Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects

Study Overview
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Brief Summary
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There is conflicting evidence in the literature suggesting that the use of proton pump inhibitors (PPIs), and/or some statins can interfere with clopidogrel antiplatelet effect and result in adverse cardiovascular outcomes in patients treated with coronary artery stents and dual antiplatelet therapy. The primary aim of the study is to determine the effect of various currently used PPI on platelet aggregation in patients undergoing percutaneous coronary intervention (PCI) and treated with dual antiplatelet therapy. The secondary aim of the study is to evaluate how statins and 2C19*2 polymorphism modulate the effect of PPI on clopidogrel efficacy.

Official Title
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Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Rosuvastatin-omeprazole
* Drug: Rosuvastatin-pantoprazole
* Drug: Rosuvastatin-esomeprazole
* Drug: Rosuvastatin-ranitidine
* Drug: Atorvastatin-omeprazole
* Drug: Atorvastatin-pantoprazole
* Drug: Atorvastatin-esomeprazole
* Drug: Atorvastatin-ranitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be 18 years of age or older Bare metal stent implantation Discharged with dual antiplatelet therapy for at least 60 days Written informed consent Exclusion Criteria: Patients who do not consent to participate in the study Premenopausal women not using contraceptive methods or without a negative pregnancy test in the past week Patients treated or planned to be treated with oral anticoagulants Present treatment with or clear indication for treatment with a PPI or H2 antagonists Allergy or intolerance to study medications including ranitidine, Proton pump inhibitors, atorvastatin, rosuvastatin, aspirin and/or clopidogrel Patient treated with a strong CYP2C19 interacting drug History of a bleeding diathesis, or evidence of active abnormal bleeding within 30 days before enrollment History of intracranial hemorrhage or intracranial surgery in the last 3 months History of gastro-intestinal ulcers in the last 3 months Any serious illness or any condition that the investigator feels would influence the impact of this therapy on the subject Known platelet count < 100000/mm3 at time of enrollment or within 24 hours prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rosuvastatin-omeprazole<br>Rosuvastatin-omeprazole | Drug: Rosuvastatin-omeprazole<br>* Rosuvastatin 20 mg for 1 month. Then rosuvastatin 20mg and omeprazole 20mg for 11 months<br>|
| Experimental: Rosuvastatin-pantoprazole<br>Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 40 mg for 11 months | Drug: Rosuvastatin-pantoprazole<br>* Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 40 mg for 11 months<br>|
| Experimental: Rosuvastatin-esomeprazole<br>Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and esomeprazole 40 mg for 11 months | Drug: Rosuvastatin-esomeprazole<br>* Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and esomeprazole 40 mg for 11 months<br>|
| Active Comparator: Rosuvastatin-ranitidine<br>Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300 mg for 11 months | Drug: Rosuvastatin-ranitidine<br>* Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300mg for 11 months<br>|
| Experimental: Atorvastatin-omeprazole<br>Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months | Drug: Atorvastatin-omeprazole<br>* Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months<br>|
| Experimental: Atorvastatin-pantoprazole<br>Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40mg for 11 months | Drug: Atorvastatin-pantoprazole<br>* Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40 mg for 11 months<br>|
| Experimental: Atorvastatin-esomeprazole<br>Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months | Drug: Atorvastatin-esomeprazole<br>* Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months<br>|
| Active Comparator: Atorvastatin-ranitidine<br>Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months | Drug: Atorvastatin-ranitidine<br>* Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in residual platelet aggregation by light transmittance aggregometry and percent change in platelet reactivity index by VASP |  | At 30 and 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resistance to clopidogrel by light transmittance aggregometry (defined by RPA >55%), resistance to clopidogrel by vasodilator-stimulated phosphoprotein (VASP) (defined by PRI >55%) |  | 30 and 60 days | 
| Prevalence and role of CYP 2C19*2 polymorphism on the effect of PPIs and statins on the antiplatelet activity of clopidogrel |  | 30 and 60 days | 
| The composite of death from all causes, myocardial infarction, ischemia-driven repeat revascularization, and stroke |  | 30 days, 60 days and 1 year | 
| Need to stop any antiplatelet medication for gastrointestinal bleeding or peptic ulcer disease |  | 30 days, 60 days and one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ranitidine, pantoprazole, esomeprazole, omeprazole, atorvastatin, rosuvastatin, statin, clopidogrel resistance, antiplatelet therapy, coronary artery disease, percutaneous coronary intervention, stent, clopidogrel, proton pump inhibitors, drug interactions, drug resistance, genetic polymorphism