf was not significantly altered with exercise

compared with controls (MD 0.01 [95 % CI -0.23 to 0.24,

p = 0.96]; see Fig. S11 in the ESM).

3.8 Study Quality Assessment

Study quality assessment is presented in Table S1 of the

ESM. Overall, quality of the included trials was modest,

with on average six of the eleven quality criteria being

present (mean 6.3 ± 1.1, range 4–9/11). Common limita-

tions were concealment of randomization, blinding of


123

subjects, therapists and assessors, and intention-to-treat

analyses. Twenty-six studies (63.4 %) reported at least one

key outcome from more than 85 % of the subjects initially

allocated to groups. Therefore, a greater than 15 % drop-

out rate may have disguised true treatment effects in 15

studies. Only 19 studies (46.3 %) performed intention-to-

treat analyses, or stated all subjects received treatment or

control conditions originally allocated. No studies blinded

therapists administering exercise interventions, only one

(2 %) blinded participants. Only seven studies (17 %)

blinded assessors who measured at least one key outcome.

Thus, assessor’s belief in intervention efficacy in 34 of the

41 trials (82.9 %) may have biased treatment outcomes

[66]. Eighty-eight percent of studies provided supervision

for every exercise session. Five studies provided supervi-

sion of at least one weekly exercise session during inter-

vention periods.

3.9 Heterogeneity

The Cochrane I2 scores indicated there was moderate to

high heterogeneity between studies.

Study or Subgroup

Allen 2010Bronas 2011 ArmBronas 2011 WalkCollins 2003Crowther 2008Crowther 2012Gardener 2001Gardner 2011 HomeGardner 2011 SupervisedGardner 2012Hiatt 1990Hiatt 1994 AerobicHiatt 1994 PRTHodges 2008Regensteiner 1997Sanderson 2006 BikeSanderson 2006 WalkSavage 2001Tew 2009Treat-Jacobsen 2009 ArmTreat-Jacobsen 2009 CombTreat-Jacobsen 2009 WalkWang 2008Wood 2006Zwierska 2005 ArmZwierska 2005 Bike

Total (95% CI)

Heterogeneity: Chi² = 69.96, df = 25 (P < 0.00001); I² = 64%Test for overall effect: Z = 8.03 (P < 0.00001)

Mean

1.31.471.49

20.2

0.981

0.60.31.63.71.9

-0.3-0.27

2.51.40.60.8

11.50.71.42.41.4

2.262.48

SD

2.33572.066

2.09411.44410.28113.66742.591

1.58470.85

8.27085.14412.64160.39245.584

3.47582.54070.998

1.19712.41111.76661.77852.26982.33131.52284.81415.5389

Total

151010111010282933

10610109

141015131125101211147

3437

504

Mean

0.6-0.38-0.38-1.1-0.1

-2.99-0.5

-1-1

0.30.2

-0.4-0.4

-0.051.4

-0.2-0.20.9

-0.6-0.6-0.6-0.60.10.4

-0.530.53

SD

1.21240.45710.45713.84320.14968.33921.18971.98411.98410.89070.26160.48120.48122.04741.96760.34810.34811.26491.28821.00561.00560.63710.14960.38361.50161.5016

Total

1844

10116

24151536944

141077

1020332

116

3333

319

Weight

1.3%1.3%1.2%0.4%

60.3%0.0%2.0%1.7%2.1%0.9%0.2%0.8%8.0%0.2%0.4%1.3%6.4%2.1%1.9%0.9%1.0%0.9%1.5%1.7%0.8%0.7%

100.0%

IV, Fixed, 95% CI

0.70 [-0.61, 2.01]1.85 [0.49, 3.21]1.87 [0.50, 3.24]3.10 [0.57, 5.63]0.30 [0.10, 0.50]

3.97 [-3.08, 11.02]1.50 [0.43, 2.57]1.60 [0.44, 2.76]1.30 [0.25, 2.35]

1.30 [-0.30, 2.90]3.50 [0.31, 6.69]2.30 [0.60, 4.00]

0.10 [-0.44, 0.64]-0.22 [-3.34, 2.90]1.10 [-1.38, 3.58]1.60 [0.29, 2.91]0.80 [0.20, 1.40]

-0.10 [-1.16, 0.96]1.60 [0.50, 2.70]2.10 [0.52, 3.68]

