Clinical trial NCT00132743: Claudication: Exercise Versus Endoluminal Revascularization (CLEVER)
Official title: Claudication: Exercise Versus Endoluminal Revascularization (CLEVER)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Cardiovascular Diseases
Peripheral Vascular Diseases
Atherosclerosis
Lead sponsor: Rhode Island Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2005-08-22
Enrollment: 119
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the effectiveness of aortic stent surgery versus exercise therapy in individuals with aortoiliac insufficiency.

Detailed description: BACKGROUND:

Peripheral arterial disease (PAD) is a major source of morbidity and mortality, particularly in older individuals. Despite its high prevalence, clinicians often fail to diagnose PAD, particularly in patients who do not have classic claudication symptoms. Even in those individuals with documented PAD, cardiac risk factors are not often aggressively treated, and only a minority of patients receive pharmacologic therapy with cilostazol. Although there is a growing body of literature demonstrating the value of exercise rehabilitation in individuals with peripheral vascular disease and claudication, exercise rehabilitation is not often prescribed as supervised exercise rehabilitation for claudication, is not reimbursed by Medicare, and is rarely covered by private insurance. Therefore, few individuals with PAD and intermittent claudication have access to supervised exercise rehabilitation.

The use of surgical intervention and stent placement to improve blood flow in patients who do not have ischemic pain at rest or limb-threatening ischemia (Fontaine class III or IV) remains controversial. There is data suggesting that patients with intermittent claudication who have had revascularization with stents have improved exercise capacity and walking times. However, the patients in the various studies often differ substantially in their clinical characteristics, and a variety of techniques were employed, including balloon angioplasty and stents, which makes it difficult to come to a definitive conclusion about the relative efficacy of stenting to improve functional performance. Additionally, to our knowledge, the combination of stent revascularization with supervised exercise rehabilitation has not been studied.

DESIGN NARRATIVE:

The broad objective of the study is to optimize physical functioning, increase activity levels, and reduce cardiovascular disease risk in older individuals with PAD. The specific aim of the trial is to test the primary hypothesis that aortoiliac stenting/pharmacotherapy improves maximum walking duration (MWD) better than supervised exercise rehabilitation/exercise maintenance/pharmacotherapy for those with aortoiliac artery obstruction at 6 months. Other aims are to compare these two treatment groups with two other treatment groups, optimal medical care/pharmacotherapy and combined stent plus supervised exercise rehabilitation, at 6 months, and to compare all 4 groups with regard to the following variables: MWD change score at 18 months, changes in free-living daily activity levels, patient-perceived quality of life (QoL), and cost-effectiveness. The study also will perform exploratory analyses of demographic and biochemical risk factors for atherosclerosis, including body mass index (BMI), blood pressure, lipid profile, hemoglobin Alc (HgbAlc), fibrinogen, and C-reactive protein. An estimated 252 patients (at up to 30 study sites) with aortoiliac insufficiency and intermittent claudication will be randomly divided into four groups: optimal medical care/pharmacotherapy, supervised exercise rehabilitation/maintenance/pharmacotherapy, stent/pharmacotherapy, and stent/supervised exercise rehabilitation/pharmacotherapy. Recruitment will be performed over 28 months and patients will be followed for 18 months; the total study duration will be 5 years.

Eligibility criteria: Inclusion Criteria:

* Subject has symptoms suggestive of intermittent claudication, such as exercise-induced pain, cramps, fatigue, or other equivalent discomfort, involving large muscle groups of the leg(s) (calf, thigh, buttocks), relieved by rest
* Claudication score consistent with "Rose", "atypical", or "noncalf" claudication by San Diego Claudication Questionnaire
* Positive noninvasive evaluation for significant aortoiliac PAD on the most symptomatic side(s) (bilaterally if symptoms are equal):

  * Contrast Arteriography: Contrast arteriogram showing at least 50% stenosis in the aorta, common iliac artery, or external iliac artery, OR
  * CTA or MRA: Ankle-brachial index less than or equal to 0.9 (or abnormal ankle PVR waveform at ankle if arteries are incompressible\*) with at least 60% stenosis in the aorta, common iliac artery, external iliac artery, accompanied by a biphasic or monophasic Doppler wave form at the common femoral artery (loss of early diastolic flow reversal or loss of forward flow during diastole), OR
  * Duplex Ultrasound: Ankle-brachial index less than or equal to 0.9 (or abnormal ankle PVR waveform at ankle if arteries are incompressible\*) with occlusion or focal doubling of peak systolic velocity in the aorta, common iliac artery, or external iliac artery, accompanied by a biphasic or monophasic Doppler wave form at the common femoral artery (loss of early diastolic flow reversal or loss of forward flow during diastole), OR
  * Vascular Noninvasive Physiologic Tests: Ankle-brachial index less than or equal to 0.9 (or abnormal ankle PVR waveform at ankle if arteries are incompressible\*) with resting thigh-brachial index (thigh-BI) less than 1.1, and common femoral artery Doppler systolic acceleration time greater than 140 msec \[these tests may be ordered for study screening\].

