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The Claudication: Exercise Vs. Endoluminal Revascularization (CLEVER) Study is a prospective multicenter randomized clinical trial designed to compare the relative clinical and cost-effectiveness of invasive revascularization with stents to supervised exercise rehabilitation in a cohort with moderate to severe claudication due to aortoiliac insufficiency. The study is currently enrolling at twenty-eight sites in the U.S. and Canada. Enrollment of 217 participants is planned, with data collected at baseline, 6 months, and 18 months. The primary study endpoint is maximum walking duration (MWD) on a graded treadmill test; secondary endpoints include community-based walking, markers of cardiovascular disease risk (body mass index, waist circumference, blood pressure, lipid profile, glucose tolerance, and plasma fibrinogen), health-related quality of life, and cost effectiveness. There are currently sixty randomized participants; recruitment is projected to end in July 2010 and final study results reported in June 2012.
The Claudication: Exercise Vs. Endoluminal Revascularization Study (CLEVER) is an NIH-sponsored partially blinded prospective, multicenter randomized clinical trial that tests the hypothesis that stent placement results in improved exercise treadmill test performance compared with supervised exercise rehabilitation for people with claudication due to aortoiliac insufficiency1. Data are collected at baseline, 6 months, and 18 months. There are multiple secondary endpoints, including measurement of community-based walking using pedometers, physiological variables associated with coronary heart disease risk (body mass index, waist circumference, blood pressure, lipid profile, glucose tolerance, c-reactive protein, and fibrinogen), health-related quality of life, and cost effectiveness1. The rationale for the study is that although stent-based revascularization may achieve arterial patency and improve symptoms, it is a local treatment for a systemic disease that may or may not improve community-based walking and patient satisfaction and whose relative efficacy and durability compared to exercise training is not established. Increasing activity levels is proven to be important to lower rates of myocardial infarction and stroke. Supervised exercise rehabilitation, supported by provision of exercise-focused behavioral medicine component in CLEVER, is designed to improve claudication symptoms and walking ability. Improved walking ability and activity levels may result in weight loss, improved blood pressure and lipid profiles, improved glycemic control, and fewer heart attacks, strokes, and cardiovascular-related deaths.
Study participants commit to an 18-month timeframe of participation, with data collected at baseline, 6 months, and 18 months. There are currently three treatment groups with asymmetric randomization including optimal medical care for 20% of patients (instructions to perform home exercise), supervised exercise rehabilitation (3 times a week for 6 months with 12 months followup with a behavioral intervention) for 40% and aortoilic stent placement for 40%. A combined stent plus supervised exercise treatment arm, included for exploratory analyses, has been discontinued. All study participants receive cilostazol as a background claudication therapy throughout the course of their participation in the study, so long as the medication is well-tolerated, since cilostazol has been proven to improve walking ability in those with claudication2. Exercise sessions for individuals in this group are provided 3 times a week for one hour per session. Upon completing supervised exercise, the participant is contacted by a health educator, who begins a program of regular contact designed to foster adoption of regular exercise between 6 and 18 months. A combined stent plus supervised exercise treatment group, originally included as an exploratory analyses of this potential additive or synergistic benefit, has been discontinued so that recruitment could be focused on the primary study endpoints.
For all study participants, anatomic eligibility is determined by arterial imaging studies and/or by use of noninvasive tests without regard to “anatomic suitability” for revascularization by stent or “TASC” classification of the lesion. A secondary recruitment and treatment plan that would expand study inclusion to participants with only femoropopliteal artery stenoses1 was considered as a potentially important expansion of the CLEVER study goals to a particularly relevant contemporary symptomatic PAD cohort. However, inclusion of this expanded study population was not activated due to concerns that aorto-iliac and femoropopliteal revascularization might be associated with differential relative treatment effects. ASCM and AHA/ACC exclusions for individuals who could not reliably undergo exercise training and exercise testing, respectively, are also utilized (Table 1, available in online version only).
