Safety and Efficacy of Selective, Clopidogrel-Based Strategies in Acute Coronary Syndrome: A Study-Level Meta-analysis

Abstract

Objectives To investigate outcomes with selective, clopidogrel-based therapies versus conventional treatment in patients undergoing percutaneous coronary intervention (PCI), especially for acute coronary syndrome.

Background Safety and efficacy of alternative, selective, clopidogrel-based therapies after PCI are not robustly established.

Methods We performed a study-level meta-analysis on six randomized trials investigating selective clopidogrel-based therapies (three on unguided de-escalation, N = 3,473; three on guided clopidogrel therapy, N = 7,533). Control groups received ticagrelor or prasugrel treatment. Main endpoints were major bleeding, any bleeding, major adverse cardiovascular events (MACE), and net clinical endpoint.

Results The incidence of major bleeding and MACE was similar in the selective, clopidogrel-based therapy versus the conventional treatment arm (odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.51–1.01, p = 0.06; OR: 0.93, 0.72–1.20, p = 0.58; respectively). The rates of any bleeding were lower in the selective, clopidogrel-based therapy versus conventional treatment group (OR: 0.57, 95% CI: 0.40–0.80, p = 0.001); this greater safety was significant for unguided de-escalation (OR: 0.43, 95% CI: 0.32–0.58, p = 0.00001) and nonsignificant for guided clopidogrel therapy (OR: 0.72, 95% CI: 0.51–1.02, p = 0.07; p for interaction: 0.03). The incidence of the net clinical endpoint was fewer in the selective, clopidogrel-based therapy versus the conventional treatment arm (OR: 0.59, 95% CI: 0.41–0.85, p = 0.004); this benefit was significant for unguided de-escalation (OR: 0.50, 95% CI: 0.39–0.64, p < 0.00001) and nonsignificant for guided clopidogrel therapy (OR 0.85, 95% CI: 0.62–1.16, p = 0.30; p for interaction: 0.01).

Conclusion As compared with prasugrel/ticagrelor treatment, alternative, selective, clopidogrel-based approaches provide a similar protection from cardiovascular events, reduce the risk of any bleeding, and are associated with a greater net benefit. These beneficial effects were prevalent with unguided de-escalation to clopidogrel.

Keywords

acute coronary syndrome - percutaneous coronary intervention - de-escalation - guided clopidogrel therapy - MACE

Competency in Medical Knowledge

An approach of unguided, but not a guided, de-escalation to clopidogrel reduces major or minor bleeding complications and net clinical endpoint compared with ticagrelor/prasugrel use, while maintaining similar ischemic protection in patients with ACS undergoing PCI.

Translational Outlook

Specific, ad hoc studies are needed to confirm whether an unguided de-escalation to clopidogrel provides adequate protection from thrombotic events in high-risk patients (also including those with older age) or in those with high PCI complexity (e.g., bifurcation stenting, long stented segments, or multivessel intervention).

