NSAIDs vs. Coxibs in the Presence of Aspirin

Cardiovascular Diseases Clinical Trial

Official title:

NSAIDs vs. Coxibs in the Presence of Aspirin: Effects on Platelet Function, Endothelial Function, and Biomarkers of Inflammation in Subjects With Rheumatoid Arthritis and Increased Cardiovascular Risk or Cardiovascular Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03699293
• Other study ID #: 17-2915
• Status: Recruiting
• Phase: Phase 4
• Start date: September 22, 2018
• Est. completion date: November 24, 2019

Study information

• Verified date: September 2018
• Source: Inova Health Care Services
• Contact: Kevin Bliden, BS, MBA
• Phone: (703) 776-7702
• Email: kevin.bliden[@]inova.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: November 24, 2019
• Est. primary completion date: September 24, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 ? 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-

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Cardiovascular Diseases
• Rheumatoid Arthritis

Intervention

Drug:
• celecoxib 200mg capsule
celecoxib 200mg twice a day for 4 weeks
• naproxen sodium 550mg tablet
naproxen sodium 550mg twice a day for 4 weeks
• Aspirin 81mg tablet
81mg aspirin for 4 weeks in the run-in period, and for 8 weeks during treatment and crossover period

Locations

Country	Name	City	State
United States	Inova Heart and Vascular Institute	Falls Church	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Inova Health Care Services

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Platelet aggregation	Change in platelet aggregation by light transmittance aggregometry between treatment groups	12 weeks
Secondary	Serum TxB2	Changes in serum TxB2 between treatment groups	12 weeks
Secondary	Urine thromboxane	Changes in urine thromboxane between treatment groups	12 weeks
Secondary	Urine 8 iso prostaglandin	Changes in urine 8 iso prostaglandin between treatment groups	12 weeks
Secondary	Endothelial function by EndoPAT	Changes in endothelial function by EndoPAT (Endothelial Peripheral Arterial Tone) between treatment groups	12 weeks
Secondary	Soluble markers of circulating adhesion molecules (VCAM, ICAM).	Changes in soluble markers of circulating adhesion molecules (VCAM, and ICAM) between treatment groups	12 weeks
Secondary	hsCRP	Changes in hsCRP between treatment groups	12 weeks
Secondary	Oxidized LDL	Changes in Oxidized LDL between treatment groups	12 weeks