Clinical trial NCT00491751: Clinical Utility of Endothelial Dysfunction in PAD
Official title: Clinical Utility of Endothelial Dysfunction in PAD
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Peripheral Arterial Disease
Keywords: endothelium
nitric oxide
statins
ascorbic acid
Lead sponsor: Boston University
Sponsor class: OTHER
First posted: 2007-06-26
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: This study will seek to determine whether non-invasive measures of endothelial function have utility as surrogate markers of cardiovascular risk in patients with peripheral arterial disease undergoing vascular surgery. Measurements of endothelial function will be made before and after initiation of atorvastatin, ascorbic acid, or placebo therapy during the pre-operative period. We will then examine cardiovascular events following surgery. We hypothesize that patients who have no improvement in endothelial function will have increased cardiovascular risk compared to patients with improvement in endothelial function.

Detailed description: Part 1 of the study will involve only patients with PAD who are undergoing non-cardiac surgery and is an intervention study. Part 2 will involve patients with PAD who have participated in Part 1 and patients with PAD who are not undergoing surgery. This part of the study does not involve an intervention.

The protocol for patients undergoing surgery is as follows: Part 1. Intervention study with follow-up for 30 days after surgery. Patients with planned surgery will be enrolled. We will test endothelial function at baseline using ultrasound and tonometry. They will then be randomzied to one of three groups: Atorvastatin 80 mg/d, Vitamin C 500 mg/d, or placebo. Subjects already on a statin medication at the time of enrollment will receive 40 mg/d of atorvastatin. Patients taking high dose statin (\>40 mg/day) will be randomized to received vitamin C or placebo, and will not be eligible to receive any additional statin as part of the study. In the week immediately prior to surgery, we will test endothelial function a second time. They will then be followed for 30 days beginning with the day of surgery for cardiovascular events. Part 1 of the study involves 4 visits as follows: Visit 1 at enrollment will take place within 7-30 days of non-emergent vascular surgery and will last approximately 60 minutes Visit 2 will take place within approximately 1 week of surgery and will last approximately 30-40 minutes Visit 3 will occur on the 1st post-operative day and will last approximately 10-15 minutes Visit 4 will take place only if the subject is still an in-patient. It will take approximately 10-15 minutes Telephone contact will occur at 30 days post surgery and every six months thereafter for two years. The duration of telephone follow-up is expected to be approximately 5-10 minutes. Part 2 (long term follow-up): Patients who have completed Part 1 will be continued on in Part 2 of the study. Part 2 involves two year follow-up with no study medication. Telephone contact will be made every 6 months. subjects will make a visit to our research unit one year after the initial visit for physical examination, and if applicable, an ultrasound study of their bypass grafts.

The protocol for patients with PAD who are not undergoing surgery is as follows. These patients will participate in Part 2 of the study only (long-term follow-up with no intervention). Visit 1: will last approximately 60 minutes and involve measurement of endothelial function by ultrasound and tonometry. We will contact the subject every 6 months by telephone (5-10 minutes) for two years to determine whether a cardiovascular event has occurred. Visit 2 will occur at 1 year post enrollment and will last approximately 20-30 minutes. If the subject has had peripheral bypass surgery, we will perform an ultrasound study to determine graft blood flow.

Eligibility criteria: Inclusion Criteria:

1. Male and female subjects age 21-99 years old.
2. Peripheral Arterial Disease. PAD is defined clinically and by angiography, magnetic resonance imaging, vascular ultrasound, or ankle brachial index less than 0.9.
3. Able to provide informed consent and complete the study procedure.
4. Patients undergoing non-emergent vascular surgery (peripheral arterial bypass, abdominal aortic aneurysm repair, carotid endarterectomy, or limb amputation) or other non-cardiac surgery.

Exclusion Criteria:

1. Emergent or urgent surgery that must be performed sooner than one week after enrollment
2. Unstable angina, myocardial infarction, stroke, coronary revascularization, or decompensated heart failure within 1 month of enrollment. Patients who require cardiac catheterization and surgical or percutaneous coronary revascularization prior to vascular surgery will be excluded.
3. Clinically evident major illness of other organ systems, including cancer, end-stage renal disease, hepatic failure, or other conditions that make participation inappropriate.
4. Women who are lactating, pregnant, or of childbearing potential and not using a reliable contraceptive method. Pregnancy will be excluded by a urine pregnancy test.
5. Patients with liver function tests or serum creatine kinase \>3 times the upper limit of normal.
6. Patients who have received an investigational drug within 30 days of enrollment.
7. Patients or subjects with a history of a psychological illness or condition such as to interfere with the subject's ability to understand the requirements of the study.
8. Known occlusive atherosclerosis of the subclavian artery or upper extremity, because such disease will interfere with induction of reactive hyperemia during the brachial artery ultrasound studies.
9. Patients will be excluded if they are taking vitamin C in a dose greater than 2 times the Recommended Daily Allowance (\>120 mg/day) within 1 month of enrollment.

Primary outcomes:
measure: Change in FMD
timeFrame: 1-4 weeks
Secondary outcomes:
measure: Percentage Change in FMD in All Participants With and Without a CVD Event (Not by Treatment Group)
timeFrame: 2 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
Study officials:
affiliation: Boston University
name: Naomi Hamburg, MD
role: PRINCIPAL_INVESTIGATOR
References: