Claudication: Exercise Versus Endoluminal Revascularization (CLEVER)

Cardiovascular Diseases Clinical Trial

— CLEVER  

Official title:

Claudication: Exercise Versus Endoluminal Revascularization (CLEVER)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00132743
• Other study ID #: 224
• Secondary ID: U01HL081656U01HL
• Status: Active, not recruiting
• Phase: Phase 3
• First received: August 19, 2005
• Last updated: April 24, 2013
• Start date: February 2007
• Est. completion date: July 2013

Study information

• Verified date: April 2013
• Source: Rhode Island Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 119
• Est. completion date: July 2013
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Atherosclerosis
• Cardiovascular Diseases
• Peripheral Arterial Disease
• Peripheral Vascular Diseases
• Vascular Diseases

Intervention

Device:
• Stent
Stent

Behavioral:
• Supervised Exercise Therapy
Supervised exercise therapy, three times per week

Drug:
• Cilostazol
Cilostazol, 100 mg twice a day

Locations

Country	Name	City	State
Canada	Capital Health	Halifax	Nova Scotia
United States	Rapides Regional Medical Center	Alexandria	Louisiana
United States	VA Ann Arbor	Ann Arbor	Michigan
United States	Asheville Cardiology	Asheville	North Carolina
United States	Johns Hopkins	Baltimore	Maryland
United States	Charleston Area Medical Center	Charleston	West Virginia
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	The Iowa Clinic	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Aiyan Diabetes Center	Evans	Georgia
United States	VA Loma Linda	Loma Linda	California
United States	Vascular Endovascular Specialists of Ohio	Mansfield	Ohio
United States	Baptist Cardiac and Vascular Institute	Miami	Florida
United States	Abbott Northwestern Vascular Center	Minneapolis	Minnesota
United States	Ochsner Clinic	New Orleans	Louisiana
United States	St. Joseph Hospital	Orange	California
United States	VA Palo Alto Health Care Systems	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health Science University (DOTTER)	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	UC Davis	Sacramento	California
United States	Providence Medical Research	Spokane	Washington
United States	Stony Brook	Stony Brook	New York
United States	Jobst Vascular	Toledo	Ohio
United States	Vasek Polak Research Program	Torrance	California
United States	Forsyth-Salem Surgical	Winston Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Joselyn Cerezo, MD	National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (3)

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. — View 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 — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MWD change score	Aortoiliac revascularization with stent (ST) combined with optimal medical care (OMC) improves maximum walking duration (MWD) compared to optimal medical care alone in patients with claudication and peripheral arterial disease (PAD) who are amenable to peripheral stenting	Measured at 6 months	No
Primary	MWD change score	Regular supervised exercise (SE) combined with optimal medical care (OMC) improves maximum walking duration compared to optimal medical care along in patients with claudication and PAD who are amenable to peripheral stenting.	Measured at 6 months	No
Primary	MWD change score	Aortoiliac revascularization with stent (ST) combined with optimal medical care improves maximum walking duration compared to supervised exercise (SE) combined with optimal medical care in patients with claudication and PAD who are amenable to peripheral stenting.	Measured at 6 months	No
Secondary	MWD change score	To evaluate the mid-term durability of any treatment effect by performing pair-wise comparison of change in MWD between baseline and 18 month time points among all three treatment groups of primary interest.	Measured at 18 months	No
Secondary	Free-living daily activity	To assess a treatment effect on free-living daily activity levels of any treatment group, comparing baseline electronic step monitors values with those obtained at both follow up intervals (6 and 18 months)	Measured at 6 and 18 months	No
Secondary	Quality of Life	To examine treatment effects on patient-perceived health-related quality of life (physical function) between all groups at 6 and 18 months	Measured at 6 and 18 months	No
Secondary	Cost-effectiveness	To Examine inpatient and outpatient costs associated with the three treatment strategies, and to evaluate the relative cost-benefit by calculating incremental cost-effectiveness and cost effectiveness acceptability curves using health utility change in the denominator.	Measured at 18 months	No
Secondary	Cardiovascular risk factors	To evaluate the impact of cardiovascular disease risk factors by comparing these values at baseline, 6 months, and 18 months.	Measured at baseline, 6 months, and 18 months	No
Secondary	Interaction effect	To evaluate the interaction effect, if any, of gender or race on improvements in MWD, improvement in free-living daily activities, and quality-of-life.	Measured at 18 months	No
Secondary	Major adverse peripheral events	To track major adverse peripheral events (MAPEs) associated with aortoiliac stenting and femoropopliteal endovascular intervention.	Measured from randomization to 18 months	Yes
Secondary	Major complication	Rate of major complication defined as any occurrence of death, myocardial infarction, amputation of the target limb (limb treated in this study), or occurrence of critical limb ischemia or repeat target limb revascularization (TLiR).	Measured from randomization to 18 months	Yes