ppi and antiplatelet therapy thienopyridines 质子泵抑制剂与抗血小板药

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 Benefits and Risks


• 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

Clopidogrel and Proton Pump Inhibitors

Shrestha K. et al. Qual Prim Care. 2011;19(1):35-42


• 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


2008 Expert Consensus

ACCF/ACG/AHA 2008 Expert Consensus Document on

Reducing the GI Risks of Antiplatelet Therapy and NSAID Use


• 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


Potential adverse interaction

2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines

JACC Vol. 56, No. 24, 2010


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).


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.


The 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.


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.


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


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


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.


2010 Expert Consensus （ 1 ）


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.




JACC Vol. 56, No. 24, 2010

• Platelet function testing

– Really reflect the clinical events?

• Pharmacogenomic testing

– CYP2C19, high cost

– no practical and no feasibility


Individualed TEST

• Clinical observational studies : interactions yes

• A single randomized clinical trial (RCT): interactions No




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.

François Voltaire 伏尔泰 1694 – 1778


ppi and antiplatelet therapy thienopyridines 质子泵抑制剂与抗血小板药

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