Avoid Coadministration of PPI & Clopidogrel (Plavix)? To be or not to be? That is the question! 黃以信 Yi-Shin Huang, MD, FACG 台北榮民總醫院胃腸科醫師國立陽明大學醫學院教授

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1 Avoid Coadministration of PPI & Clopidogrel (Plavix)? To be or not to be? That is the question! 黃以信 Yi-Shin Huang, MD, FACG 台北榮民總醫院胃腸科醫師國立陽明大學醫學院教授

2 A story of drug interaction: PPI vs. clopidogrel GI meets CV

3 楔子 :Metabolism of clopidogrel Courtesy of Micromedex

4 Drug interaction of PPI & clopidogrel (Plavix) The anti-platelet effect of clopidogrel depends on CYP2C19, to be active metabolites. Many drugs, esp. PPI, can competitively inhibit CYP2C19. Absorption of clopidogrel is increased in an acidic environment. PPIs can decrease acidity and may diminish its absorption. Concomitant use of clopidogrel and PPI may decrease the therapeutic effect of clopidogrel and increase the cardiovascular events.

5 始作俑者 Inhibition effects of PPI on CYP450: In vitro test (Sweden) Drug Metabolism and Disposition 2004;32:

6 Inhibition effects of PPI on CYP450: In vitro test (Sweden) Drug Metabolism and Disposition 2004;32:

7 Inhibition effects of PPI on CYP450: In vitro test (Sweden) The five PPIs (omeprazole, esomeprozole, lansoprazole, pantoprazole and rabeprazole) showed competitive inhibition of CYP2C19 in the in vitro human liver microsomes or recombinant CYP2C19 system. Lansoprazole and pantoprazole are the most potent inhibitor of CYP2C19 and CYP2C9, respectively. Drug Metabolism and Disposition 2004;32:

8 戰火開始 First clinical ex vivo study (French) J Am Coll Cardiol 2008;51:

9 First clinical ex vivo study (French) J Am Coll Cardiol 2008;51:

10 Nested case control study (Canada) CMAJ 2009;180:713-8.

11 Nested case control study (Canada) CMAJ 2009;180:713-8.

12 Nested case control study (Canada) Pantoprazole did not show significant increase in heart attacks. Esomeprazole was not included in the study. CMAJ 2009;180:713-8.

13 Metabolic Pathways of PPIs and Their Cytochrome P450 (CYP) Isoforms Involved 5-O-Desmethyl-omeprazole CYP2C19 CYP2C19 Omeprazole 3-Hydroxy-omeprazole CYP3A4 CYP3A4 CYP2C19 Lansoprazole CYP3A4 5-Hydroxy-omeprazole Omeprazole sulphone Hydroxy-lansoprazole Lansoprazole sulphone CYP3A4 CYP2C19 Demethylatedrabeprazole Omeprazole hydroxysulphone Rabeprazole CYP3A4 Rabeprazole Sulphone CYP2C19 nonenzymatic Rabeprazole thioether Pantoprazole CYP2C19 CYP3A4 Dealkylated metabolite Pantoprazole sulphone Pantoprazole sulfate sulfotransferase Arrows indicate approximate contribution of CYP isoforms to each of the metabolic pathways. Ishizaki, T. and Horai, Y. : Aliment. Pharmacol Ther. 13 (Suppl.3), (1999)

14 倖免於難? 硝煙四起!? Pantoprazole did not show significant increase in heart attacks. Esomeprazole was not included in the study. CMAJ 2009;180:713-8.