1.30 [-0.22, 2.82]2.00 [0.39, 3.61]2.30 [1.08, 3.52]

1.00 [-0.17, 2.17]2.79 [1.09, 4.49]1.95 [0.09, 3.81]

0.62 [0.47, 0.77]

Exercise Control Mean Difference Mean DifferenceIV, Fixed, 95% CI

-10 -5 0 5 10Favours Control Favours Exercise

Fig. 1 Mean difference in peak VO2 exercise versus control groups. PRT progressive resistance training, VO2 aerobic capacity

Study or Subgroup

Gardener 2001Gardner 2012McDermott 2004McDermott 2009 PRTMcDermott 2009 WalkMcDermott 2013McGuigan 2001Parmenter 2013 HighParmenter 2013 LowTsai 2002

Total (95% CI)

Heterogeneity: Chi² = 14.86, df = 9 (P = 0.09); I² = 39%Test for overall effect: Z = 7.37 (P < 0.00001)

Mean

452840-221

42.485

59.9-8.8

45

SD

64.4702144.739169.250937.8734

48.55168.435

127.19156.0214

5.057113.2181

Total

28106174650881177

27

387

Mean

25-10

13.7-15-15

-11.4-23

-9.9-9.9

3

SD

59.484729.690816.481

38.699638.699666.843

30.087431.4223172.0747.4623

Total

2436

8242490

934

26

248

Weight

7.6%10.1%7.1%

23.9%20.4%21.7%1.4%2.9%0.3%4.7%

100.0%

IV, Fixed, 95% CI

20.00 [-13.71, 53.71]38.00 [8.79, 67.21]

26.30 [-8.54, 61.14]13.00 [-5.96, 31.96]36.00 [15.49, 56.51]53.80 [33.92, 73.68]

108.00 [30.31, 185.69]69.80 [15.15, 124.45]

1.10 [-167.57, 169.77]42.00 [-0.80, 84.80]

34.85 [25.59, 44.12]


-200 -100 0 100 200Favours Control Favours Exercise

Fig. 2 Mean difference in 6MWD exercise versus control groups. 6MWD 6-minute walk distance, PRT progressive resistance training


123

3.10 Egger Plots

Egger Plots (Figs. S12–S16, see ESM) indicated low risk of

publication bias for 6MWD but moderate risk of publica-

tion bias for peak VO2 and significant risk of publication

bias for graded treadmill analyses.

4 Discussion

Despite several recent systematic reviews [7, 8, 11] and

Cochrane meta-analyses [9, 17], ours is the first meta-

analysis of RCTs to analyze homogenous treadmill proto-

cols only (i.e., Gardner–Skinner Protocol), 6-minute walk,

aerobic capacity, ABI, and FMD. In addition, we have also

completed sub-analyses looking at the effect of exercise

intensity, study duration, pain, and modality on these out-

comes. Our findings suggest that despite small but signif-

icant improvements in cardio-respiratory fitness and

walking distances, diagnostic and prognostic measures

such as ankle-brachial blood pressure index and FMD

remained unchanged following exercise training. These

findings are in accordance with previous findings of no

significant changes in blood flow or pressure with exercise

training [11], suggesting but not confirming that changes in

blood flow and/or pressure are not the mechanism to

explain why exercise improves walking ability in this

cohort.

Baseline peak VO2 was, on average, very poor com-

pared with age-adjusted norms [30]. However, our anal-

yses did show small improvements in peak VO2 with

exercise training. A 0.6 ml�kg-1�min-1 peak VO2

increase may not be clinically meaningful in persons with

PAD; however, Leeper and colleagues [6] recently

demonstrated an association between reduced exercise

capacity and mortality in PAD. Furthermore, Swank et al.

[67] recently reported a relationship between a 6 %

increase in peak VO2 in heart failure patients and

improvements in all-cause and cardiovascular hospital-

ization and mortality rates. Cress and Meyer [68] have

shown that a peak VO2 of 20 ml�kg-1�min-1 is needed

for independent living in adults aged 65–97 years. Only

three [26, 34, 65] of 19 trials reported participants’ peak

VO2 as being close to 20 ml�kg-1�min-1 with exercise

training, none of these trials employed walking inter-

vention. Sub-analyses of arm cranking is a good adjunct

to lower limb exercise training as it shows peak VO2

improvements superior to the overall analysis and allows

PAD patients to train without pain and therefore com-

plete a greater volume of exercise.

