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. Author manuscript; available in PMC: 2012 Jan 29.
Published in final edited form as: JAMA. 2009 Jan 14;301(2):165–174. doi: 10.1001/jama.2008.962

TREADMILL EXERCISE AND RESISTANCE TRAINING IN PATIENTS WITH PERIPHERAL ARTERIAL DISEASE WITH AND WITHOUT INTERMITTENT CLAUDICATION: A RANDOMIZED CONTROLLED TRIAL

Mary M McDermott a, Philip Ades b, Jack M Guralnik c, Alan Dyer a, Luigi Ferrucci c, Kiang Liu a, Miriam Nelson d, Donald Lloyd-Jones a, Linda Van Horn a, Daniel Garside a, Melina Kibbe a, Kathryn Domanchuk a, James H Stein e, Yihua Liao a, Huimin Tao a, David Green a, William H Pearce a, Joseph R Schneider f, David McPherson g, Susan T Laing g, Walter J McCarthy h, Adhir Shroff i, Michael H Criqui j
PMCID: PMC3268032  NIHMSID: NIHMS345226  PMID: 19141764

Abstract

Background

The role of strength training in peripheral arterial disease (PAD) is unclear. Benefits of supervised treadmill exercise in PAD patients without intermittent claudication (IC) are not established.

Objective

To determine whether supervised treadmill exercise and lower extremity resistance training, respectively, improve functional performance compared to a control group in PAD persons with and without IC.

Design

Randomized controlled clinical trial performed between 4/1/04 and 8/19/08.

Participants

156 people with PAD (ankle brachial index ≤ 0.95), including 81.4% without IC.

Measurements

Primary outcomes were six-minute walk performance and the short physical performance battery (SPPB). Additional outcomes were brachial artery flow-mediated dilation (FMD), treadmill walking performance, the Walking Impairment Questionnaire (WIQ), and the Short-Form 36 Physical Functioning score (SF-36 PF).

Interventions

Three parallel arms: supervised treadmill exercise, supervised lower extremity resistance training, and a control group.

Results

Compared to control, the treadmill exercise group increased six-minute walk distance (+35.9 meters, 95% confidence interval (CI), +15.3 to +56.5; P <0.001), while the resistance trained group did not improve (+12.4 meters, 95% CI, −8.42 to +33.3; P=0.24). Neither exercise group improved the SPPB. Compared to control, treadmill exercise improved brachial artery FMD (+1.53%, 95% CI, +0.35 to +2.70, P=0.018), time on treadmill (+3.44 minutes, 95% CI, +2.05 to +4.84; P<0.001), the WIQ distance score P=0.015), and the SF-36 PF score (P=0.02). Compared to control, resistance training improved time on treadmill (+1.98 minutes, 95% CI, +0.56 to +3.39; P=0.007), the WIQ distance score (P=0.02), the WIQ stair climbing score (P=0.02), and the SF-36 PF score (P=0.04).

Conclusion

Supervised treadmill exercise improved six-minute walk distance, treadmill walking performance, brachial artery FMD, and quality of life, but not the SPPB, in PAD participants with and without classic IC symptoms. Resistance training improved treadmill walking performance, quality of life, and stair climbing ability in patients with PAD.

Lower extremity peripheral arterial disease (PAD) affects one in sixteen men and women in the United States age 40 and older (1). Men and women with PAD have greater functional impairment and faster rates of functional decline than persons without PAD (2–4).

Supervised treadmill exercise improves treadmill walking performance in people with PAD who have symptoms of intermittent claudication (IC) (5). However, important questions regarding exercise in PAD remain unanswered. Most people with PAD do not have classic symptoms of IC, either because they are asymptomatic or because they have exertional leg symptoms other than IC (2,6–9). People with PAD who do not have classic IC symptoms have comparable or greater functional impairment and functional decline compared to those without PAD (2,3,6,9). However, no prior exercise interventions have been tested in PAD participants with and without classic symptoms of IC.

Additionally, benefits of lower extremity resistance (strength) training in PAD are unclear. Men and women with PAD have smaller calf muscle area and poorer leg strength than those without PAD, and these muscle characteristics are associated with greater functional impairment among people with PAD (10,11). However, clinical trials of lower extremity resistance training in persons with PAD have been small, yielded mixed results, and excluded PAD participants without classic symptoms of IC (12,13).

We performed a randomized controlled clinical trial in men and women with PAD to address two clinical questions. First, we determined whether supervised treadmill exercise improves functional performance and other outcomes in PAD participants with and without classic IC symptoms. Second, we determined whether lower extremity resistance training improves functional performance and other outcomes in PAD participants with and without classic IC symptoms. Each intervention group was compared to an attention control group.

