Ranitidin Versus Omeprazole in Patients Taking Clopidogrel

• Sponsor: University of Sao Paulo General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01896557
• Collaborator: InCor Heart Institute (Other)
• Enrollment: 92
• Arms: 2
• Duration (Months): 20

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease; Drug Interaction Potentiation	Drug: omeprazole; Drug: Ranitidine; Drug: Clopidogrel	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Possible Drug Interaction Between Clopidogrel and Ranitidin or Omeprazole in Patients With Stable Coronary Heart Disease: a Comparative Study
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

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: Peprazol Losec PPI ; 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: Ranitidine; Influence of ranitidine on clopidogrel pharmacodynamics will be evaluated.; Other Names: Antak H2 receptor blocker ; 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

Outcome Measures

Primary Outcome Measures

1. 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 randomized treatment exposure (omeprazole or ranitidine)]

   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.

2. Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, Using VerifyNow Method. [One week after drug exposure (omeprazole/ranitidine); 2 weeks after baseline]

   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.

Other Outcome Measures

1. Comparison of the Primary Outcome With Bioimpedance Aggregometry [1 week after drug exposure]

   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

2. Comparing the Main Outcome on Pre-specified Subgroups [1 week after drug exposure]

   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.

3. Comparison of the Primary Outcome With PFA-100 (Collagen/ADP Cartridge) [1 week after drug exposure]

   After 1 week of randomization to ranitidin or omeprazole, the platelet function will also be analysed by other method: PFA-100(Collagen/ADP cartridge).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• University of Sao Paulo General Hospital
• InCor Heart Institute

Investigators

• Principal Investigator: José C Nicolau, Professor, Director of Acute Coronary Care Unit

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Sao Paulo General Hospital
• ClinicalTrials.gov Identifier: NCT01896557
• Other Study ID Numbers: 0136/11
• First Posted: Jul 11, 2013
• Last Update Posted: Jul 6, 2018
• Last Verified: Oct 1, 2011

• Keywords provided by University of Sao Paulo General Hospital: clopidogrel; omeprazole; ranitidin; interaction; aggregability
• Additional relevant MeSH terms: Coronary Artery Disease; Omeprazole; Ranitidine; Ranitidine bismuth citrate; Clopidogrel; Purinergic P2Y Receptor Antagonists

Study Results

Participant Flow

Arm/Group Title	Omeprazole	Ranitidine
Arm/Group Description	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. omeprazole: Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.	Ranitidine 150 mg BID oral route was added to clopidogrel.
Period Title: Clopidogrel Alone
STARTED	44	48
COMPLETED	43	48
NOT COMPLETED	1	0
Period Title: Clopidogrel Alone
STARTED	43	48
COMPLETED	41	44
NOT COMPLETED	2	4

Baseline Characteristics

Arm/Group Title	Omeprazole	Ranitidine	Total
Arm/Group Description	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. omeprazole: Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.	Ranitidine 150 mg BID oral route was added to clopidogrel.	Total of all reporting groups
Overall Participants	44	48	92
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	24 54.5%	26 54.2%	50 54.3%
>=65 years	20 45.5%	22 45.8%	42 45.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.6 (10.9)	62.5 (8.9)	62.6 (9.9)
Sex: Female, Male (Count of Participants)
Female	11 25%	14 29.2%	25 27.2%
Male	33 75%	34 70.8%	67 72.8%

Outcome Measures

1. Primary Outcome

Title	Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, After One Week of Randomized Treatment
Description	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.
Time Frame	One week after randomized treatment exposure (omeprazole or ranitidine)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omeprazole	Ranitidine
Arm/Group Description	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. omeprazole: Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.	Ranitidine 150 mg BID oral route was added to clopidogrel.
Measure Participants	41	44
Mean (Standard Deviation) [P2Y12 Reactivity Units]	173.54 (72.28)	153.61 (70.12)

2. Primary Outcome

Title	Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, Using VerifyNow Method.
Description	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.
Time Frame	One week after drug exposure (omeprazole/ranitidine); 2 weeks after baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omeprazole	Ranitidine
Arm/Group Description	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. omeprazole: Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.	Ranitidine 150 mg BID oral route was added to clopidogrel.
Measure Participants	41	44
Mean (Standard Deviation) [Percentage]	17.4 (33.1)	30.1 (31.3)

3. Other Pre-specified Outcome

Title	Comparison of the Primary Outcome With Bioimpedance Aggregometry
Description	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
Time Frame	1 week after drug exposure

Outcome Measure Data

Analysis Population Description

Platelet aggregation was measured after one week of randomized treatment therapy

Arm/Group Title	Omeprazole	Ranitidine
Arm/Group Description	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. omeprazole: Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.	Ranitidine 150 mg BID oral route was added to clopidogrel.
Measure Participants	41	44
Mean (Standard Deviation) [Ohms]	2 (2.55)	2.77 (3.84)

4. Other Pre-specified Outcome

Title	Comparing the Main Outcome on Pre-specified Subgroups
Description	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.
Time Frame	1 week after drug exposure

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Comparison of the Primary Outcome With PFA-100 (Collagen/ADP Cartridge)
Description	After 1 week of randomization to ranitidin or omeprazole, the platelet function will also be analysed by other method: PFA-100(Collagen/ADP cartridge).
Time Frame	1 week after drug exposure

Outcome Measure Data

Analysis Population Description

Platelet aggregation by PFA-100 was measured after one week of randomized treatment therapy

Arm/Group Title	Omeprazole	Ranitidine
Arm/Group Description	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. omeprazole: Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.	Ranitidine 150 mg BID oral route was added to clopidogrel.
Measure Participants	33	36
Mean (Standard Deviation) [seconds]	95.1 (46.2)	97.2 (79)

Adverse Events

Arm/Group Title	Omeprazole		Ranitidine
Arm/Group Description	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. omeprazole: Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.		Ranitidine 150 mg BID oral route was added to clopidogrel.
All Cause Mortality
	Omeprazole		Ranitidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Omeprazole		Ranitidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/48 (0%)
Other (Not Including Serious) Adverse Events
	Omeprazole		Ranitidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/44 (2.3%)		0/48 (0%)
Gastrointestinal disorders
Dyspepsia	1/44 (2.3%)	1	0/48 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.