15 山姆叔叔的呼應 Retrospective cohort study (USA) JAMA 2009;301:

16 Retrospective cohort study (USA) JAMA 2009;301:

17 Retrospective cohort study (USA) JAMA 2009;301:

18 Retrospective cohort study (USA) Concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI. 59.7% ompeprazole, 2.9% rabeprozole, 0.4% lansoprazole, 0.2% pantoprazole, 36.7% more than 1 OR: omeprazole: 1.24; rabeprazole: The association of lansoprazole and pantoprazole was not explored due to small size. Esomeprazole was not included in the study. JAMA 2009;301:

19 CYP2C19 polymorphism and response to Plavix (TRITON-TIMI38 TIMI38 study, USA) Adobe Acrobat 7.0 Document N Engl J Med 2009;360:

20 CYP2C19 polymorphism and response to Plavix (TRITON-TIMI38 TIMI38 study, USA) CYP2C19*2: 681G>A CYP2C19*3: 636G>A Adobe Acrobat 7.0 Document N Engl J Med 2009;360:

21 CYP2C19 polymorphism and response to Plavix (TRITON-TIMI38 TIMI38 study, USA) Adobe Acrobat 7.0 Document N Engl J Med 2009;360:

22 CYP2C19 polymorphism and response to Plavix (TRITON-TIMI38 TIMI38 study, USA) Primary efficacy outcome: death from cardiovascular cause, myocardial infarction, or stroke. N Engl J Med 2009;360:

23 CYP2C19 polymorphism and response to Plavix (TRITON-TIMI38 TIMI38 study, USA) Secondary outcome: stent thrombosis. N Engl J Med 2009;360:

24 國人無法倖免 High frequency of PMs of CYP2C19 in Asians Asian homem hetem 35% 50% PM 15% White homem 70~75% hetem 20% PM 2-5% homem (homozygous extensive metabolizer) : Fast hetem (heterozygous extensive metabolizer) : Intermediate PM (poor metabolizer) : Slow

25 捉隊廝殺 Prospective ex vivo study (Austria) In 300 CAD patients with PCI Responsiveness to clopidogrel: 1. Vasodilator-stimulated phosphoprotein phosphorylation (VASP) 2. Aggregometry Am Heart J 2009;157:148.e1-148.e5.

26 Prospective ex vivo study (Austria) Am Heart J 2009;157:148.e1-148.e5.

27 Meta-analysis analysis

28 Concomitant use of clopidogrel and PPIs or cimetidine after AMI would increase the risk of re-infarction (Kaohsiung, Taiwan) From: 健保局歸人檔資料庫 Am J Gastroenterol 2009; 104:

29 Drug interaction of PPI & clopidogrel and prasugrel Lancet 2009; 374:

30 翻案? PRINCIPLE-TIMI 44 & TRITON-TIMI TIMI 38 trials: RCT clopidogrel vs prasugrel (USA) ,608 CAD patients with PCI Lancet 2009, 374:

31 PRINCIPLE-TIMI 44 & TRITON-TIMI TIMI 38 trials: RCT clopidogrel vs prasugrel (USA) Lancet 2009, 374:

32 PRINCIPLE-TIMI 44 & TRITON-TIMI TIMI 38 trials: RCT clopidogrel vs prasugrel (USA) 6 hrs after loading dose 15 days after maintain dose Lancet 2009, 374:

33 PRINCIPLE-TIMI 44 & TRITON-TIMI TIMI 38 trials: RCT clopidogrel vs prasugrel (USA)

34 PRINCIPLE-TIMI 44 & TRITON-TIMI TIMI 38 trials: RCT clopidogrel vs prasugrel (USA) Lancet 2009, 374:

35 PRINCIPLE-TIMI 44 & TRITON-TIMI TIMI 38 trials: RCT clopidogrel vs prasugrel (USA) Lancet 2009, 374:

36 PRINCIPLE-TIMI 44 & TRITON-TIMI TIMI 38 trials: RCT clopidogrel vs prasugrel (USA) This study does not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel. Only a randomized trial of PPI use can definitively establish the clinical implications of combining a PPI with a thienopyridine. Lancet 2009, 374:

37 撲朔迷離 Risk of combining PPIs with thienopyridines: fact or fiction? The interaction is a fact in terms of pharmacodynamics. This interaction seems to be a fiction in clinical outcome. Patients can safely be treated with a PPI on top of their thienopyridine. However, caution is needed when prescribing PPIs for selected high-risk patients with an intrinsically reduced response to thienopyridines. Comment from Lancet 2009; 374:

38 又一個來踢館 Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial A phase 3 RCT: compare CGT-2168 (75 mg clopidogrel + 20 mg omeprazole combination) to clopidogrel Primary endpoint: GI events Secondary endpoints: CV events (MI, revascularization) This study has been halted due to bankruptcy of Cogentius Pharmaceuticals.