METHODS

The institutional review boards of Northwestern University, Catholic Health Partners Hospital, Evanston Northwestern Hospital, Rush Medical Center, University of Illinois-Chicago, Jesse Brown Veterans Administration, University of Wisconsin School of Medicine, and Chicago’s Mt. Sinai Hospital approved the protocol. Participants gave written informed consent.

The study was a randomized controlled clinical trial. Participants were randomized to one of three groups: supervised treadmill exercise, supervised lower extremity resistance training, or an attention control group. The resistance training intervention included only lower extremity exercises. Data collection and study interventions were performed at Northwestern University Feinberg School of Medicine between 4/1/04 and 8/19/08.

Participant Identification

Most participants were recruited from newspaper and radio advertisements (n=85) and from among consecutive patients diagnosed with PAD in the non-invasive vascular laboratories and relevant clinics at Northwestern Memorial Hospital and other Chicago-area hospitals (n=37). Previous study demonstrates that most patients diagnosed with PAD in non-invasive vascular laboratories do not have classic IC symptoms (3,6). Remaining participants were recruited from mailings to Chicago residents age 60 and older, posted flyers, recruitment mailings to people identified with PAD in the Lifeline of Screening program, and community outreach methods (14).

Inclusion and Exclusion Criteria

The inclusion criterion was an ankle brachial index (ABI) ≤ 0.95 (15–17). Exclusion criteria were dementia, critical limb ischemia, foot ulcers, major amputation, nursing home residence, inability to walk on a treadmill, inability exercise at the medical center three times weekly, failure to complete exercise run-in sessions, major surgery or a myocardial infarction within the past three months, major surgery planned in the next year, current participation in other clinical trials, baseline exercise comparable to that offered in either exercise arm, abnormal baseline exercise stress test, walking limitation from a cause other than PAD, poorly controlled hypertension, and a baseline short physical performance batter (SPPB) score of 12 (i.e. maximal possible score).

Ankle Brachial Index (ABI) Measurement

A hand-held Doppler probe (Nicolet Vascular Pocket Dop II; Nicolet Biomedical Inc, Golden, CO) was used to obtain systolic pressures in the right and left brachial, dorsalis pedis, and posterior tibial arteries (2,3,18). Each pressure was measured twice. The ABI was calculated by dividing the mean of the dorsalis pedis and posterior tibial pressures in each leg by the mean of the four brachial pressures (18). Average pressures in the arm with highest pressure were used when 1 brachial pressure was higher than the opposite brachial pressure in both measurement sets and the 2 brachial pressures differed by ≥ 10 mm Hg in one measurement set (19).

Medical history

Medical history, race, and demographics were obtained using patient report (20). Race data were obtained to determine whether African-Americans were equally distributed across the three study groups. Prior study indicates that among persons with PAD, African-Americans have poorer functional performance than Caucasians (21).

Leg Symptoms

Leg symptoms were characterized using the San Diego claudication questionnaire (22). IC was defined as exertional calf pain that does not begin at rest, causes the participant to stop walking, and resolves within ten minutes of rest (21). Participants without IC were either asymptomatic (i.e. no exertional leg symptoms) or had exertional leg symptoms not consistent with IC (22).

Outcomes

Outcomes were measured before randomization and at six-month follow-up. Examiners were blinded to participant group assignment. The two pre-specified primary outcomes were the six-minute walk test and the SPPB. The six-minute walk was a primary outcome because persons with PAD are primarily limited in walking endurance (2,3,6). Treadmill walking performance was not a primary outcome because treadmill performance is susceptible to a learning effect (23) and participants randomized to treadmill exercise “practiced” treadmill walking during exercise sessions. Furthermore, corridor walking such as that measured in the six-minute walk may better represent community walking performance than treadmill walking (19,24–26). The SPPB is a functional performance measure that depends upon leg strength and balance (27,28), which were targets of the lower extremity resistance training intervention. Lower SPPB scores are associated with increased mobility loss among persons with PAD (4).

Secondary outcomes were brachial artery flow mediated dilation (FMD) and physical activity. Exploratory outcomes were treadmill walking performance, quality-of-life, and leg strength.

Six-minute walk

Following a standardized protocol (2–4,6,29), participants walk up and down a 100- foot hallway for six minutes after instructions to cover as much distance as possible. The distance completed after six-minutes was recorded. The intra-class correlation coefficient for test re-test reliability of the six-minute walk was 0.90 (P<.001) among 155 PAD participants in our laboratory who completed two tests 1–2 weeks apart.

