Abstract
Background
Treatment for claudication due to aortoiliac peripheral artery disease (PAD) often relies on stent revascularization. However, supervised exercise is known to provide comparable short-term (6-month) improvements in functional status and quality of life. Longer-term outcomes are not known.
Objectives
The goal of this study was to report the longer-term (18-month) efficacy of supervised exercise compared with stenting and optimal medical care.
Methods
Of 111 patients with aortoiliac PAD randomly assigned to receive optimal medical care (OMC), OMC plus supervised exercise (SE), or OMC plus stent revascularization (ST), 79 completed the 18-month clinical and treadmill follow-up assessment. SE consisted of 6 months of supervised exercise and an additional year of telephone-based exercise counseling. Primary clinical outcomes included objective treadmill-based walking performance and subjective quality of life.
Results
Peak walking time improved from baseline to 18 months for both SE (5.0 ± 5.4 min) and ST (3.2 ± 4.7 min; p < 0.001) compared with OMC (0.2 ± 2.1 min, p = 0.04). The difference between SE and ST was not significant (p = 0.16). Improvement in claudication onset time (COT) was greater for SE compared with OMC, but not for ST compared with OMC. Many disease-specific quality-of-life scales demonstrated durable improvements that were greater for ST compared with SE or OMC.
Conclusions
Both SE and ST had better 18-month outcomes than OMC. SE and ST provided comparable durable improvement in functional status and in quality of life up to 18 months. The durability of claudication exercise interventions merits its consideration as a primary PAD claudication treatment.
Claudication: Exercise Versus Endoluminal Revascularization [CLEVER]: NCT00132743
Keywords: angioplasty, ankle brachial index, cilostazol, exercise rehabilitation, quality of life, walking
Introduction
Peripheral artery disease (PAD) is one of the most prevalent cardiovascular diseases (1) affecting up to 5% of individuals over 55 years of age (2-6). Claudication is the most frequent symptom of PAD and is associated with significant disability and substantial reductions in patient-reported health status and quality of life (7). Multiple clinical trials have demonstrated that supervised exercise is an effective treatment, as it significantly improves walking performance (8) and quality of life (9,10). Despite this, access to supervised exercise is limited, as clinicians do not actively prescribe this claudication treatment and it is usually not reimbursed by Medicare or by third-party payers.
Lower extremity endovascular revascularization is 1 of the most frequent peripheral vascular procedures (11). Over the last decade, the number of such procedures has increased 3-fold (12). Although outcomes of aortoiliac artery stent placement for claudication in uncontrolled studies are excellent (13,14), it is also known that patients with PAD appreciate the benefits of low-risk interventions when available (15). CLEVER (Claudication: Exercise Versus Endoluminal Revascularization) is a comparative effectiveness study that compared outcomes for aortoiliac stenting (ST) or supervised exercise (SE) with optimal medical therapy (OMT) at 6 and 18 months. The study, designed to measure a primary peak walking treadmill time outcome at 6 months, demonstrated that supervised exercise achieved a greater early functional status improvement compared with stent revascularization (16). This paper describes the results of the CLEVER study at 18 months.
Methods
Study design and oversight
The CLEVER study was a randomized, multicenter clinical trial conducted at 29 centers in the United States and Canada. The study was designed to test the hypothesis that stent revascularization plus optimal medical care (OMC) and supervised exercise plus OMT would be associated with a greater improvement in peak walking time (PWT) on a graded treadmill test than with OMT alone. CLEVER secondarily tested whether stent revascularization plus OMT resulted in more improvement in PWT than supervised exercise plus OMC The study was approved by the U.S. Food and Drug Administration, the Canadian Therapeutic Products Directorate, and institutional review boards at all participating centers, and was supported by the National Institutes of Health National Heart Lung and Blood Institute. The study has been registered as NCT00132743with Clinicaltrials.gov since August 19, 2005, and was overseen by an independent data safety and monitoring committee. Details of the study design, methods and early results were published previously (16,17). The lead author wrote the first draft of the manuscript, and all coauthors participated in and approved subsequent revisions.
Population
Study participants were adults over 40 years of age with moderate to severe claudication due to aortoiliac PAD, who were enrolled between April 24, 2007 and January 11, 2011. A total of 999 patients were screened, 119 were enrolled, and 79 completed the 18-month follow-up clinical and treadmill assessment (Figure 1). Eight of the 119 enrolled patients were enrolled in a treatment group that included both stent revascularization and supervised exercise therapy. Due to slow enrollment, this group was terminated early in the recruitment phase and their results are not included in this report.
Figure 1. CONSORT Diagram.
Participants were randomized after consenting for study participation and undergoing eligibility testing. Potentially eligible study participants were screened at the discretion of the study site. The proportion that did not expire, withdraw consent, exit the study, or were not lost to follow-up before completion of the 18-month follow-up was 93/111 (84%). Of the 93 who remained in the study for the entire 18 months of follow-up, treadmill test data were available for 79/111 (71%) at 18 months. Of the 14 who remained in the study for the duration of follow-up, but did not undergo the treadmill test at 18 months, there were 9 in ST, 2 in SE, and 3 in OMC. The reasons for 9 ST participants missing PWT were: could not be contacted (1), comorbid condition (recent laminectomy in 1); out of 2-week window (2), and refused (5, 3 of whom had crossed over to structured exercise). The reasons for 3 OMC participants missing PWT were: comorbid condition (unknown, 1); no show (2). The reasons for 2 SE participants missing PWT were: refused (1) and unknown (1). Of the 14 patients who did not have the 18-month PWT, 7 had other 18-month endpoints collected, and 13 had QOL data collected by telephone. All study participants were confirmed to be alive at the 18-month follow-up interval, except for 1 person in SE who expired before the 6-month follow-up.
