Safety of Clopidogrel-Proton Pump Inhibitors Combination Therapy on Cardiovascular Events: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

KUANG Jieyun ^1,2 , TAN Jie ¹ ,  ZOU Jianjun ¹ , CHEN Shaoliang ³

1. Department of Pharmacy, China Pharmaceutical University Jiangning Campus, Nanjing 211198 ,China;2. Department of Clinical Pharmacology Base, NanJing First Hospital of NanJing Medical University, Nanjing 210006, China;3. Department of Cardiology, NanJing First Hospital of NanJing Medical University, Nanjing 210006, China;

Corresponding author：

ZOU Jianjun, Email: zoujianjun100@126.com

Keywords：

Clopidogrel; Proton pump inhibitor; Cardiovascular event; Gastrointestinal bleeding; Systematic review; Meta-analysis

DOI：

10.7507/1672-2531.20110048

Video：

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Objective　 To perform a systematic review on the safety (i.g. cardiovascular, mortality and gastrointestinal bleeding) of clopidogrel versus clopidogrel combined with proton pump inhibitors (PPIs) for the patients with coronary heart disease.
Methods 　Such databases as The Cochrane Library, PubMed, EMbase, SSCI, VIP, CNKI, and CBM were searched from the date of their establishment to September 2010. The bibliographies of the retrieved articles were also checked. The data was extracted and evaluated by two reviewers independently. The RevMan 5.0 software was used for meta-analyses.
Results 　A total of 29 studies were included. The results of meta-analyses showed that the use of clopidogrel combined with PPIs was associated with increasing the risk of cardiovascular events (RR=1.27, 95%CI 1.09 to 1.47), as well as myocardial infarction (RR=1.45, 95% CI 1.20 to 1.76), total mortality (RR=1.23, 95%CI 1.06 to 1.43), and rethrombosis (RR=1.37, 95%CI 1.01 to 1.86). However, there was no enough evidence to reach the conclusion that the combination use could benefit the situation of gastrointestinal bleeding (RR=0.84, 95%CI 0.47 to 1.50).
Conclusion? Compared with clopidogrel, the combination use of clopidogrel and PPIs increases cardiovascular events, mortality, and the risks of myocardial infarction and rethrombosis. However, more clinical studies are required to assess the effect of reducing gastrointestinal bleeding.

Citation： KUANG Jieyun,TAN Jie,ZOU Jianjun,CHEN Shaoliang. Safety of Clopidogrel-Proton Pump Inhibitors Combination Therapy on Cardiovascular Events: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2011, 11(3): 283-291. doi: 10.7507/1672-2531.20110048 Copy