Short Physical Performance Battery

The SPPB combines data from usual paced four-meter walking velocity, time to rise from a seated position five times, and standing balance (4,27,28). Individuals receive a zero score for each task they are unable to complete. Scores of one to four are assigned for remaining tasks, according to established methods (4,27,28). Scores are summed to obtain the SPPB, ranging from 0 to 12 (22,23). Test re-test reliability of the SPPB was 0.72 (P<.001) among 144 PAD participants in our laboratory who completed two tests 1–2 weeks apart.

Repeated chair rises

Participants sit in a straight-backed chair with arms folded across their chest and stand five times consecutively as quickly as possible. Time to complete five chair rises is measured (27,28).

Standing balance

Participants are asked to hold three increasingly difficult standing positions for ten seconds each: the side-by-side stand, semi-tandem stand (standing with feet parallel and the heel of one foot touching the base of the 1st toe of the opposite foot), and the full tandem stand (standing with one foot directly in front of the other) (27,28). Scores range from zero (unable to hold the side-by-side stand for ten seconds) to four (able to hold the full tandem stand for ten seconds) (27,28).

Four-meter walking velocity

Walking velocity was measured with a four-meter walk performed at usual pace, according to previously described methods (2–4,22,23).

To account for possible learning effects, we measured the SPPB and six-minute walk at two separate baseline visits, approximately 1–2 weeks apart. Performance at the second visit was used as the baseline value. However, 12 participants had the SPPB measured at only one baseline visit and their first (only) SPPB score was used as their baseline value.

Brachial Artery Flow-Mediated Dilation

Brachial artery flow-mediated dilation (FMD) was measured after a 12 hour fast by trained Registered Diagnostic Cardiac Sonographers, using standard procedures (30,31). Participants were instructed to hold medications and not exercise or smoke prior to testing. Participants whose brachial systolic pressure differed by > 15 mm Hg between the right and left arms, those with a radical mastectomy, and those with a history of Raynaud’s phenomenon were excluded from FMD testing. The proximal brachial artery was imaged (B-mode and Doppler) using a linear array vascular ultrasound transducer (Siemens Medical Solutions, Sequoia Model #256, frequency 8MHz, range 5–8MHz). A blood pressure cuff proximal to the visualized brachial artery segment was inflated for four minutes at 50 mm Hg above systolic pressure. Longitudinal images of the brachial artery and Doppler blood flow were obtained 60 seconds after cuff deflation (30). Images were interpreted by a single reader at the University of Wisconsin Atherosclerosis Imaging Research Program Core Laboratory, using established standards (31). Measurement reproducibility in the core laboratory has a median FMD difference of 0.02% (inter-quartile range: −0.03–0.04) on blinded repeated readings.

Physical Activity

Habitual physical activity was measured objectively over seven days using a vertical accelerometer (Caltrac, Muscle Dynamics Fitness Network, Inc., Torrance, CA) according to established methods, yielding “activity units”(32–34).

Treadmill Walking Performance

Maximal treadmill walking time and time to onset of ischemic leg symptoms were measured using the Gardner-Skinner protocol (23,35). This protocol has a CV of approximately 12% in persons with PAD (23,35).

Quality of Life

The Walking Impairment Questionnaire (WIQ) is a PAD-specific measure of self-reported walking limitations with three domains: walking distance, walking speed, and stair climbing (36). Each domain is scored on a 0–100 scale, where 0 represents the most extreme limitation and 100 represents no difficulty walking long distances, walking rapidly, or climbing three stair flights, respectively (36). We used the Medical Outcomes Study Short-Form 36 (SF-36) to assess functional status in the physical functioning domain (37).

Strength Measures

Maximum isometric knee extension and plantar flexion strength were measured in Newtons over six seconds with a computerized strength chair (Good Strength Chair, Metitur Oy, Jyvasklya, Finland) (11,38). Two trials were performed, and the maximum was used in analyses (11). The Good Strength Chair has high test re-test reliability (Pearson product moment correlations = 0.88–0.96) (38). Knee extension power was measured in watts using the Nottingham power rig (11,39).

Other Measures

Height and weight were measured at baseline. Body mass index (BMI) was calculated as weight (kg)/(height (Meters))2.

Randomization

After baseline testing, eligible participants were randomized by computer using a randomly permuted block method. Randomization was stratified by the presence vs. absence of IC.

Study Interventions

The supervised treadmill exercise intervention consisted of three times weekly treadmill exercise for 24 weeks, supervised by an exercise physiologist. Participants began with 15 minutes of exercise and increased to 40 minutes by week eight. Initial treadmill walking speed was 2.0 miles per hour (MPH) or lower if the participant was unable to walk at 2.0 MPH. Between weeks eight and twenty-four, attempts to increase exercise intensity were made at least weekly either by increasing treadmill speed or by increasing the treadmill grade. Participants with leg symptoms were encouraged to exercise to near maximal leg symptoms. Asymptomatic participants were encouraged to exercise to a level of 12–14 (moderately hard) on Borg’s Rating of Perceived Exertion (RPE) scale (40).

Supervised lower extremity resistance training

Participants in the lower extremity resistance training group exercised three times weekly for 24 weeks with a certified trainer. Participants performed three sets of eight repetitions of knee extension, leg press, and leg curl exercises using standard equipment. For each exercise, the one repetition maximum (1RM) was measured at baseline and subsequently every four weeks. Participants began exercising at 50% of their 1RM. Weights were increased over the first five weeks until participants were lifting 80% of their 1RM. Weights were adjusted after each monthly 1RM and as needed to achieve an exercise intensity of an RPE=12–14. Participants also performed three sets of eight repetitions of squat and toe rise exercises. The toe rise exercises were plantar extension exercises, in which participants assumed a tip-toe position and lowered themselves eight times consecutively.

Attention Control

The attention control group consisted of eleven one hour group nutritional information sessions over six months and was intended to provide regular contact with participants in the control group. Session topics included nutritional supplements, healthy restaurant eating, and increasing fruit and vegetable consumption. Sessions were led by Registered Dieticians but were not designed to change behavior.

Sample Size Calculations

Power calculations assumed that 50 people in each group would complete 6-month follow-up and that two separate two sample t-tests using a two-sided alpha of 0.05 would be conducted. The study was designed to have 80% power to detect a difference of 30 meters change in 6-minute walk distance and a difference of 0.97 change in the SPPB between baseline and 6-month follow-up between each exercise and control group. These differences represent clinically meaningful change in study outcomes (41). Power analyses assumed pooled standard deviations of 54 meters and 1.74 units, respectively. Because the number of participants who actually completed 6-month follow-up testing was slightly lower, power was reduced to 0.76 to 0.79 for comparisons of each exercise group with the control group.

Statistical Analyses

Chi-square tests and one-way analyses of variance were used to compare characteristics of participants across the three groups at baseline. Two sample, two-sided T-tests were used to compare changes in outcomes between baseline and six-month follow-up between each exercise group and the control group, respectively, without adjustments for multiple comparisons. A priori, the p value considered statistically significant was p <0.05. Because of skewed distributions for quality of life measures and brachial artery FMD, differences in median values for these outcomes were compared using Kruskal Wallis ANOVA and Wilcoxon rank sum tests, with Hodges-Lehman 95 percent confidence intervals computed for between group differences (42). Intention-to-treat analyses were performed (43). Analyses were repeated using multiple imputation for persons who died or dropped out before completing 6-month follow-up testing (44,45). The multiple imputation for missing six-month data was performed using SAS Proc MI to obtain five imputed data sets. Results were combined using Proc Combine. Variables used to impute data sets included age, ABI, BMI, sex, race, smoking status, baseline outcome values, leg symptoms, and comorbidities. Imputations were performed with and without four participants: two who died, one diagnosed with end stage renal disease, and one diagnosed with lung cancer. Analyses were performed using SAS version 9.2.

RESULTS

Of 1,009 potential participants who scheduled a baseline visit, 263 failed to show for their appointment and 261 had an ABI > 0.95. Of the remaining 485, 329 met an exclusion criterion, leaving 156 eligible, randomized participants (Figure 1). Among those who scheduled a baseline visit, the average age of randomized vs. non-randomized participants was 73.73 vs. 70.62, (p=0.002). Randomized vs. non-randomized participants included 52% vs. 46% women (p=0.17) and 39.7% vs. 36.0% blacks (p=0.37). There were no differences in baseline characteristics across the three groups (Table 1).

Figure 1.

Figure 1

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Study participation and follow-up rates among participants in the Study to Improve Leg Circulation (SILC).

**52 individuals either attended the attention control sessions or received a make-up packet in the mail and a telephone call. 11 individuals did not attend any attention control sessions but did receive a make-up packet and phone call (4 of these individuals did not complete follow-up).

Table 1.

Baseline Characteristics of Study Participants in the Study to Improve Leg Circulation.

