Advertisement

Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI—the POPular Risk Score study

  • Paul W. A. JanssenEmail author
  • Thomas O. Bergmeijer
  • Gert-Jan A. Vos
  • Johannes C. Kelder
  • Khalid Qaderdan
  • Thea C. Godschalk
  • Nicoline J. Breet
  • Vera H. M. Deneer
  • Christian M. Hackeng
  • Jurriën M. ten Berg
Pharmacogenetics

Abstract

Purpose

The POPular Risk Score was developed for the selective intensification of P2Y12 inhibitor treatment with prasugrel instead of clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI) with stent implantation. This score is based on platelet reactivity (VerifyNow P2Y12 assay), CYP2C19 genotyping, and clinical risk factors. Our aim was to determine if the use of this score in clinical practice is associated with a reduction in thrombotic events without increasing bleeding events.

Methods

In a single-center prospective cohort study, patients with a high risk score were treated with prasugrel and patients with a low risk score with clopidogrel. The risk score–guided cohort was compared with a historic cohort of clopidogrel-treated patients. The endpoint consisted of all-cause death, myocardial infarction, stroke, or stent thrombosis during 1 year of follow-up. TIMI major and minor bleeding events were also analyzed.

Results

The guided cohort contained 1127 patients, 26.9% of whom were switched to prasugrel according to the POPular Risk Score. The historic cohort contained 893 patients. The incidence of the combined thrombotic endpoint was significantly lower in the guided cohort as compared with the historic cohort (8.4% versus 3.7%, p < 0.001). This strategy was safe with respect to bleeding (4.0% versus 1.3%, p < 0.001, for TIMI major or minor bleeding). Results were comparable after multivariate and propensity score matched and weighted analysis.

Conclusion

Selective intensification of P2Y12 inhibitor treatment after non-urgent PCI based on the POPular Risk Score is associated with a reduction in thrombotic events without an increase in bleeding events.

Keywords

Platelet aggregation CYP2C19 Percutaneous coronary intervention P2Y12 inhibitor Clopidogrel Prasugrel 

Notes

Acknowledgments

The authors would like to thank all personnel of the St. Antonius Hospital and the referring hospitals involved in this project.

Authors’ contributions

PWAJ, TOB, GJAV, and JCK had full access to all the study data and took responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: PWAJ, TOB, JCK, NJB, VHMD, CMH, and JMB. Drafting of the manuscript: PWAJ, TOB, JCK, TCG, and KQ. Critical revision of the manuscript for important intellectual content: all authors. Acquisition, analysis, or interpretation of data: all authors.

Funding

This study was supported by the St. Antonius Innovation fund and a ZonMw TopZorg grant. ZonMw is a Dutch organization funded by the government promoting health care research and the implementation of study results in daily practice. The authors were solely responsible for the design and conduct of this study, all study analyses, and the drafting and editing of the paper and its final contents.

Compliance with ethical standards

The study was conducted according to the principles of the Declaration of Helsinki and received approval from the local human research ethics committee. Approval for this registry included a waiver of the need for written informed consent.

Conflict of interest

JMtB reports receiving advisory/consulting/speakers fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, the Medicines Company, Accumetrics, Boehringer-Ingelheim, BMS, Pfizer, Bayer. All other authors have nothing to declare. The department of cardiology of the St. Antonius Hospital has received research grants from ZonMw and AstraZeneca.

Supplementary material

228_2019_2696_MOESM1_ESM.docx (18 kb)
Appendix 1 (DOCX 18 kb)
228_2019_2696_MOESM2_ESM.docx (23 kb)
Appendix 2 (DOCX 22 kb)
228_2019_2696_MOESM3_ESM.docx (21 kb)
Appendix 3 (DOCX 21 kb)
228_2019_2696_MOESM4_ESM.docx (116 kb)
Appendix 4 (DOCX 116 kb)
228_2019_2696_MOESM5_ESM.docx (130 kb)
Appendix 5 (DOCX 129 kb)

