Claudication: Exercise Versus Endoluminal Revascularization (CLEVER)

Condition(s) targeted: Cardiovascular Diseases; Peripheral Vascular Diseases; Atherosclerosis

Intervention: Stent (Device); Supervised Exercise Therapy (Behavioral); Cilostazol (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: National Heart, Lung, and Blood Institute (NHLBI)

Official(s) and/or principal investigator(s):
Don Cutlip, MD, Principal Investigator, Affiliation: Brigham and Women's Hospital
Timothy Murphy, MD, Principal Investigator, Affiliation: Rhode Island Hospital

Overall contact:
Joselyn Cerezo, MD, Phone: 401-444-1739, Email: jcerezo@lifespan.org

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

Official title: Claudication: Exercise Versus Endoluminal Revascularization (CLEVER)

Study design: Treatment, Randomized, Double Blind (Investigator, Outcomes Assessor), Parallel Assignment, Efficacy Study

Primary outcome:

MWD change score

Participant-perceived QoL

Cost-effectiveness

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.

Minimum age: 40 Years. Maximum age: N/A. Gender(s): Both.

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):

1. Contrast Arteriography: Contrast arteriogram showing at least 50% stenosis in the aorta, common iliac artery, or external iliac artery, OR

2. 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

3. 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

4. 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.

Joselyn Cerezo, MD, Phone: 401-444-1739, Email: jcerezo@lifespan.org

Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, United States; Recruiting
Mohammed Moursi, MD, Phone: 501-257-6864
Mohammed Moursi, MD, Principal Investigator

VA Loma Linda, Loma Linda, California 92357, United States; Recruiting
Vicki Bishop, RN, Phone: 909-825-7084, Ext: 2852

St. Joseph Hospital, Orange, California 92868, United States; Recruiting
Sandy Chung, RN, Phone: 714-744-8776
Mahmood Razavi, MD, Principal Investigator

VA Palo Alto Health Care Systems, Palo Alto, California 94304, United States; Recruiting
Dona Bahmani, Phone: 650-493-5000, Ext: 60357
Fritz Bech, MD, Principal Investigator

UC Davis, Sacramento, California 95817, United States; Recruiting
Christy Pifer, BS, Phone: 916-734-4156, Email: christy.pifer@ucdmc.ucdavis.edu
David Dawson, MD, Principal Investigator

Vasek Polak Research Program, Torrance, California 90505, United States; Recruiting
Suellen Hosino, RN, Phone: 310-325-9110, Ext: 2939, Email: suellen.hosino@tmmc.com
Mark Lurie, MD, Principal Investigator

Baptist Cardiac and Vascular Institute, Miami, Florida 33176, United States; Recruiting
Sarah Orendorff-Alegre, RN, Phone: 786-596-5336
Barry Katzen, MD, Principal Investigator

Northwestern Memorial Hospital, Chicago, Illinois 60611, United States; Recruiting
Wendy Meadows, RN, Phone: 312-695-2928
Anna Busman, RN, Phone: 312-695-3410, Email: abusman@nmh.org
Mark Eskandari, MD, Principal Investigator

The Iowa Clinic, Des Moines, Iowa 50309, United States; Recruiting
John H Matsuura, MD, Phone: 515-241-5700, Email: jmatsuura@iowaclinic.com
Karla Barkema, RN, Phone: 515-241-6056, Email: barkemkm@ihs.org
John Matsuura, MD, Principal Investigator

Rapides Regional Medical Center, Alexandria, Louisiana 71303, United States; Recruiting
Therese Peters, RN, Phone: 318-767-9764, Email: theresa.peters@christushealth.org
William Long, MD, Principal Investigator

Ochsner Clinic, New Orleans, Louisiana 70002, United States; Recruiting
Yunh-Wei Chi, DO, Phone: 504-842-9567
Yunh-Wei Chi, DO, Principal Investigator

Maine Medical Center, Portland, Maine 04102, United States; Recruiting
Joanne Burgess, RN, Phone: 207-662-6317
Peter Higgins, MD, Principal Investigator

Johns Hopkins, Baltimore, Maryland 21287, United States; Recruiting
Elizabeth Ratchford, MD, Phone: 410-955-5897, Email: eratchf1@jhmi.edu
Elizabeth Ratchford, MD, Principal Investigator

VA Ann Arbor, Ann Arbor, Michigan 48109, United States; Recruiting
Eric Henricks, Phone: 734-615-4039, Email: ehenrick@umich.edu
Venkat Krishnamurthy, MD, Principal Investigator

Henry Ford Hospital, Detroit, Michigan 48202, United States; Recruiting
Matt Saval, Phone: 313-972-1919, Email: msaval1@hfhs.org
Jonathan Ehrman, PhD, Principal Investigator

Abbott Northwestern Vascular Center, Minneapolis, Minnesota 55407, United States; Recruiting
Holly Macdonald, RN, Phone: 612-863-6051
Alan Hirsch, MD, Principal Investigator

Stony Brook, Stony Brook, New York 11794-8191, United States; Recruiting
Eileen Finnin, RN, Phone: 631-444-5454
Apostolos Tassiopoulos, MD, Principal Investigator

Asheville Cardiology, Asheville, North Carolina, United States; Recruiting
Jan Blakely, RN, Phone: 828-274-6000, Ext: 393
William Abernethy, MD, Principal Investigator

Forsyth-Salem Surgical, Winston Salem, North Carolina 27103, United States; Recruiting
Keisha Rodriguez, RN, Phone: 336-718-5807
Daniel Golwyn, MD, Principal Investigator

Capital Health, Halifax, Nova Scotia B3H 2Y9, Canada; Recruiting
Colleen Schwartz, BSC, RTNM, Phone: 902-473-8485, Email: colleen.schwartz@cdha.nshealth.ca
Robert Berry, MD, Principal Investigator

Vascular Endovascular Specialists of Ohio, Mansfield, Ohio 44907, United States; Recruiting
Jill Carr, PA, Phone: 419-756-0011
William Miller, MD, Principal Investigator

Jobst Vascular, Toledo, Ohio 43606, United States; Recruiting
Anthony Comerota, MD, Phone: 419-383-6212
Anthony Comerota, MD, Principal Investigator

Oregon Health Science University (DOTTER), Portland, Oregon 97239, United States; Recruiting
Lori Watson, RN, Phone: 503-494-7226
John A. Kaufman, MD, Principal Investigator

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Recruiting
Emile Mohler, MD, Phone: 215-614-0090
Emile Mohler, MD, Principal Investigator

Rhode Island Hospital, Providence, Rhode Island 02903, United States; Recruiting
Michelle Risctuccia, BS, Phone: 401-444-6208
Timothy Murphy, MD, Principal Investigator

Providence Medical Research, Spokane, Washington 99204, United States; Recruiting
Claudia Flores, RN, Phone: 509-474-4306
Stuart Cavalieri, MD, Principal Investigator

Charleston Area Medical Center, Charleston, West Virginia 25304, United States; Recruiting
Cyndi Mann, RN, Phone: 304-388-9956, Email: cynthia.mann@camc.org
Arvinda Nanjudappa, MD, Principal Investigator

Starting date: February 2007
Ending date: January 2012
Last updated: July 14, 2009