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直接PCI中基因型指导的口服P2Y12抑制剂选择策略
A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI


Daniel M.F. Claassens ... 心脑血管疾病 • 2019.10.24
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基因检测指导直接PCI患者口服P2Y12抑制剂的选择

 

席子惟,刘巍*

首都医科大学附属北京安贞医院心内科

*通讯作者

 

由阿司匹林和P2Y12受体抑制剂组成的双联抗血小板药物是急性冠状动脉综合征(ACS)患者治疗的基石。基于此前的PLATO1和TRITON-TIMI 382研究,现有指南一致认为,ACS患者在没有禁忌证的情况下,应优先选择强效抗血小板药物替格瑞洛和普拉格雷。

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摘要


背景

目前尚不了解接受直接经皮冠状动脉介入治疗(PCI)的患者可否从基因型指导的口服P2Y12抑制剂选择策略中获益。

 

方法

我们开展了一项随机、开放标签、评估人设盲的试验。试验将通过支架置入术接受直接PCI的患者以1∶1的比例分组,分别根据早期CYP2C19基因检测接受一种P2Y12抑制剂治疗(基因型指导组),或接受替格瑞洛或普拉格雷标准治疗(标准治疗组),为期12个月。在基因型指导组中,CYP2C19*2CYP2C19*3功能丧失型等位基因携带者接受了替格瑞洛或普拉格雷治疗,非携带者接受了氯吡格雷治疗。两项主要结局是12个月时的净临床不良事件(定义为全因死亡、心肌梗死、明确支架内血栓形成、卒中或根据血小板抑制和患者结局[Platelet Inhibition and Patient Outcomes,PLATO]试验标准定义的大出血)(主要复合结局;进行非劣效性检验,非劣效性界值是绝对差异2个百分点)和12个月时的PLATO大出血或小出血(主要出血结局)。

 

结果

主要分析纳入了2,488例患者:基因型指导组1,242例,标准治疗组1,246例。基因型指导组63例患者(5.1%)和标准治疗组73例患者(5.9%)发生了主要复合结局(绝对差异,-0.7个百分点;95%置信区间[CI],-2.0~0.7;非劣效性P<0.001)。基因型指导组122例患者(9.8%)和标准治疗组156例患者(12.5%)发生了主要出血结局(风险比,0.78;95% CI,0.61~0.98;P=0.04)。

 

结论

在接受直接PCI的患者中,在血栓形成事件方面,CYP2C19基因型指导的口服P2Y12抑制剂选择策略在12个月时不劣于替格瑞洛或普拉格雷标准治疗,且出血发生率较低(由荷兰卫生研究与发展组织[Netherlands Organization for Health Research and Development]资助;POPular Genetics在ClinicalTrials.gov注册号为NCT01761786;在Netherlands Trial Register注册号为NL2872)。





作者信息

Daniel M.F. Claassens, M.D., Gerrit J.A. Vos, M.D., Thomas O. Bergmeijer, M.D., Renicus S. Hermanides, M.D., Ph.D., Arnoud W.J. van ’t Hof, M.D., Ph.D., Pim van der Harst, M.D., Ph.D., Emanuele Barbato, M.D., Ph.D., Carmine Morisco, M.D., Ph.D., Richard M. Tjon Joe Gin, M.D., Folkert W. Asselbergs, M.D., Ph.D., Arend Mosterd, M.D., Ph.D., Jean-Paul R. Herrman, M.D., Ph.D., Willem J.M. Dewilde, M.D., Ph.D., Paul W.A. Janssen, M.D., Ph.D., Johannes C. Kelder, M.D., Ph.D., Maarten J. Postma, Ph.D., Anthonius de Boer, M.D., Ph.D., Cornelis Boersma, Pharm.D., Ph.D., Vera H.M. Deneer, Pharm.D., Ph.D., and Jurriën M. ten Berg, M.D., Ph.D.
From the Department of Cardiology, St. Antonius Hospital, Nieuwegein (D.M.F.C., G.J.A.V., T.O.B., P.W.A.J., J.C.K., J.M.B.), the Department of Cardiology, Isala Hospital, Zwolle (R.S.H., A.W.J.H.), the Department of Cardiology, University Medical Center Maastricht, Maastricht (A.W.J.H.), the Department of Cardiology, Zuyderland Medical Center, Heerlen (A.W.J.H.), the Department of Cardiology, University Medical Center Groningen (P.H., J.M.B.), the Department of Pharmacy, University of Groningen (M.J.P.), and the Unit of Global Health, Department of Health Sciences, University of Groningen, University Medical Center Groningen (M.J.P., C.B.), Groningen, the Department of Cardiology, Rijnstate Hospital, Arnhem (R.M.T.J.G.), the Department of Cardiology, Division of Heart and Lungs (F.W.A.), and the Department of Clinical Pharmacy, Division of Laboratories, Pharmacy, and Biomedical Genetics (V.H.M.D.), University Medical Center Utrecht, and the Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (A.B.), Utrecht University, Utrecht, the Department of Cardiology, Meander Medical Center, Amersfoort (A.M.), the Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam (J.-P.R.H.), and the Department of Cardiology, Amphia Hospital, Breda (W.J.M.D.) — all in the Netherlands; the Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy (E.B., C.M.); the Cardiovascular Research Center, Onze Lieve Vrouwe Hospital, Aalst (E.B.), and the Department of Cardiology, Imelda Hospital, Bonheiden (W.J.M.D.) — both in Belgium; and the Institute of Cardiovascular Science, Faculty of Population Health Sciences, and Health Data Research UK and Institute of Health Informatics, University College London, London (F.W.A.). Address reprint requests to Dr. ten Berg at St. Antonius Hospital, Koekoekslaan 1, 3435CM, Nieuwegein, the Netherlands, or at jurtenberg@gmail.com.