Treadmill Walking Exercise (n=51) Lower Extremity Resistance Training (n=52) Attention Control Group (n=53) P value*
Age (years) 71.7 (8.7) 71.7 (8.7) 68.5 (11.9) 0.19
Female (27) 52.9% (26) 50.0% (28) 52.8% 0.94
Black (21) 41.2% (15) 28.9% (26) 49.1% 0.10
Intermittent claudication (12) 23.5% (9) 17.3% (8) 15.1% 0.52
Ankle Brachial Index 0.60 (0.18) 0.62 (0.15) 0.60 (0.18) 0.89
Diabetes Mellitus (20) 39.2% (24) 46.2% (25) 48.1% 0.64
Current Smoker (11) 21.6% (9) 17.3% (17) 32.1% 0.19
Body Mass Index kg/M2 30.4 (6.2) 30.4 (7.0) 29.9 (7.1) 0.92
Baseline Performance on Study Outcomes
Six minute walk performance (meters) 327.8 (87.0) 304.5 (92.9) 316.6 (83.2) 0.40
SPPB 9.2 (2.1) 8.4 (2.3) 8.5 (2.7) 0.24
Maximum treadmill walking distance (meters) 404 (245) 356 (190) 350 (209) 0.38
Treadmill distance to onset of leg symptoms (meters) 160 (135) 152 (111) 144 (114) 0.82
WIQ Distance Score 26.0 (19.1) 27.7 (27.9) 30.5 (24.0) 0.66
WIQ Speed Score 32.1 (22.9) 23.7 (21.1) 27.9 (18.0) 0.14
WIQ Stair Climbing Score 41.0 (24.7) 35.9 (25.5) 42.2 (24.9) 0.41
Short-Form 36 Physical Functioning Score 40.5 (19.4) 37.2 (19.0) 42.6 (18.9) 0.37
Mean Baseline Brachial Artery Diameter (millimeters) 4.5 (0.8) 4.4 (0.7) 4.4 (0.7) 0.95
Relative Brachial Artery FMD- 60 seconds (percent) 5.4 (4.2) 6.0 (4.8) 6.1 (4.0) 0.71
Absolute Brachial Artery FMD – 60 seconds (millimeters) 0.23 (0.16) 0.25 (0.20) 0.26 (0.17) 0.69
Statin Use (34) 66.7% (33) 63.5% (31) 58.5% 0.6847
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WIQ = Walking Impairment Questionnaire. FMD- Flow Mediated Dilation

*

P value represents the overall comparison between the three study groups.

Values shown for continuous variables are means (standard deviations). Values shown for categorical variables are (number) percent.

Among participants in the treadmill exercise, resistance training, and control groups, median session attendance rates were 85%, 92%, and 100%, and six-month follow-up data were obtained in 98%, 89%, and 91%, respectively. Two participants (one in the resistance trained group and one in the control group) died from cancer before six-month follow-up.

Primary Outcomes

At six month follow-up, participants in the treadmill exercise group improved their six-minute walk performance, compared to the control group (+35.9 meters, 95% Confidence Interval (CI) = +15.3 to +56.5, p<0.001) (Table 2). Participants in the lower extremity resistance trained group did not experience greater change in six-minute walk performance compared to the control group (+12.4 meters, 95% CI = −8.42 to +33.3, p=0.24) (Table 2). There were no differences in change in SPPB score between the treadmill exercise and control groups or between the resistance trained and the control groups at six-month follow-up (Table 2). Results for primary outcomes were not substantially changed when analyses were repeated employing multiple imputation methods with and without the four participants with extreme outcomes (death or serious illness). Similarly, results were not substantially changed when analyses were repeated substituting baseline values for the six-month follow-up time point for participants who did not return for follow-up, with and without exclusion of the four participants with extreme outcomes. Findings would be unchanged with multiple comparison adjustment (p <0.025).

Table 2.

Associations of Supervised Treadmill Exercise and Lower Extremity Resistance Training with Primary and Secondary Study Outcomes in Peripheral Arterial Disease Participants with and without Intermittent Claudication

