Cardiovascular Diseases, Rheumatoid Arthritis
Conditions
Brief summary
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.
Detailed description
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.
Interventions
celecoxib 200mg twice a day for 4 weeks
DRUGnaproxen sodium 550mg tablet
naproxen sodium 550mg twice a day for 4 weeks
DRUGAspirin 81mg tablet
81mg aspirin for 4 weeks in the run-in period, and for 8 weeks during treatment and crossover period
Sponsors
Platelet and Thrombosis Research, LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Qualified 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 before the aspirin run-in period (baseline), 24±4 hrs after the last dose of aspirin in the run-in period, 24±4 hr after the last dose of the study drug in the first period and 24±4 hr after the last dose of the study drug in the second period. Assays for platelet function, biomarkers of inflammation and endothelial function will be performed at these time points
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Arachidonic Acid (AA)-Induced Platelet Aggregation | End of 4-week aspirin run-in period and after completion of each 4-week treatment period | Percent change in AA-induced platelet aggregation measured by light transmission aggregometry in platelet-rich plasma. Measurements were obtained at: * End of 4-week aspirin 81 mg daily run-in period (baseline) * After completion of the first 4-week treatment period following randomization * After completion of the second 4-week treatment period (crossover period) Aspirin 81 mg daily was administered during the run-in period and continued throughout the study. Each participant received celecoxib (200 mg twice daily) and naproxen sodium (550 mg twice daily) in two separate treatment periods in a randomized crossover design. The primary analysis was performed within-subject, comparing platelet aggregation during celecoxib exposure versus naproxen exposure. |
| Change in Collagen-induced Platelet Aggregation (%) | End of 4-week aspirin run-in period and after completion of each 4-week treatment period | Percent change in collagen-induced platelet aggregation measured by light transmission aggregometry in platelet-rich plasma. Measurements were obtained at: * End of aspirin 81 mg daily run-in period (baseline) * After completion of the first 4-week treatment period following randomization * After completion of the second 4-week treatment period (crossover period) Aspirin 81 mg daily was continued throughout the study. Each participant received celecoxib (200 mg twice daily) and naproxen sodium (550 mg twice daily) in two separate treatment periods in a randomized crossover design. The primary analysis compared within-subject differences between celecoxib and naproxen exposure periods. |
| Change in Adenosine Diphosphate (ADP)-Induced Platelet Aggregation (%) | End of 4-week aspirin run-in period and after completion of each 4-week treatment period. | Percent change in ADP-induced platelet aggregation measured by light transmission aggregometry in platelet-rich plasma. Measurements were obtained at: * End of 4-week aspirin 81 mg daily run-in period (baseline) * After completion of the first 4-week treatment period following randomization * After completion of the second 4-week treatment period (crossover period) Aspirin 81 mg daily was administered during the run-in period and continued throughout the study. This was a randomized crossover study in which each participant received celecoxib (200 mg twice daily) and naproxen sodium (550 mg twice daily) in two separate treatment periods. The primary analysis compared within-subject differences in platelet aggregation between celecoxib exposure and naproxen exposure periods. |
| Change in Epinephrine-induced Platelet Aggregation (%) | End of 4-week aspirin run-in period and after completion of each 4-week treatment period. | Percent change in epinephrine induced platelet aggregation measured by light transmission aggregometry in platelet-rich plasma. Measurements were obtained at: * End of 4-week aspirin 81 mg daily run-in period (baseline) * After completion of the first 4-week treatment period following randomization * After completion of the second 4-week treatment period (crossover period) Aspirin 81 mg daily was administered during the run-in period and continued throughout the study. This was a randomized crossover study in which each participant received celecoxib (200 mg twice daily) and naproxen sodium (550 mg twice daily) in two separate treatment periods. The primary analysis compared within-subject differences in platelet aggregation between celecoxib exposure and naproxen exposure periods. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORPaul Gurbel, MD
LifeBridge Health
Participant flow
Pre-assignment details
Eight participants (8) completed a 4-week aspirin 81 mg daily run-in period prior to randomization. All participants were then randomized to one of two treatment sequences.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 30 years STANDARD_DEVIATION 38 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 8 | 0 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 0 / 6 |
Outcome results
None listed