Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI—the POPular Risk Score study
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.
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.
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.
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.
KeywordsPlatelet aggregation CYP2C19 Percutaneous coronary intervention P2Y12 inhibitor Clopidogrel Prasugrel
The authors would like to thank all personnel of the St. Antonius Hospital and the referring hospitals involved in this project.
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.
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.
- 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.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.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
- 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
- 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
- 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
- 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.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.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
- 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.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.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
- 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.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.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.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
- 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.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.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
- 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