Outcome measures Group N Baseline Value Six month Value Within Group Changes (95% CL)* Compare to Control Group (95% CL)* Pair-wise P value P value
Primary Outcome Measures
Six minute walk (Meters) Control 47 320(87) 305(93) −15.0(−29.7, −0.37) NA NA <0.001
Strength 46 311(90) 309(89) −2.60(−17.4, 12.2) 12.4 (−8.42, 33.3) 0.241
Treadmill 48 327 (89) 348(80) 20.9(6.41, 35.4) 35.9(15.3, 56.5) <0.001
SPPB (0–12 score, 12=best) Control 48 8.44(2.77) 8.98(2.98) 0.54(0.02, 1.06) NA NA 0.816
Strength 46 8.54(2.25) 9.09(2.73) 0.54(0.02, 1.07) 0.00 (−0.74, 0.74) 0.996
Treadmill 50 9.12(2.06) 9.46(2.00) 0.34(−0.17, 0.85) −0.20 (−0.93, 0.52) 0.583
Secondary Outcome Measures
Relative change in brachial artery FMD 60 seconds after cuff release (Percent) Control 28 5.97(3.80, 8.91)* 5.28(3.60, 7.44) −0.86 (−2.86, 0.60) NA NA 0.071
Strength 36 4.89(2.59, 9.24)* 6.13(2.20, 8.37) 0.11 (−2.03, 1.33) 0.90(−0.58,2.37) 0.231
Treadmill 37 5.54(3.09, 6.87)* 5.39(3.27, 8.16) 0.70 (−0.77, 1.82) 1.53(0.35, 2.70) 0.018
Absolute change in brachial artery FMD 60 seconds after cuff release (millimeters) Control 28 0.29(0.16, 0.40)* 0.24(0.17, 0.34) −0.04 (−0.11, 0.03) NA NA 0.142
Strength 36 0.22(0.11, 0.37)* 0.27(0.10, 0.35) 0.02 (−0.09, 0.06) 0.04(−0.03,0.10) 0.218
Treadmill 37 0.24(0.17, 0.29)* 0.23(0.15, 0.32) 0.02 (−0.05, 0.07) 0.06(0.00, 0.11) 0.043
Physical activity (Activity units) Control 41 702(530) 689(441) −12.9(−226, 200) NA NA 0.485
Strength 37 578(391) 529(353) −49.0(−274, 175) −36.2(−346, 273) 0.818
Treadmill 46 658(317) 780(869) 122(−79.5, 323) 135(−159, 428) 0.365
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*

Baseline and six-month data shown are means (standard deviations) for all outcomes except the brachial artery flow mediated diameter. Baseline and six-month data for the brachial artery flow mediated diameter are medians (interquartile ranges). Within group changes shown are mean changes (95% confidence intervals) for all outcomes except brachial artery flow mediated diameter. Within group changes for brachial artery flow mediated diameter are median changes (interquartile ranges). Between group changes shown are means (95% confidence intervals) for all outcomes except brachial artery flow mediated diameter. Within group changes for brachial artery flow mediated diameter are median changes (Hodges-Lehmann confidence limits).

Secondary Outcomes

One hundred-one participants met inclusion criteria for brachial artery FMD testing and adhered to requirements for testing. At six-month follow-up, participants in the treadmill exercise group had more favorable changes in brachial arterial FMD than the control group (+1.53%, 95% CI = +0.35 to +2.70, p=0.018 and +0.06 millimeters, 95% CI = 0.00 to +0.11, p=0.04). Changes in brachial artery FMD among participants in the resistance trained group were not different than the control group (Table 2).

At six month follow-up, there were no differences in changes in accelerometer-measured physical activity in either exercise group, compared to the control group (Table 2).

Exploratory Outcomes

At six month follow-up, participants in the treadmill exercise and the resistance trained groups each had significantly greater increases in maximum treadmill walking time, compared to the control group (+3.44 minutes, 95% confidence interval = +2.05 to +4.84, p<0.001 and +1.98 minutes, 95% confidence interval = +0.56 to +3.39, p=0.007, respectively) (Table 3). Participants in the treadmill exercise group had greater increases in treadmill time to onset of ischemic leg symptoms compared to the control group (+1.65 minutes, 95% CI = +0.34 to +2.95, p=0.014) (Table 3).

Table 3.

Associations of Supervised Treadmill Exercise and Lower Extremity Resistance Training with Exploratory Outcome Measures in Peripheral Arterial Disease Participants with and without Intermittent Claudication