Moderate to severe claudication was defined as the ability to walk at least 2 minutes on a treadmill at 2 miles per hour at no grade, but <11 min on a graded treadmill test using the Gardner-Skinner protocol (18). Walking 11 min on the Gardner-Skinner protocol is consistent with an approximately 5.5-MET workload, which is considered moderate-intensity physical activity (19). All subjects were enrolled on the basis of the presence of at least a 50% diameter stenosis of the distal aorta or iliac arteries involving the more symptomatic leg, which was confirmed by either noninvasive vascular laboratory testing (n = 92) or catheter angiography (n = 19), as previously described (16). Distal angiographic anatomy was not evaluated because individuals with claudication due to aortoiliac PAD are known to achieve substantial functional (treadmill) and quality of life benefit from aortoiliac stent revascularization, regardless of the presence of distal arterial stenosis (7). Additionally, baseline angiographic study is invasive and was not considered necessary or appropriate for a study in which 2 of 3 treatment strategies were noninvasive.
Randomization and Interventions
Randomization was designed to be unbalanced in order to achieve twice as many participants in the ST and SE cohorts compared with OMC. OMC was consistent with published evidence-based PAD care guidelines (20) and included: use of atherosclerosis risk factor management; the claudication medication, cilostazol (Pletal, Otsuka America, Rockville, MD); and home exercise counseling, as described previously (16). Other details of the OMC intervention, including risk factor management, have been reported previously (16).
ST participants received optimal medical care in addition to stent revascularization of hemodynamically significant stenoses in the aorta and iliac arteries in the symptomatic leg(s), as indicated (16).
SE participants received OMC plus SE, which was designed on the basis of a meta-analysis that described optimal features of such therapy (8) and was consistent with current guidelines (20). It consisted of treadmill walking for up to 78 scheduled exercise sessions that were 1 h long, 3 days a week, for 6 months, as previously described (21). Patients in the SE group received quarterly contact by research coordinators during the supervised phase, and then participated in a telephone-based maintenance program designed to promote exercise adherence during the unsupervised phase of the study. This telephone support system was provided to SE patients from the beginning of month 7 to the end of month 18. This program consisted of initial contact with a trained health educator in month 5; biweekly telephone consultation between months 7 and 12; and then monthly telephone contact between months 13 and 18. Participants received log books to monitor their exercise, exercise tip sheets, and a pedometer. Telephone-based counseling utilized several behavioral strategies based on social cognitive theory that included goal setting, relapse prevention, time management, increasing social support, self-efficacy for exercise, enjoyment of exercise, and motivation (22). At each session, the participant set goals and reported on the attainment of those goals in the following session.
Endpoints
All endpoints were assessed at 6 months and at 18 months. The 6-month outcomes were reported previously (16). Functional status was measured by treadmill performance measurements that included the PWT and claudication onset time (COT).
Observers blinded to the treatment group administered treadmill tests. Three quality-of-life health status measures were used: the SF-12 (23), the Walking Impairment Questionnaire (WIQ) (10), and the Peripheral Artery Questionnaire (PAQ) (24). To determine the adequacy of revascularization procedures in the stent group, as well as changes in lower extremity perfusion among all participants throughout the study, ankle-brachial indexes (ABI) were obtained at baseline and both follow-up intervals.
Adverse events were monitored throughout the study. Restenosis was monitored long-term at scheduled visit intervals or prompted by recurrent symptoms between those scheduled visits on the basis of clinical symptoms and ankle-brachial index values, indicated by a decrease in the ABI by ≥0.10 compared with the first post-procedure ABI. Cost-effectiveness data were collected prospectively and will be reported in a subsequent paper.
Definitions
PWT was defined as the maximal time a participant could walk during the graded treadmill test, and COT was defined as the time when claudication was first noticed by a participant. COT was assumed to equal PWT if no claudication was experienced (16). Major complications were defined as death, amputation of the target limb, critical limb ischemia, target limb revascularization, or myocardial infarction and were adjudicated by a blinded clinical events committee.
Statistical Analysis
All endpoints were analyzed according to the intention-to-treat (ITT) principle. Secondary analyses were performed on a per-protocol population, which excluded those patients who did not receive their assigned treatment. Baseline characteristics were compared using 1-way analysis-of-variance (ANOVA) for continuous variables and the Fisher exact test for binary characteristics.
The sample size was determined by the anticipated treatment effect on the primary endpoint, the change in peak walking time at 6 months, as previously reported (16). All 3 pairwise comparisons of change in PWT between baseline and 18 months among the 3 treatment groups (OMC, ST and SE) were of interest and were carried out using analysis of covariance (ANCOVA) adjusted for baseline PWT, baseline cilostazol use, and study region, as previously reported (16). Sequential testing was performed so as to allow a 2-sided 0.05 level of significance for each pairwise comparison (16). Nonparametric tests using rank ANCOVA adjusted for study region, baseline cilostazol use, and baseline value of PWT were also done. Interaction tests were done to compare the effect of enrollment volume on outcomes for PWT, COT, and ABI. All p values are 2-sided and p values of 0.05 were considered statistically significant, without adjustments for multiple comparisons. Statistical analyses were performed using SAS for Windows (version 9.1.3, SAS, Cary, North Carolina).
Results
Population
Study design and patient flow from enrollment through the 18-month endpoint assessment, as well as reasons for missing follow-up, are shown in Figure 1. Baseline characteristics of the 3 study groups were similar (Table 1). There were more participants with a history of stroke in the SE group compared to other groups, but subjects with residual neurological deficits that might affect walking performance were excluded from study participation. The baseline PWT demonstrated severe ambulatory limitation at slightly over 5 min, which was similar across treatment groups. The population that completed the 18-month follow-up was similar to the baseline population (Table 1); there were no significant differences in baseline characteristics between the 79 patients who completed the 18-month treadmill test and the 32 patients who did not (Table 1).
