Ranitidin Versus Omeprazole in Patients Taking Clopidogrel

Study Overview
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Brief Summary
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Previous reports have shown a possible drug interaction between clopidogrel and proton pump inhibitors (PPI´s), which could result in increased number of adverse cardiovascular events among patients on dual antiplatelet therapy(DAPT). Because of this, ranitidin has been proposed as an alternative drug to PPI´s for prophylaxis of gastrointestinal bleeding in patients who need DAPT. The study´s aim is to test the hypothesis that ranitidin doesn´t have any influence on clopidogrel pharmacodynamic.

Detailed Description
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Study population: 100 patients with Stable Coronary Artery Disease from Heart Institute Inclusion Criteria: Age > 18 years old Coronary artery disease, defined as previous myocardial infarction and/or coronary angioplasty and/or Coronary Artery Bypass Graft (CABG) surgery and/or coronariography showing obstruction of at least 50 % in one of major epicardial vessels Treatment with Acetylsalicylic Acid (ASA) 100 mg/day Exclusion Criteria: Use in the last 7 days of oral anticoagulant or any other antiplatelet drug beside ASA Previous utilization of PPI or ranitidine in the last 7 days before randomization Active bleeding Pregnancy or woman of childbearing age without contraceptive method Hemoglobin < 10 g/dL or hematocrit < 30 %, hematocrit > 50 %, platelets < 100.000/mm3 or > 500.000/mm3; creatinin clearance < 50 ml/minute Percutaneous coronary intervention (PCI) on the last 30 days before randomization (or PCI on the last year when drug-eluted stents are used); CABG surgery on the last 90 days; acute coronary syndrome on the last 60 days Active malignant neoplasm Active peptic ulcer disease on the last 60 days or upper gastrointestinal bleeding any time in life Known allergy to the drugs clopidogrel, ranitidine or omeprazole Refuse to participate in the study] Methodology: The study has a double-blind, double-dummy prospective design. Clopidogrel action is evaluated by platelet function tests: VerifyNow, bioimpedance aggregometry and Platelet Function Analyzer-100 (PFA-100). The patients have measurements of platelet function on three moments: before starting clopidogrel; 1 week after DAPT with clopidogrel (without loading dose) plus ASA; and after 1 week of randomization to ranitidin 150 mg bid or omeprazole 20 mg bid.

Official Title
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Possible Drug Interaction Between Clopidogrel and Ranitidin or Omeprazole in Patients With Stable Coronary Heart Disease: a Comparative Study

Conditions
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Coronary Artery Disease, Drug Interaction Potentiation

Intervention / Treatment
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* Drug: omeprazole
* Drug: Ranitidine
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years old Coronary artery disease, defined as previous myocardial infarction and/or coronary angioplasty and/or CABG surgery and/or coronariography showing obstruction of at least 50 % in one of major epicardial vessels Treatment with Acetylsalicylic Acid (ASA) 100 mg/day Exclusion Criteria: Use on the last 7 days of any other antiplatelet drug beside ASA or oral anticoagulant Previous utilization of PPI or ranitidine in the last 7 days before randomization Any active bleeding Pregnancy or woman of childbearing age without contraceptive method Hemoglobin < 10 g/dL or hematocrit < 30 %, hematocrit > 50 %, platelets < 100.000/mm3 or > 500.000/mm3; creatinin clearance < 50 ml/minute Percutaneous coronary intervention (PCI) on the last 30 days before randomization (or PCI on the last year when drug-eluted stents are used); CABG surgery on the last 90 days; acute coronary syndrome on the last 60 days Active malignant neoplasm Active peptic ulcer disease on the last 60 days or upper gastrointestinal bleeding any time in life Known allergy to the drugs clopidogrel, ranitidine or omeprazole Refuse to participate in the study

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: omeprazole<br>Omeprazole 20 mg (oral route) twice a day will be given to the subjects for one week. This intervention will be compared with ranitidin 150 mg (oral route) twice a day. | Drug: omeprazole<br>* Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.<br>* Other names: PPI;Drug: Clopidogrel<br>* Clopidogrel added to ASA therapy at the first medical visit, Open label 75 mg once a day will be given to all individuals as part of the protocol (since main outcome of interest is clopidogrel effect. Actual comparison arms are double blind ranitidine and omeprazole<br>* Other names: ADP receptor blocker;|
| Experimental: ranitidine<br>Ranitidine 150 mg (oral route) twice a day will be given to the subjects for one week. | Drug: Ranitidine<br>* Influence of ranitidine on clopidogrel pharmacodynamics will be evaluated.<br>* Other names: H2 receptor blocker;Drug: Clopidogrel<br>* Clopidogrel added to ASA therapy at the first medical visit, Open label 75 mg once a day will be given to all individuals as part of the protocol (since main outcome of interest is clopidogrel effect. Actual comparison arms are double blind ranitidine and omeprazole<br>* Other names: ADP receptor blocker;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, After One Week of Randomized Treatment | One week after starting double-blind, double-dummy, randomized therapy with ranitidin or omeprazole on patients treated with DAPT, platelet function will be compared with the method VerifyNow, in P2Y12 Reactivity Units. | One week after randomized treatment exposure (omeprazole or ranitidine) | 
| Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, Using VerifyNow Method. | One week after starting double-blind, double-dummy, randomized therapy with ranitidin or omeprazole on patients treated with DAPT, platelet function will be compared with the method VerifyNow, in percent Inhibition of Platelet Aggregation (IPA) from baseline. IPA was calculated as the percent change in aggregability from baseline, with the formula IPA = (on-treatment aggregability minus baseline aggregability)/baseline aggregability. Since baseline aggregation is always, per definition, equal or more than on-treatment aggregation, there is no possibility that this number might be negative. | One week after drug exposure (omeprazole/ranitidine); 2 weeks after baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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clopidogrel, omeprazole, ranitidin, interaction, aggregability