Semin Thromb Hemost 2020; 46(04): 446-456
DOI: 10.1055/s-0039-3399567
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Benefits and Harm of Treatment with P2Y12 Inhibitors beyond 12 Months in Patients with Coronary Artery Disease

Mads Lamm Larsen
1   Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Medicine, Regional Hospital Horsens, Horsens, Denmark
,
Erik Lerkevang Grove
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
4   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Steen Dalby Kristensen
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
4   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Anne-Mette Hvas
1   Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
4   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
› Author Affiliations
Further Information

Publication History

Publication Date:
20 December 2019 (online)

Abstract

The trade-off between the benefits and harm of long-term (> 12 months) treatment with P2Y12 inhibitors in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI) remains controversial. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed and Embase were searched without time restrictions to identify randomized controlled trials comparing > 12-month P2Y12 inhibition versus ≤ 12-month treatment in patients with acute coronary syndrome (ACS) or stable CAD undergoing PCI. A qualitative assessment was performed using the assessment tool from the National Heart, Lung, and Blood Institute of the National Institutes of Health. We performed a meta-analysis of the following endpoints: primary outcome (primarily major cardiovascular events), all-cause death, and major bleeding. Eight trials, comprising 40,218 patients, were included. Five studies were rated “good,” two studies “fair,” and one study “poor.” The meta-analysis showed that > 12-month P2Y12 inhibition significantly reduced the primary outcomes compared with ≤ 12-month treatment (hazard ratio [HR]: 0.85; 95% confidence interval (CI): 0.75–0.97; p = 0.01). No significant difference was demonstrated between groups in all-cause death (HR: 1.02; 95% CI: 0.76–1.36; p = 0.91) or major bleedings (HR: 1.26; 95% CI: 0.93–1.70; p = 0.14). I 2 test showed low to moderate heterogeneity among the included studies (21.6–62.3%). This systematic review and meta-analysis therefore demonstrates a reduction in major cardiovascular events during extended P2Y12-inhibitor treatment beyond 12 months compared with ≤ 12 months in patients with ACS or stable CAD undergoing PCI. There was no significant difference in all-cause death or major bleedings.

 
  • References

  • 1 Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357 (24) 2482-2494
  • 2 Benjamin EJ, Virani SS, Callaway CW. , et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 2018; 137 (12) e67-e492
  • 3 Freynhofer MK, Bruno V, Wojta J, Huber K. The role of platelets in athero-thrombotic events. Curr Pharm Des 2012; 18 (33) 5197-5214
  • 4 Clappers N, Brouwer MA, Verheugt FW. Antiplatelet treatment for coronary heart disease. Heart 2007; 93 (02) 258-265
  • 5 Neumann FJ, Sousa-Uva M, Ahlsson A. , et al. 2018 ESC/EACTS guidelines on myocardial revascularization. EuroIntervention 2019; 14 (14) 1435-1534
  • 6 Grove EL, Würtz M, Thomas MR, Kristensen SD. Antiplatelet therapy in acute coronary syndromes. Expert Opin Pharmacother 2015; 16 (14) 2133-2147
  • 7 Degrauwe S, Pilgrim T, Aminian A, Noble S, Meier P, Iglesias JF. Dual antiplatelet therapy for secondary prevention of coronary artery disease. Open Heart 2017; 4 (02) e000651
  • 8 Montalescot G, Sechtem U, Achenbach S. , et al; Task Force Members; ESC Committee for Practice Guidelines; Document Reviewers. 2013 ESC guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34 (38) 2949-3003
  • 9 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
  • 10 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 Thorac Cardiovasc Surg 2016; 152 (05) 1243-1275
  • 11 Pareek M, Bhatt DL, Ten Berg JM, Kristensen SD, Grove EL. Antithrombotic strategies for preventing long-term major adverse cardiovascular events in patients with non-valvular atrial fibrillation who undergo percutaneous coronary intervention. Expert Opin Pharmacother 2017; 18 (09) 875-883
  • 12 Udell JA, Bonaca MP, Collet JP. , et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J 2016; 37 (04) 390-399
  • 13 Navarese EP, Andreotti F, Schulze V. , et al. Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials. BMJ 2015; 350: h1618
  • 14 D'Ascenzo F, Moretti C, Bianco M. , et al. Meta-analysis of the duration of dual antiplatelet therapy in patients treated with second-generation drug-eluting stents. Am J Cardiol 2016; 117 (11) 1714-1723
  • 15 Mauri L, Kereiakes DJ, Yeh RW. , et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371 (23) 2155-2166
  • 16 Costa F, Valgimigli M. The optimal duration of dual antiplatelet therapy after coronary stent implantation: to go too far is as bad as to fall short. Cardiovasc Diagn Ther 2018; 8 (05) 630-646
  • 17 Didier R, Morice MC, Barragan P. , et al. 6- Versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: final results of the ITALIC trial (is there a life for des after discontinuation of clopidogrel). JACC Cardiovasc Interv 2017; 10 (12) 1202-1210
  • 18 Nakamura M, Iijima R, Ako J. , et al; NIPPON Investigators. Dual antiplatelet therapy for 6 versus 18 months after biodegradable polymer drug-eluting stent implantation. JACC Cardiovasc Interv 2017; 10 (12) 1189-1198
  • 19 Helft G, Steg PG, Le Feuvre C. , et al; OPTImal DUAL Antiplatelet Therapy Trial Investigators. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J 2016; 37 (04) 365-374
  • 20 Collet JP, Silvain J, Barthélémy O. , et al; ARCTIC investigators. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014; 384 (9954): 1577-1585
  • 21 Lee CW, Ahn JM, Park DW. , et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129 (03) 304-312
  • 22 Valgimigli M, Campo G, Monti M. , et al; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012; 125 (16) 2015-2026
  • 23 Vranckx P, Valgimigli M, Jüni P. , et al; GLOBAL LEADERS Investigators. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet 2018; 392 (10151): 940-949
  • 24 Moher D, Liberati A, Tetzlaff J, Altman DG. ; PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. Open Med 2009; 3 (03) e123-e130
  • 25 The National Heart LaBIotNIoH. Study quality assessment tools. 2013 . Available at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools . Accessed February, 2019
  • 26 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): 557-560
  • 27 Sterne JA, Sutton AJ, Ioannidis JP. , et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343: d4002
  • 28 Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive Meta-Analysis Version 3 [computer program]. Englewood, NJ: Biostat; 2013
  • 29 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 (04) 256-265
  • 30 Mehran R, Rao SV, Bhatt DL. , et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
  • 31 Schulman S, Kearon C. ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
  • 32 Montalescot G, White HD, Gallo R. , et al; STEEPLE Investigators. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006; 355 (10) 1006-1017
  • 33 GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329 (10) 673-682
  • 34 Gilard M, Barragan P, Noryani AAL. , et al. 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol 2015; 65 (08) 777-786
  • 35 Kim BK, Hong MK, Shin DH. , et al; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60 (15) 1340-1348
  • 36 Feres F, Costa RA, Abizaid A. , et al; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013; 310 (23) 2510-2522
  • 37 Gwon HC, Hahn JY, Park KW. , et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125 (03) 505-513
  • 38 Colombo A, Chieffo A, Frasheri A. , et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014; 64 (20) 2086-2097
  • 39 Schulz-Schüpke S, Byrne RA, Ten Berg JM. , et al; Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) Trial Investigators. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J 2015; 36 (20) 1252-1263
  • 40 Han Y, Xu B, Xu K. , et al. Six versus 12 months of dual antiplatelet therapy after implantation of biodegradable polymer sirolimus-eluting stent: randomized substudy of the I-LOVE-IT 2 Trial. Circ Cardiovasc Interv 2016; 9 (02) e003145
  • 41 Hong SJ, Shin DH, Kim JS. , et al; IVUS-XPL Investigators. 6-Month versus 12-month dual-antiplatelet therapy following long everolimus-eluting stent implantation: the IVUS-XPL randomized clinical trial. JACC Cardiovasc Interv 2016; 9 (14) 1438-1446
  • 42 Lee JM, Cho DK, Hahn JY. , et al. Safety of 6-month duration of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndromes: rationale and design of the Smart Angioplasty Research Team-safety of 6-month duration of Dual Antiplatelet Therapy after percutaneous coronary intervention in patients with acute coronary syndromes (SMART-DATE) prospective multicenter randomized trial. Am Heart J 2016; 182: 1-8
  • 43 Gent M, Beaumont D, Blanchard J. , et al; CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348 (9038): 1329-1339
  • 44 Bhatt DL, Fox KA, Hacke W. , et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354 (16) 1706-1717
  • 45 Fanari Z, Malodiya A, Weiss SA, Hammami S, Kolm P, Weintraub WS. Long-term use of dual antiplatelet therapy for the secondary prevention of atherothrombotic events: meta-analysis of randomized controlled trials. Cardiovasc Revasc Med 2017; 18 (01) 10-15
  • 46 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
  • 47 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
  • 48 Bonaca MP, Bhatt DL, Cohen M. , et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800
  • 49 Bhatt DL. EXAMINATION of new drug-eluting stents--top of the class!. Lancet 2012; 380 (9852): 1453-1455
  • 50 Costa F, Valgimigli M. Impact of clinical presentation on dual antiplatelet therapy duration: let's re-evaluate our priorities. J Am Coll Cardiol 2015; 66 (10) 1203-1204
  • 51 Costa F, Vranckx P, Leonardi S. , et al. Impact of clinical presentation on ischaemic and bleeding outcomes in patients receiving 6- or 24-month duration of dual-antiplatelet therapy after stent implantation: a pre-specified analysis from the PRODIGY (Prolonging Dual-Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial. Eur Heart J 2015; 36 (20) 1242-1251
  • 52 Yeh RW, Secemsky EA, Kereiakes DJ. , et al; DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016; 315 (16) 1735-1749
  • 53 Mauri L, Kereiakes DJ, Normand SL. , et al. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am Heart J 2010; 160 (06) 1035-1041 , 1041.e1