Whilst intermittent walking training is the gold standard

prescription for PAD and improves treadmill distances, it

seems other modes of exercise provide greater improve-

ments in peak VO2 and functional walking outcomes. As

walking ability is compromised in persons with PAD,

walking prescriptions may not provide sufficient training

stimulus to improve aerobic capacity. In PAD, peak VO2

predicts mortality [6] and physical activity protects against

mortality [10]. If functional walking performance (e.g.,

6MWD) correlates with physical activity levels during

daily life better than treadmill measures [13], then maybe it

would be optimal for PAD patients to complete an exercise

prescription that improves treadmill walking ability but

also peak VO2 and 6-minute walk outcomes. It appears

that treadmill prescriptions improve treadmill outcomes,

possibly due to training specificity. It therefore seems

appropriate to recommend, in conjunction with an interval

walking program, persons with PAD also complete an

alternative mode of aerobic exercise (e.g., arm cranking)

at a higher intensity (recommendations below), avoiding

claudication pain, yet providing a stimulus sufficient to

improve peak VO2. As peak VO2 only improved margin-

ally, there must be further explanations why exercise

improves walking ability in PAD. Recently, it has been

shown that muscle strength is related to flat ground

walking ability in PAD [54, 69]. In addition, trials that

used lower extremity aerobic exercises, which involved a

muscle strengthening component, seemed to yield the

larger improvements in walking ability. In light of these

findings, further research is needed into changes in muscle

strength and endurance and improvements in walking

ability and aerobic capacity in this cohort. Evidence

provided in this meta-analysis suggests the optimal exer-

cise prescription for this cohort may be a non-walking,

high-intensity aerobic exercise, combined with interval

walking and moderate- to high-intensity muscle strength

training.

Walking is not the only exercise mode offering benefit

to persons with PAD [7]. It might be that both alternative

modes and also alternative delivery (e.g., continuous versus

interval training) may optimize outcomes. Most published

studies to date have employed aerobic interval exercise at

an intensity based upon claudication pain. PAD patients are

perhaps best suited to intermittent activity with program

progression achieved by shortening rest intervals. High-

intensity intermittent exercise has been purported to be

optimal in heart failure patients [70].

4.1 Recommendation for Exercise Prescription

in People with PAD

The following recommendations are based upon previous

work and our current analysis. We have referenced those

recommendations which are not based upon our analysis.


123

4.1.1 Exercise Intensity

Vigorous as per ACSM [30] and Exercise and Sports Sci-

ence Australia (ESSA) [29] guidelines and where tolerated

due to claudication or other illness (e.g., unstable angina),

based upon our analyses. Vigorous intensity exercise is

activity at 70–90 % maximum heart rate [29]. The ratio-

nale for performing this intensity exercise is that when

Study or Subgroup

Allen 2010Bronas 2011 ArmBronas 2011 WalkCrowther 2008Crowther 2012Cucato 2013Gardener 2001Gardner 2011 HomeGardner 2011 SupervisedGardner 2012Hiatt 1994 AerobicHiatt 1994 PRTMcDermott 2004McDermott 2009 PRTMcDermott 2009 WalkMcDermott 2013Mika 2006Nicolai 2010Regensteiner 1997Savage 2001Treat-Jacobsen 2009 ArmTreat-Jacobsen 2009 CombTreat-Jacobsen 2009 WalkTsai 2002

Total (95% CI)