Table 1. Demographic and Background Characteristics.
| Variable | All Patients (N = 111) | Patients with 18-month PWT (N = 79) | Optimal Medical Care with 18-month PWT (N = 15) | Supervised Exercise with 18-month PWT (N = 32) | Stent with 18-month PWT (N = 32) |
|---|---|---|---|---|---|
| Age, mean ± SD (N), yrs | 64.4 ± 9.5 (111) | 65.0 ± 9.5 (79) | 62.3 ± 8.5 (15) | 65.9 ± 8.8 (32) | 65.2 ± 10.5 (32) |
| Male (%) | 62.2% (69/111) | 62.0% (49/79) | 60.0% (9/15) | 56.3% (18/32) | 68.8% (22/32) |
| Risk factor history | |||||
| Diabetes (%) | 23.9% (26/109) | 24.7% (19/77) | 21.4% (3/14) | 18.8% (6/32) | 32.3% (10/31) |
| Hypertension (%) | 84.7% (94/111) | 87.3% (69/79) | 93.3% (14/15) | 90.6% (29/32) | 81.3% (26/32) |
| Current smoking (%) | 54.1% (60/111) | 53.2% (42/79) | 53.3% (8/15) | 53.1% (17/32) | 53.1% (17/32) |
| Former smoking (%) | 37.8% (42/111) | 38.0% (30/79) | 40.0% (6/15) | 37.5% (12/32) | 37.5% (12/32) |
| Hypercholesterolemia (%) | 80.2% (89/111) | 77.2% (61/79) | 73.3% (11/15) | 78.1% (25/32) | 78.1% (25/32) |
| Statin use (%) | 75.7% (84/111) | 74.7% (59/79) | 73.3% (11/15) | 78.1% (25/32) | 71.9% (23/32) |
| Antiplatelet agent use (%)* | 78.4% (87/111) | 81.0% (64/79) | 86.7% (13/15) | 78.1% (25/32) | 81.3% (26/32) |
| Comorbid cardiovascular diseases | |||||
| Prior TIA (%) | 5.4% (6/111) | 5.1% (4/79) | 6.7% (1/15) | 3.1% (1/32) | 6.3% (2/32) |
| Prior stroke (%) | 8.1% (9/111) | 7.6% (6/79) | 0.0% (0/15) | 18.8% (6/32) | 0.0% (0/32) |
| Prior angina (%) | 2.7% (3/111) | 3.8% (3/79) | 6.7% (1/15) | 0.0% (0/32) | 6.3% (2/32) |
| Prior myocardial infarction (%) | 21.5% (23/107) | 21.8% (17/78) | 33.3% (5/15) | 16.1% (5/31) | 21.9% (7/32) |
| Prior percutaneous coronary revascularization (%) | 18.0% (20/111) | 17.7% (14/79) | 26.7% (4/15) | 9.4% (3/32) | 21.9% (7/32) |
| Prior coronary artery bypass graft (%) | 18.0% (20/111) | 19.0% (15/79) | 13.3% (2/15) | 15.6% (5/32) | 25.0% (8/32) |
| Peripheral artery disease history | |||||
| Prior lower extremity endovascular procedure (%) | 4.5% (5/111) | 3.8% (3/79) | 6.7% (1/15) | 0.0% (0/32) | 6.3% (2/32) |
| Prior lower extremity open surgical revascularization procedure (%) | 3.6% (4/111) | 2.5% (2/79) | 6.7% (1/15) | 0.0% (0/32) | 3.1% (1/32) |
| Cilostazol use prior to randomization (%) | 18.0% (20/111) | 19.0% (15/79) | 13.3% (2/15) | 18.8% (6/32) | 21.9% (7/32) |
| Risk Factors | |||||
| Blood Pressure | |||||
| SBP, mean ± SD (N), mm Hg | 135.6 ± 19.0 (111) | 135.7 ± 19.6 (79) | 136.7 ± 13.4 (15) | 135.9 ± 22.6 (32) | 134.8 ± 19.3 (32) |
| DBP, mean ± SD (N), mm Hg | 74.4 ± 11.4 (110) | 74.0 ± 11.0 (78) | 77.8 ± 10.2 (14) | 74.0 ± 13.0 (32) | 72.3 ± 8.9 (32) |
| Lipid Profile | |||||
| LDL, mean ± SD (N), mg/dl | 103.2 ± 36.4 (107) | 103.6 ± 35.5 (77) | 104.6 ± 40.6 (15) | 97.9 ± 36.3 (31) | 108.8 ± 32.4 (31) |
| HDL, mean ± SD (N), mg/dl | 48.6 ± 14.4 (109) | 49.3 ± 14.9 (79) | 48.5 ± 13.5 (15) | 51.9 ± 16.0 (32) | 47.0 ± 14.4 (32) |
| Triglycerides, Mean ± SD (N), mg/dl | 144.7 ± 108.1 (109) | 149.1 ± 119.1 (79) | 139.8 ± 72.8 (15) | 141.5 ± 83.0 (32) | 161.0 ± 161.8(32) |
| HbA1c, mean ± SD (N), % | 6.2±1.2 (108) | 6.2±1.2 (79) | 6.1±0.7 (15) | 6.0±1.2 (32) | 6.4±1.3 (32) |
| C-reactive protein, mean ± SD (N), mg/dl | 0.99 ± 0.28 (109) | 0.97 ± 0.27 (79) | 0.98 ± 0.27 (15) | 0.96 ± 0.22 (32) | 0.99 ± 0.31 (32) |
| Fibrinogen, mean ± SD (N), mg/dl | 408.0 ± 94.0 (107) | 419.6 ± 90.1 (77) | 428.7 ± 63.3 (15) | 423.1 ± 100.5 (30) | 409.6 ± 92.4 (32) |
| Anthropometric characteristics | |||||
| BMI, mean ± SD (N) | 28.5 ± 5.7 (111) | 28.4 ± 5.7 (79) | 29.0 ± 5.9 (15) | 27.5 ± 5.0 (32) | 28.9 ± 6.4 (32) |
| Waist circumference, mean ± SD (N), cm | 99.9 ± 14.3 (109) | 99.4 ± 14.7 (79) | 100.0 ± 15.4 (15) | 96.5 ± 13.3 (32) | 102.0 ± 15.6 (32) |
| PAD characteristics | |||||
| Prior lower extremity endovascular procedure (%) | 4.5% (5/111) | 3.8% (3/79) | 6.7% (1/15) | 0.0% (0/32) | 6.3% (2/32) |
| Prior lower extremity open surgical revascularization procedure (%) | 3.6% (4/111) | 2.5% (2/79) | 6.7% (1/15) | 0.0% (0/32) | 3.1% (1/32) |
| Prior to randomization use of cilostazol (%) | 18.0% (20/111) | 19.0% (15/79) | 13.3% (2/15) | 18.8% (6/32) | 21.9% (7/32) |
| Baseline Performance, mean ± SD (N) | |||||
| PWT, min | 5.3 ± 2.2 (111) | 5.5 ± 2.3 (79) | 5.7 ± 2.6 (15) | 5.6 ± 2.4 (32) | 5.2 ± 2.1 (32) |