Exploratory outcomes
Outcome measures Group N Baseline* Six month* Within Group Changes (95% Confidence Limits)* Between Group Changes Compared to the Control Group (95% Confidence Limits)* Pair-wise P value P value
Maximal treadmill walking time (Minutes) Control 44 354(219) 381(221) 26.9(−28.2, 82.1) NA NA <.0001
Strength 44 360(195) 501(225) 142(86.6, 197) 115(36.8, 193) <.001
Treadmill 48 409(252) 622(302) 213(160, 266) 186(110, 262) <.0001
Treadmill distance to onset of leg symptoms Control 33 125(93.8) 194(175) 69.4(17.8, 121) NA NA 0.043
Strength 36 159(113) 259(144) 100(50.6, 149) 30.6(−40.8, 102) 0.397
Treadmill 35 135(113) 295(175) 160(110, 210) 90.5(18.6, 162) 0.014
Short-form 36 physical functioning score Control 40 42.5(30.0, 55.0) 45.0(32.5, 55.0) 5.00(−5.00,15.0) NA NA 0.041
Strength 40 35.0(22.5, 52.5) 50.0(25.0, 65.0) 10.0(0.00, 17.5) 7.50(0.00, 15.0) 0.043
Treadmill 46 35.0(25.0, 50.0) 52.5(40.0, 70.0) 10.0(0.00, 30.0) 7.50(0.00, 15.0) 0.021
WIQ distance score Control 34 26.6(11.6, 43.5) 28.1(12.1, 46.7) 0.25(−6.39,9.16) NA NA 0.023
Strength 43 18.5(3.98, 46.8) 26.5(10.5, 62.8) 8.52(0.00, 17.0) 6.92(1.07, 12.8) 0.025
Treadmill 41 20.1(10.2, 36.1) 37.1(16.9, 65.9) 9.94(−0.21,25.0) 10.7(1.56, 19.9) 0.015
WIQ speed score Control 36 25.0(10.9, 35.9) 27.7(15.8, 46.7) 0.00(−5.43,17.9) NA NA 0.657
Strength 42 19.6(6.52, 37.0) 27.2(10.9, 43.5) 4.34(−3.26,18.5) 1.63(−5.43,8.70) 0.547
Treadmill 44 25.0(15.8, 45.1) 40.8(25.4, 54.3) 10.3(−3.80,21.7) 3.80(−4.35,12.0) 0.394
WIQ stair climbing score Control 37 41.7(16.7, 66.7) 41.7(16.7, 66.7) 0.00(−12.5,8.33) NA NA 0.043
Strength 42 29.2(16.7, 45.8) 43.8(25.0, 66.7) 12.5(0.00, 25.0) 10.4(0.00, 20.8) 0.018
Treadmill 42 39.6(20.8, 50.0) 43.8(29.2, 66.7) 4.17(0.00, 25.0) 8.33(0.00, 16.7) 0.058
Knee extension isometric strength (Newtons) Control 30 296(141) 310(114) 14.7(−15.1,44.6) NA NA <.0001
Strength 27 232(104) 326(142) 94.9(63.4, 126) 80.2(36.8, 124) <.0001
Treadmill 28 274(100) 286(114) 11.4(−19.5,42.3) −3.32(−46.3, 39.7) 0.878
Knee extension power (Watts) Control 41 92.9(59.0) 98.5(62.0) 5.63(−4.13,15.4) NA NA 0.085
Strength 45 84.4(51.4) 100.2(58.5) 15.8(6.50, 25.1) 10.2(−3.32, 23.7) 0.138
Treadmill 48 101.8(48.3) 103.2(49.4) 1.42(−7.61,10.4) −4.22(−17.5, 9.09) 0.532
Plantarflexion isometric strength (Newtons) Control 30 301(116) 379(151) 78.2(15.9, 140) NA NA 0.686
Strength 29 318(176) 435(202) 117(53.7, 180) 38.8(−50.0, 128) 0.387
Treadmill 29 336(167) 435(161) 98.7(35.4, 162) 20.6(−68.2, 110) 0.646
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*

Baseline and six-month data shown are means (standard deviations) for all outcomes except the short-form 36 physical functioning score and the walking impairment questionnaire scores. Baseline and six-month data shown for the short-form 36 physical functioning score and the walking impairment questionnaire scores are medians (interquartile ranges). Within group changes shown are mean changes (95% confidence intervals) for all outcomes except the short-form 36 physical functioning score and the walking impairment questionnaire scores. Within group changes for the short-form 36 physical functioning score and the walking impairment questionnaire scores are median changes (interquartile ranges). Between group changes shown are means (95% confidence intervals) for all outcomes except the short-form 36 physical functioning score and the walking impairment questionnaire scores. Within group changes for the short-form 36 physical functioning score and the walking impairment questionnaire scores are median changes (Hodges-Lehmann confidence limits).

At six month follow-up, the treadmill exercise group had significantly greater improvement in their SF-36 physical functioning score (+7.5, 95% CI= 0.00 to +15.0, p=0.02) and WIQ distance score (+10.7, 95% CI= +1.56 to +19.9, p=0.015), compared to the control group (Table 3). The resistance trained group had greater improvement in their SF-36 physical functioning score (+7.5, 95% CI= 0.0 to +15.0, p=0.04), WIQ distance score (+6.92, 95% CI= +1.07 to +12.8, p=0.02), and WIQ stair climbing score (+10.4, 95% CI = 0.00 to +20.8, p=0.02), compared to the control group (Table 3).

At six-month follow-up, participants in the treadmill trained group did not have greater improvement in any leg strength measure, compared to the control group (Table 3). The resistance trained group improved isometric knee extension strength, compared to the control group (+80.2 Newtons, 95% CI = +36.8 to +124, p<0.001) (Table 3).

