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
Proton Pump Inhibitors on Marketing
• 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
Great success to control Acid related diseases in the past 2 decades
- NV-UGIB, Peptic Ulcer,GERD, etc.
解放军总医院消化病中心
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
Clopidogrel and Proton Pump Inhibitors
• 791 residents studied
The Prevalence of Co-administration
– 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.
Shrestha K. et al. Qual Prim Care. 2011;19(1):35-42
解放军总医院消化病中心
2008 Expert Consensus
• 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.
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
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
Metabolism of clopidogrel and PPI
解放军总医院消化病中心
Metabolism
clopidogrel and PPI
Metabolism of 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).
Fock KM et al. Clin Pharmacokinet 2008; 47: 1-6
解放军总医院消化病中心
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.
The data from the manufacturer of clopidogrel
解放军总医院消化病中心
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
H2 receptor 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
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
Alternative antiplatelet therapy
• 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
2010 Expert Consensus（1）
• 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.
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
2010 Expert Consensus（2）
• 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.
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
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
2010 Expert Consensus（3）
• Clinical observational studies : interactions
yes
• A single randomized clinical trial (RCT): interactions No
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
解放军总医院消化病中心
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