| COT, min | 1.7 ± 0.8 (111) | 1.8 ± 0.9 (79) | 1.8 ± 0.7 (15) | 1.8 ± 0.9 (32) | 1.8 ± 1.0 (32) |
| 7-day free-living steps | 19,294.6 ± 1,2853.0 (81) | 18,517.1 ± 12,731.1 (60) | 18,671.1 ± 15,990.2 (13) | 18,287.6 ± 11,060.1 (25) | 18,687.0 ± 13,013.8 (22) |
| Hourly free-living steps | 286.8 ± 253.0 (93) | 298.2 ± 285.9 (65) | 333.5 ± 461.7 (14) | 301.5 ±230.3 (27) | 273.9 ± 213.6 (24) |
BMI = body mass index; COT = claudication onset time on the graded treadmill test; DBP = diastolic blood pressure; HDL = plasma high-density lipoproteins; LDL = plasma low-density lipoproteins; PAD = peripheral artery disease; PWT = peak walking time on the graded treadmill test; SBP = systolic blood pressure; TIA = transient ischemic attack.
Antiplatelet use means use either of aspirin, clopidogrel, or both.
Adherence to Assigned Treatment and Missing Data
Compliance with the therapeutic assignment was high and crossovers were minimal. There were 8/111 (7%) participants in the original randomized population who did not receive their assigned treatment or crossed over to 1 of the alternative treatments during study follow-up, but did not withdraw from the study (Figure 1). This included 1 participant in the OMC group and 2 participants in the SE group who underwent stent revascularization between the 6-month and 18-month visits. Two participants in ST, who were incorrectly identified as having aortoiliac disease, did not undergo their assigned stent treatment. One additional participant in the ST group refused their assigned treatment after being diagnosed with colon cancer after randomization, but before stent placement. Two patients in the stent group self-enrolled in structured exercise programs and are therefore defined as crossovers. To clarify the treatment-specific benefits, a per-protocol analysis was done that excluded these 8 participants. Endpoints such as quality-of-life and medication compliance were collected within the same time windows but by telephone and therefore have better data compliance than treadmill test data.
Treatment Compliance and Results
The initial revascularization was technically successful for all ST group participants for whom it was attempted (16). One ST patient underwent a revascularization procedure for restenosis, which occurred between 6 and 18 months.
Among SE participants, 29/41 (71%) attended at least 70% of their scheduled supervised exercise training sessions. Most subjects (36/41; 88%) randomized to the SE treatment arm sustained participation in the home-based telephone support exercise adherence program after the supervised exercise component ended in month 6.
At 18 months, 91% of all study participants were taking cilostazol, with no statistically significant differences in compliance among treatment groups.
Treadmill Walking and Hemodynamic Endpoints
Peak walking time at 18 months improved least for OMC patients (0.2 ± 2.1 min), more for ST (3.2 ± 4.7 minutes), and most for SE patients (5.0 ± 5.4 min) between baseline and 18 months (Table 2, Central Illustration). The extent of the PWT improvement was greater for ST and SE compared with OMC, but the groups did not differ statistically (95% confidence limits -0.8, 4.2, p = 0.16). Claudication onset time increased from baseline to 18 months by 0.9 ± 1.3 min for OMC patients, 3.0 ± 4.5 min for ST, and 3.4 ± 3.9 min for SE (Table 2). The difference between OMC and SE was statistically significant, but no other COT comparisons achieved significance. For both PWT and COT, the nonparametric analysis produced results similar to those of the ANCOVA. Rank ANCOVA p values for PWT comparisons were: SE versus OMC p < 0.001; ST versus OMC p = 0.06; and ST versus SE p = 0.04. Rank ANCOVA p values for COT comparisons were: SE versus OMC p < 0.0001; ST versus OMC p = 0.19; ST versus SE p = 0.26. The per-protocol analysis at 18 months also showed statistical superiority for SE and ST for the PWT endpoint compared with OMC (5.0 ± 5.4 vs. 3.2 ± 4.7, vs. 0.2 ± 2.1; p = 0.001 and 0.04, respectively), and no statistically significant difference was observed between ST and SE (p = 0.16). For COT, the per-protocol improvements were similar for ST and SE compared to OMC (3.0 ± 4.5 and 3.4 ± 4.0, respectively, vs. 0.9 ± 1.3; p = 0.12 and 0.02, respectively), and the COT difference between ST and SE at 18 months by the per-protocol analysis was not significant (p = 0.77).
