Effectiveness and Safety of Clopidogrel Co‐administered With Statins and Proton Pump Inhibitors: A Korean National Health Insurance Database Study

Abstract

Simultaneous competition for cytochrome P450 (CYP) 2C19 and CYP3A4 might diminish clopidogrel's antiplatelet effect by impacting its metabolic activation. This pharmacoepidemiologic study investigated whether proton pump inhibitors (PPIs) and CYP3A4-metabolized statins individually and jointly increase thrombotic events by attenuating clopidogrel's effectiveness. From Korean nationwide claims data (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015), we selected 59,233 patients who initiated clopidogrel and statins after coronary stenting and compared thrombotic risks by PPI or CYP3A4metabolized statin use or both. PPIs were associated with increased thrombotic risks (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45), unlike CYP3A4-metabolized statins (HR 1.03, 95% CI 0.98-1.07). PPIs with high CYP2C19-inhibitory potential were more relevant than those with low potential (HR 1.28, 95% CI 1.02-1.61). Joint effects of PPIs and CYP3A4-metabolized statins were nonsignificant (relative excess risk due to interaction −0.14, 95% CI −0.34 to 0.07). Concurrent PPIs were associated with increased thrombotic risks in patients receiving clopidogrel and statins; CYP3A4-metabolized statins did not exacerbate PPI-associated risks.Antiplatelet therapy is the cornerstone of treatment in patients with acute coronary syndrome (ACS), especially following percutaneous coronary intervention (PCI) with stenting. According to several large randomized clinical trials (RCTs), clopidogrel, the most widely used antiplatelet agent administered with aspirin, is beneficial in reducing ischemic complications. 1-4 However, in clinical settings in which factors affecting the response to clopidogrel are not well controlled, the recurrence of ischemic complications is observed in a considerable number of patients despite clopidogrel therapy. This observation is considered attributable to a Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Proton pump inhibitors (PPIs) and cytochrome P450 (CYP) 3A4-metabolized statins affect clopidogrel conversion into an active metabolite, although clinical implications are disputed. The joint effects of administering PPIs and CYP3A4-metabolized statins with clopidogrel have been rarely studied. WHAT QUESTION DID THIS STUDY ADDRESS? We assessed the potential for additional risks associated with simultaneously administering PPI and CYP3A4-metabolized statins in combination with clopidogrel, in addition to the independent effects of PPI and CYP3A4-metabolized statins on clopidogrel. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? PPI co administration with clopidogrel and statin was associated with increased risks for major thrombotic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention with stenting but CYP3A4-metabolized statin did not synergistically exacerbate PPI-associated risks. HOW MIGHT THIS CHANGE CLINICAL PHARMA COLOGY OR TRANSLATIONAL SCIENCE? The results suggest that PPI co administration should be avoided in patients with ACS recei...

2020 Korean Society of Myocardial Infarction Expert Consensus Document on Pharmacotherapy for Acute Myocardial Infarction

“… 50) From the Korean nationwide claims data (2007–2015; n=59,233), PPIs were associated with increased thrombotic risks (HR, 1.27; 95% CI, 1.12–1.45); PPIs with high CYP2C19-inhibitory potential (omeprazole, esomeprazole, and lansoprazole) were more relevant than those with low potential (HR, 1.28; 95% CI, 1.02–1.61). 72) There were no randomized data comparing use vs. non-use of PPIs in patients with coronary artery disease receiving prasugrel or ticagrelor in addition to aspirin. However, the risk of GI bleeding was higher with DAPT in the form of prasugrel or ticagrelor compared with clopidogrel.…”

Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects

“…The number of PPI users increased 10.6 times over 12 years, and the prescription rate of atorvastatin generally increased over 13 years ( Kim et al, 2018 ; Son and Bae, 2019 ). PPIs and HMG-CoA reductase inhibitors are frequently co-administered with clopidogrel in Korea ( Kim et al, 2019 ). The frequency of co-administering PPIs and atorvastatin would increase over time, and thus it is necessary to evaluate the drug interactions between P-CABs and atorvastatin.…”