Prasugrel and Ticagrelor for Acute Coronary Syndrome: A Meta-Analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 TANXiao-hui ^1,2 , LIANGZhuan-he ² , LIUJie-qiang ² , LUOYi-zhi ² , ZHUKe-yun ² ,  LIZhi-liang ³

1. Southern Medical University, Guangzhou 510515, China;
2. Department of Cardiovasology, Xinhui Hospital Affiliated to Southern Medical University, Jiangmen 529100, China;
3. Department of Cardiovasology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China;

Corresponding author：

LIZhi-liang, Email: lizhouxiaoyu@163.com

Keywords：

Acute coronary syndrome; Prasugrel; Ticagrelor; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.20140141

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Objective To systematically review the therapeutic effects and safety of new platelet inhibition regimens targeting P2Y₁₂-receptors (prasugrel/ticagrelor) in patients with acute coronary syndrome (ACS). Methods Such databases as PubMed (1980 to 2013.7), EMbase (1980 to 2013.5), The Cochrane Library (Issue 7, 2013), CBM (1990 to 2013.7), CNKI (1994 to 2013.7), VIP (1989 to 2013.7) and WanFang Data (1980 to 2013.7) were electronically searched to collect the randomized controlled trials (RCTs) about comparing prasugrel/ticagrelor with clopidogrel in treating patients with ACS. Two reviewers screened literature according to the inclusion and exclusion criteria, extracted data, and assessed the methodological quality of the included studies. Then meta-analysis was performed using RevMan 5.2 software. Results Five studies involving 43 452 patients were finally included. The results of meta-analysis showed that:compared with standard clopidogrel, prasugrel/ticagrelor reduced the incidences of myocardial infarction (OR=0.83, 95%CI 0.77 to 0.89, P < 0.000 01), cardiovascular death (OR=0.86, 95%CI 0.78 to 0.94, P=0.002), and stent thrombosis (OR=0.61, 95%CI 0.38 to 0.97, P=0.04); while no advantage was found in reducing the incidences of stroke (OR=1.06, 95%CI 0.88 to 1.26, P=0.54), intracranial hemorrhage (OR=1.18, 95%CI 0.81 to 1.71, P=0.39), and severe bleeding after thrombolysis due to myocardial infarction (OR=1.17, 95%CI 0.94 to 1.47, P=0.16). Conclusion New platelet inhibition regimens targeting P2Y₁₂-receptors for ACS could effectively decrease the incidences of myocardial infarction, cardiovascular death, and stent thrombosis events. However, compared with clopidogrel, it could not improve the clinical outcomes of patients with stroke and intracranial hemorrhage. Additionally, due to the increased risk of non-CABG related bleeding, more attention should be paid to the application of new platelet inhibition regimens.

Citation： TANXiao-hui, LIANGZhuan-he, LIUJie-qiang, LUOYi-zhi, ZHUKe-yun, LIZhi-liang. Prasugrel and Ticagrelor for Acute Coronary Syndrome: A Meta-Analysis. Chinese Journal of Evidence-Based Medicine, 2014, 14(7): 849-858. doi: 10.7507/1672-2531.20140141 Copy

1.	Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med, 2001, 345(7):494-502.
2.	CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med, 2010, 363(10):930-942.
3.	Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting:response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation, 2003, 107(23):2908-2913.
4.	Gurbel PA, Bliden KP. Durability of platelet inhibition by clopidogrel. Am J Cardiol, 2003, 91(9):1123-1125.
5.	Muller I, Besta F, Schulz C, et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost, 2003, 89(5):783-787.
6.	Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation:The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J, 2011, 32(23):2999-3054.
7.	Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J, 2012, 33(20):2569-2619.
8.	Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update):a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 2012, 60(7):645-681.
9.	O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction:executive summary:a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation, 2013, 127(4):529-555.
10.	Palacio S, Hart RG, Pearce LA, et al. Effect of addition of clopidogrel to aspirin on mortality:systematic review of randomized trials. Stroke, 2012, 43(8):2157-2162.
11.	Helton TJ, Bavry AA, Kumbhani DJ, et al. Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease:a meta-analysis of randomized trials. Am J Cardiovasc Drugs, 2007, 7(4):289-297.
12.	Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials:the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet, 1999, 354(9139):1896-1900.
13.	Bero L, Rennie D. The Cochrane Collaboration. Preparing, maintaining, and disseminating systematic reviews of the effects of health care. JAMA, 1995, 274(24):1935-1938.
14.	Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol, 2004, 44(3):671-719.
15.	Cannon CP, Battler A, Brindis RG, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol, 2001, 38(7):2114-2130.
16.	Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med, 1991, 115(4):256-265.
17.	Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med, 2007, 356(10):1020-1029.
18.	Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0).[cited 2012 Jan 5]. Available at:http://www.cochrane-handbook.org.
19.	Guyatt G, Oxman A, Montori V, 等. GRADE指南:Ⅳ.证据质量分级——研究的局限性(偏倚风险).中国循证医学杂志, 2011, 11(4):456-463.
20.	Guyatt G, Oxman A, Montori V, 等. GRADE指南:V.证据质量评价——发表偏倚.中国循证医学杂志, 2011, 11(12):1430-1434.
21.	van Tulder M, Furlan A, Bombardier C, et al. Updated method guidelines for systematic reviews in the cochrane collaboration back review group. Spine, 2003, 28(12):1290-1299.
22.	Rosenthal R. The File Drawer Problem and Tolerance for Null Results. Psychol Bull, 1979, 86:638-641.
23.	Orwin R. A fail-safe N for effect size in meta-analysis. J Educ Stat, 1983.
24.	Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y₁₂ antagonist, with clopidogrel in percutaneous coronary intervention:results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation, 2005, 111(25):3366-3373.
25.	Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 2007, 357(20):2001-2015.
26.	Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med, 2012, 367(14):1297-1309.
27.	Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome:primary results of the DISPERSE-2 trial. J Am Coll Cardiol, 2007, 50(19):1844-1851.
28.	Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 2009, 361(11):1045-1057.
29.	Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention:a randomized controlled trial. JAMA, 2002, 288(19):2411-2420.
30.	Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med, 2005, 352(12):1179-1189.
31.	Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45, 852 patients with acute myocardial infarction:randomised placebo-controlled trial. Lancet, 2005, 366(9497):1607-1621.
32.	Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel:clinical implications, management, and future perspectives. J Am Coll Cardiol, 2007, 49(14):1505-1516.
33.	CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med, 2010, 363(10):930-942.
34.	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.
35.	Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial:a subanalysis of a randomised trial. Lancet, 2008, 371(9621):1353-1363.
36.	Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO):a randomised double-blind study. Lancet, 2010, 375(9711):283-293.

1. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med, 2001, 345(7):494-502.
2. CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med, 2010, 363(10):930-942.
3. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting:response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation, 2003, 107(23):2908-2913.
4. Gurbel PA, Bliden KP. Durability of platelet inhibition by clopidogrel. Am J Cardiol, 2003, 91(9):1123-1125.
5. Muller I, Besta F, Schulz C, et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost, 2003, 89(5):783-787.
6. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation:The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J, 2011, 32(23):2999-3054.
7. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J, 2012, 33(20):2569-2619.
8. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update):a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 2012, 60(7):645-681.
9. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction:executive summary:a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation, 2013, 127(4):529-555.
10. Palacio S, Hart RG, Pearce LA, et al. Effect of addition of clopidogrel to aspirin on mortality:systematic review of randomized trials. Stroke, 2012, 43(8):2157-2162.
11. Helton TJ, Bavry AA, Kumbhani DJ, et al. Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease:a meta-analysis of randomized trials. Am J Cardiovasc Drugs, 2007, 7(4):289-297.
12. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials:the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet, 1999, 354(9139):1896-1900.
13. Bero L, Rennie D. The Cochrane Collaboration. Preparing, maintaining, and disseminating systematic reviews of the effects of health care. JAMA, 1995, 274(24):1935-1938.
14. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol, 2004, 44(3):671-719.
15. Cannon CP, Battler A, Brindis RG, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol, 2001, 38(7):2114-2130.
16. Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med, 1991, 115(4):256-265.
17. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med, 2007, 356(10):1020-1029.
18. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0).[cited 2012 Jan 5]. Available at:http://www.cochrane-handbook.org.
19. Guyatt G, Oxman A, Montori V, 等. GRADE指南:Ⅳ.证据质量分级——研究的局限性(偏倚风险).中国循证医学杂志, 2011, 11(4):456-463.
20. Guyatt G, Oxman A, Montori V, 等. GRADE指南:V.证据质量评价——发表偏倚.中国循证医学杂志, 2011, 11(12):1430-1434.
21. van Tulder M, Furlan A, Bombardier C, et al. Updated method guidelines for systematic reviews in the cochrane collaboration back review group. Spine, 2003, 28(12):1290-1299.
22. Rosenthal R. The File Drawer Problem and Tolerance for Null Results. Psychol Bull, 1979, 86:638-641.
23. Orwin R. A fail-safe N for effect size in meta-analysis. J Educ Stat, 1983.
24. Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y₁₂ antagonist, with clopidogrel in percutaneous coronary intervention:results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation, 2005, 111(25):3366-3373.
25. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 2007, 357(20):2001-2015.
26. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med, 2012, 367(14):1297-1309.
27. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome:primary results of the DISPERSE-2 trial. J Am Coll Cardiol, 2007, 50(19):1844-1851.
28. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 2009, 361(11):1045-1057.
29. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention:a randomized controlled trial. JAMA, 2002, 288(19):2411-2420.
30. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med, 2005, 352(12):1179-1189.
31. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45, 852 patients with acute myocardial infarction:randomised placebo-controlled trial. Lancet, 2005, 366(9497):1607-1621.
32. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel:clinical implications, management, and future perspectives. J Am Coll Cardiol, 2007, 49(14):1505-1516.
33. CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med, 2010, 363(10):930-942.
34. 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.
35. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial:a subanalysis of a randomised trial. Lancet, 2008, 371(9621):1353-1363.
36. Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO):a randomised double-blind study. Lancet, 2010, 375(9711):283-293.

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