Table 2. Primary and Secondary Endpoints–Patients with 18-Month Visit.
| Difference, 95% CI and p Value* | ||||||
|---|---|---|---|---|---|---|
| Measure | OMC min, mean ± SD, (n) | Supervised Exercise min, mean ± SD, (n) | Stent min, mean ± SD, (n) | Supervised Exercise vs. OMC | Stent vs. OMC | Stent vs. Supervised Exercise |
| PWT | ||||||
|
| ||||||
| Baseline | 5.7 ± 2.6 (15) | 5.6 ± 2.4 (32) | 5.2 ± 2.1 (32) | |||
|
| ||||||
| 18 months | 5.9 ± 2.9 (15) | 10.6 ± 5.7 (32) | 8.4 ± 5.6 (32) | |||
|
| ||||||
| Baseline to 18-month change | 0.2 ± 2.1 (15) | 5.0 ± 5.4 (32) | 3.2 ± 4.7 (32) | 4.7 [2.6,6.9], (p < 0.001) | 3.0 [1.1,5.0], (p = 0.04) | 1.7 [-0.8,4.2], (p = 0.16) |
|
| ||||||
| COT | ||||||
|
| ||||||
| Baseline | 1.8 ± 0.7 (15) | 1.8 ± 0.9 (32) | 1.8 ± 0.9 (32) | |||
|
| ||||||
| 18 months | 2.6 ± 1.7 (15) | 5.1 ± 4.0 (32) | 4.8 ± 4.7 (32) | |||
|
| ||||||
| Baseline to 18-month change | 0.9 ± 1.3 (15) | 3.4 ± 3.9 (32) | 3.0 ± 4.5 (32) | 2.5 [1.0,4.0], (p = 0.03) | 2.2 [0.5,3.9], (p = 0.12) | 0.3 [-1.7,2.4], (p = 0.77) |
|
| ||||||
| ABI | ||||||
|
| ||||||
| Baseline | 0.7 ± 0.2 (15) | 0.7 ± 0.2 (32) | 0.6 ± 0.2 (32) | |||
|
| ||||||
| 18 months | 0.8 ± 0.1 (15) | 0.7 ± 0.2 (32) | 0.9 ± 0.2 (31) | |||
|
| ||||||
| Baseline to 18-month change | 0.0 ± 0.1 (15) | 0.0 ± 0.1 (32) | 0.2 ± 0.2 (31) | -0.0 [-0.1,0.1], (p = 0.82) | 0.2 [0.1,0.3], (p = 0.002) | -0.2 [-0.3,-0.1], (p < 0.001) |
ABI = ankle-brachial index in the most symptomatic leg; CI = confidence interval; OMC = optimal medical care. Other abbreviations as in Table 1.
The p values were calculated using change scores, and are on the basis of analysis of covariance, adjusting for study region, baseline cilostazol use, and baseline value of the endpoint.
Central Illustration. Exercise or Intervention for Claudication Due to Aortoiliac Peripheral Artery Disease: Peak Walking Time and Claudication Onset Time.
Upper Panel: Peak Walking Time (PWT). Patients with 18-month follow-up visit only.
Lower Panel: Claudication Onset Time.
ABI = ankle brachial index in the most symptomatic leg; COT = claudication onset time on a graded treadmill test; PWT = peak walking time on a graded treadmill test.
Mean ankle-brachial index values were normalized in the stented patients and changed by 0.00 ± 0.1 for OMC, 0.2 ± 0.2 for ST, and 0.00 ± 0.1 for SE (p = 0.002 for ST vs. OMC and <0.001 for ST vs. SE, Table 2, Central Illustration). The per-protocol analysis of ABI also showed statistically significant differences for the comparison of ST versus OMC (p = 0.001) and ST versus SE (p < 0.0001).
Interaction tests did not show any significant difference in outcomes for PWT, COT, or ABI on the basis of enrollment volume when comparing high-enrolling (>10 participants) versus low-enrolling centers (all p values >0.4). Considering the number of participants who did not have treadmill test data obtained at 18 months, 6-month PWT and COT results were compared among participants who lacked 18-month follow-up data (Online Table 1). Although, participants who missed the 18-month treadmill test in all 3 treatment groups tended to have better outcomes at 6 months than those who complied, this analysis is flawed because more than half of those who missed the 18-month treadmill test also missed the 6-month treadmill test.
Quality of Life
There were no baseline differences in quality of life among the treatment groups. At 18 months, improvement in disease-specific scales (WIQ, PAQ) was statistically superior for ST and SE compared with OMC, but ST and SE differed significantly from each other (favoring ST) only for PAQ-symptoms, PAQ-treatment satisfaction, PAQ-quality of life, and PAQ-summary (Table 3, Figure 2).
