Cardiovascular and Gastrointestinal Outcomes in Clopidogrel Users on Proton Pump Inhibitors: Results of a Large Dutch Cohort Study 소화기 내과 R1 박지윤 Ofke S. van Boxel, MD 1, Martijn G.H. van Oijen, PhD 1, 2, Matthijs P. Hagenaars 3, A.J.P.M. Smout, PhD 1, Peter D. Siersema, MD, PhD 1 Am J Gastroenetology August 24, 2010

Inhibiting platelet aggregation - decrease first and recurrent events of stroke, MI, unstable angina Clopidogrel - inhibits platelet activation by adenosine diphosphate - biotransformation to active metabolite by cytochrome P450 enzymes, including CYP2C19 Increased incidence of GI bleeding events in using clopidogrel - American College of Cardiology guidelines : prophylactic PPI in pt with risk factors INTRODUCTION

Recent studies - PPI reduce antiplatelet effects of clopidogrel interaction by CYP2C19 Two retrospective cohort studies from the US and Canada - clopidogrel with PPI increased risk of rehospitalization for ACS O ’ Donoghue et al. analyzed a subgroup of the TRITON TIMI-38 trial - concurrent use of PPIs  not attenuate efficacy of clopidogrel

Data source Anonymized computerized databases of two Dutch health insurance companies Clopidogrel & PPI use Retrospective cohort study from 1 January 2006 to 31 December 2007 Clopidogrel user : prescription for clopidogrel 1 January December 2007 PPI user : minimum of 80 % overlap between PPI and clopidogrel use PPI type : omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole METHOD

Covariate Age, Gender Use of anti-hypertensive medication, cholesterol lowering drugs, aspirin, NASIDs, anti-coagulants Drugs known to be involved in GI complications : SSRI, steroids, selective cyclooxygenase-2 inhibitors History of heart failure, MI, CVD(hemorrhagic or ischemic stroke, transient ischemic attack), COPD, CRF, DM with complications, PUD

Baseline characteristics of clopidogrel use with and without concurrent PPI use RESULT vsBaseline characteristics of clopidogrel use with and without concurrent PPI use

Association between Clopidogrel + PPI use & Adverse outcomes Event – free survival (P<0.0001)

Association between PPI types & Adverse outcomes

Occurrence of cardiovascular events - higher than by Juurlink et al : 8.7 % Vs 5.7 %  explained by differences in the definition of the primary outcome ex) Juurlink et al. : died or readmission for MI - lower than by Ho et al. : 8.7 % Vs 26.5 %  explained by patient selection from Veterans Health Administration O ’ Donoghue et al - patients having severe comorbidity were excluded  study population healthier than this study DISCUSSION

No difference between PPI types in outcome of cardiovascular events - remains unclear because not assessed under identical condition PPI users more likely to use concomitant medication & more comorbidity  Clopidogrel + PPI users have inferior cardiovascular risk profile Increase incidence of PUD in clopidogrel users + PPIs - PPIs prescribed to higher GI risk patient

Strengths First European cohort study investigating association between concomitant use of clopidogrel and PPIs & cardiovascular events First investigation of occurrence of GI events Database covering a large proportion (approximately 25 % ) of Dutch population Retrospective study  both physicians and patients was not affected by being observed

Limitations Over-the-counter medications cannot be accounted Incidence of uncomplicated PUD underestimated :diagnostic test for ulcer is patient an physician dependent

New clopidogrel users taking PPIs concurrently are at an increased risk of both cardiovascular and GI complications, including all cause death when compared with those not using a PPI. The inferior cardiovascular profile of clopidogrel users on PPIs and the occurrence of channeling bias may be important factors underlying this observation CONCLUSION