There are currently twenty-eight active enrollment centers in CLEVER (Table 2, available in online version only), and current plans are to activate as many as 30 U.S. sites and 4 Canadian sites. As of April 2009, there are 60 participants enrolled. Slow recruitment has been often observed in “strategy of care” randomized trials3. Nevertheless, since the study does not use a time-to-event endpoint slow recruitment does not affect study power and the sponsor, the National Heart, Lung, and Blood Institute, is very committed to getting the important data the CLEVER will produce. Enrollment is scheduled to end in July of 2010, and given 18 months of follow-up, study results should be available by June 2012.
We note that a major component of the recently signed America Recovery and Reinvestment Act is money for increasing comparative effectiveness research, with one of the studies specifically mentioned being a comparison of invasive vs. noninvasive treatment for people with, “…leg pain that results from blockage of the arteries in the lower legs”4. The treatment of PAD is extremely costly5, and the durability and effectiveness of current treatments needs to be demonstrated to ensure reimbursement in the future. Clearly the community of vascular healthcare professionals needs to participate more actively in multicenter randomized clinical trials like CLEVER, as do practitioners focused on other diseases such as cancer, heart disease, and infectious diseases, in order to acquire the knowledge of how best to manage the patients that they serve and to ensure reimbursement for their services. NIH multicenter clinical trials of PAD will prove to be the most important PAD studies of our time and will validate care and payor policy well into the future.
Ascertainment of eligibility is satisfactory to date, with only one participant enrolled who was found to not have aortoiliac insufficiency but rather had femoropopliteal artery obstruction only. However, eligibility criteria were not followed correctly for this participant, but according to intention-to-treat principles they remain in their assigned treatment group. The population currently has an average age of 65.2+/-9.5 years, ha a 2:1 male predominance, and is approximately 20% ethnic minorities, with 37.5% reporting prior myocardial infarction, 23.4% with prior coronary artery revascularization, 25% a history of diabetes mellitus.
Compliance with the CLEVER study protocol has been satisfactory and well within assumptions made for power calculations. Four study participants have elected to withdraw from subsequent follow-up, and data compliance for participants remaining in the study is over 90%. Of the other 20 participants in the supervised exercise group, compliance with supervised exercise has been excellent, with subjects achieving an average of 72% attendance of a total of 78 (26 weeks, three times a week) exercise sessions scheduled for each participant. Since the study sample size was inflated by 30%, this high compliance with the study protocol and high rate of complete data collection, demonstrates that CLEVER is likely to have sufficient power to definitively inform the primary study hypotheses on trial completion.
The CLEVER study compares treatment strategies that are based on known treatments that have low risk. CLEVER does not use any devices or drugs that are no approved by the U.S. Food and Drug Administration. The safety profile of the study has been excellent, with no unanticipated device or exercise-related adverse events, and only three significant adverse events (SAE's) observed, none felt to be related to a study treatment.
CLEVER has been designed to provide one planned interim data evaluation, which will occur after half of the study participants have completed their 6-month follow up visit. Subject compliance data do not suggest any clinically relevant outcome advantage or disadvantage for any treatment group. Acceptance of supervised exercise has been high. We have also anecdotally observed improvements in exercise performance for all treatment groups. Whether this anecdotal experience will translate into a better relative treatment effect for any treatment group will await formal analysis.
CLEVER represents one of the most important randomized clinical trials that is designed to evaluate the clinical efficacy and risk of the three major claudication treatments, and is underway with 48 patients randomized as of February, 2009. The only existing randomized clinical trials have demonstrated no benefit of treatment strategies that use only plain balloon angioplasty or arterial stents as compared with supervised exercise6,7. Payors including the federal government are demanding data to support reimbursement for medical services. Although all other aspects of study execution are satisfactory, subject recruitment in CLEVER has underperformed. Although this is common in treatment strategy trials3, it is particularly relevant for the vascular community that has long striven to have access to well-funded clinical trials. The CLEVER study provides a unique opportunity to provide important scientific evidence that will inform physicians and patients regarding optimal management of people with claudication, and we call on the vascular healthcare community to take an enlightened stance on this and other PAD treatment strategy trials, to embrace their role as scientists as well as clinicians, and to contribute in spirit and in fact to the successful completion of the CLEVER Study.
Supported by U01 HL077221 from the National Heart, Lung, and Blood Institute, the NIH Office for Research on Women's Health, and research grants from Boston Scientific, Cordis/Johnson & Johnson, and Guidant Corporation.
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