Table 3. Quality of Life Endpoints—Patients With 18-Month Visit.
| Difference, 95% CI and p Value* | ||||||
|---|---|---|---|---|---|---|
| Measure | OMC (n = 15) (mean ± SD) | Supervised Exercise (n = 32) (mean ± SD) | Stent (n = 32) (mean ± SD) | Supervised Exercise vs. OMC | Stent vs. OMC | Supervised Exercise vs. Stent |
| SF-12 Physical | ||||||
|
| ||||||
| Baseline | 32.3 ± 9.8 (15) | 33.6 ± 9.3 (32) | 34.6 ± 9.1 (32) | |||
|
| ||||||
| 18 months | 31.0 ± 7.6 (14) | 38.0 ± 10.0 (31) | 37.9 ± 9.4 (32) | |||
|
| ||||||
| Baseline to 18-month change† | -1.0 ± 7.6 (14) | 4.3 ± 8.6 (31) | 3.3 ± 11.1 (32) | 5.4 [0.4,10.4], (p = 0.03) | 4.3 [-1.2,9.9], (p = 0.05) | 1.0 [-3.9,5.9], (p = 0.61) |
|
| ||||||
| WIQ Pain Severity | ||||||
|
| ||||||
| Baseline | 28.3 ± 20.8 (15) | 32.8 ± 26.5 (32) | 34.4 ± 28.2 (32) | |||
|
| ||||||
| 18 months | 38.3 ± 24.8 (15) | 63.3 ± 26.2 (32) | 75.0 ± 29.1 (32) | |||
|
| ||||||
| Baseline to 18-month change† | 10.0 ± 24.6 (15) | 30.5 ± 35.8 (32) | 40.6 ± 43.0 (32) | 20.5 [2.9,38.0], (p = 0.02) | 30.6 [11.2,50.0], (p = 0.002) | -10.2 [-29.5,9.2], (p = 0.17) |
|
| ||||||
| WIQ Walking Distance | ||||||
|
| ||||||
| Baseline | 23.3 ± 30.9 (15) | 13.6 ± 12.2 (32) | 15.8 ± 15.6 (32) | |||
|
| ||||||
| 18 months | 19.6 ± 20.7 (15) | 43.0 ± 32.7 (31) | 56.8 ± 37.8 (32) | |||
|
| ||||||
| Baseline to 18-month change† | -3.7 ± 27.6 (15) | 29.9 ± 30.6 (31) | 41.0 ± 34.7 (32) | 33.6 [16.0,51.2], (p < 0.001) | 44.8 [26.4,63.2], (p < 0.001) | -11.2 [-27.3,4.9], (p = 0.16) |
|
| ||||||
| PAQ Physical Limitation | ||||||
|
| ||||||
| Baseline | 33.6 ± 30.4 (14) | 32.4 ± 18.6 (30) | 29.7 ± 20.3 (30) | |||
|
| ||||||
| 18 months | 28.2 ± 17.0 (13) | 44.2 ± 24.0 (30) | 56.8 ± 32.7 (32) | |||
|
| ||||||
| Baseline to 18-month change† | 0.0 ± 24.4 (12) | 9.4 ± 24.4 (28) | 24.4 ± 31.0 (30) | 9.4 [-7.1,25.8], (p = 0.22) | 24.4 [6.7,42.1], (p = 0.01) | -15.1 [-29.4,-0.8], (p = 0.04) |
|
| ||||||
| PAQ Symptoms | ||||||
|
| ||||||
| Baseline | 43.7 ± 17.8 (15) | 42.6 ± 19.2 (32) | 50.4 ± 20.7 (32) | |||
|
| ||||||
| 18 months | 53.0 ± 20.7 (14) | 58.8 ± 24.3 (30) | 74.3 ± 27.7 (32) | |||
|
| ||||||
| Baseline to 18-month change† | 8.1 ± 17.2 (14) | 17.3 ± 22.9 (30) | 23.8 ± 25.6 (32) | 9.2 [-3.0,21.4], (p = 0.19) | 15.7 [3.1,28.3], (p = 0.05) | -6.5 [-18.6,5.6], (p = 0.26) |
|
| ||||||
| PAQ Quality of Life | ||||||
|
| ||||||
| Baseline | 43.9 ± 25.9 (15) | 46.4 ± 19.0 (32) | 43.5 ± 18.3 (32) | |||
|
| ||||||
| 18 months | 49.4 ± 25.3 (13) | 60.3 ± 23.1 (30) | 70.2 ± 27.4 (32) | |||
|
| ||||||
| Baseline to 18-month change† | 5.8 ± 25.5 (13) | 13.3 ± 25.9 (30) | 26.7 ± 28.5 (32) | 7.6 [-9.1,24.3], (p = 0.33) | 20.9 [3.9,38.0], (p = 0.02) | -13.4 [-26.9,0.2], (p = 0.04) |
|
| ||||||
| PAQ Summary | ||||||
|
| ||||||
| Baseline | 46.3 ± 23.6 (15) | 45.8 ± 16.3 (32) | 44.8 ± 18.1 (32) | |||
|
| ||||||
| 18 months | 45.1 ± 21.3 (14) | 58.0 ± 21.6 (31) | 69.1 ± 26.7 (32) | |||
|
| ||||||
| Baseline to 18-month change† | -2.3 ± 19.8 (14) | 12.2 ± 21.5 (31) | 24.3 ± 27.4 (32) | 14.5 [1.6,27.3], (p = 0.03) | 26.5 [12.5,40.6], (p = 0.002) | -12.0 [-24.2,0.1], (p = 0.04) |
The WIQ includes sections to ascertain PAD specificity and differential diagnosis, as well as 14 questions about walking distance, walking speed, and stair climbing. The PAQ consists of 14 questions designed to elicit information about disease-specific quality of life across a range of PAD-specific domains.
PAQ = Peripheral Artery Questionnaire; WIQ = Walking Impairment Questionnaire. Other abbreviations as in Tables 1 and 2.
The p values are calculated using change scores, and are based on analysis of covariance adjusting for study center, baseline cilostazol use, and baseline value of the endpoint.
Baseline to 18-month change values were calculated only for participants for whom both baseline and 18-month data were collected.
Figure 2. Mean (+1 Standard Error) Quality of Life by Treatment Group.
Patients with 18-month follow-up visit only. PAQ = Peripheral Artery Questionnaire; WIQ = Walking Impairment Questionnaire.
Safety
There were 3 pre-specified major adverse events, all of which occurred in the first 6 months (16). These included a myocardial infarction in the OMC group, a death in the SE group, and a target limb revascularization in the ST group. Four stent procedure-related adverse events occurred in 3 of the 46 ST participants and were previously reported (16).
Discussion
The 18-month follow-up results of the CLEVER study demonstrate a comparable, clinically important, and durable benefit in functional status, as measured by the PWT, for both ST and SE compared with OMC. The robustness of this result is reinforced by the improvement in COT that was greater in subjects assigned to the SE strategy of care compared with OMC, and comparable to that seen in ST participants. The durability of the functional status and quality of life improvements in response to provision of an SE strategy of care should be of particular interest, as this study provides the first data to demonstrate the preservation of this benefit for a full year after formal supervised exercise ended.
Exercise therapy for claudication, first described in 1966 (25), is known to substantially improve functional status, as defined by treadmill walking performance (26). Home exercise for claudication has been compared with supervised exercise in prior randomized trials. Notably, when the home regimen is comprised solely of informal clinician advice about exercise, PAD home exercise results have been consistently inferior to those achieved with supervised exercise, which provides a more consistent therapeutic environment and workload progression (9,27-29). Further, patients with claudication treated with supervised exercise in prior randomized studies have enjoyed at least as much or greater functional improvement as those treated with angioplasty (30-32). The biological adaptive response of supervised exercise is well established (26). Evidence from pre-clinical and multiple human investigations suggests several mechanisms for such clinical benefits, including improved endothelial function, angiogenesis and capillary density, oxidative metabolism and oxygen extraction, decreased blood viscosity, muscle innervation, and improved walking economy. The durability of the treatment effect of SE up to a year after termination of SE provides evidence that the benefits in treadmill walking are not solely due to a treadmill-specific training effect.
Individuals treated by primary iliac artery stenting also demonstrated an improved PWT compared with OMC, and this benefit is gained with a low risk of adverse events or clinical evidence of restenosis.
Patients assigned to supervised exercise, which required regular walking until symptomatic throughout the study, reported higher claudication symptom levels as assessed by the PAQ instrument at 18 months compared with those treated with supervised exercise or OMC. This subjective finding was present despite no significant difference in claudication onset time between the groups, and therefore may be attributable to an anomaly related to the questionnaire and the supervised exercise treatment. That is, patients in the exercise group who were instructed to walk regularly to claudication may be expected to report more frequent claudication symptoms. Subjective symptom improvement in the stent group may be attributable in part to a placebo effect, since there was no sham treatment and all participants were aware that they were revascularized. Such subjective symptom improvements are often reported in that context even when no objective improvement can be measured (33). Alternatively, the closer association of quality-of-life with claudication pain versus peak walking distance may relate to better ability to achieve activities of daily living when pain is minimized.
Limitations
Randomized comparative effectiveness strategy-of-care studies, especially those that compare invasive and noninvasive treatments, are difficult to conduct. Although screening criteria were broadly defined, this study had an almost 10:1 ratio of those screened to those enrolled (Figure 1). This enrollment fraction is common and is similar to rates reported from most other randomized trials of similar populations (34, 35). Another limitation is that of the 93 participants with 18 months of follow-up, treadmill test data at that interval was only available for 79 (Figure 1). Although the patients with and without the treadmill test were similar (Table 1), it is impossible to be certain that the reasons for their missing data are random.
Conclusions
Patients with aortoiliac artery PAD and moderate to severe claudication, a population widely regarded as optimal for stent revascularization, achieve significant improvements in clinical outcomes when treated with either supervised exercise or stent revascularization compared to optimal medical care alone and this benefit is durable for at least 18 months. The benefit of supervised exercise, a strategy of care that provides several proven biological benefits that improve limb muscle strength, efficiency and performance, was equal to the invasive stent strategy and was maintained for a full year after completion of the supervised training phase with use of a telephone-based counseling program. These data provide strong support in favor of comparable access to both supervised exercise and stent revascularization to improve the primary ischemic symptom of PAD, claudication.
Supplementary Material
Online Supplemental Table 1. Change from baseline to 6 months - By treatments Supervised Exercise Only
Clinical Perspectives.
Competency in Patient Care: Treatment options for patients with claudication attributed to aortoiliac artery disease include revascularization and supervised exercise rehabilitation.
Translational Outlook: Longer-term studies are needed to compare the durability of revascularization and supervised exercise rehabilitation, alone and in combination, on the symptomatic and functional status of patients with aortoiliac arterial obstructive disease.
Acknowledgments
The CLEVER Study (Claudication: Exercise Versus Endoluminal Revascularization) was sponsored primarily by the National Heart Lung and Blood Institute (grants HL77221 and HL081656), and also received financial support from Cordis/Johnson & Johnson (Warren, New Jersey), eV3 (Plymouth, Minnesota), and Boston Scientific (Natick, MA). Throughout the study, Otsuka America, Inc., (San Francisco, California) donated cilostazol for all study participants. Omron Healthcare, Inc. (Lake Forest, Illinois) donated pedometers. Krames Staywell, San Bruno, Californai, donated print materials on exercise and diet for study participants.