Associations of treadmill exercise with greater absolute change in brachial artery FMD and associations of lower extremity resistance training with improved SF-36 physical functioning score compared to the control group would not be statistically significant after multiple comparison adjustment at p <0.025.

The study was not designed to have statistical power for comparing differences in outcomes between the two exercise groups. However, the treadmill exercise group had greater increases in six-minute walk distance compared to the resistance group (+23.5 meters, 95% CI = +2.8 to +44.2, p=0.027). Participants in the resistance group experienced greater increases in knee extension isometric strength (+83.5 Newtons, 95% CI = +36.4 to +127.6, p=0.0003) and knee extension power (+14.4 Watts, 95% CI = +1.42 to +27.4, p=0.03), compared to the treadmill exercise group.

The study was not designed to have statistical power for comparing differences in outcomes between different leg symptom groups. The magnitude of change for our primary outcomes was reasonably similar between a) participants with vs. without IC and b) asymptomatic participants vs. symptomatic participants (data not shown).

DISCUSSION

This randomized controlled clinical trial demonstrates that a six month supervised treadmill exercise intervention increases walking endurance, measured by the six minute walk and treadmill walking performance, in PAD participants both with and without classic IC symptoms. Supervised treadmill exercise also increased brachial arterial FMD and improved quality of life. A six month lower extremity resistance training intervention did not improve six-minute walk distance in PAD participants. However, resistance training improved maximal treadmill walking distance and quality of life measures, particularly stair climbing ability. Supervised treadmill exercise was associated with greater increases in six-minute walk performance, compared to the resistance trained group.

To our knowledge, this is the first randomized controlled clinical trial of exercise in PAD to include participants with and without classic symptoms of IC. Most people with PAD do not have classic IC symptoms (6–9). Results reported here indicate that clinicians should recommend supervised treadmill exercise to PAD patients, whether or not they have classic symptoms of IC. To our knowledge, this is also the first randomized controlled clinical trial to demonstrate that supervised treadmill exercise improves brachial artery FMD in persons with PAD. Patients with PAD typically have severe systemic atherosclerosis and poorer endothelial function than patients without PAD (46). Among persons with PAD, poorer brachial arterial FMD is associated with higher cardiovascular event rates (47,48). Our findings suggest that supervised treadmill exercise confers a favorable systemic vascular effect that may reduce cardiovascular events in persons with PAD.

Reasons for lack of SPPB improvement in either exercise group are unclear. Balance and leg strength are important determinants of the SPPB. Our results suggest that treadmill exercise does not improve balance and leg strength significantly. One potential explanation for the lack of improved SPPB in the resistance-trained group is that baseline leg strength was relatively high in our cohort (49). Resistance training may more effectively improve SPPB components in persons with poorer baseline strength. The poorer test re-test reliability of the SPPB as compared to the six-minute walk may also make meaningful change in the SPPB more difficult to achieve.

Despite their associations with improved walking performance, the exercise interventions did not increase accelerometer-measured physical activity during daily life. Interventions specifically targeted to physical activity behavior may be necessary to increase daily physical activity in persons with PAD.

This study has limitations. First, our exclusion criterion of the maximum SPPB score (SPPB=12) and the relatively large proportion of potential participants who were unwilling to attend on-site exercise sessions three times weekly reduces the generalizability of our findings. Second, missing data at follow-up were more common in more frail participants. However, sensitivity analyses demonstrated that these missing data are not likely to have significantly altered our findings. Third, median session attendance rates varied from 85% for the treadmill exercise group to 100% for the control sessions. This difference may have influenced results. Fourth, because of additional exclusion criteria for FMD and patient refusal to adhere to test requirements, the sample size for FMD measurement was lower than that for the entire cohort. Sample sizes for secondary and exploratory outcomes were smaller than for the primary outcomes. Finally, the sample size was not large enough to allow meaningful comparisons in outcomes between categories of leg symptoms.

Based on findings reported here, physicians should recommend supervised treadmill exercise programs for PAD patients, regardless of whether they have classic symptoms of IC. Our findings regarding brachial artery FMD suggest that supervised treadmill exercise improves global vascular health in people with PAD. Lower extremity resistance training improves treadmill walking performance and quality of life, particularly stair climbing, in PAD persons with and without IC.

Acknowledgments

Supported by R01-HL073551 from the National Heart Lung and Blood Institute and by grant #RR-00048 from the National Center for Research Resources, National Institutes of Health (NIH). Supported in part by the Intramural Research Program, National Institutes on Aging, NIH.

The study principal investigator (MMM) had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

The funding agency played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Footnotes

ClinicalTrials.gov Identifier: NCT00106327

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