References

  1. 1.
    Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, Stone GW, Curzen N, Geisler T, ten Berg J, Kirtane A, Siller-Matula J, Mahla E, Becker RC, Bhatt DL, Waksman R, Rao SV, Alexopoulos D, Marcucci R, Reny JL, Trenk D, Sibbing D, Gurbel PA (2013) Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 62:2261–2273CrossRefGoogle Scholar
  2. 2.
    Authors/Task Force members, Windecker S, Kolh P et al (2014) 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 35:2541–2619CrossRefGoogle Scholar
  3. 3.
    Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, Deneer VH, Harmsze AM, van der Heyden J, Rensing BJ, Suttorp MJ, Hackeng CM, ten Berg J (2010) Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 303:754–762CrossRefGoogle Scholar
  4. 4.
    Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM (2003) Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107:2908–2913CrossRefGoogle Scholar
  5. 5.
    Hochholzer W, Trenk D, Frundi D, Blanke P, Fischer B, Andris K, Bestehorn HP, Büttner HJ, Neumann FJ (2005) Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 111:2560–2564CrossRefGoogle Scholar
  6. 6.
    Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ (2005) Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 45:246–251CrossRefGoogle Scholar
  7. 7.
    Scott S, Sangkuhl K, Stein C, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR, Clinical Pharmacogenetics Implementation Consortium (2013) Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 94:317–323CrossRefGoogle Scholar
  8. 8.
    Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360:363–375CrossRefGoogle Scholar
  9. 9.
    Bouman HJ, Harmsze AM, van Werkum JW, Breet NJ, Bergmeijer TO, ten Cate H, Hackeng CM, Deneer VHM, ten Berg JM (2011) Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting. Heart 97:1239–1244CrossRefGoogle Scholar
  10. 10.
    Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF (2011) Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J 11:199–206CrossRefGoogle Scholar
  11. 11.
    Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, de Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015CrossRefGoogle Scholar
  12. 12.
    Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, PLATO Investigators, Freij A, Thorsén M (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057CrossRefGoogle Scholar
  13. 13.
    Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Macaya C (2005) Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 54:2430–2435CrossRefGoogle Scholar
  14. 14.
    Sibbing D, von Beckerath O, Schomig A, Kastrati A, von Beckerath N (2007) Platelet function in clopidogrel-treated patients with acute coronary syndrome. Blood Coagul Fibrinolysis 18:335–339CrossRefGoogle Scholar
  15. 15.
    Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, Goodman SG, Corbalan R, Purdy DA, Murphy SA, McCabe C, Antman EM, TRITON-TIMI 38 Investigators (2008) Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38. Circulation 118:1626–1636CrossRefGoogle Scholar
  16. 16.
    Farooq V, van Klaveren D, Steyerberg EW, Meliga E, Vergouwe Y, Chieffo A, Kappetein AP, Colombo A, Holmes DR Jr, Mack M, Feldman T, Morice MC, Ståhle E, Onuma Y, Morel MA, Garcia-Garcia HM, van Es GA, Dawkins KD, Mohr FW, Serruys PW (2013) Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet 381:639 <last_page> 650–650CrossRefGoogle Scholar
  17. 17.
    Yan BP, Ajani AE, New G, Duffy SJ, Farouque O, Shaw J, Sebastian M, Lew R, Brennan A, Andrianopoulos N, Reid C, Clark DJ (2008) Are drug-eluting stents indicated in large coronary arteries? Insights from a multi-centre percutaneous coronary intervention registry. Int J Cardiol 130:374–379CrossRefGoogle Scholar
  18. 18.
    Tcheng JE, Lim IH, Srinivasan S, Jozic J, Gibson CM, O’Shea JC, Puma JA, Simon DI (2009) Stent parameters predict major adverse clinical events and the response to platelet glycoprotein IIb/IIIa blockade: findings of the ESPRIT trial. Circ Cardiovasc Interv 2:43–51CrossRefGoogle Scholar
  19. 19.
    Michelson AD, Frelinger AL 3rd, Braunwald E et al (2009) Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J 30:1753–1763CrossRefGoogle Scholar
  20. 20.
    Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es G, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW, Academic Research Consortium (2007) Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 115:2344–2351CrossRefGoogle Scholar
