NSAIDs vs. Coxibs in the Presence of Aspirin

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-