Mean

122.889.6

106.7202.2294.3

204230

119.3146.9197.6181.6

16-5.386.6

156.8276.36173.6

310160.2242.6

906292

155

SD

220.632373.8921

147.5281281.1204355.7741335.8458329.5145

174.687232.7628

1,021.4442252.48

20.69919.1757

166.8488261.6025131.7342243.1068878.6182222.7274359.1941

74.222110.0901149.1592217.0597

Total

151010101013282933

10610

9174650772793101110121127

674

Mean

68.57.37.3

44.8621.45

-7540

-14.2-14.264.1

-37.4-37.453.470.270.2

22.435.3

17032.04

80.6444

16

SD

138.41774.62514.6251

67.126920.57

118.65395.175525.769825.7698

188.570723.695523.695564.2397

177.9107177.9107132.3272

13.7321453.3486

45.0301113.2778

45.31225.314418.387939.7989

Total

1844

116

1224151536

448

24246828831010

332

26

442

Weight

1.3%9.8%2.5%0.7%0.4%0.6%1.3%4.9%3.2%0.5%0.8%

28.8%10.4%

2.8%2.0%

11.2%2.5%0.5%1.0%0.4%4.4%4.4%2.5%3.0%

100.0%

IV, Fixed, 95% CI

54.30 [-74.37, 182.97]82.30 [36.28, 128.32]

99.40 [7.85, 190.95]157.34 [-21.36, 336.04]272.85 [51.73, 493.97]279.00 [84.48, 473.52]190.00 [62.15, 317.85]133.50 [68.60, 198.40]161.10 [80.62, 241.58]

133.50 [-70.47, 337.47]219.00 [60.80, 377.20]

53.40 [26.53, 80.27]-58.70 [-103.43, -13.97]

16.40 [-69.57, 102.37]86.62 [-14.99, 188.23]

53.93 [10.86, 97.00]168.30 [76.46, 260.14]

140.00 [-63.47, 343.47]128.16 [-12.68, 269.00]162.00 [-61.58, 385.58]

86.00 [17.11, 154.89]58.00 [-10.56, 126.56]

88.00 [-3.76, 179.76]139.00 [55.71, 222.29]

68.78 [54.35, 83.21]


-500 -250 0 250 500Favours [experimental] Favours [control]

Fig. 3 Mean difference in graded treadmill (ICD) exercise versus control groups. ICD initial claudication distance, PRT progressive resistance

training

Study or Subgroup

Allen 2010Bronas 2011 ArmBronas 2011 WalkCrowther 2008Crowther 2012Cucato 2013Gardener 2001Gardner 2011 HomeGardner 2011 SupervisedGardner 2012Gelin 2001Hiatt 1990Hiatt 1994 AerobicHiatt 1994 PRTHodges 2008McDermott 2004McDermott 2009 PRTMcDermott 2009 WalkMcDermott 2013Mika 2006Nicolai 2010Regensteiner 1997Savage 2001Treat-Jacobsen 2009 ArmTreat-Jacobsen 2009 CombTreat-Jacobsen 2009 WalkTsai 2002Wang 2008

Total (95% CI)


Mean

231.4181.1297.6359.5

384316306

110.4191.4280.4

-11400.5272.3106.8310.6

59.7124.31209.3

82.2194340

341.8220.4

182217295272

153.9

SD

415.7518251.7849413.7558499.8159282.6087520.2318438.3976161.655303.273

1,449.458347.3566

556.8185378.581

138.1662274.98761.2346

197.3525733.1041166.6974271.6747963.6458475.2074326.3248120.3817169.1877212.9998380.9047158.2439

Total

151010101013282933

106731010

91417465086279310111012112714

794

Mean

82.846.346.357.464.5-5746

-8.9-8.953.4-11

58.7-5.3-5.343.6

4635.47-98.128.318.714016

182.845.345.345.369.50.01

SD

167.313755.698429.334285.891361.853990.1762

109.451816.151516.1515158.54948.352775.9397

3.35793.3579

75.893939.9968144.447

233.4178167.879648.4509

373.345922.4869

254.148443.057943.057943.0579

172.87650.01

Total

1844

116

122415153676

944

148

24248728831010

332

2611

571

Weight

0.3%0.5%0.2%0.2%0.4%0.2%0.5%4.2%1.4%0.2%

62.6%0.1%0.3%1.8%0.7%9.2%2.2%0.3%6.0%1.4%0.3%0.2%0.2%1.9%1.3%0.8%0.6%2.2%

100.0%

IV, Fixed, 95% CI

148.60 [-75.54, 372.74]134.80 [-30.53, 300.13]251.30 [-6.75, 509.35]

302.10 [-11.81, 616.01]319.50 [137.48, 501.52]373.00 [85.64, 660.36]260.00 [91.82, 428.18]119.30 [59.90, 178.70]200.30 [96.51, 304.09]

227.00 [-53.75, 507.75]0.00 [-15.37, 15.37]