39 COGENT Trial-Results 3627 patients (above the initial target of 3200) 393 sites Median follow-up 133 days (maximum 362 days) 136 adjudicated CV events 105 adjudicated GI events Transcatheter Cardiovascular Therapeutics (TCT) meeting San Francisco, Sept 24, 2009.

40 COGENT Trial: CV events

41 COGENT Trial: GI events

42 Concerns in decision-making Less impact in Taiwan due to restrict prescription of PPI Increased incidence of GI bleeding if DC PPI Given 12 hours apart still have drug interaction Not recommended: replace PPI with cimetidine Wait for the powerful anti-platelet: prasugrel Pharmacogenetic screen for high risk patients

43 Position statement from FDA (2/6/2009) FDA has not reached a conclusion. Change label in clopidrogrel: add the impact of CYP2C19 variant alleles on PK, PD and clinical response, and drug interaction with PPIs. Neither mandates genetic testing nor offers specific dosing guidance.

44 Position statement from EMEA (5/29/2009) Product information for all clopidogrel should be amended to discourage concomitant use of PPI and clopidogrel unless absolutely necessary.

45 Position from T-FDAT (7/10/2009) ADR committee for this issue. No report case of this drug-interaction to date. Close monitor the interaction between PPI and Plavix. Add drug interaction information to label of clopidogrel, but not for all PPIs. Rebut safety claim about pantoprazole in clopidogrel.

46 行政院衛生署 公告 發文日期 : 中華民國 98 年 11 月 19 日 主旨 : 公告 Clopidogrel 類藥品仿單應加刊警語 含 Clopidogrel 成分藥品會與氫離子幫浦抑制劑 (proton pump inhbitor,ppis) 產生交互作用, 因此病人併用該二類藥品可能增加病人心血管血栓及心血管疾病再發風險, 經本署再評估含 Clopidogrel 藥品與 PPIs 藥品併用之風險效益後, 含 Clopidogrel 成分藥品仿單應加刊警語, 內容如下 : clopidogrel 為一種 pro-drug, 須於體內經 CYP2C19 酶代謝成活性代謝物以達到預防凝血的作用 而氫離子幫浦抑制劑 (proton pump inhbitor,ppis) 是用於治療消化性潰瘍與胃食道逆流性疾病的藥物, 這一類之藥物可能會抑制 CYP2C19 酶之活性, 而減少 clopidogrel 轉換成活性代謝物, 進而影響其療效 已有臨床試驗顯示, 病人併用 clopidogrel 與 PPIs 可能會增加心血管血栓與心血管疾病再發之風險 因此, 除非必要否則應避免合併使用該二類藥品 倘若臨床醫療需併用該二類藥品時, 亦應經臨床醫師審慎評估病人之風險效益

47 Position statement from FDA (11/17/2009) The concomitant use of omeprazole (or esomeprazole), cimetidine and clopidogrel should be avoided. Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction. Consider other H2 blocker: ranitidine, famotidine and nizatidine..

48 Take Home Message The anti-platelet effect of clopidogrel depends on CYP2C19, to be active metabolites. PPI can competitively inhibit CYP2C19 activity. PPIs and CYP2C19 genetic polymorphism may interact the anti-platelet effect of clopidogrel. Some retrospective or ex-vivo studies shows concomitant use of PPIs and clopidrogrel have adverse impacts on CV outcomes. Although 2 latest prospective studies rebut PPI in increasing CV risk, co-administration of PPI (esp. omeprazole & esomeprazole) and clopidogrel should be avoided unless absolutely necessary.

49 故事完了嗎