The investigators were solely responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The National Heart Lung and Blood Institute had an ex-officio member of the study operations committee, a data safety and monitoring board convened by the National Heart Lung and Blood Institute conducted study oversight.
Investigators and Roles: The CLEVER investigators, coauthors, and committee members were as follows: Principal investigators (in order of decreasing number of patients randomly assigned to a treatment group): T. Murphy, Rhode Island Hospital, Providence, Rhode Island; J. Ehrman, Henry Ford Hospital, Detroit, Michigan; V. Krishnamurthy, VA Ann Arbor, Ann Arbor, Michigan; J. Nadarajah, Aiyan Diabetes Center, Augusta, Georgia; A. T. Hirsch, University of Minnesota and Minneapolis Heart Institute Foundation, Minneapolis, Minnesota; A. Comerota, Jobst Vascular Center, Toledo, Ohio; M. Lurie, Torrance Memorial Medical Center, Torrance, California; W. Miller, Vascular Endovascular Specialists of Ohio, Mansfield, Ohio; O. Osinbowale, Ochsner Health Center, Metairie, Louisiana; S. Cavalieri, Providence Medical Research Center, Spokane, Washington; M. Razavi, St. Joseph Hospital, Orange, California; R. Workman, Forsyth Medical Center, Winston-Salem, North Carolina; R. Berry, Capital Health, Nova Scotia, Canada; E. Ratchford, Johns Hopkins, Baltimore, Maryland; A. Tassiopoulos, Stony Brook, New York; E. Mohler, University of Pennsylvania, Philadelphia, Pennsylvania; W. Abernethy, Asheville Cardiology, Asheville, North Carolina; J. Matsuura, Iowa Clinic, Des Moines, Iowa; J. Kaufman, Oregon Health Science University, Portland, Oregon; J. Martinez, Peripheral Vascular Associates, San Antonio, Texas; M. Moursi, VA Central Arkansas, Little Rock, Arkansas; F. Bech, VA Palo Alto, Palo Alto, California.
Coauthors: D.E. Cutlip, Beth Israel Deaconess Medical Center, Harvard Clinical Research Institute, Boston, Massachusetts; J.G. Regensteiner, University of Colorado Denver School of Medicine, Aurora, Colorado; E.R. Mohler III, Vascular Medicine University of Pennsylvania, Philadelphia, Pennsylvania; D.J. Cohen, St. Luke's Mid America Heart Institute, Kansas City, Missouri; M.R. Reynolds, Harvard Medical School, Harvard Clinical Research Institute, Boston, Massachusetts; E.A. Lewis, University of Minnesota School of Kinesiology, Minneapolis, Minnesota; J.V. Cerezo, Vascular Disease Research Center, Rhode Island Hospital, Providence, Rhode Island; N.C. Oldenburg, Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota; C.C. Thum, Harvard Clinical Research Institute, Boston, Massachusetts; S. Goldberg, National Heart, Lung, Blood Institute, Bethesda, Maryland; M. Jaff, Massachusetts General Hospital, Boston, Massachusetts; A.J. Comerota, M.D., Toledo, OH; M.W. Steffes, University of Minnesota Laboratory Medicine and Pathology, Minneapolis, Minnesota; I.H. Abrahamsen, M.S., Boston, Massachusetts; S. Goldberg, M.S.N., Bethesda, Maryland; A.T. Hirsch, Vascular Medicine Program, Lillehei Heart Institute, Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minnesota;
Steering Committee: A.T. Hirsch (chair), T.P. Murphy, J. G. Regensteiner, M. Jaff, D.J. Cohen, A.J. Comerota, D.E. Cutlip, E.R. Mohler, E.A. Lewis, M.W. Steffes, S. Goldberg
Exercise Training Committee: J.G. Regensteiner (chair), E.A. Lewis, A. Ershaw, D. Treat-Jacobson, T. Collins, D. Badenhop, J.K. Ehrman, M.E. Walsh, U. Bronas, N.C. Oldenburg
Data and Safety Monitoring Board: T.A Pearson (chair), B.H. Annex, M. Hlatky, M.T. Hughes, M.M. Brooks, R.J. Powell, A. Roberts, J.A. Vita.
Dr. Murphy has reported receiving research grant support from Abbott Vascular, Cordis/Johnson&Johnson, and Otsuka Pharmaceuticals. Dr. Cutlip has reported receiving either a research contract or grant support paid to his institution from Medtronic, Boston Scientific, and Abbott Vascular. Dr. Cohen has reported receiving research grant support from Medtronic, Boston Scientific, Abbott Vascular, and Cardiovascular Systems, Inc (CSI). He has also served as a consultant to Medtronic, Abbott Vascular, and CSI. Dr. Reynolds has reported serving as a consultant to Medtronic, Inc. Dr. Jaff has reported having equityin Micell, Inc. and PQ Bypass; serving on the board of VIVA Physicians, Inc.; and serving as a consultant to Becker Venture Services Group, Abbott Vascular, Cordis Corporation, Covidien/eV3, and Medtronic Vascular. Dr. Hirsch has reported receiving research grants from Abbott Vascular, Aastrom Biosciences, Viromed, and AstraZeneca; and serving as a consultant to Novartis and Merck.
Abbreviations
- ABI
ankle-brachial index
- COI
claudication onset time
- OMT
optimal medial therapy treatment group
- PAD
peripheral artery disease
- PAQ
Peripheral Artery Questionnaire
- PWT
peak walking time
- SE
supervised exercise treatment group
- ST
stenting treatment group
- WIQ
Walking Impairment Questionnaire
Footnotes
Disclosures: All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Online Supplemental Table 1. Change from baseline to 6 months - By treatments Supervised Exercise Only