Clinical Utility of Endothelial Dysfunction in PAD

• ClinicalTrials.gov Identifier: NCT00491751
• Recruitment Status: Terminated
• First Posted: June 26, 2007
• Results First Posted: July 27, 2018
• Last Update Posted: July 27, 2018
• Sponsor: Boston University
• Information provided by (Responsible Party): Boston University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Peripheral Arterial Disease	Drug: atorvastatin; Drug: ascorbic acid; Drug: Placebo	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 108 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: Clinical Utility of Endothelial Dysfunction in PAD
• Study Start Date: May 2004
• Actual Primary Completion Date: June 2012
• Actual Study Completion Date: June 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Atorvastatin; Atorvastatin 40 or 80 mg/day	Drug: atorvastatin; atorvastatin 40 or 80 mg/day; Other Name: Lipitor
Experimental: Ascorbic Acid; Ascorbic Acid 500 mg/day	Drug: ascorbic acid; ascorbic acid 500 mg/day; Other Name: Vitamin C
Placebo Comparator: Placebo; Placebo atorvastatin and Placebo ascorbic acid	Drug: Placebo; matching placebo

Outcome Measures

Primary Outcome Measures :

1. Change in FMD [ Time Frame: 1-4 weeks ]
   Change in flow mediated dilation with treatment: FMD visit 2 - FMD visit 1 FMD is measured by using vascular ultrasound to determine the baseline diameter of the brachial artery. Endothelium-dependent vasodilation is induced by 5-minute arterial occlusion with a blood pressure cuff. When the cuff is released, the resultant increase in blood flow (reactive hyperemia) stimulates vasodilation of the brachial artery. This flow-mediated dilation (FMD) is expressed as the percent change from baseline. Healthy individuals typical dysplay a 10 to 12% dilation. Individuals with PAD had markedly impaired dilation of 6-7. The currernt study sought to determine whether a change in FMD would occur following intervention.

Secondary Outcome Measures :

1. Percentage Change in FMD in All Participants With and Without a CVD Event (Not by Treatment Group) [ Time Frame: 2 months ]
   This outcome is independent of the treatment group so the groups are 'CVD event' and ' No CVD Event'. Cardiovascular events (CVD) included cardiovascular disease, myocardial infarction, congestive heart failure, stroke, and unstable angina.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Massachusetts

Boston Medical Center

Boston, Massachusetts, United States, 02118

Sponsors and Collaborators

Boston University

Investigators

• Principal Investigator: Naomi Hamburg, MD; Boston University

More Information

• Responsible Party: Boston University
• ClinicalTrials.gov Identifier: NCT00491751
• Other Study ID Numbers: H-23184
• First Posted: June 26, 2007
• Results First Posted: July 27, 2018
• Last Update Posted: July 27, 2018
• Last Verified: May 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Boston University:

endothelium; nitric oxide; statins; ascorbic acid

Additional relevant MeSH terms:

Peripheral Arterial Disease; Peripheral Vascular Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Ascorbic Acid; Atorvastatin; Vitamins; Micronutrients; Physiological Effects of Drugs; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors; Antioxidants; Protective Agents