Efficacy and safety of 600 mg versus 300 mg loading dose of clopidogrel for Chinese patients underwent percutaneous coronary intervention: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

SONG Baili ^1,2 , HANG Jing ³ , TANG Dan ² ,  ZOU Jianjun ^1,2

1. Department of Clinical Pharmacology, Nanjing First Hospital; the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, 210006, P.R.China;
2. School of Basic Medical Sciences and Clinical Pharmacy, Pharmaceutical University of China, Nanjing, 211100, P.R.China;
3. The Affiliated Nanjing Hospital of Nanjing Medical University; Department of Neurology, Nanjing First Hospital, Nanjing, 210006, P.R.China;

Corresponding?author：

ZOU Jianjun, Email: zoujianjun100@126.com

Keywords：

Percutaneous coronary intervention; Chinese patient; Clopidogrel; Loading dose; Meta-analysis; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.201705099

Video：

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Objectives To systematically review the efficacy and safety of clopidogrel 600 mg and 300 mg loading dose in Chinese patients underwent percutaneous coronary intervention (PCI). Methods We searched The Cochrane Library, EMbase, PubMed, CNKI, WanFang Data, CBM and VIP databases to collect randomized controlled trials (RCTs) of the efficacy and safety of clopidogrel 600 mg and 300 mg loading dose in Chinese patients underwent PCI from inception to April, 2017. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Meta-analysis was then performed using Stata 14.0 software. Results A total of 10 RCTs involving 1 166 patients were included. The results of meta-analysis showed that: the 600 mg loading dose group had lower incidence rate of major adverse cardiovascular events (MACE) in comparison with the 300 mg loading dose group (RR=0.29, 95%CI 0.17 to 0.48, P<0.000 1). However, no significant difference was found in the incidence of major bleeding events within 30 days between two groups (RR=1.64, 95%CI 0.70 to 3.80,P=0.252). Conclusions The current evidence shows that in Chinese patients underwent PCI, administration of a 600 mg loading dose of clopidogrel is associated with a lower risk of MACE than is administration of a 300 mg loading dose of clopidogrel, without increasing major bleeding risk in 30 days. Due to limited quality and quantity of the included studies, more high quality studies are required to verify above conclusions.

Citation： SONG Baili, HANG Jing, TANG Dan, ZOU Jianjun. Efficacy and safety of 600 mg versus 300 mg loading dose of clopidogrel for Chinese patients underwent percutaneous coronary intervention: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2018, 18(1): 29-34. doi: 10.7507/1672-2531.201705099 Copy

1.	中華醫學會心血管病學分會介入心臟病學組, 中國醫師協會心血管內科醫師分會, 血栓防治專業委員會, 等. 中國經皮冠狀動脈介入治療指南 (2016). 中華心血管病志, 2016, 44(5): 382-400.
2.	Mao L, Jian C, Chang ZL, et al. Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23, 035 subjects. Arch Cardiovasc Dis, 2013, 106(10): 517-527.
3.	Kitzmiller JP, Groen DK, Phelps MA, et al. Pharmacogenomic testing: relevance in medical practice: why drugs work in some patients but not in others. Cleve Clin J Med, 2011, 78(4): 243-257.
4.	Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2014, 130(25): e431-e432.
5.	Endorsed by the Latin American Society of Interventional Cardiology, PCI writing committee, Levine GN, et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv, 2016, 87(6): 1001-1019.
6.	Widimsky P, Motovska Z, Simek S, et al. Clopidogrel pre-treatment in stable angina: for all patients >6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8. Eur Heart J, 2008, 29(12): 1495-1503.
7.	Di Sciascio G, Patti G, Pasceri V, et al. Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing percutaneous coronary intervention: results of the ARMYDA-5 PRELOAD (Antiplatelet Therapy for Reduction of MYocardial Damage during Angioplasty) randomized trial. J Am Coll Cardiol, 2010, 56(7): 550-557.
8.	Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet, 2001, 358(9281): 527-533.
9.	Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet, 2010, 376(9748): 1233-1243.
10.	Choi CU, Rha SW, Oh DJ, et al. Standard versus high loading doses of clopidogrel in Asian ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention: insights from the Korea Acute Myocardial Infarction Registry. Am Heart J, 2011, 161(2): 373-382.
11.	Kim JY, Jeong MH, Moon JH, et al. Impact of clopidogrel loading dose in patients with chronic kidney disease undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Am J Cardiol, 2012, 110(11): 1598-1606.
12.	Song PS, Hahn JY, Song YB, et al. Effects of 600 mg versus 300 mg loading dose of clopidogrel in Asian patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: long-term follow-up study. Yonsei Med J, 2012, 53(5): 906-914.
13.	盛力, 李悅, 李為民, 等. 不同負荷劑量氯吡格雷對急性冠脈綜合征患者 PCI 的療效觀察. 中國急救醫學, 2008, 28(8): 712-714.
14.	王海洋, 任長杰, 孫曉斐. 雙倍負荷量及維持量氯吡格雷對急性冠脈綜合征患者 PCI 的近期療效. 濟寧醫學院學報, 2011, 34(3): 189-190.
15.	Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol, 2006, 48(7): 1339-1345.
16.	Dangas G, Mehran R, Guagliumi G, et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol, 2009, 54(15): 1438-1446.
17.	Fernandez A, Aboodi MS, Milewski K, et al. Comparison of adverse cardiovascular events and bleeding complications of loading dose of clopidogrel 300 mg versus 600 mg in stable patients undergoing elective percutaneous intervention (from the CADICE study). Am J Cardiol, 2011, 107(1): 6-9.
18.	Abuzahra M, Pillai M, Caldera A, et al. Comparison of higher clopidogrel loading and maintenance dose to standard dose on platelet function and outcomes after percutaneous coronary intervention using drug-eluting stents. Am J Cardiol, 2008, 102(4): 401-403.
19.	Mangiacapra F, Muller O, Ntalianis A, et al. Comparison of 600 versus 300-mg Clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary coronary angioplasty. Am J Cardiol, 2010, 106(9): 1208-1211.
20.	Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention - Results from the ARMYDA-2 (Antiplatelet therapy for reduction of myocardial Damage during Angioplasty) study. Circulation, 2005, 111(16): 2099-2106.
21.	Patti G, Barczi G, Orlic D, et al. Outcome comparison of 600 and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. J Am Coll Cardiol, 2011, 58(15): 1592-1599.
22.	陳劍, 龍衛平, 何漢康, 等. 術前高負荷量氯吡格雷預防急診冠脈介入術后不良事件的臨床研究. 廣西醫學, 2015, 37(2): 189-191.
23.	陳燕春, 楊松, 沈杰, 等. 不同負荷劑量氯吡格雷對急性冠脈綜合征患者 PCI 術后近期預后的影響. 國際心血管病雜志, 2010, 37(6): 371-373, 376.
24.	蔣景奎, 李成東. 雙倍負荷劑量氯吡格雷對 ACS 患者 PCI 近期療效及血清炎性因子的影響. 河北醫學, 2015, 21(2): 213-216.
25.	嚴章林, 古紅梅, 陽貽紅, 等. 超負荷量氯吡格雷對急診經皮冠脈介入治療患者圍術期的影響. 贛南醫學院學報, 2012, 32(4): 527-529.
26.	梁孫英, 張明, 鄧珍. 不同負荷劑量氯吡格雷治療急性冠脈綜合征的臨床應用研究. 現代醫院, 2009, 9(7): 24-27.
27.	潘力健, 肖踐明, 楊源, 等. 冠狀動脈介入術前高負荷量氯吡格雷預治療的近期療效. 臨床心血管病雜志, 2008, 24(2): 120-123.
28.	吳鏗, 葉少強. 不同負荷劑量氯吡格雷在急性 ST 段抬高心肌梗死中應用的臨床對比研究. 中華老年多器官疾病雜志, 2010, 9(4): 337-341.
29.	熊龍根, 劉世明, 江中喜, 等. 氯吡格雷聯合阿司匹林對 ACS 患者行 PCI 術的療效及抗感染作用. 中華醫院感染學雜志, 2011, 21(24): 5220-5221.
30.	Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org.
31.	Vyas A, El Accaoui R, Blevins A, et al. Outcome comparison of 600 mg versus 300 mg loading dose of clopidogrel for patients with ST-elevation myocardial infarction: a meta-analysis. Postgrad Med, 2014, 126(5): 176-186.
32.	Siller-Matula JM, Huber K, Christ G, et al. Impact of clopidogrel loading dose on clinical outcome in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Heart, 2011, 97(2): 98-105.
33.	Howell LA, Stouffer GA, Polasek M, et al. Review of clopidogrel dose escalation in the current era of potent P2Y12 inhibitors. Expert Rev Clin Pharmacol, 2015, 8(4): 411-421.
34.	Zhang Y, Zhao Y, Pang M, et al. High-dose clopidogrel versus ticagrelor for treatment of acute coronary syndromes after percutaneous coronary intervention in CYP2C19 intermediate or poor metabolizers: a prospective, randomized, open-label, single-centre trial. Acta Cardiol, 2016, 71(3): 309-316.
35.	Levine GN, Jeong YH, Goto S, et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol, 2014, 11(10): 597-606.
36.	Jeong YH. " East asian paradox”: challenge for the current antiplatelet strategy of " one-guideline-fits-all races” in acute coronary syndrome. Curr Cardiol Rep, 2014, 16(5): 485.
37.	Kim IS, Choi BR, Jeong YH, et al. The CYP2C192 and CYP2C193 polymorphisms are associated with high post-treatment platelet reactivity in Asian patients with acute coronary syndrome. J Thromb Haemost, 2009, 7(5): 897-899.

1. 中華醫學會心血管病學分會介入心臟病學組, 中國醫師協會心血管內科醫師分會, 血栓防治專業委員會, 等. 中國經皮冠狀動脈介入治療指南 (2016). 中華心血管病志, 2016, 44(5): 382-400.
2. Mao L, Jian C, Chang ZL, et al. Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23, 035 subjects. Arch Cardiovasc Dis, 2013, 106(10): 517-527.
3. Kitzmiller JP, Groen DK, Phelps MA, et al. Pharmacogenomic testing: relevance in medical practice: why drugs work in some patients but not in others. Cleve Clin J Med, 2011, 78(4): 243-257.
4. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2014, 130(25): e431-e432.
5. Endorsed by the Latin American Society of Interventional Cardiology, PCI writing committee, Levine GN, et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv, 2016, 87(6): 1001-1019.
6. Widimsky P, Motovska Z, Simek S, et al. Clopidogrel pre-treatment in stable angina: for all patients >6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8. Eur Heart J, 2008, 29(12): 1495-1503.
7. Di Sciascio G, Patti G, Pasceri V, et al. Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing percutaneous coronary intervention: results of the ARMYDA-5 PRELOAD (Antiplatelet Therapy for Reduction of MYocardial Damage during Angioplasty) randomized trial. J Am Coll Cardiol, 2010, 56(7): 550-557.
8. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet, 2001, 358(9281): 527-533.
9. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet, 2010, 376(9748): 1233-1243.
10. Choi CU, Rha SW, Oh DJ, et al. Standard versus high loading doses of clopidogrel in Asian ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention: insights from the Korea Acute Myocardial Infarction Registry. Am Heart J, 2011, 161(2): 373-382.
11. Kim JY, Jeong MH, Moon JH, et al. Impact of clopidogrel loading dose in patients with chronic kidney disease undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Am J Cardiol, 2012, 110(11): 1598-1606.
12. Song PS, Hahn JY, Song YB, et al. Effects of 600 mg versus 300 mg loading dose of clopidogrel in Asian patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: long-term follow-up study. Yonsei Med J, 2012, 53(5): 906-914.
13. 盛力, 李悅, 李為民, 等. 不同負荷劑量氯吡格雷對急性冠脈綜合征患者 PCI 的療效觀察. 中國急救醫學, 2008, 28(8): 712-714.
14. 王海洋, 任長杰, 孫曉斐. 雙倍負荷量及維持量氯吡格雷對急性冠脈綜合征患者 PCI 的近期療效. 濟寧醫學院學報, 2011, 34(3): 189-190.
15. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol, 2006, 48(7): 1339-1345.
16. Dangas G, Mehran R, Guagliumi G, et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol, 2009, 54(15): 1438-1446.
17. Fernandez A, Aboodi MS, Milewski K, et al. Comparison of adverse cardiovascular events and bleeding complications of loading dose of clopidogrel 300 mg versus 600 mg in stable patients undergoing elective percutaneous intervention (from the CADICE study). Am J Cardiol, 2011, 107(1): 6-9.
18. Abuzahra M, Pillai M, Caldera A, et al. Comparison of higher clopidogrel loading and maintenance dose to standard dose on platelet function and outcomes after percutaneous coronary intervention using drug-eluting stents. Am J Cardiol, 2008, 102(4): 401-403.