341.80 [-6.86, 690.46]277.60 [42.93, 512.27]112.10 [21.77, 202.43]

267.00 [117.57, 416.43]13.70 [-26.49, 53.89]88.84 [7.65, 170.03]

307.40 [83.77, 531.03]53.90 [4.04, 103.76]

175.30 [71.27, 279.33]200.00 [-11.68, 411.68]325.80 [30.94, 620.66]

37.60 [-211.40, 286.60]136.70 [47.59, 225.81]171.70 [64.29, 279.11]

249.70 [110.40, 389.00]202.50 [44.20, 360.80]153.89 [71.00, 236.78]

41.00 [28.83, 53.16]


-500 -250 0 250 500Favours [experimental] Favours [control]

Fig. 4 Mean difference in graded treadmill (ACD) exercise versus control groups. ACD absolute claudication distance, PRT progressive

resistance training


123

peak VO2 is very low, activities of daily living are per-

formed at near maximal to maximal effort.

4.1.2 Interval Duration

If walking, then to mild pain, based upon our analyses. For

alternative modes that do not induce claudication, short

intervals of 1–2 minutes’ duration will suffice. For pro-

gressive resistance training, 2–3 sets of 8–12 reps [30].

4.1.3 Repetitions

The number should be determined by interval duration but

progression towards a total exercise time of about

16 minutes has been successful in heart failure patients

[71]. Previous recommendations have suggested a total

exercise time of 40 minutes to be effective [7]; however,

more research is needed in this area.

4.1.4 Recovery

Low-intensity activity, of the same mode of exercise such

as very slow arm cranking, is preferred to stationary rest

periods; however, when walking is the mode then rest is

recommended to eliminate claudication pain and/or short-

ness of breath [72, 73].

4.1.5 Program duration

Preferably ongoing but at least 24 weeks seems optimal

based upon our analyses.

4.1.6 Progression

Slowly increase interval duration up to 4 minutes and

shorten recovery periods so session time is kept as short as

possible to optimize adherence [74].

4.2 Limitations

Our analyses exhibited moderate to high evidence of

between-study heterogeneity. While the investigators per-

forming assessment measures were aware of group

assignment, this was consistent since all studies would

have found it difficult to blind participants and investiga-

tors to exercise training or sedentary control allocation

unless ‘sham’ exercise is used. Perhaps of greater relevance

is that the standard exercise care program in many parts of

the world is advice to exercise, this may mean that there

would have been significant crossover to exercise if

patients were assumed to be sedentary controls. While the

authors recognize that claudication distance, rather than

peak VO2, is the primary endpoint for claudication, we did

not include a comparison of incremental treadmill and

constant load treadmill results of rehabilitation. The reason

for this is that trials that did perform a constant load

treadmill protocol used a variety of speeds and grades in

their protocols which created great heterogeneity. Egger

plots showed minimal evidence of publication bias, with

the exception of graded treadmill measures, understandably

so, as older studies may not have used the Gardner protocol

[18]. In addition, this bias may be due to specificity of

training mode and testing mode. It is therefore unlikely

unpublished negative or neutral datasets exist for our out-

come measures and significance levels suggest unpublished

data would not change presented findings. A further limi-

tation of this field of study is that several desired measures

such as cardiac function, exercise blood pressure moni-

toring, neurohormonal, muscle strength and metabolism,

blood vessel compliance and flow are unavailable, making

it difficult to provide mechanistic interpretations.

5 Conclusions

Exercise training improves peak VO2, total and pain-free

walking distances, and graded treadmill performance in

PAD. Sub-analyses suggest that exercise at vigorous

intensity for at least 24 weeks may be optimal and perhaps

exercising to mild pain may yield better results than

exercising to moderate or maximal pain. Exercise pre-

scription for this cohort may be even more beneficial were

it to include arm cranking exercise. Lower limb exercise

should be performed at short, high-intensity intervals, but

only to a threshold of mild pain.

Acknowledgments We acknowledge Mr Glenn Phipps for his

assistance with literature searching, Glenn was not paid for this work.

The authors Neil Smart, Gudrun Dieberg, and Belinda Parmenter

have no conflicts of interest to declare.

We would also like to thank included study authors who provided

additional information.

There are no financial disclosures.

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