Recurrence of Acute Myocardial Infarction in Patients Discharged on Clopidogrel and a Proton Pump Inhibitor After Stent Placement for Acute Myocardial Infarction

Abstract

Background: The purpose of this study was to determine the readmission rate for acute myocardial infarction (AMI) in patients discharged on clopidogrel and a proton-pump inhibitor (PPI) versus patients discharged on clopidogrel alone after experiencing an AMI and undergoing stent placement. Clopidogrel is a prodrug that requires metabolism in the liver by the cytochrome P450 system (CYP450), in particular cytochrome P450 2C19 (CYP2C19).1 Recent studies have suggested that medications metabolized by CYP450, such as PPIs, influence the effect of clopidogrel on platelet function 2,3 with an increased risk of cardiovascular events. 4,5 PPIs are often administered with clopidogrel due to the increased bleeding risk of dual antiplatelet therapy, a strategy endorsed by existing consensus guidelines.6Hypothesis: Treatment with a PPI in combination with clopidogrel would increase the risk of readmission for an AMI after stent placement for AMI. Methods: We collected data on all patients discharged on clopidogrel after stent placement for an AMI between January 2003 and January 2008. Patients were followed for 1 year after their index hospitalization for readmission for an AMI. Rates of readmission were determined for those discharged on clopidogrel alone versus those discharged on clopidogrel and a PPI.Results: Patients discharged on clopidogrel and a PPI had higher rates of readmission for AMI within 1 year of stent implantation for AMI. Conclusions: Patients discharged on clopidogrel and a PPI, including esomeprazole and pantoprazole, seem to be at an increased risk of recurrent AMI within 1 year after stent placement for an AMI. IntroductionClopidogrel is a prodrug that is metabolized to its active metabolite by the cytochrome P450 enzyme system. Protom pump inhibitors (PPIs) are frequently prescribed in combination with clopidogrel to help reduce the risk of gastrointestinal bleeding. Several recent studies have suggested that many PPIs, especially those that undergo extensive metabolism by the cytochrome P450 2C19 system such as omeprazole, may diminish the antiplatelet effects and clinical effectiveness of clopidogrel. In contrast, other reports have not found any association between the use of PPIs in combination with clopidogrel and an increased risk of adverse cardiovascular outcomes. Therefore, we sought to assess the association between PPI and clopidogrel combination therapy after stent placement for an AMI and recurrent AMI.

Recent Safety Concerns With Proton Pump Inhibitors

“…As shown in Table 3, there is inconsistency among these studies' conclusions. Twenty found a statistically significant association of PPI use and worse CV outcomes in patients on clopidogrel [2][3][4][5]60,[62][63][64]66,68,69,71,74,77,78,82,[85][86][87][88] ; of the other 15, one did not report the level of statistical significance, 84 and 14 found no evidence of an association. 6,7,38,39,57,58,65,70,76,[79][80][81]83,89 Eight systematic reviews published within 2010 have examined this association, 28,90-96 and 5 have attempted a meta-analysis of the results (Table 4).…”

“…Table 3 summarizes 41 studies that assessed whether coadministration of 1 or more PPIs affects clinical outcomes in patients on clopidogrel. [2][3][4][5][6][7]38,39, Only 2 were randomized controlled trials (RCTs), 39,58 another 2 were posthoc analyses of data from previous RCTs that had been designed to address a different question, 39,58 [2][3][4][5][6][7]38,39,57,58,60,[62][63][64][65][66][68][69][70][71]74,[76][77][78][79][80][81][82][83][84][85][86][87][88][89]. As shown in Table 3, there is inconsistency among these studies' conclusions.…”

Clopidogrel Resistance: Identifying and Overcoming a Barrier to Effective Antiplatelet Treatment

“…However, in a stratified analysis, pantoprazole, which does not inhibit CYP2C19, was not associated with readmission (adjusted OR: 1.02; 95%CI = 0.70–1.47); the adjusted OR for other PPIs was 1.40 (95%CI = 1.10–1.77). Other studies have revealed that esomeprazole [37] and omeprazole [31] are associated with adverse outcomes of clopidogrel therapy, likely because of their potent inhibition of CYP2C19 [38]. Interestingly, in the COGENT randomized controlled study [38] of patients with ACS or undergoing placement of a coronary stent, there was no difference in the effects of a fixed‐dose combination of clopidogrel (75 mg) with omeprazole (20 mg) or clopidogrel alone (both groups also used aspirin at 75–325 mg/day) on the cardiovascular endpoint (a composite of cardiovascular death, nonfatal MI, CABG or PCI or ischemic stroke; HR = 1.02, 95%CI = 0.70–1.51).…”

Role of Antiplatelet Therapy in Secondary Prevention of Acute Coronary Syndrome

“…After 1 month, omeprazole group had significantly more nonresponders according VASP assay than pantoprazole group (44% vs. 23%; p<0.05). However, clinical impact of this interaction was unclear and has been evaluated in number of observational studies with often conflicting conclusion [69][70][71][72]. The only randomized controlled trial assessing the clinical impact of this interaction was the COGENT trial [73].…”