质子泵抑制剂与抗血小板药

Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,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,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,Proton Pump Inhibitors on Marketing,解放军总医院消化病中心,Great success to control Acid related diseases in the past 2 decades,- NV-UGIB, Peptic,Ulcer,GERD, etc.,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.,Balance between B,enefits and Risks,解放军总医院消化病中心,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.,The Prevalence of Co-administration,C,lopidogrel,and Proton Pump Inhibitors,Shrestha,K.,et al,.,Qual Prim Care. 2011;19(1):35-42,解放军总医院消化病中心,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.,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,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,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,解放军总医院消化病中心,Potential adverse interaction,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,Metabolism of,clopidogrel,and PPI,Metabolism of,PPIs,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,Metabolism of,clopidogrel,and PPI,Fock,KM et al.,Clin,Pharmacokinet,2008; 47: 1-6,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,T,he data from the manufacturer of,clopidogrel,Effect of PPI on the metabolite levels of,clopidogrel,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,FDA alert in 2009 11,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,H2,receptor blockers,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,Alternative PPI,Pantoprazole,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,解放军总医院消化病中心,Alternative,antiplatelet,therapy,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,2010 Expert Consensus,（,1,）,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,2010 Expert Consensus,（,2,）,2010 Expert Consensus Document on the Concomitant Use of,PPIs,and,Thienopyridines,JACC Vol. 56, No. 24, 2010,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,Individualed,TEST,C,linical observational studies : interactions yes,A single randomized clinical trial (RCT): interactions No,解放军总医院消化病中心,2010 Expert Consensus,（,3,）,2010 Expert Consensus Document on the Concomitant Use of,PPIs,and,Thienopyridines,JACC Vol. 56, No. 24, 2010,A clinically important interaction cannot be excluded,particularly in certain subgroups, such as poor,metabolizers,of,clopidogrel,.,Individualized treatment,Inconsistent effects on CV outcomes of concomitant use of,thienopyridines,and,PPIs,.,A physician is one who pours drugs of which he knows little into a body of which he knows less.,Franois Voltaire ,伏尔泰,1694 1778,解放军总医院消化病中心,