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

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Rosuvastatin-omeprazole; Drug: Rosuvastatin-pantoprazole; Drug: Rosuvastatin-esomeprazole; Drug: Rosuvastatin-ranitidine; Drug: Atorvastatin-omeprazole; Drug: Atorvastatin-pantoprazole; Drug: Atorvastatin-esomeprazole; Drug: Atorvastatin-ranitidine

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Quebec City, Quebec, Canada, G1V4G5
      • Institut Universitaire de cardiologie et de pneumologie de Quebec

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rosuvastatin-omeprazole	Drug: Rosuvastatin-omeprazole; Rosuvastatin 20 mg for 1 month. Then rosuvastatin 20mg and omeprazole 20mg for 11 months
Experimental: Rosuvastatin-pantoprazole; Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 40 mg for 11 months	Drug: Rosuvastatin-pantoprazole; Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 40 mg for 11 months
Experimental: Rosuvastatin-esomeprazole; Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and esomeprazole 40 mg for 11 months	Drug: Rosuvastatin-esomeprazole; Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and esomeprazole 40 mg for 11 months
Active Comparator: Rosuvastatin-ranitidine; Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300 mg for 11 months	Drug: Rosuvastatin-ranitidine; Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300mg for 11 months
Experimental: Atorvastatin-omeprazole; Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months	Drug: Atorvastatin-omeprazole; Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months
Experimental: Atorvastatin-pantoprazole; Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40mg for 11 months	Drug: Atorvastatin-pantoprazole; Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40 mg for 11 months
Experimental: Atorvastatin-esomeprazole; Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months	Drug: Atorvastatin-esomeprazole; Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months
Active Comparator: Atorvastatin-ranitidine; Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months	Drug: Atorvastatin-ranitidine; Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent change in residual platelet aggregation by light transmittance aggregometry and percent change in platelet reactivity index by VASP	At 30 and 60 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Resistance to clopidogrel by light transmittance aggregometry (defined by RPA >55%), resistance to clopidogrel by vasodilator-stimulated phosphoprotein (VASP) (defined by PRI >55%)	30 and 60 days
Prevalence and role of CYP 2C19*2 polymorphism on the effect of PPIs and statins on the antiplatelet activity of clopidogrel	30 and 60 days
The composite of death from all causes, myocardial infarction, ischemia-driven repeat revascularization, and stroke	30 days, 60 days and 1 year
Need to stop any antiplatelet medication for gastrointestinal bleeding or peptic ulcer disease	30 days, 60 days and one year

Collaborators and Investigators

• Sponsor: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec
• Investigators: Principal Investigator: Jean-Pierre Dery, MD, MHS, Institut universitaire de cardiologie et de pneumologie de Québec, University Laval

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: June 29, 2009
• First Submitted That Met QC Criteria: June 29, 2009
• First Posted (Estimate): June 30, 2009

Study Record Updates

• Last Update Posted (Estimate): February 9, 2012
• Last Update Submitted That Met QC Criteria: February 8, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: percutaneous coronary intervention; coronary artery disease; stent; clopidogrel; drug resistance; esomeprazole; omeprazole; atorvastatin; rosuvastatin; drug interactions; statin; antiplatelet therapy; genetic polymorphism; pantoprazole; proton pump inhibitors; clopidogrel resistance; ranitidine
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Gastrointestinal Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; Histamine Antagonists; Histamine Agents; Histamine H2 Antagonists; Atorvastatin; Rosuvastatin Calcium; Omeprazole; Ranitidine; Ranitidine bismuth citrate; Esomeprazole; Pantoprazole
• Other Study ID Numbers: SPICE