  21. 21.
    Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H (2011) Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 123:2736–2747CrossRefGoogle Scholar
  22. 22.
    Ridgeway G, McCaffrey D, Morral A, Griffin B, Burgette L (2014) TWANG: toolkit for weighting and analysis of nonequivalent groups. R package version 1.4-0. 18-3-2014Google Scholar
  23. 23.
    Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, Puri S, Robbins M, Garratt KN, Bertrand OF, Stillabower ME, Aragon JR, Kandzari DE, Stinis CT, Lee MS, Manoukian SV, Cannon CP, Schork NJ, Topol EJ, GRAVITAS Investigators (2011) Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305:1097–1105CrossRefGoogle Scholar
  24. 24.
    Collet JP, Cuisset T, Range G et al (2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367:2100–2109CrossRefGoogle Scholar
  25. 25.
    Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C, Delarche N, Bellemain-Appaix A, Range G, el Mahmoud R, Carrié D, Belle L, Souteyrand G, Aubry P, Sabouret P, du Fretay XH, Beygui F, Bonnet JL, Lattuca B, Pouillot C, Varenne O, Boueri Z, van Belle E, Henry P, Motreff P, Elhadad S, Salem JE, Abtan J, Rousseau H, Collet JP, Vicaut E, Montalescot G (2016) 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 388:2015–2022CrossRefGoogle Scholar
  26. 26.
    Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, Orban M, Hadamitzky M, Merkely B, Kiss RG, Komócsi A, Dézsi CA, Holdt L, Felix SB, Parma R, Klopotowski M, Schwinger RHG, Rieber J, Huber K, Neumann FJ, Koltowski L, Mehilli J, Huczek Z, Massberg S, Parma R, Parma Z, Lesiak M, Komosa A, Huczek Z, Koltowski L, Kowara M, Rymuza B, Klopotowski M, Malek L, Aradi D, Veress G, Dézsi AD, Merkely B, Lux Á, Kiss RG, Papp J, Kovács A, Dézsi CA, Amer S, Ruzsa Z, Róna S, Komócsi A, Ili R, Ungi I, Nagy F, Zweiker R, Tóth-Gayor G, Huber K, Haller P, von Scheidt W, Blüthgen A, Neumann FJ, Trenk D, Leggewie S, Kreider-Stempfle HU, Remp T, Kara K, Mügge A, Wutzler A, Fichtlscherer S, Zeiher AM, Seeger F, Hinterseer M, König A, Lederle S, Jacobshagen C, Czepluch F, Maier L, Schillinger W, Sossalla S, Hummel A, Felix S, Karakas M, Sydow K, Rudolph T, Halbach M, Gori T, Münzel T, May A, Gerstenberg CM, Pilecky D, Rieber J, Deichstetter M, Sibbing D, Mehilli J, Gross L, Kääb S, Löw A, Orban M, Orban M, Sattler S, Deuschl S, Teupser D, Holdt L, Mudra H, Räder T, Schütz T, Vahldiek F, Divchev D, Ince H, Nienaber CA, Radunski H, Boekstegers P, Horstkotte J, Mueller R, Geisler T, Müller K, Schwinger R, Rasp O (2017) 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 390:1747–1757CrossRefGoogle Scholar
  27. 27.
    Mayer K, Schulz S, Bernlochner I, Morath T, Braun S, Hausleiter J, Massberg S, Schunkert H, Laugwitz KL, Kastrati A, Sibbing D (2014) A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity. Results of the ISAR-HPR registry. Thromb Haemost 112:342–351CrossRefGoogle Scholar
  28. 28.
    Aradi D, Tornyos A, Pinter T et al (2014) Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol 63:1061–1070CrossRefGoogle Scholar
  29. 29.
    Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schömig A, von Beckerath N, Kastrati A (2010) Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 121:512–518CrossRefGoogle Scholar
  30. 30.
    Lewis J, Stephens S, Horenstein R et al (2013) The CYP2C19*17 variant is not independently associated with clopidogrel response. J Thromb Haemost 11:1640–1646CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Paul W. A. Janssen
    • 1
    • 2
    Email author
  • Thomas O. Bergmeijer
    • 1
    • 2
  • Gert-Jan A. Vos
    • 1
    • 2
  • Johannes C. Kelder
    • 1
    • 2
  • Khalid Qaderdan
    • 1
    • 2
  • Thea C. Godschalk
    • 1
    • 2
  • Nicoline J. Breet
    • 2
    • 3
  • Vera H. M. Deneer
    • 2
    • 4
  • Christian M. Hackeng
    • 2
    • 5
  • Jurriën M. ten Berg
    • 1
    • 2
  1. 1.Department of CardiologySt Antonius HospitalNieuwegeinThe Netherlands
  2. 2.St Antonius Centre for Platelet Function ResearchSt Antonius HospitalNieuwegeinThe Netherlands
  3. 3.Department of CardiologyGelre ziekenhuizenApeldoornThe Netherlands
  4. 4.Department of Clinical PharmacyUniversity Medical Centre UtrechtUtrechtThe Netherlands
  5. 5.Department of Clinical ChemistrySt Antonius HospitalNieuwegeinThe Netherlands

Personalised recommendations