Ranitidin Versus Omeprazole in Patients Taking Clopidogrel

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

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Drug Interaction Potentiation
• Intervention / Treatment: Drug: omeprazole; Drug: Clopidogrel; Drug: Ranitidine

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.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: omeprazole; 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; Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.; Other Names: PPI; Losec; Peprazol; Drug: Clopidogrel; 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; Other Names: Plavix; ADP receptor blocker
Experimental: ranitidine; Ranitidine 150 mg (oral route) twice a day will be given to the subjects for one week.	Drug: Clopidogrel; 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; Other Names: Plavix; ADP receptor blocker; Drug: Ranitidine; Influence of ranitidine on clopidogrel pharmacodynamics will be evaluated.; Other Names: Antak; H2 receptor blocker

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the Primary Outcome With Bioimpedance Aggregometry	After 1 week of randomization to ranitidin or omeprazole, the platelet function will also be analysed by other method: bioimpedance aggregometry with ADP 10 mcM as reagent	1 week after drug exposure
Comparing the Main Outcome on Pre-specified Subgroups	The main outcome will be compared on pre-specified subgroups: elderly (age > 65 yrs-old) versus non-elderly; male versus female; smoking versus non-smoking patients; obese (BMI > 30 kg/m2) versus non-obese; diabetic versus non-diabetic; patients in use or not in use of statins; presence or not of genetic polymorphisms on cytochrome 2C19.	1 week after drug exposure
Comparison of the Primary Outcome With PFA-100 (Collagen/ADP Cartridge)	After 1 week of randomization to ranitidin or omeprazole, the platelet function will also be analysed by other method: PFA-100(Collagen/ADP cartridge).	1 week after drug exposure

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Collaborators: InCor Heart Institute
• Investigators: Principal Investigator: José C Nicolau, Professor, Director of Acute Coronary Care Unit

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: June 19, 2013
• First Submitted That Met QC Criteria: July 10, 2013
• First Posted (Estimate): July 11, 2013

Study Record Updates

• Last Update Posted (Actual): July 6, 2018
• Last Update Submitted That Met QC Criteria: July 5, 2018
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: clopidogrel; omeprazole; interaction; aggregability; ranitidin
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Histamine Antagonists; Histamine Agents; Histamine H2 Antagonists; Clopidogrel; Omeprazole; Ranitidine; Ranitidine bismuth citrate; Purinergic P2Y Receptor Antagonists
• Other Study ID Numbers: 0136/11