NSAIDs vs. Coxibs in the Presence of Aspirin
NSAIDs vs. Coxibs in the Presence of Aspirin
The objectives of this single site, randomized, crossover study is to evaluate the
 pharmacodynamic interactions between aspirin, NSAIDs and Coxibs with respect to platelet
 function, biomarkers of inflammation and endothelial function.
The relative cardiovascular safety of NSAIDs, particularly among patients with cardiovascular
 disease (CVD) or at higher CVD risk, has generated considerable concern among both patients
 and physicians because of knowledge gaps in the evidence relative to comparative safety and
 pharmacodynamic interactions between aspirin and NSAIDs. In the recently reported PRECISION
 trial, a moderate dose of celecoxib was found to be noninferior to ibuprofen or naproxen with
 respect to cardiovascular safety in patients with arthritis at increased CVD risk. At this
 time, no comparative prior data are available analyzing the effects of NSAIDs vs. Coxibs in
 the presence of aspirin on platelet function, biomarkers of inflammation and endothelial
 function.

 Thirty patients with rheumatoid arthritis who are at high cardiovascular (CV) risk or with
 established CV disease will be enrolled in the study. Patients taking anticoagulant therapy
 or any other antiplatelet agent other than aspirin will be excluded.

 Patients will be treated with immediate release 81mg aspirin for 4 weeks in the run-in period
 followed by randomization to celecoxib (200 mg bid) vs. naproxen sodium (550 mg bid) for 4
 weeks and then cross over to the other drug for another 4 weeks. Blood and urine samples will
 be collected at baseline before the aspirin run in period, 24±4 hr after the last dose of
 aspirin in the run in period, 24±4 hr after the last dose of the first period study drug and
 24±4 hr after the last dose of the second period study drug. Assays for platelet function,
 biomarkers of inflammation and endothelial function will be performed at these time points.
Inclusion Criteria:Qualified patients should have all 4 main criteria

 1. Age 18-75 years of age for patients who regularly use NSAIDs.

 2. Age 18-65 years of age for patients who do not regularly use NSAIDs

 3. Able to give informed consent

 4. Subjects with CVD or increased CV risk. Please see definitions for each criteria
 below:

 -  Increased CV risk (Subjects should have at least 3 of the following)

 -  > 55 years of age

 -  Hypertension

 -  Dyslipidemia (LDL > 160 mg/dL or HDL < 40 mg/dL in females and < 35 mg/dL in
 males or subjects currently receiving lipid lowering therapy as standard of
 care (i.e. statin drugs, prescription ω 3-acid ethyl esters, fibrates or
 prescription niacin [≥1,000 mg/d])

 -  Family history of premature CV disease (MI, angina pectoris, heart failure,
 cardiac death or coronary revascularization, stroke, carotid endarterectomy,
 or other arterial surgery or angioplasty for atherosclerotic vascular
 disease in a parent, grandparent, or sibling with symptom onset or diagnosis
 before age 55 y for males and 65 y for females)

 -  Current smoker

 -  Left ventricular hypertrophy

 -  Documented ankle brachial index of <0.9

 -  History of microalbuminuria, urine protein-creatinine ratio of >2

 -  CV disease (defined as one of the following):

 -  Calcium score of >0

 -  ≥ 50 % occlusion of a coronary artery by angiography

 -  ≥ 50 % occlusion of a carotid artery by angiography or ultrasound

 -  History of stable angina

 -  Symptomatic peripheral arterial disease

 -  Prior MI, unstable angina, percutaneous coronary intervention, CABG, TIA,
 ischemic stroke, carotid endarterectomy, or other arterial surgery or
 angioplasty, which have occurred > 3 months prior to screening visit

 -  Diabetes Mellitus type 1 or 2 (considered a CV disease equivalent).

 -  Clinical diagnosis of rheumatoid arthritis, as determined by individual patient
 and physician, requiring daily treatment with NSAIDs.

 Exclusion Criteria: Subjects with any of the following criteria will be excluded from this
 study:

 1. Unstable angina, MI, CVA, CABG <3 months from screening visit

 2. Planned coronary, cerebrovascular, or peripheral revascularization

 3. Undergone major surgery within 3 months prior to screening visit or has planned major
 surgery during the study period

 4. Uncontrolled hypertension (SBP >190, DBP >100 mm Hg) during screening visit

 5. Uncontrolled arrhythmia < 3 months from screening visit

 6. NYHA class III-IV heart failure or if available, ejection fraction ≤ 35 %

 7. Within 6 months prior to screening visit, a history of ACS or hospitalization for
 heart failure

 8. Oral corticosteroid, prednisone (or equivalent) > 20 mg daily

 9. Anticoagulation therapy

 10. Antiplatelet therapy except for aspirin

 11. GI ulceration < 60 days before screening visit

 12. GI bleeding, perforation, obstruction < 6 months of screening visit

 13. Inflammatory bowel disease, diverticulitis active < 6 months of screening visit

 14. AST, ALT, or BUN >2x the upper limit normal (within 30 days prior to screening visit)

 15. Creatinine level >1.7 mg/dL in men, 1.5 mg/dL in women (within 30 days prior to
 screening visit)

 16. On fluconazole, methotrexate, or lithium therapy

 17. Malignancy < 5 years before screening visit

 18. Other known, active, significant GI, hepatic, renal, or coagulation disorders

 19. Allergy, allergic-type reactions or hypersensitivity (e.g. asthma, urticaria, etc.) to
 any of the study medications and its components (i.e. sulfonamides)

 20. History of any disease of condition that, in the opinion of the investigator would
 place the subject at an unacceptable risk to participate in this study

 21. Any clinically relevant abnormal findings in physical examination, vital signs, or
 previous laboratory works that, in the opinion of the investigator, may compromise the
 safety of the subject to participate

 22. Subjects who are legally institutionalized

 23. Lactating females or females of childbearing potential except for those who are
 surgically sterile or postmenopausal-