    * Abnormal PVR waveform must lack augmentation at the ankle, have a delayed, rounded systolic peak, and straight or convex downslope, and must be reviewed by the core lab.

Note: MRA/CTA, and contrast arteriogram images images must be submitted to the Clinical Coordinating Center and Doppler waveform tracings to the Noninvasive Test Committee for over read pre- or post-randomization

* Highest ankle pressure reduced by at least 25 mm Hg after exercise compared to resting pressure (or loss of previously present Doppler signal for both the posterior tibial and anterior tibial arteries immediately after exercise if arteries were incompressible) Note: The highest ankle pressure result is determined by using the higher result of either the dorsalis pedis or posterior tibial artery measurement.
* Subject has moderate to severe claudication symptoms, defined as less than 11 minutes MWD at baseline (initial) Gardner treadmill test

Exclusion Criteria:

* Presence of critical limb ischemia (Rutherford Grade II or III59 PAD, defined as pain at rest, ischemic ulceration, gangrene) or acute limb ischemia (pain, pallor, pulselessness, paresthesias, paralysis) in either leg
* Common femoral artery (CFA) occlusion or greater than or equal to 50% stenosis by angiography, MRA, CTA, or duplex ultrasound or doubling of systolic velocity in the ipsilateral common femoral artery by duplex ultrasound, or 50% diameter stenosis by visual estimate in the CFA by angiography, MRA, or CTA, (inadequate outflow for iliac stent intervention), if available pre-randomization
* Known total aortoiliac occlusion from the renal arteries to the inguinal ligaments (all other occlusions, including aortic occlusion, ARE eligible)
* Participant has bilateral claudication symptoms and the limb that is more symptomatic does not show evidence of aortoiliac insufficiency as described in inclusion criterion number 5
* Participant has bilateral claudication symptoms, but both limbs are equally symptomatic and one side does not show evidence of aortoiliac insufficiency as described in inclusion criterion number 5
* Subject meets the following exclusions based upon modified American College of Sports Medicine criteria for exercise training:

  i. Ambulation limited by co-morbid condition other than claudication, for example:1. severe coronary artery disease; 2. angina pectoris; 3. chronic lung disease;4. neurological disorder such as hemiparesis;5. arthritis, or other musculoskeletal conditions including amputation ii. Poorly-controlled hypertension (SBP greater than 180 mm Hg) iii.Poorly-controlled diabetes mellitus iv. Other active significant medical problems such as cancer, known chronic renal disease (serum creatinine greater than 2.0 mg/dl within 60 days or renal replacement therapy), known chronic liver disease or anemia, active substance abuse, or known history of dementia
* Contraindication to exercise testing according to AHA/ACC guideline, specifically: Acute myocardial infarction (within 3-5 days), unstable angina, uncontrolled cardiac arrhythmias causing symptoms or hemodynamic compromise, active endocarditis, symptomatic severe aortic stenosis, acute pulmonary embolus or pulmonary infarction, acute noncardiac disorder that may affect exercise performance or be aggravated by exercise such as infection, thyrotoxicosis, acute myocarditis or pericarditis, known physical disability that would preclude safe and adequate test performance, known thrombosis of the lower extremity, known left main coronary stenosis or its equivalent, moderate stenotic valvular heart disease, electrolyte abnormalities, known pulmonary hypertension, tachyarrhythmias or bradyarrhythmias, hypertrophic cardiomyopathy, mental impairment leading to inability to cooperate, or high degree atrioventricular block
* Arterial insufficiency of target lesion due to restenosis of an angioplasty/stent or bypass is not eligible
* Recent (less than 3 months) infrainguinal revascularization (surgery or endovascular intervention)
* Recent major surgery in the last 3 months
* Abdominal aortic aneurysm greater than 4 cm or iliac artery aneurysm greater than 1.5 cm is present
* Patients who are pregnant, planning to become pregnant, or lactating
* Unwilling or unable to attend regular (3 times a week) supervised exercise sessions. (Please review this commitment carefully with each prospective participant.)
* Weight greater than 350 lbs or 159 kg (may exceed treadmill and angiography table limits)
* Inability to understand and sign informed consent forms due to cognitive or language barriers (interpreter permitted)
* Absolute contraindication to iodinated contrast due to prior near-fatal anaphylactoid reaction (laryngospasm, bronchospasm, cardiorespiratory collapse, or equivalent) and which would preclude patient from participation in angiographic procedures
* Allergy to stainless steel or nitinol
* Allergy or other intolerance to cilostazol (bleeding history) or history of congestive heart failure \[if ejection fraction is shown to be greater than or equal to 50% patient may be enrolled\]
* Nonatherosclerotic cause of PAD (fibromuscular dysplasia, dissection, trauma, etc)
* Inability to walk on a treadmill without grade at a speed of at least 2 mph for at least 2 minutes on the first treadmill test
* ST-segment depression greater than 1 mm in any of the standard 12 ECG leads or sustained (greater than 30 seconds) arrhythmia other than tachycardia or occasional premature atrial or ventricular contractions during exercise testing
* Post-exercise systolic blood pressure within the first five minutes after eligibility treadmill test lower than pre-exercise systolic blood pressure
* A peak heart rate greater than 80% of maximum (calculated by subtracting age from 220) while reporting "onset" of claudication symptoms (level 3 or 4) during the second baseline examination
* Repeat treadmill test shows a MWD result that is greater than 25% different than the subject's initial Gardner treadmill test result. Current active involvement in a supervised exercise program (e.g., with a trainer, exercise protocol, and goals, such as in cardiac or pulmonary rehabilitation) for more than 2 weeks within the prior 6 weeks.

Primary outcomes:
measure: MWD change score
timeFrame: Measured at 6 months
measure: MWD change score
timeFrame: Measured at 6 months
measure: MWD change score
timeFrame: Measured at 6 months
Secondary outcomes:
measure: MWD change score
timeFrame: Measured at 18 months
measure: Free-living daily activity
timeFrame: Measured at 6 and 18 months
measure: Quality of Life
timeFrame: Measured at 6 and 18 months
measure: Cost-effectiveness
timeFrame: Measured at 18 months
measure: Cardiovascular risk factors
timeFrame: Measured at baseline, 6 months, and 18 months
measure: Interaction effect
timeFrame: Measured at 18 months
measure: Major adverse peripheral events
timeFrame: Measured from randomization to 18 months
measure: Major complication
timeFrame: Measured from randomization to 18 months
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: VA Loma Linda
state: California
city: Orange
country: United States
facility: St. Joseph Hospital
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care Systems
state: California
city: Sacramento
country: United States
facility: UC Davis
state: California
city: Torrance
country: United States
facility: Vasek Polak Research Program
state: California
city: Miami
country: United States
facility: Baptist Cardiac and Vascular Institute
state: Florida
city: Evans
country: United States
facility: Aiyan Diabetes Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Des Moines
country: United States
facility: The Iowa Clinic
state: Iowa
city: Alexandria
country: United States
facility: Rapides Regional Medical Center
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Clinic
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Ann Arbor
country: United States
facility: VA Ann Arbor
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Abbott Northwestern Vascular Center
state: Minnesota
city: Stony Brook
country: United States
facility: Stony Brook
state: New York
city: Asheville
country: United States
facility: Asheville Cardiology
state: North Carolina
city: Winston Salem
country: United States
facility: Forsyth-Salem Surgical
state: North Carolina
city: Mansfield
country: United States
facility: Vascular Endovascular Specialists of Ohio
state: Ohio
city: Toledo
country: United States
facility: Jobst Vascular
state: Ohio
city: Portland
country: United States
facility: Oregon Health Science University (DOTTER)
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Spokane
country: United States
facility: Providence Medical Research
state: Washington
city: Charleston
country: United States
facility: Charleston Area Medical Center
state: West Virginia
city: Halifax
country: Canada
facility: Capital Health
state: Nova Scotia
Study officials:
affiliation: Brigham and Women's Hospital
name: Don Cutlip, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rhode Island Hospital
name: Timothy Murphy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bronas UG, Hirsch AT, Murphy T, Badenhop D, Collins TC, Ehrman JK, Ershow AG, Lewis B, Treat-Jacobson DJ, Walsh ME, Oldenburg N, Regensteiner JG; CLEVER Research Group. Design of the multicenter standardized supervised exercise training intervention for the claudication: exercise vs endoluminal revascularization (CLEVER) study. Vasc Med. 2009 Nov;14(4):313-21. doi: 10.1177/1358863X09102295.
citation: Murphy TP, Hirsch AT, Cutlip DE, Regensteiner JG, Comerota AJ, Mohler E, Cohen DJ, Massaro J; CLEVER Investigators. Claudication: exercise vs endoluminal revascularization (CLEVER) study update. J Vasc Surg. 2009 Oct;50(4):942-945.e2. doi: 10.1016/j.jvs.2009.04.076. Epub 2009 Aug 5.
citation: Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, Massaro JM, Lewis BA, Cerezo J, Oldenburg NC, Thum CC, Goldberg S, Jaff MR, Steffes MW, Comerota AJ, Ehrman J, Treat-Jacobson D, Walsh ME, Collins T, Badenhop DT, Bronas U, Hirsch AT; CLEVER Study Investigators. Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: six-month outcomes from the claudication: exercise versus endoluminal revascularization (CLEVER) study. Circulation. 2012 Jan 3;125(1):130-9. doi: 10.1161/CIRCULATIONAHA.111.075770. Epub 2011 Nov 16.
citation: Reynolds MR, Apruzzese P, Galper BZ, Murphy TP, Hirsch AT, Cutlip DE, Mohler ER 3rd, Regensteiner JG, Cohen DJ. Cost-effectiveness of supervised exercise, stenting, and optimal medical care for claudication: results from the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) trial. J Am Heart Assoc. 2014 Nov 11;3(6):e001233. doi: 10.1161/JAHA.114.001233.