Publication History

Received: 28 December 2021

Accepted: 15 April 2022

Accepted Manuscript online:
18 April 2022

Article published online:
13 June 2022

• References

• 1 Wallentin L, Becker RC, Budaj A. et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
• 2 Wiviott SD, Braunwald E, McCabe CH. et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
• 3 Collet J-P, Thiele H, Barbato E. et al; ESC Scientific Document Group. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021; 42 (14) 1289-1367
• 4 Ibanez B, James S, Agewall S. et al; ESC Scientific Document Group. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018; 39 (02) 119-177
• 5 Levine GN, Bates ER, Bittl JA. et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68 (10) 1082-1115
• 6 Antman EM, Wiviott SD, Murphy SA. et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 2008; 51 (21) 2028-2033
• 7 Becker RC, Bassand JP, Budaj A. et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2011; 32 (23) 2933-2944
• 8 Bagai A, Wang Y, Wang TY. et al. In-hospital switching between clopidogrel and prasugrel among patients with acute myocardial infarction treated with percutaneous coronary intervention: insights into contemporary practice from the national cardiovascular data registry. Circ Cardiovasc Interv 2014; 7 (04) 585-593
• 9 Bagai A, Peterson ED, Honeycutt E. et al. In-hospital switching between adenosine diphosphate receptor inhibitors in patients with acute myocardial infarction treated with percutaneous coronary intervention: Insights into contemporary practice from the TRANSLATE-ACS study. Eur Heart J Acute Cardiovasc Care 2015; 4 (06) 499-508
• 10 Zanchin T, Temperli F, Karagiannis A. et al. Frequency, reasons, and impact of premature ticagrelor discontinuation in patients undergoing coronary revascularization in routine clinical practice: results from the Bern Percutaneous Coronary Intervention Registry. Circ Cardiovasc Interv 2018; 11 (05) e006132
• 11 Angiolillo DJ, Patti G, Chan KT. et al. De-escalation from ticagrelor to clopidogrel in acute coronary syndrome patients: a systematic review and meta-analysis. J Thromb Thrombolysis 2019; 48 (01) 1-10
• 12 Breet NJ, van Werkum JW, Bouman HJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010; 303 (08) 754-762
• 13 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376 (9749): 1312-1319
• 14 Wallentin L, James S, Storey RF. et al; PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376 (9749): 1320-1328
• 15 Galli M, Benenati S, Capodanno D. et al. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Lancet 2021; 397 (10283): 1470-1483
• 16 Claassens DMF, Vos GJA, Bergmeijer TO. et al. A genotype-guided strategy for oral P2Y₁₂ inhibitors in primary PCI. N Engl J Med 2019; 381 (17) 1621-1631
• 17 Sibbing D, Aradi D, Jacobshagen C. et al; TROPICAL-ACS Investigators. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017; 390 (10104): 1747-1757
• 18 Kim H-S, Kang J, Hwang D. et al; HOST-REDUCE-POLYTECH-ACS investigators. Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial. Lancet 2020; 396 (10257): 1079-1089
• 19 Cuisset T, Deharo P, Quilici J, Johnson TW. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017; 38 (41) 3070-3078
• 20 Pereira NL, Farkouh ME, So D. et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial. JAMA 2020; 324 (08) 761-771
• 21 Park M-W, Kim CJ, Kim M-C. et al. A prospective, multicentre, randomised, open-label trial to compare the efficacy and safety of clopidogrel versus ticagrelor in stabilised patients with acute myocardial infarction after percutaneous coronary intervention: rationale and design of the TALOS-AMI trial. EuroIntervention 2021; 16 (14) 1170-1176
• 22 Ueno T, Koiwaya H, Sasaki KI. et al. Changes in P2Y12 reaction units after switching treatments from prasugrel to clopidogrel in Japanese patients with acute coronary syndrome followed by elective coronary stenting. Cardiovasc Interv Ther 2017; 32 (04) 341-350
• 23 Guo C, Li M, Lv Y-H, Zhang M-B, Wang Z-L. De-escalation versus standard dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Platelets 2020; 31 (01) 15-25
• 24 Shoji S, Kuno T, Fujisaki T. et al. De-escalation of dual antiplatelet therapy in patients with acute coronary syndromes. J Am Coll Cardiol 2021; 78 (08) 763-777
• 25 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535-b2535
• 26 Cayla G, Cuisset T, Silvain J. et al; ANTARCTIC investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016; 388 (10055): 2015-2022
• 27 Tuteja S, Glick H, Matthai W. et al. Prospective CYP2C19 genotyping to guide antiplatelet therapy following percutaneous coronary intervention: a pragmatic randomized clinical trial. Circ Genom Precis Med 2020; 13 (01) e002640
• 28 Higgins JPT, Altman DG, Gøtzsche PC. et al; Cochrane Bias Methods Group, Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928-d5928
• 29 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7 (03) 177-188
• 30 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22 (04) 719-748
• 31 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): 557-560
• 32 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50 (04) 1088-1101
• 33 Thompson SG, Higgins JPT. How should meta-regression analyses be undertaken and interpreted?. Stat Med 2002; 21 (11) 1559-1573
• 34 Valentine JC, Pigott TD, Rothstein HR. How many studies do you need?: a primer on statistical power for meta-analysis. J Educ Behav Stat 2010; 35: 215-247
• 35 Kim CJ, Park MW, Kim MC. et al; TALOS-AMI investigators. Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicentre, non-inferiority, randomised trial. Lancet 2021; 398 (10308): 1305-1316
• 36 Claassens DMF, Bergmeijer TO, Vos GJA. et al. Clopidogrel versus ticagrelor or prasugrel after primary percutaneous coronary intervention according to CYP2C19 genotype: a POPular genetics subanalysis. Circ Cardiovasc Interv 2021; 14 (04) e009434
• 37 Neumann F-J, Sousa-Uva M, Ahlsson A. et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
• 38 Valgimigli M, Bueno H, Byrne RA. et al; ESC Scientific Document Group, ESC Committee for Practice Guidelines (CPG), ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
• 39 Galli M, Benenati S, Franchi F. et al. Comparative effects of guided vs. potent P2Y12 inhibitor therapy in acute coronary syndrome: a network meta-analysis of 61 898 patients from 15 randomized trials. Eur Heart J 2022; 43 (10) 959-967
• 40 Mehran R, Baber U, Sharma SK. et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med 2019; 381 (21) 2032-2042
• 41 Mennuni MG, Pagnotta PA, Stefanini GG. Coronary stents: the impact of technological advances on clinical outcomes. Ann Biomed Eng 2016; 44 (02) 488-496
• 42 Theodoropoulos K, Mennuni MG, Dangas GD. et al. Resistant in-stent restenosis in the drug eluting stent era. Catheter Cardiovasc Interv 2016; 88 (05) 777-785
• 43 D'Ascenzo F, De Filippo O, Gallone G. et al; PRAISE study group. Machine learning-based prediction of adverse events following an acute coronary syndrome (PRAISE): a modelling study of pooled datasets. Lancet 2021; 397 (10270): 199-207