Coronary Artery Disease, Drug Interaction Potentiation
Conditions
Keywords
clopidogrel, omeprazole, ranitidin, interaction, aggregability
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.
Interventions
DRUGomeprazole
Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated.
DRUGRanitidine
Influence of ranitidine on clopidogrel pharmacodynamics will be evaluated.
DRUGClopidogrel
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
Sponsors
InCor Heart Institute
University of Sao Paulo General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
omeprazole: Influence of omeprazole on clopidogrel pharmacodynamics will be evaluated. | 44 |
| Ranitidine Ranitidine 150 mg BID oral route was added to clopidogrel. | 48 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Clopidogrel Alone | Adverse Event | 1 | 0 |
| Clopidogrel + GI Protector | low adherence | 1 | 1 |
| Clopidogrel + GI Protector | Reading error | 1 | 3 |
Baseline characteristics
| Characteristic | Omeprazole | Ranitidine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 20 Participants | 22 Participants | 42 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 26 Participants | 50 Participants |
| Age, Continuous | 62.6 years STANDARD_DEVIATION 10.9 | 62.5 years STANDARD_DEVIATION 8.9 | 62.6 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 11 Participants | 14 Participants | 25 Participants |
| Sex: Female, Male Male | 33 Participants | 34 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 44 | 0 / 48 |
| serious Total, serious adverse events | 0 / 44 | 0 / 48 |
Outcome results
Primary
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.
Time frame: One week after randomized treatment exposure (omeprazole or ranitidine)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omeprazole | Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, After One Week of Randomized Treatment | 173.54 P2Y12 Reactivity Units | Standard Deviation 72.28 |
| Ranitidine | Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, After One Week of Randomized Treatment | 153.61 P2Y12 Reactivity Units | Standard Deviation 70.12 |
Primary
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.
Time frame: One week after drug exposure (omeprazole/ranitidine); 2 weeks after baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omeprazole | Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, Using VerifyNow Method. | 17.4 Percentage | Standard Deviation 33.1 |
| Ranitidine | Comparing Platelet Function of Patients on Dual Antiplatelet Therapy With ASA + Clopidogrel, Between the Groups Ranitidin and Omeprazole, Using VerifyNow Method. | 30.1 Percentage | Standard Deviation 31.3 |
Other Pre-specified
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.
Time frame: 1 week after drug exposure
Other Pre-specified
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
Time frame: 1 week after drug exposure
Population: Platelet aggregation was measured after one week of randomized treatment therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omeprazole | Comparison of the Primary Outcome With Bioimpedance Aggregometry | 2 Ohms | Standard Deviation 2.55 |
| Ranitidine | Comparison of the Primary Outcome With Bioimpedance Aggregometry | 2.77 Ohms | Standard Deviation 3.84 |
Other Pre-specified
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).
Time frame: 1 week after drug exposure
Population: Platelet aggregation by PFA-100 was measured after one week of randomized treatment therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omeprazole | Comparison of the Primary Outcome With PFA-100 (Collagen/ADP Cartridge) | 95.1 seconds | Standard Deviation 46.2 |
| Ranitidine | Comparison of the Primary Outcome With PFA-100 (Collagen/ADP Cartridge) | 97.2 seconds | Standard Deviation 79 |