1.	3 Rude MK, Chey WD. Proton-pump inhibitors, clopidogrel and cardiovascular adverse events: fact, fiction or something in between? Gastroenterology , 2009, 137: 1168-1171.
2.	张勇, 余长永, 邹建军, 等. 质子泵抑制剂对氯吡格雷作用机制及临床研究进展. 世界华人消化杂志, 2010, 18(1): 75-80.
3.	Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC) [2009-11-17] http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm.
4.	Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? Lancet , 2009, 374: 952-954.
5.	Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther , 2010, 31, 810-823.
6.	Higgins JPT, Green S(editors). Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]; Section 8. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
7.	Higgins JPT, Green S, editors. Assessment of study quality. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]; Section 6. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd.
8.	Higgins JP, Thompson SG, Deeks JJ. Measuring inconsistency in meta analyses. BMJ , 2003, 327: 557-560.
9.	Evanchan J, Donnally MR, Binkley P, et al . Recurrence of acute myocardial infarction in patients discharged on clopidogrel and a proton pump inhibitor after stent placement for acute myocardial infarction. Clin Cardiol , 2010, 33(3): 168-171.
10.	Gupta E, Bansal D, Sotos J, et al . Risk of adverse clinical outcomes with concomitant use of clopidogrel and proton pump inhibitors following percutaneous coronary intervention. Dig Dis Sci , 2010, 55(7): 1964-1968.
11.	Ho PM, Maddox TM, Wang L, et al . Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA , 2010, 301(9): 937-944.
12.	Kreutz RP, Stanek EJ, Aubert R, et al . Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: the clopidogrel medco outcomes study. Pharmacotherapy , 2010, 30(8): 787-796.
13.	Rassen JA, Choudhry NK, Avorn J, et al . Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation , 2009, 120(23): 2322-2329.
14.	Hsiao FY, Tsai YW, Huang WF, et al . A comparison of aspirin and clopidogrel with or without proton pump inhibitors for the secondary prevention of cardiovascular events in patients at high risk for gastrointestinal bleeding. Clin Ther , 2009, 31(9): 2038-2047.
15.	Huang CC, Chen YC, Leu HB, et al . Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention. Am J Cardiol , 2010, 105(12): 1705-1709.
16.	Ray WA, Murray KT, Griffin MR, et al . Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med , 2010, 152(6): 337-345.
17.	Stockl KM, Le L, Zkharyan A, et al . Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med , 2010, 170(8): 704-710.
18.	Banerjee S, Varghese C, Weideman R, et al . P653: proton pump inhibitors increase the risk of major adverse cardiovascular events in post-PCI patients who are on clopidogrel. Eur Heart J , 2009, 30(Abstract Supplement): 92.
19.	Bhatt DL, Cryer B, Contant CF, et al . I In: COGENT: A prospective, randomized, placebo- controlled trial of omeprazole in patients receiving aspirin and clopidogrel. Transvascular Cardiovascular Therapeutics Annual Meeting, (TCT); September 24; San Fransico, CA.; 2009.
20.	advers Ching G, Li D, McKay M, et al . Abstract 4324: pump proton inhibitors increase major cardiovascular events among post-percutaneous coronary intervention patients on clopidogrel. Circulation , 2009, 120: S936-937.
21.	Dunn SP, Macaulay TE, Brennan DM, et al . Abstract 3999: baseline proton pump inhibitors use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation , 2008, 118: S815.
22.	Gaspar A, Ribeiro S, Naibas S, et al . P2679: proton pump inhibitors in patients treated with aspirin and clopidogrel. Eur Heart J , 2009, 30(Abstract Supplement): 444.
23.	Hall NL, Mathews KD, May HT, et al . Abstract 997: cardiovascular risk associated with concurrent proton pump inhibitor and clopidogrel therapy: how much? How specific? Circulation , 2009, 120: S422-a.
24.	Jarai R, Brosovic I, Tentzeris I, et al . P675: effect of proton pump inhibitors on outcome of patients discharged on dual-antiplatelet therapy after percutaneous coronary intervention and stent implantation. Eur Heart J , 2009, 30 (Abstract Supplement): 98.
