PPI and Antiplatelet Therapy Thienopyridines 质子泵抑制剂与抗血小板药

1. PPI and Antiplatelet Therapy Thienopyridines 质子泵抑制剂与抗血小板药 杨云生 Yunsheng Yang M.D.& Ph.D. 解放军总医院消化病中心 Digestive Disease Center DDC. Chinese PLA General Hospital

2. Proton Pump Inhibitors on Marketing Great success to control Acid related diseases in the past 2 decades - NV-UGIB, Peptic Ulcer,GERD, etc. Omeprazole 奥美拉唑 1988 Lansoprazole 兰索拉唑 1991 Pantoprazole 泮托拉唑 1994 Ilaprazole 艾普拉唑 1998 Rabeprazole 雷贝拉唑 1999 Esomeprazole 埃索美拉唑 2000 Dexlansoprazole 右旋兰索拉唑 2009 解放军总医院消化病中心

3. Balance between Benefits and Risks • The potential benefits of antiplatelet therapy for atherosclerotic cardiovascular (CV) disease have been amply demonstrated over the past 20 years, especially thienopyridine drugs in preventing stent thrombosis. • Antiplatelet agents increase the risk of bleeding associated with mucosal breaks in the upper and lower gastrointestinal (GI) tract. • Rational use of thienopyridines is based on weighing their risks against their benefits. 解放军总医院消化病中心

4. The Prevalence of Co-administration Clopidogrel and Proton Pump Inhibitors Shrestha K. et al. Qual Prim Care. 2011;19(1):35-42 791 residents studied • 60 were prescribed clopidogrel • 248 were on aspirin • 326 were prescribed a PPI. Among residents who were prescribed PPIs • 155 were prescribed omeprazole; 72 pantoprazole • 51 rabeprazole ;44 esomeprazole ;15 lansoprazole. 39 residents took a combination of clopidogrel and a PPI (any PPI) for a mean 203 days. 9 residents took the combination of clopidogrel, aspirin and a PPI (any PPI) for a mean of 173 days. 解放军总医院消化病中心

5. 2008 Expert Consensus ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the GI Risks of Antiplatelet Therapy and NSAID Use Oral antiplatelet therapy may increase bleeding complications, the largest proportion due to GI hemorrhage. Gastroprotection strategies consist of use of PPIs in patients at high risk of GI bleeding. 解放军总医院消化病中心

6. 2008 Expert Consensus ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the GI Risks of Antiplatelet Therapy and NSAID Use 解放军总医院消化病中心

7. Potential adverse interaction • Many investigations of potential adverse interaction has been conducted recently • Evidence of a possible adverse drug interaction between PPIs and thienopyridines has emerged • It has been difficult for physicians including cardiologists, gastroenterologists and all practioners • How to treat our patients with both kinds of drugs 2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines JACC Vol. 56, No. 24, 2010 解放军总医院消化病中心

8. Metabolism of clopidogrel and PPI 解放军总医院消化病中心

9. Metabolism of PPIs Metabolism of clopidogrel and PPI Fock KM et al. Clin Pharmacokinet 2008; 47: 1-6 All PPIs are hepatically metabolized to an extent via the cytochrome P450 mixed oxidase system. The isoenzymes CYP3A4, particularly CYP2C19 are the major isoforms that cause PPI biotransformation. The relative contribution of CYP2C19 pathway differs among drugs and has been reported to be omeprazole = esomeprazole > pantoprazole > lansoprazole > rabeprazole in general metabolism In contrast to the situation with clopidogrel, reduced CYP2C19 function results in less inactivation of PPI and an increase in pharmacodynamic effect (greater acid inhibition). 解放军总医院消化病中心

10. The data from the manufacturer of clopidogrel Effect of PPI on the metabolite levels of clopidogrel A reduction in active metabolite levels of about 45% was found in people who received clopidogrel with omeprazole compared to those taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in people receiving clopidogrel and omeprazole together. 解放军总医院消化病中心

11. FDA alert in 2009 11 The concomitant use of omeprazole and clopidogrel should be avoided Other drugs that should be avoided in combination with clopidogrel because they may have a similar interaction include: esomeprazole, cimetidine, fluconazole, etc. 解放军总医院消化病中心

12. H2receptor blockers Except cimetidine No evidence that other drugs reduce stomach acid, • H2 blockers • ranitidine (Zantac) • famotidine (Pepcid) • nizatidine (Axid) • (Tagamet and Tagamet HB - a CYP2C19 inhibitor) • antacids interfere with the anti-clotting activity of clopidogrel. 解放军总医院消化病中心

13. Alternative PPI Pantoprazole Pantoprazole is less potent than omeprazole to inhibit CYP2C19 and does not appear to attenuate the pharmacodynamic response to clopidogrel Pantoprazole had no association with recurrent MI in a large population-based, case-control study of patients receiving clopidogrel 解放军总医院消化病中心

14. 噻吩吡啶类抗血小板药包括普拉格雷、替卡格雷.噻吩吡啶类抗血小板药包括普拉格雷、替卡格雷. 普拉格雷（prasugrel） 通过细胞色素P450系统代谢（包括CYP3A、 CYP2B6、CYP2C9和CYP2C19）活化 CYP2C19不是其主要代谢途径。 尚未在我国上市 替卡格雷（ticagrelor） 替卡格雷通过CYP3A4代谢 不受CYP2C19变异的影响 尚未在美国及我国上市 Alternative antiplatelet therapy 解放军总医院消化病中心

15. 2010 Expert Consensus（1） 2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines JACC Vol. 56, No. 24, 2010 Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding. Use of a PPI or histamine H2 receptor antagonist (H2RA) reduces the risk of upper GI bleeding compared with no therapy. PPIs reduce upper GI bleeding to a greater degree than do H2RAs. 解放军总医院消化病中心

16. 2010 Expert Consensus（2） 2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines JACC Vol. 56, No. 24, 2010 Pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints, suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel. The strongest evidence for an interaction is between omeprazole and clopidogrel. 解放军总医院消化病中心

17. Individualed TEST Platelet function testing • Really reflect the clinical events? Pharmacogenomic testing • CYP2C19, high cost • no practical and no feasibility 解放军总医院消化病中心

18. 2010 Expert Consensus（3） Inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs. A clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel. Individualized treatment 2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines JACC Vol. 56, No. 24, 2010 Clinical observational studies : interactions yes A single randomized clinical trial (RCT): interactions No 解放军总医院消化病中心

19. A physician is one who pours drugs of which he knows little into a body of which he knows less. François Voltaire  伏尔泰1694 – 1778 解放军总医院消化病中心