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 older patients who do not have classic claudication symptoms. Even in those individuals with documented peripheral arterial disease, cardiac risk factors are often not 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 often not prescribed as supervised exercise rehabilitation for claudication, is not reimbursed by Medicare, and rarely covered by private insurance. Therefore, few individuals with peripheral arterial disease 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 are 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 including balloon angioplasty, stents, were employed making it difficult to come to a definitive conclusion about the relative efficacy of stenting to improve functional performance.

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 peripheral arterial disease. 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 a third group, usual care/pharmacotherapy, at 6 months, and to compare all 3 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, and cost-effectiveness. The study also will perform exploratory analyses of demographic and biochemical risk factors for atherosclerosis, including BMI, blood pressure, lipid profile, HgbAlc, fibrinogen, and C-reactive protein. An estimated 246 patients (at 9 study sites) with aortoiliac insufficiency and intermittent claudication randomly will be divided into 3 groups: usual care/pharmacotherapy, exercise rehabilitation/maintenance/pharmacotherapy, and stent/pharmacotherapy. Recruitment will be done over 28 months and patients will be followed for 18 months; the total study duration will be 5 years.

Medical History Inclusion Criteria (Screening Phase I)

1. Age >50 years
2. Complaint of exercise-induced pain, cramps, fatigue, or other equivalent, involving large muscle groups of the leg(s) (calf, thigh, buttocks) (Rutherford Grade I59)
3. Leg pain typical of intermittent claudication Pain never begins while standing still or sitting Pain never disappears while walking Pain relieved by rest within 10 minutes or less

Medical History Exclusion Criteria (Screening Phase I)

1. Limb-threatening ischemia (Rutherford Grade II or HI59i59--pain at rest, ischemic ulceration, gangrene) in either leg

2. Patients will be excluded based on American College of Sports Medicine86 criteria for exercise training

   a) Ambulation limited by comorbid condition other than claudication

   i. severe coronary artery disease ii. angina pectoris iii. congestive heart failure iv. chronic lung disease

   v. neurological disorder such as hemiparesis vi. arthritis, or other musculoskeletal conditions including amputation b) Poorly-controlled hypertension (SBP>180 mm Hg)85 c) Poorly-controlled diabetes mellitus (HbA1c >7% for those with a known history of diabetes mellitus) d) History of diabetes mellitus with known history of lower extremity peripheral neuropathy e) Other active significant medical problems such as cancer30, known chronic renal or liver disease, known anemia, active substance abuse, or known history of dementia e)

3. Contraindication to exercise testing according to AHA/ACC (Acute myocardial infarction (within 3-5 days), unstable angina, uncontrolled cardiac arrhythmias causing symptoms or hemodynamic compromise, active endocarditis, symptomatic severe aortic stenosis, uncontrolled symptomatic heart failure, acute pulmonary embolus or pulmonary infarction, acute noncardisc disorder that may affect exercise performance or be aggravated by exercise such as infection, renal failure, thyrotoxicosis, acute myocarditis or pericarditis, physical disability that would preclude safe and adequate test performance, thrombosis of the lower extremity, known left main coronary stenosis or its equivalent, moderate stenotic valvular heart disease, electrolyte abnormalities, significant arterial or pulmonary hypertension, tachyarrhythmias or bradyarrhythmias, hypertrophic cardiomyopathy, mental impairment leading to inability to cooperate, high degree atrioventricular block
4. Previous ipsilateral aortic or iliac artery revascularization (surgery or intervention)
5. Recent (<1 year) infrainguinal revascularization (surgery or intervention)
6. Abdominal aortic aneurysm > 3 cm or iliac artery aneurysm >1.5 cm
7. Pregnant female
8. Prior lower extremity revascularization within one year
9. Primary residence >50 air miles from study exercise training facility (for compliance if randomized to exercise training group)
10. Weight >350 Ibs (159 kg) (may exceed treadmill and angiography table limits)
11. Language barrier for primary QoL instruments (available in English and Spanish)
12. Inability to understand and sign informed consent forms due to cognitive or language barriers (interpreter permitted)
13. Absolute contraindication to iodinated contrast due to prior near-fatal anaphylactoid reaction (laryngospasm, bronchospasm, cardiorespiratory collapse, o" equivalent)
14. Allergy to stainless steel or nitinol
15. Allergy or other intolerance to cilostazol (heart failure, bleeding history)
16. Nonatherosclerotic cause of PAD (fibromuscular dysplasia, dissection, trauma, etc.)

Survey and Noninvasive Testing Inclusion Criteria (Screening Phase II) (done in sequence, if any indicate exclusion, stop)

1. Resting ipsilateral ankle-brachial index (ABI) <0.946''''87

2. Positive noninvasive evaluation for significant aortoiliac PAD:

   a. Thigh-brachial index (TBI) <1.0, and

   b. Doubling of aortic or iliac artery peak systolic velocity by pulsed Doppler71''''. OR occluded iliac artery by pulsed or color Doppler75, OR common femoral artery Doppler systolic acceleration time >140 ms ''''88''''89

3. Ankle pressure reduced by at least 25 mm Hg after exercise59
4. Moderate to severe claudication symptoms, defined as less than 7 minutes MWD at baseline on Hiatt treadmill test.