 

参考文献

1. Ibanez B, James S, Agewall S, et al. 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;39:119-177.

2. 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;68:1082-1115.

3. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-1057.

4. 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.

5. 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;303:754-762.

6. 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. JAMA 2010;304:1821-1830.

7. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009;373:309-317.

8. Harmsze AM, van Werkum JW, Ten Berg JM, et al. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J 2010;31:3046-3053.

9. Shuldiner AR, O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849-857.

10. 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;376:1312-1319.

11. Wallentin L, James S, Storey RF, et al. 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;376:1320-1328.

12. Cavallari LH, Lee CR, Beitelshees AL, et al. Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv 2018;11:181-191.

13. Bergmeijer TO, Janssen PW, Schipper JC, et al. CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients — rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. Am Heart J 2014;168(1):16.e1-22.e1.

14. 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;32:2999-3054.

15. Bergmeijer TO, Vos GJ, Claassens DM, et al. Feasibility and implementation of CYP2C19 genotyping in patients using antiplatelet therapy. Pharmacogenomics 2018;19:621-628.

16. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60:1581-1598.

17. 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.

18. 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;123:2736-2747.

19. Van’t Hof AW, Ten Berg J, Heestermans T, et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised controlled trial. Lancet 2008;372:537-546.

20. Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Grüntzig Lecture ESC 2014. Eur Heart J 2015;36:3320-3331.

21. Kedhi E, Fabris E, van der Ent M, et al. Six months versus 12 months dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI): randomised, multicentre, non-inferiority trial. BMJ 2018;363:k3793-k3793.

22. Sibbing D, Aradi D, Jacobshagen C, et al. 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;390:1747-1757.

23. Sánchez-Ramos J, Dávila-Fajardo CL, Toledo Frías P, et al. Results of genotype-guided antiplatelet therapy in patients who undergone percutaneous coronary intervention with stent. Int J Cardiol 2016;225:289-295.

24. Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012;379:1705-1711.

25. Janssen PWA, Bergmeijer TO, Vos GA, et al. Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI — the POPular Risk Score study. Eur J Clin Pharmacol 2019;75:1201-1210.

26. Notarangelo FM, Maglietta G, Bevilacqua P, et al. Pharmacogenomic approach to selecting antiplatelet therapy in patients with acute coronary syndromes: the PHARMCLO Trial. J Am Coll Cardiol 2018;71:1869-1877.

27. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87-165.

28. Cayla G, Cuisset T, Silvain J, et al. 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;388:2015-2022.

29. Généreux P, Giustino G, Witzenbichler B, et al. Incidence, predictors, and impact of post-discharge bleeding after percutaneous coronary intervention. J Am Coll Cardiol 2015;66:1036-1045.

30. Czarny MJ, Nathan AS, Yeh RW, Mauri L. Adherence to dual antiplatelet therapy after coronary stenting: a systematic review. Clin Cardiol 2014;37:505-513.

31. Cutlip DE, Kereiakes DJ, Mauri L, Stoler R, Dauerman HL. Thrombotic complications associated with early and late nonadherence to dual antiplatelet therapy. JACC Cardiovasc Interv 2015;8:404-410.

32. Straub N, Beivers A, Lenk E, Aradi D, Sibbing D. A model-based analysis of the clinical and economic impact of personalising P2Y12-receptor inhibition with platelet function testing in acute coronary syndrome patients. Thromb Haemost 2014;111:290-299.

33. Sibbing D, Aradi D, Alexopoulos D, et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv 2019 June 10 (Epub ahead of print).

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