Network meta-analysis of prasugrel, ticagrelor, high- and standard-dose clopidogrel in patients scheduled for percutaneous coronary interventions

Sabine Steiner; Deddo Moertl; Li Chen; Doug Coyle; George A. Wells

doi:10.1160/TH11-08-0586

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(02): 318-327
DOI: 10.1160/TH11-08-0586

Platelets and Blood Cells

Schattauer GmbH

Network meta-analysis of prasugrel, ticagrelor, high- and standard-dose clopidogrel in patients scheduled for percutaneous coronary interventions

Authors

Sabine Steiner

¹Department of Internal Medicine II, Division of Angiology, Medical University Vienna, Vienna, Austria

²Minto Prevention and Rehabilitation Centre, University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada
Deddo Moertl

³Department of Internal Medicine III (Cardiology), Landesklinikum St. Poelten, St. Poelten, Austria
Li Chen

⁴Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Canada
Doug Coyle

⁵Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
George A. Wells

⁴Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Canada

Abstract

Summary

Since novel antiplatelet treatments (prasugrel, ticagrelor, high-dose clopidogrel) have been predominantly tested against standard-dose clopidogrel, data on direct comparisons between these therapies are scarce. We therefore indirectly compared their efficacy and safety in patients undergoing percutaneous coronary intervention. Electronic databases were searched systematically to identify head-to-head randomised controlled trials (RCTs). Network meta-analysis was performed using generalised linear mixed models with adjustment for length of follow-up. Findings were corroborated by mixed treatment comparison through Bayesian methods. Fourteen RCTs were identified and included in the analysis (high- vs. standard-dose clopidogrel: 9 trials, prasugrel vs. high-dose clopidogrel: 2 trials, prasugrel vs. standard-dose clopidogrel: 2 trials, ticagrelor vs. standard-dose clopidogrel: 1 trial). No significant differences were found for efficacy outcomes except for stent thrombosis favouring prasugrel (vs. ticagrelor: odds ratio [OR] 0.63, 95% confidence interval [CI]: 0.42, 0.94; vs. high-dose clopidogrel: OR 0.70, 95%CI: 0.48, 1.01). Prasugrel exhibited a similar bleeding risk as high-dose clopidogrel, but more major (OR 1.43, 95%CI 1.07, 1.90) and major or minor bleeding (OR 1.36, 95%CI 1.09, 1.69) compared to ticagrelor. Ticagrelor was also associated with less major or minor bleeding compared to high-dose clopidogrel (OR 0.81, 95%CI 0.69, 0.96). No differences were seen for non CABG-related major bleeding between the three strategies. Results were corroborated in a subgroup analysis comprising only patients with acute coronary syndromes. In the absence of head-to-head clinical trials, network meta-analysis suggests potentially relevant differences in efficacy and bleeding risk among novel antiplatelet treatments and may thereby advance understanding of their differential therapeutic properties.