25.	O’Donoghue ML, Braunwalk E, Antman EM, et al . Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomized trials. Lancet , 2009, 374: 989-997.
26.	Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol , 2008, 52: 1038-1039.
27.	Ramirez JF, Selzer F, Chakaprani R, et al . Proton pump inhibitor and clopidogrel combination is not associated with adverse clinical outcomes after PCI: the NHLBI dynamic registry. JACC , 2009, 53(Suppl.1): A27.
28.	Sarafoff N, Sibbing D, Sonntag U, et al . P894: higher stent thrombosis rate after coronary stenting in patients on dula antiplatelet treatment and concomitant treatment with proton pump inhibitors. Eur Heart J , 2009, 30 (Abstract Supplement): 150.
29.	Simon T, Verstuyft C, Mary-Krause M, et al . Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med , 2009, 360: 363-375.
30.	Simon T, Quandealle PH, Machcourt J, et al . P2121: proton pump inhibitors and clopidogrel response on the cardiovascular major events in patients after acute myocardial infarction. Data from the FAST-MI registry of the French society of cardiology. Eur Heart J , 2009, 30(Abstract Supplement): 335.
31.	Sweeny JM, Kini A, Muntner P, et al . Abstract 4323: mortality associated with proton pump inhibitors following percutaneous coronary interventions with drug eluting stents. Circulation , 2009, 120: S936.
32.	Torgusen R, Chou C, Kaneshige K, et al . Abstract 4542: does proton pump inhibitor use following percutaneous coronary intervention with drug-eluting stents impact clinical outcomes? Circulation , 2009, 120: S968.
33.	Yasuda H, Yamada M, Sawada S, et al . Upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy after coronary stenting. Inter Med , 2009, 48: 1725-1730.
34.	Zairis M, Patsourakos N, Makrygiannis S, et al . The impact of oral proton pump inhibitors on the effectiveness of combined aspirin and clopidogrel drug therapy during the first year after elective coronary stenting. Eur Heart J , 2008, 29(Abstract Supplement): 134.
35.	Van Boxel OS, Van Oijen MG, Hagenaars MP, et al . Cardiovascular and Gastrointestinal Outcomes in Clopidogrel Users on Proton Pump Inhibitors: Results of a Large Dutch Cohort Study. Am J Gastroenterol, 2010 Aug 24 [Epub ahead of print].
36.	Luinstra M, Naunton M, Peterson GM, et al . PPI use in patients commenced on clopidogrel: a retrospective cross-sectional evaluation. J Clin Pharm Ther , 2010, 35(2): 213-217.
37.	Gaglia MJ, Torguson R, Hanna N, et al . Relation of proton pump inhibitor use after percutaneous coronary intervention with drug-eluting stents to outcomes. Am J Cardiol , 2010, 105(6): 833-838.
38.	Savi P, Pereillo JM, Uzabiaga MF, et al . Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost , 2000, 84: 891-896.
39.	Kim KA, Park PW, Hong SJ, et al . The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther , 2008, 84: 236-242.
40.	Mega JL, Close SL, Wiviott SD, et al . Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med , 2009, 360: 354-362.
41.	Li XQ, Andersson TB, Ahlstrom M, et al . Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos , 2004, 32: 821-827.
42.	Gilard M, Arnaud B, Cornily JC, et al . Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol , 2008, 51: 256-260.
43.	Aubert RE, Epstein RS, Teagarden JR, et al . Abstract 3998: Proton pump inhibitors effect on clopidogrel effectiveness: the Clopidogrel Medco Outcomes Study. Circulation , 2008, 118: S-815.
44.	Tsai YW, Wen YW, Huang WF, et al . Cardiovascular and gastrointestinal events of three antiplatelet therapies: clopidogrel, clopidogrel plus proton-pump inhibitors, and aspirin plus proton-pump inhibitors in patients with previous gastrointestinal bleeding. J Gastroenterol, 2010 Sep 2 [Epub ahead of print].
45.	钟益钢, 王宁夫. 不同的质子泵抑制剂与氯吡格雷相互作用的研究进展. 心血管病学进展, 2010, 31(2): 276-279.
46.	Wu CY, Chan FK, Wu MS, et al . Histamine-2-receptor antagonist are an alternative to proton pump inhibitor in patients receiving clopidogrel. Gastroenterology , 2010, 139(4): 1165-1171.
47.	Kenngott S, Olze R, Kollmer M, et al . Gross MClopidogrel and proton pump inhibitor (PPI) interaction: separate intake and a non-omeprazole PPI the solution? Eur J Med Res , 2010, 15(5):220-224.

