氯吡格雷与质子泵抑制剂联用治疗冠心病安全性的系统评价_《中国循证医学杂志》

作者：

邝洁云 ^1,2 , 谭洁 ¹ ,  邹建军 ¹ , 陈绍良 ³

1. 南京医科大学附属南京第一医院临床药理实验室（南京?210006）；2. 中国药科大学江宁校区药学院（南京?211198）；3. 南京医科大学附属南京第一医院心内科（南京?210006）;

关键词：

氯吡格雷质子泵抑制剂心血管事件消化道出血系统评价 Meta分析

DOI：

10.7507/1672-2531.20110048

视频：

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摘要 全文 图表 视频 参考文献 施引文献 补充材料

目的　对冠心病患者单用氯吡格雷和联合使用氯吡格雷质子泵抑制剂（PPI）的安全性（心血管事件、死亡或胃肠道出血等）进行系统评价。
方法　计算机检索Cochrane图书馆、PubMed、EMbase、SSCI、VIP、CNKI及CBM数据库，检索时间均从建库至2010年9月，并追踪已获文献的参考文献，由2名研究者独立进行质量评价及数据提取，而后采用RevMan 5.0软件进行Meta分析。
结果　共纳入29篇文献，合计142 401例患者。Meta分析结果显示：氯吡格雷与质子泵抑制剂联用有增加心血管事件的风险［RR=1.27，95% CI（1.09，1.47）］，同时存在增加心肌梗死［RR=1.45，95%CI（1.20，1.76）］、总病死率［RR=1.23，95%CI（1.06，1.43）］、再次血栓［RR=1.37，95%CI（1.01，1.86）］的风险。此外，两者联用与胃肠道出血风险的关系还不明确［RR=0.84，95%CI（0.47，1.50）］。
结论　氯吡格雷与质子泵抑制剂联用会增加心血管事件、病死率、心肌梗死及再次血栓的风险，但在降低胃肠道出血的作用方面尚需更多临床研究证实。

引用本文： 邝洁云,谭洁,邹建军,陈绍良. 氯吡格雷与质子泵抑制剂联用治疗冠心病安全性的系统评价. 中国循证医学杂志, 2011, 11(3): 283-291. doi: 10.7507/1672-2531.20110048 复制

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.

《中国循证医学杂志》

氯吡格雷与质子泵抑制剂联用治疗冠心病安全性的系统评价

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《中国循证医学杂志》

氯吡格雷与质子泵抑制剂联用治疗冠心病安全性的系统评价

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