Keywords

Antiplatelet agents - meta-analysis - percutaneous coronary intervention

Full Text

References

References
1 Bowry AD, Brookhart MA, Choudhry NK. Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. Am J Cardiol 2008; 101: 960-966.
2 Bainey KR, Lai TF, Mehta SR. Clopidogrel in acute coronary syndromes: where are we now?. Thromb Haemost 2011; 105: 766-773.
3 O'Donoghue M, Wiviott SD. Clopidogrel response variability and future therapies: clopidogrel: does one size fit all?. Circulation 2006; 114: e600-606.
4 Fernando H, Dart AM, Peter K. et al. Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy. Thromb Haemost 2011; 105: 933-944.
5 Gremmel T, Panzer S. Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel. Thromb Haemost 2011; 106: 211-218.
6 Aradi D, Komocsi A, Vorobcsuk A. et al. Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis. Am Heart J 2010; 160: 543-551.
7 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
8 Sibbing D, Byrne RA, Bernlochner I. et al. High platelet reactivity and clinical outcome - fact and fiction. Thromb Haemost 2011; 106: 191-202.
9 Gurbel PA, Tantry US. Clopidogrel response variability and the advent of personalised antiplatelet therapy. A bench to bedside journey. Thromb Haemost 2011; 106: 265-271.
10 Fefer P, Matetzky S. The genetic basis of platelet responsiveness to clopidogrel. A critical review of the literature. Thromb Haemost 2011; 106: 203-210.
11 Mega JL, Simon T, Collet JP. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. J Am Med Assoc 2010; 304: 1821-1830.
12 Pare G, Mehta SR, Yusuf S. et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704-1714.
13 Wiviott SD, Antman EM, Braunwald E. Prasugrel. Circulation 2010; 122: 394-403.
14 Behan MW, Chew DP, Aylward PE. The role of antiplatelet therapy in the secondary prevention of coronary artery disease. Curr Opin Cardiol 2010; 25: 321-328.
15 Mehta SR, Bassand JP, Chrolavicius S. et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930-942.
16 Price MJ, Berger PB, Teirstein PS. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc 2011; 305: 1097-1105.
17 Glenny AM, Altman DG, Song F. et al. Indirect comparisons of competing interventions. Health Technol Assess 2005; 09: 1-134. iii-iv.
18 Hoaglin DC, Hawkins N, Jansen JP. et al. Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2. Value Health 2011; 14: 429-437.
19 Drug Approval Package: Effient (prasugrel) Tablet. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000TOC.cfm Accessed June 6, 2011.
20 Ticagrelor for acute coronary syndromes, NDA 22–433. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM220192.pdf Accessed June 6, 2011.
21 Cutlip DE, Windecker S, Mehran R. et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
22 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: 3366-3373.
23 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: 256-265.
24 Higgins J, Green S. Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons; 2008: 187-241.
25 Higgins JP, Thompson SG, Deeks JJ. et al. Measuring inconsistency in meta-analyses. Br Med J 2003; 327: 557-560.
26 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 07: 177-188.
27 Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med 1998; 17: 873-890.
28 Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 2004; 23: 3105-3124.
29 Biondi-Zoccai G, Lotrionte M, Agostoni P. et al. Adjusted indirect comparison meta-analysis of prasugrel versus ticagrelor for patients with acute coronary syndromes. Int J Cardiol 2011; 150: 325-331.
30 Hao PP, Zhang MX, Li RJ. et al. Clopidogrel 150 vs. 75 mg day(-1) in patients undergoing percutaneous coronary intervention: a meta-analysis. J Thromb Haemost 2011; 09: 627-637.
31 Lambert PC, Sutton AJ, Burton PR. et al. How vague is vague? A simulation study of the impact of the use of vague prior distributions in MCMC using WinBUGS. Stat Med 2005; 24: 2401-2428.
32 von Beckerath N, Kastrati A, Wieczorek A. et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007; 28: 1814-1819.
33 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: 401-403.
34 Angiolillo DJ, Bernardo E, Palazuelos J. et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions. Results of a randomized study. Thromb Haemost 2008; 99: 161-168.
35 Aleil B, Jacquemin L, De Poli F. et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. Jacc: Cardiovasc Interv 2008; 01: 631-638.
36 Han Y-L, Wang B, Li Y. et al. A high maintenance dose of clopidogrel improves short-term clinical outcomes in patients with acute coronary syndrome undergoing drug-eluting stent implantation. Chin Med J 2009; 122: 793-797.
37 Aradi D, Vorobcsuk A, Pinter T. et al. Doubling the maintenance dose of clopidogrel in patients with high post-clopidogrel platelet reactivity after percutaneous coronary intervention: the DOSER randomized, placebo-controlled trial. Conference of the European Society of Cardiology (ESC), Stockholm, Sweden. Eur Heart J 2010; 31 (Suppl. 01) 971.
38 Palmerini T, Barozzi C, Tomasi L. et al. A randomised study comparing the antiplatelet and antiinflammatory effect of clopidogrel 150 mg/day versus 75 mg/day in patients with ST-segment elevation acute myocardial infarction and poor responsiveness to clopidogrel: results from the DOUBLE study. Thrombosis Research 2010; 125: 309-314.
39 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: 1233-1243.
40 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
41 Wiviott SD, Trenk D, Frelinger AL. et al. Prasugrel compared with high loading-and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923-2932.
42 Alexopoulos D, Dimitropoulos G, Davlouros P. et al. Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: The importance of cyp2c19 (*)2 genotyping. Jacc: Cardiovasc Interv 2011; 04: 403-410.
43 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: 283-293.
44 Bucher HC, Guyatt GH, Griffith LE. et al. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997; 50: 683-691.
45 Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. Br Med J 2005; 331: 897-900.
46 O'Regan C, Ghement I, Eyawo O. et al. Incorporating multiple interventions in meta-analysis: an evaluation of the mixed treatment comparison with the adjusted indirect comparison. Trials 2009; 10: 86.
47 Song F, Loke YK, Walsh T. et al. Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. Br Med J 2009; 338: b1147.
48 Parodi G, Bellandi B, Venditti F. et al. Residual Platelet Reactivity, Bleedings, and Adherence to Treatment in Patients Having Coronary Stent Implantation Treated With Prasugrel. Am J Cardiol 2012; 02: 214-218.
49 Mahaffey KW, Wojdyla DM, Carroll K. et al. Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Circulation 2011; 124: 544-554.

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