Antiplatelet therapy has proven efficacy in reducing the incidence of cerebrovascular accidents and myocardial infarctions in patients with known atherosclerotic cardiovascular disease and in patients at increased risk for such events.1 Clopidogrel can be prescribed as monotherapy in patients with contraindications to aspirin (ASA) therapy or in patients with ASA resistance. Dual antiplatelet therapy with ASA in combination with clopidogrel is commonly used in patients with a recent acute coronary syndrome (ACS) or after coronary revascularization procedures (percutaneous coronary intervention or coronary artery bypass grafting).2,3 Combination therapy with clopidogrel is especially important in patients having received coronary stents. The American College of Cardiology/American Heart Association recommends that a medication should be prescribed to minimize the risk of gastrointestinal (GI) bleeding in patients receiving antiplatelet therapy with a history of GI bleeding.4
A study by Ho and colleagues in 2009 evaluated all-cause mortality and rehospitalization for ACS in patients concomitantly using clopidogrel and a proton-pump inhibitor (PPI).5 Of the PPIs, the drug prescribed in 60% of the patients was omeprazole, followed by rabeprazole with 2.9% of the prescriptions. Approximately 37% were prescribed more than one type of PPI during follow-up. This combination therapy was associated with increased adverse outcomes. The findings were thought to be mechanistic, resulting from competitive inhibition of CYP2C19 of clopidogrel by omeprazole. A warning was issued for Plavix® (clopidogrel) stating that “Co-administration of Plavix® with omeprazole, a PPI that is an inhibitor of CYP2C19, reduces the pharmacologic activity of Plavix® if given concomitantly…”
Ray and colleagues performed a retrospective cohort study of 20,596 patients who had been hospitalized for acute myocardial infarction (AMI), coronary artery revascularization, or unstable angina pectoris from January 1, 1999, to December 31, 2005, and were prescribed clopidogrel.6 The authors studied the effects of concurrent PPI use compared with nonusers on the risk of serious gastroduodenal bleeding (defined as “a hospital admission with diagnostic and procedure codes compatible with bleeding at a gastroduodenal site by using validated diagnostic codes”) and serious cardiovascular disease (defined as “AMI, sudden cardiac death, nonfatal or fatal stroke, or other cardiovascular death”).
Of the patients currently taking clopidogrel, 13,003 were not using PPI initially and 7593 had concurrent PPI use. The PPI prescribed most was pantoprazole (62%). Only 9% were taking omeprazole. Users of PPIs were more likely to be women. Additionally, these patients had more cardiovascular and GI disease, as well as being on medications that increased their risk of bleeding. In the primary outcome for gastroduodenal bleeding, patients that were not using PPIs had 12.2 hospitalizations for bleeding per 1000 person-years of follow-up as compared with 6.1 for concurrent users of “any” PPI. These numbers were reduced to 5.6 hospitalizations for bleeding per 1000 person-years of follow-up for pantoprazole-specific users.
For patients that were not taking PPIs, their risk of bleeding was stratified by the presence of recognized risk factors; age ≥ 65 years old, history of admission for upper GI disease or bleeding, recent use of anticoagulant, current use of any other medications that ...