1. 3 Rude MK, Chey WD. Proton-pump inhibitors, clopidogrel and cardiovascular adverse events: fact, fiction or something in between? Gastroenterology , 2009, 137: 1168-1171.
2. 张勇, 余长永, 邹建军, 等. 质子泵抑制剂对氯吡格雷作用机制及临床研究进展. 世界华人消化杂志, 2010, 18(1): 75-80.
3. Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC) [2009-11-17] http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm.
4. Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? Lancet , 2009, 374: 952-954.
5. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther , 2010, 31, 810-823.
6. Higgins JPT, Green S(editors). Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]; Section 8. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
7. Higgins JPT, Green S, editors. Assessment of study quality. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]; Section 6. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd.
8. Higgins JP, Thompson SG, Deeks JJ. Measuring inconsistency in meta analyses. BMJ , 2003, 327: 557-560.
9. Evanchan J, Donnally MR, Binkley P, et al . Recurrence of acute myocardial infarction in patients discharged on clopidogrel and a proton pump inhibitor after stent placement for acute myocardial infarction. Clin Cardiol , 2010, 33(3): 168-171.
10. Gupta E, Bansal D, Sotos J, et al . Risk of adverse clinical outcomes with concomitant use of clopidogrel and proton pump inhibitors following percutaneous coronary intervention. Dig Dis Sci , 2010, 55(7): 1964-1968.
11. Ho PM, Maddox TM, Wang L, et al . Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA , 2010, 301(9): 937-944.
12. Kreutz RP, Stanek EJ, Aubert R, et al . Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: the clopidogrel medco outcomes study. Pharmacotherapy , 2010, 30(8): 787-796.
13. Rassen JA, Choudhry NK, Avorn J, et al . Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation , 2009, 120(23): 2322-2329.
14. Hsiao FY, Tsai YW, Huang WF, et al . A comparison of aspirin and clopidogrel with or without proton pump inhibitors for the secondary prevention of cardiovascular events in patients at high risk for gastrointestinal bleeding. Clin Ther , 2009, 31(9): 2038-2047.
15. Huang CC, Chen YC, Leu HB, et al . Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention. Am J Cardiol , 2010, 105(12): 1705-1709.
16. Ray WA, Murray KT, Griffin MR, et al . Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med , 2010, 152(6): 337-345.
17. Stockl KM, Le L, Zkharyan A, et al . Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med , 2010, 170(8): 704-710.
18. Banerjee S, Varghese C, Weideman R, et al . P653: proton pump inhibitors increase the risk of major adverse cardiovascular events in post-PCI patients who are on clopidogrel. Eur Heart J , 2009, 30(Abstract Supplement): 92.
19. Bhatt DL, Cryer B, Contant CF, et al . I In: COGENT: A prospective, randomized, placebo- controlled trial of omeprazole in patients receiving aspirin and clopidogrel. Transvascular Cardiovascular Therapeutics Annual Meeting, (TCT); September 24; San Fransico, CA.; 2009.
20. advers Ching G, Li D, McKay M, et al . Abstract 4324: pump proton inhibitors increase major cardiovascular events among post-percutaneous coronary intervention patients on clopidogrel. Circulation , 2009, 120: S936-937.
21. Dunn SP, Macaulay TE, Brennan DM, et al . Abstract 3999: baseline proton pump inhibitors use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation , 2008, 118: S815.
22. Gaspar A, Ribeiro S, Naibas S, et al . P2679: proton pump inhibitors in patients treated with aspirin and clopidogrel. Eur Heart J , 2009, 30(Abstract Supplement): 444.
23. Hall NL, Mathews KD, May HT, et al . Abstract 997: cardiovascular risk associated with concurrent proton pump inhibitor and clopidogrel therapy: how much? How specific? Circulation , 2009, 120: S422-a.
24. Jarai R, Brosovic I, Tentzeris I, et al . P675: effect of proton pump inhibitors on outcome of patients discharged on dual-antiplatelet therapy after percutaneous coronary intervention and stent implantation. Eur Heart J , 2009, 30 (Abstract Supplement): 98.
25. O’Donoghue ML, Braunwalk E, Antman EM, et al . Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomized trials. Lancet , 2009, 374: 989-997.
26. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol , 2008, 52: 1038-1039.
27. Ramirez JF, Selzer F, Chakaprani R, et al . Proton pump inhibitor and clopidogrel combination is not associated with adverse clinical outcomes after PCI: the NHLBI dynamic registry. JACC , 2009, 53(Suppl.1): A27.
28. Sarafoff N, Sibbing D, Sonntag U, et al . P894: higher stent thrombosis rate after coronary stenting in patients on dula antiplatelet treatment and concomitant treatment with proton pump inhibitors. Eur Heart J , 2009, 30 (Abstract Supplement): 150.
29. Simon T, Verstuyft C, Mary-Krause M, et al . Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med , 2009, 360: 363-375.
30. Simon T, Quandealle PH, Machcourt J, et al . P2121: proton pump inhibitors and clopidogrel response on the cardiovascular major events in patients after acute myocardial infarction. Data from the FAST-MI registry of the French society of cardiology. Eur Heart J , 2009, 30(Abstract Supplement): 335.
31. Sweeny JM, Kini A, Muntner P, et al . Abstract 4323: mortality associated with proton pump inhibitors following percutaneous coronary interventions with drug eluting stents. Circulation , 2009, 120: S936.
32. Torgusen R, Chou C, Kaneshige K, et al . Abstract 4542: does proton pump inhibitor use following percutaneous coronary intervention with drug-eluting stents impact clinical outcomes? Circulation , 2009, 120: S968.
33. Yasuda H, Yamada M, Sawada S, et al . Upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy after coronary stenting. Inter Med , 2009, 48: 1725-1730.
34. Zairis M, Patsourakos N, Makrygiannis S, et al . The impact of oral proton pump inhibitors on the effectiveness of combined aspirin and clopidogrel drug therapy during the first year after elective coronary stenting. Eur Heart J , 2008, 29(Abstract Supplement): 134.
35. Van Boxel OS, Van Oijen MG, Hagenaars MP, et al . Cardiovascular and Gastrointestinal Outcomes in Clopidogrel Users on Proton Pump Inhibitors: Results of a Large Dutch Cohort Study. Am J Gastroenterol, 2010 Aug 24 [Epub ahead of print].
36. Luinstra M, Naunton M, Peterson GM, et al . PPI use in patients commenced on clopidogrel: a retrospective cross-sectional evaluation. J Clin Pharm Ther , 2010, 35(2): 213-217.
37. Gaglia MJ, Torguson R, Hanna N, et al . Relation of proton pump inhibitor use after percutaneous coronary intervention with drug-eluting stents to outcomes. Am J Cardiol , 2010, 105(6): 833-838.
38. Savi P, Pereillo JM, Uzabiaga MF, et al . Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost , 2000, 84: 891-896.
39. Kim KA, Park PW, Hong SJ, et al . The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther , 2008, 84: 236-242.
40. Mega JL, Close SL, Wiviott SD, et al . Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med , 2009, 360: 354-362.
41. Li XQ, Andersson TB, Ahlstrom M, et al . Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos , 2004, 32: 821-827.
42. Gilard M, Arnaud B, Cornily JC, et al . Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol , 2008, 51: 256-260.
43. Aubert RE, Epstein RS, Teagarden JR, et al . Abstract 3998: Proton pump inhibitors effect on clopidogrel effectiveness: the Clopidogrel Medco Outcomes Study. Circulation , 2008, 118: S-815.
44. Tsai YW, Wen YW, Huang WF, et al . Cardiovascular and gastrointestinal events of three antiplatelet therapies: clopidogrel, clopidogrel plus proton-pump inhibitors, and aspirin plus proton-pump inhibitors in patients with previous gastrointestinal bleeding. J Gastroenterol, 2010 Sep 2 [Epub ahead of print].
45. 钟益钢, 王宁夫. 不同的质子泵抑制剂与氯吡格雷相互作用的研究进展. 心血管病学进展, 2010, 31(2): 276-279.
46. Wu CY, Chan FK, Wu MS, et al . Histamine-2-receptor antagonist are an alternative to proton pump inhibitor in patients receiving clopidogrel. Gastroenterology , 2010, 139(4): 1165-1171.
47. Kenngott S, Olze R, Kollmer M, et al . Gross MClopidogrel and proton pump inhibitor (PPI) interaction: separate intake and a non-omeprazole PPI the solution? Eur J Med Res , 2010, 15(5):220-224.

Chinese Journal of Evidence-Based Medicine

Safety of Clopidogrel-Proton Pump Inhibitors Combination Therapy on Cardiovascular Events: A Systematic Review

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