Clinical trial NCT00906035: The Vascular Biology of Dipyridamole in Peripheral Arterial Disease (PAD)
Official title: The Vascular Biology of Dipyridamole in Peripheral Arterial Disease (PAD)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Peripheral Arterial Disease
Keywords: Peripheral Arterial Disease
PAD
Claudication
Peripheral Vascular Disease
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2009-05-21
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This research study will evaluate the effects of aspirin and dipyridamole alone and in combination on the blood flow in the vessels of the legs. We will examine how these medications are able to inhibit the clotting of platelets in the vessels of patients with PAD, and thereby affect the blood flow in the legs. Platelets are cells in the blood that have the ability to adhere to each other to form clots.

Detailed description: Dipyridamole has been reformulated to guarantee systemic bioavailability and steady state levels compatible with inhibition of platelet aggregation ex vivo (1). This newly formulated dipyridamole has been shown to roughly equal in efficacy to low dose aspirin in the secondary prevention of stroke and the drug combination seems roughly additive (2). The present study is designed to explore two potential mechanisms which have been linked to dipyridamole action on the vessel wall; modulation of vascular eicosanoid generation and prevention of oxidant stress (3). We shall address the hypothesis that dipyridamole affects these systems in patients with PAD. These individuals have disordered platelet-vascular interactions, as reflected by increased generation of thromboxane, an index of platelet activation and of prostacyclin, probably a homeostatic response to traumatic and chemical stimulation of the endothelium (4,5). Furthermore, we shall assess the functional consequences of dipyridamole action, alone and in combination with aspirin compared with aspirin alone on local measurements of flow and oxygenation, including exercise tolerance, Doppler Ultrasound and Near Infrared Spectroscopy (NIRS). Lipid peroxidation will be quantified based on mass spectrometric analysis of the major urinary isoprostane, 8,12-iso-iPF2a-VI (6,7).

Eligibility criteria: Inclusion Criteria:

* Age between 18 - 79
* Women of child bearing potential using a medically acceptable method of birth control (oral/transdermal/vaginal hormonal contraception, depo-provera injection, IUD, condom with spermicide, progestin implant, tubal ligation, oophorectomy, TAH) or abstinence.
* Capacity for giving written consent
* Diagnosis of PAD by:

  * previous angiogram (\>0.5 stenosis of a peripheral artery)
  * ankle-brachial index (ABI) of systolic pressure \<0.80
  * previous peripheral revascularization
* Smokers who smoke \< 10 cigarettes / day

Exclusion Criteria:

* Female subjects who are pregnant or nursing a child.
* Prior bleeding event related to drug therapy
* History of gastrointestinal ulceration
* History of known dipyridamole and/or aspirin allergy or intolerance
* History of coagulation, bleeding or blood disorders.
* Recent history of myocardial infarction or stroke in the previous 6 months
* Resting blood pressure of \<110mmHg systolic or \<60mmHg diastolic or of \>165mmHg systolic or \>95mmHg diastolic
* Patients with active infection as documented by abnormal laboratory tests at screen
* Concomitant serious illness, such as cancer, as per the principal investigator's discretion
* Current use of steroids for a chronic disease process
* Presence of ischemic leg ulcers
* History of contact allergies to the metal leads of the NIRS
* History of drug or alcohol abuse within the last 6 months.
* Subject who has received an experimental drug and/or used an experimental device within 30 days of screening.
* Subject who has donated ≥ one pint of blood within 8 weeks prior to screen.
* Use of aspirin for 2 weeks prior to the study
* Use of any other NSAID or COX-inhibitor for one week prior to the start of the study
* Use of any antioxidant vitamin for 2 weeks prior to the start of the study
* Use of plavix, pletal or trental for one week prior to the start of the study
* Use of acetaminophen for one week prior to each study visit
* Use of alcohol, caffeine or high fat foods for 24 hours prior to each study visit
* Has smoked any cigarettes for 24 hours prior to each study visit
* Platelet aggregation blood test less than 60 percent at Visit 1

Primary outcomes:
measure: The Present Study is Designed to Explore Two Potential Mechanisms Which Have Been Linked to Dipyridamole Action on the Vessel Wall; Modulation of Vascular Eicosanoid Generation and Prevention of Oxidant Stress.
timeFrame: Predose and dosing days 30, 90 and 180
Secondary outcomes:
measure: Assess the Functional Consequences of Dipyridamole Action, Alone and in Combination With Aspirin Compared With Aspirin Alone on Local Measurements of Flow and Oxygenation. Blood Flow Reporting to Added Table.
timeFrame: Predose and dosing days 30, 90 and 180.
measure: Assess the Functional Consequences of Dipyridamole Action, Alone and in Combination With Aspirin Compared With Aspirin Alone on Local Measurements of Flow and Oxygenation. Reporting Blood Oxygenation.
timeFrame: Predose and dosing days 30, 90 and 180.
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Presbyterian Hospital, 51 N. 39th St.
state: Pennsylvania
city: Philadelphia
country: United States
facility: Translational Research Ctr.,3400 Civic Center Blvd, Building 421, 10th floor, Room 421
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Garret A FitzGerald, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Emile R Mohler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Tilo Grosser, MD
role: PRINCIPAL_INVESTIGATOR
References: