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Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE)

Primary Purpose

Coronary Artery Disease

Status

Completed

Phase

Phase 4

Locations

Canada

Study Type

Interventional

Intervention

Rosuvastatin-omeprazole

Rosuvastatin-pantoprazole

Rosuvastatin-esomeprazole

Rosuvastatin-ranitidine

Atorvastatin-omeprazole

Atorvastatin-pantoprazole

Atorvastatin-esomeprazole

Atorvastatin-ranitidine

About this trial

This is an interventional treatment trial for Coronary Artery Disease focused on measuring ranitidine, pantoprazole, esomeprazole, omeprazole, atorvastatin, rosuvastatin, statin, clopidogrel resistance, antiplatelet therapy, coronary artery disease, percutaneous coronary intervention, stent, clopidogrel, proton pump inhibitors, drug interactions, drug resistance, genetic polymorphism

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Subject must be 18 years of age or older
Bare metal stent implantation
Discharged with dual antiplatelet therapy for at least 60 days
Written informed consent

Exclusion Criteria:

Patients who do not consent to participate in the study
Premenopausal women not using contraceptive methods or without a negative pregnancy test in the past week
Patients treated or planned to be treated with oral anticoagulants
Present treatment with or clear indication for treatment with a PPI or H2 antagonists
Allergy or intolerance to study medications including ranitidine, Proton pump inhibitors, atorvastatin, rosuvastatin, aspirin and/or clopidogrel
Patient treated with a strong CYP2C19 interacting drug
History of a bleeding diathesis, or evidence of active abnormal bleeding within 30 days before enrollment
History of intracranial hemorrhage or intracranial surgery in the last 3 months
History of gastro-intestinal ulcers in the last 3 months
Any serious illness or any condition that the investigator feels would influence the impact of this therapy on the subject
Known platelet count < 100000/mm3 at time of enrollment or within 24 hours prior to enrollment

Sites / Locations

Institut Universitaire de Cardiologie et de Pneumologie de Quebec

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Active Comparator

Experimental

Active Comparator

Arm Label

Rosuvastatin-omeprazole

Rosuvastatin-pantoprazole

Rosuvastatin-esomeprazole

Rosuvastatin-ranitidine

Atorvastatin-omeprazole

Atorvastatin-pantoprazole

Atorvastatin-esomeprazole

Atorvastatin-ranitidine

Arm Description

Rosuvastatin-omeprazole

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 40 mg for 11 months

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and esomeprazole 40 mg for 11 months

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300 mg for 11 months

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40mg for 11 months

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months

Outcomes

Primary Outcome Measures

Percent change in residual platelet aggregation by light transmittance aggregometry and percent change in platelet reactivity index by VASP

Secondary Outcome Measures

Resistance to clopidogrel by light transmittance aggregometry (defined by RPA >55%), resistance to clopidogrel by vasodilator-stimulated phosphoprotein (VASP) (defined by PRI >55%)

Prevalence and role of CYP 2C19*2 polymorphism on the effect of PPIs and statins on the antiplatelet activity of clopidogrel

The composite of death from all causes, myocardial infarction, ischemia-driven repeat revascularization, and stroke

Need to stop any antiplatelet medication for gastrointestinal bleeding or peptic ulcer disease

Full Information

NCT ID

NCT00930670

First Posted

June 29, 2009

Last Updated

February 8, 2012

Sponsor

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec

1. Study Identification

Unique Protocol Identification Number

NCT00930670

Brief Title

Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects

Acronym

SPICE

Official Title

Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects

Study Type

Interventional

2. Study Status

Record Verification Date

February 2012

Overall Recruitment Status

Completed

Study Start Date

June 2009 (undefined)

Primary Completion Date

December 2011 (Actual)

Study Completion Date

December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

There is conflicting evidence in the literature suggesting that the use of proton pump inhibitors (PPIs), and/or some statins can interfere with clopidogrel antiplatelet effect and result in adverse cardiovascular outcomes in patients treated with coronary artery stents and dual antiplatelet therapy. The primary aim of the study is to determine the effect of various currently used PPI on platelet aggregation in patients undergoing percutaneous coronary intervention (PCI) and treated with dual antiplatelet therapy. The secondary aim of the study is to evaluate how statins and 2C19*2 polymorphism modulate the effect of PPI on clopidogrel efficacy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Coronary Artery Disease

Keywords

ranitidine, pantoprazole, esomeprazole, omeprazole, atorvastatin, rosuvastatin, statin, clopidogrel resistance, antiplatelet therapy, coronary artery disease, percutaneous coronary intervention, stent, clopidogrel, proton pump inhibitors, drug interactions, drug resistance, genetic polymorphism

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Factorial Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

320 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Rosuvastatin-omeprazole

Arm Type

Experimental

Arm Description

Rosuvastatin-omeprazole

Arm Title

Rosuvastatin-pantoprazole

Arm Type

Experimental

Arm Description

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 40 mg for 11 months

Arm Title

Rosuvastatin-esomeprazole

Arm Type

Experimental

Arm Description

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and esomeprazole 40 mg for 11 months

Arm Title

Rosuvastatin-ranitidine

Arm Type

Active Comparator

Arm Description

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300 mg for 11 months

Arm Title

Atorvastatin-omeprazole

Arm Type

Experimental

Arm Description

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months

Arm Title

Atorvastatin-pantoprazole

Arm Type

Experimental

Arm Description

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40mg for 11 months

Arm Title

Atorvastatin-esomeprazole

Arm Type

Experimental

Arm Description

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months

Arm Title

Atorvastatin-ranitidine

Arm Type

Active Comparator

Arm Description

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months

Intervention Type

Drug

Intervention Name(s)

Rosuvastatin-omeprazole

Intervention Description

Rosuvastatin 20 mg for 1 month. Then rosuvastatin 20mg and omeprazole 20mg for 11 months

Intervention Type

Drug

Intervention Name(s)

Rosuvastatin-pantoprazole

Intervention Description

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 40 mg for 11 months

Intervention Type

Drug

Intervention Name(s)

Rosuvastatin-esomeprazole

Intervention Description

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and esomeprazole 40 mg for 11 months

Intervention Type

Drug

Intervention Name(s)

Rosuvastatin-ranitidine

Intervention Description

Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300mg for 11 months

Intervention Type

Drug

Intervention Name(s)

Atorvastatin-omeprazole

Intervention Description

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months

Intervention Type

Drug

Intervention Name(s)

Atorvastatin-pantoprazole

Intervention Description

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40 mg for 11 months

Intervention Type

Drug

Intervention Name(s)

Atorvastatin-esomeprazole

Intervention Description

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months

Intervention Type

Drug

Intervention Name(s)

Atorvastatin-ranitidine

Intervention Description

Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months

Primary Outcome Measure Information:

Title

Percent change in residual platelet aggregation by light transmittance aggregometry and percent change in platelet reactivity index by VASP

Time Frame

At 30 and 60 days

Secondary Outcome Measure Information:

Title

Resistance to clopidogrel by light transmittance aggregometry (defined by RPA >55%), resistance to clopidogrel by vasodilator-stimulated phosphoprotein (VASP) (defined by PRI >55%)

Time Frame

30 and 60 days

Title

Prevalence and role of CYP 2C19*2 polymorphism on the effect of PPIs and statins on the antiplatelet activity of clopidogrel

Time Frame

30 and 60 days

Title

The composite of death from all causes, myocardial infarction, ischemia-driven repeat revascularization, and stroke

Time Frame

30 days, 60 days and 1 year

Title

Need to stop any antiplatelet medication for gastrointestinal bleeding or peptic ulcer disease

Time Frame

30 days, 60 days and one year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subject must be 18 years of age or older Bare metal stent implantation Discharged with dual antiplatelet therapy for at least 60 days Written informed consent Exclusion Criteria: Patients who do not consent to participate in the study Premenopausal women not using contraceptive methods or without a negative pregnancy test in the past week Patients treated or planned to be treated with oral anticoagulants Present treatment with or clear indication for treatment with a PPI or H2 antagonists Allergy or intolerance to study medications including ranitidine, Proton pump inhibitors, atorvastatin, rosuvastatin, aspirin and/or clopidogrel Patient treated with a strong CYP2C19 interacting drug History of a bleeding diathesis, or evidence of active abnormal bleeding within 30 days before enrollment History of intracranial hemorrhage or intracranial surgery in the last 3 months History of gastro-intestinal ulcers in the last 3 months Any serious illness or any condition that the investigator feels would influence the impact of this therapy on the subject Known platelet count < 100000/mm3 at time of enrollment or within 24 hours prior to enrollment

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jean-Pierre Dery, MD, MHS

Organizational Affiliation

Institut universitaire de cardiologie et de pneumologie de Québec, University Laval

Official's Role

Principal Investigator

Facility Information:

Facility Name

Institut Universitaire de Cardiologie et de Pneumologie de Quebec

City

Quebec City

State/Province

Quebec

ZIP/Postal Code

G1V4G5

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

26815196

Citation

Harvey A, Modak A, Dery U, Roy M, Rinfret S, Bertrand OF, Larose E, Rodes-Cabau J, Barbeau G, Gleeton O, Nguyen CM, Proulx G, Noel B, Roy L, Paradis JM, De Larochelliere R, Dery JP. Changes in CYP2C19 enzyme activity evaluated by the [(13)C]-pantoprazole breath test after co-administration of clopidogrel and proton pump inhibitors following percutaneous coronary intervention and correlation to platelet reactivity. J Breath Res. 2016 Jan 27;10(1):017104. doi: 10.1088/1752-7155/10/1/017104.

Results Reference

derived

Learn more about this trial

Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects

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