Clinical trial NCT01896557: Ranitidin Versus Omeprazole in Patients Taking Clopidogrel
Official title: Possible Drug Interaction Between Clopidogrel and Ranitidin or Omeprazole in Patients With Stable Coronary Heart Disease: a Comparative Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Coronary Artery Disease
Drug Interaction Potentiation
Keywords: clopidogrel
omeprazole
ranitidin
interaction
aggregability
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
Collaborators: name: InCor Heart Institute
First posted: 2013-07-11
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, After One Week of Randomized Treatment
timeFrame: One week after randomized treatment exposure (omeprazole or ranitidine)
measure: Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, Using VerifyNow Method.
timeFrame: One week after drug exposure (omeprazole/ranitidine); 2 weeks after baseline
Secondary outcomes:
Other outcomes:
measure: Comparison of the Primary Outcome With Bioimpedance Aggregometry
timeFrame: 1 week after drug exposure
measure: Comparing the Main Outcome on Pre-specified Subgroups
timeFrame: 1 week after drug exposure
measure: Comparison of the Primary Outcome With PFA-100 (Collagen/ADP Cartridge)
timeFrame: 1 week after drug exposure
Locations:
Study officials:
affiliation: Director of Acute Coronary Care Unit
name: José C Nicolau, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Furtado RHM, Giugliano RP, Strunz CMC, Filho CC, Ramires JAF, Filho RK, Neto PAL, Pereira AC, Rocha TR, Freire BT, D'Amico EA, Nicolau JC. Drug Interaction Between Clopidogrel and Ranitidine or Omeprazole in Stable Coronary Artery Disease: A Double-Blind, Double Dummy, Randomized Study. Am J Cardiovasc Drugs. 2016 Aug;16(4):275-284. doi: 10.1007/s40256-016-0172-5.