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

• 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 ] [ Designated as safety issue: No ]
• 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 ] [ Designated as safety issue: No ]
• The composite of death from all causes, myocardial infarction, ischemia-driven repeat revascularization, and stroke [ Time Frame: 30 days, 60 days and 1 year ] [ Designated as safety issue: No ]
• Need to stop any antiplatelet medication for gastrointestinal bleeding or peptic ulcer disease [ Time Frame: 30 days, 60 days and one year ] [ Designated as safety issue: Yes ]

• Resistance to clopidogrel by light transmittance aggregometry (defined by RPA >55%), resistance to clopidogrel by VASP (defined by PRI >55%) [ Time Frame: 30 and 60 days ] [ Designated as safety issue: No ]
• 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 ] [ Designated as safety issue: No ]
• The composite of death from all causes, myocardial infarction, ischemia-driven repeat revascularization, and stroke [ Time Frame: 30 days, 60 days and 1 year ] [ Designated as safety issue: No ]
• Need to stop any antiplatelet medication for gastrointestinal bleeding or peptic ulcer disease [ Time Frame: 30 days, 60 days and one year ] [ Designated as safety issue: Yes ]

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.

• Drug: Rosuvastatin-omeprazole
  Rosuvastatin 20 mg for 1 month. Then rosuvastatin 20mg and omeprazole 20mg for 11 months
• Drug: Rosuvastatin-pantoprazole
  Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 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
• Drug: Rosuvastatin-ranitidine
  Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300mg for 11 months
• Drug: Atorvastatin-omeprazole
  Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months
• Drug: Atorvastatin-pantoprazole
  Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40 mg for 11 months
• Drug: Atorvastatin-esomeprazole
  Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months
• Drug: Atorvastatin-ranitidine
  Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months

• Experimental: Rosuvastatin-omeprazole
  Rosuvastatin-omeprazole
  Intervention: Drug: Rosuvastatin-omeprazole
• Experimental: Rosuvastatin-pantoprazole
  Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and pantoprazole 40 mg for 11 months
  Intervention: Drug: Rosuvastatin-pantoprazole
• Experimental: Rosuvastatin-esomeprazole
  Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and esomeprazole 40 mg for 11 months
  Intervention: Drug: Rosuvastatin-esomeprazole
• Active Comparator: Rosuvastatin-ranitidine
  Rosuvastatin 20 mg for 1 month, then rosuvastatin 20 mg and ranitidine 300 mg for 11 months
  Intervention: Drug: Rosuvastatin-ranitidine
• Experimental: Atorvastatin-omeprazole
  Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and omeprazole 20 mg for 11 months
  Intervention: Drug: Atorvastatin-omeprazole
• Experimental: Atorvastatin-pantoprazole
  Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and pantoprazole 40mg for 11 months
  Intervention: Drug: Atorvastatin-pantoprazole
• Experimental: Atorvastatin-esomeprazole
  Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and esomeprazole 40 mg for 11 months
  Intervention: Drug: Atorvastatin-esomeprazole
• Active Comparator: Atorvastatin-ranitidine
  Atorvastatin 80mg for 1 month, then atorvastatin 80 mg and ranitidine 300mg for 11 months
  Intervention: Drug: Atorvastatin-ranitidine

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