19. Mangiacapra F, Muller O, Ntalianis A, et al. Comparison of 600 versus 300-mg Clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary coronary angioplasty. Am J Cardiol, 2010, 106(9): 1208-1211.
20. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention - Results from the ARMYDA-2 (Antiplatelet therapy for reduction of myocardial Damage during Angioplasty) study. Circulation, 2005, 111(16): 2099-2106.
21. Patti G, Barczi G, Orlic D, et al. Outcome comparison of 600 and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. J Am Coll Cardiol, 2011, 58(15): 1592-1599.
22. 陳劍, 龍衛平, 何漢康, 等. 術前高負荷量氯吡格雷預防急診冠脈介入術后不良事件的臨床研究. 廣西醫學, 2015, 37(2): 189-191.
23. 陳燕春, 楊松, 沈杰, 等. 不同負荷劑量氯吡格雷對急性冠脈綜合征患者 PCI 術后近期預后的影響. 國際心血管病雜志, 2010, 37(6): 371-373, 376.
24. 蔣景奎, 李成東. 雙倍負荷劑量氯吡格雷對 ACS 患者 PCI 近期療效及血清炎性因子的影響. 河北醫學, 2015, 21(2): 213-216.
25. 嚴章林, 古紅梅, 陽貽紅, 等. 超負荷量氯吡格雷對急診經皮冠脈介入治療患者圍術期的影響. 贛南醫學院學報, 2012, 32(4): 527-529.
26. 梁孫英, 張明, 鄧珍. 不同負荷劑量氯吡格雷治療急性冠脈綜合征的臨床應用研究. 現代醫院, 2009, 9(7): 24-27.
27. 潘力健, 肖踐明, 楊源, 等. 冠狀動脈介入術前高負荷量氯吡格雷預治療的近期療效. 臨床心血管病雜志, 2008, 24(2): 120-123.
28. 吳鏗, 葉少強. 不同負荷劑量氯吡格雷在急性 ST 段抬高心肌梗死中應用的臨床對比研究. 中華老年多器官疾病雜志, 2010, 9(4): 337-341.
29. 熊龍根, 劉世明, 江中喜, 等. 氯吡格雷聯合阿司匹林對 ACS 患者行 PCI 術的療效及抗感染作用. 中華醫院感染學雜志, 2011, 21(24): 5220-5221.
30. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org.
31. Vyas A, El Accaoui R, Blevins A, et al. Outcome comparison of 600 mg versus 300 mg loading dose of clopidogrel for patients with ST-elevation myocardial infarction: a meta-analysis. Postgrad Med, 2014, 126(5): 176-186.
32. Siller-Matula JM, Huber K, Christ G, et al. Impact of clopidogrel loading dose on clinical outcome in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Heart, 2011, 97(2): 98-105.
33. Howell LA, Stouffer GA, Polasek M, et al. Review of clopidogrel dose escalation in the current era of potent P2Y12 inhibitors. Expert Rev Clin Pharmacol, 2015, 8(4): 411-421.
34. Zhang Y, Zhao Y, Pang M, et al. High-dose clopidogrel versus ticagrelor for treatment of acute coronary syndromes after percutaneous coronary intervention in CYP2C19 intermediate or poor metabolizers: a prospective, randomized, open-label, single-centre trial. Acta Cardiol, 2016, 71(3): 309-316.
35. Levine GN, Jeong YH, Goto S, et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol, 2014, 11(10): 597-606.
36. Jeong YH. " East asian paradox”: challenge for the current antiplatelet strategy of " one-guideline-fits-all races” in acute coronary syndrome. Curr Cardiol Rep, 2014, 16(5): 485.
37. Kim IS, Choi BR, Jeong YH, et al. The CYP2C19*2 and CYP2C19*3 polymorphisms are associated with high post-treatment platelet reactivity in Asian patients with acute coronary syndrome. J Thromb Haemost, 2009, 7(5): 897-899.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of 600 mg versus 300 mg loading dose of clopidogrel for Chinese patients underwent percutaneous coronary intervention: a meta-analysis

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