Genotype-Phenotype Association and Impact on Outcomes following Guided De-Escalation of Anti-Platelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Genotyping Substudy

Lisa Gross; Dietmar Trenk; Claudius Jacobshagen; Anne Krieg; Meinrad Gawaz; Steffen Massberg; Monika Baylacher; Daniel Aradi; Fabian Stimpfle; Julia Hromek; Anja Vogelgesang; Martin Hadamitzky; Dirk Sibbing; Tobias Geisler

doi:10.1055/s-0038-1667337

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(09): 1656-1667
DOI: 10.1055/s-0038-1667337

Atherosclerosis and Ischaemic Disease

Georg Thieme Verlag KG Stuttgart · New York

Genotype-Phenotype Association and Impact on Outcomes following Guided De-Escalation of Anti-Platelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Genotyping Substudy

Lisa Gross

¹Department of Cardiology, LMU München, Munich, Germany

,

Dietmar Trenk

²Department of Cardiology and Angiology II, University Heart Centre Freiburg, University of Freiburg, Bad Krozingen, Germany

,

Claudius Jacobshagen

³Department of Cardiology and Pneumology, Heart Centre, Georg-August-University Göttingen, Göttingen, Germany

,

Anne Krieg

¹Department of Cardiology, LMU München, Munich, Germany

,

Meinrad Gawaz

⁴Department of Cardiology and Cardiovascular Disease, University Hospital Tübingen, University of Tübingen, Tübingen, Germany

,

Steffen Massberg

¹Department of Cardiology, LMU München, Munich, Germany

⁵DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

,

Monika Baylacher

¹Department of Cardiology, LMU München, Munich, Germany

,

Daniel Aradi

⁶Heart Centre Balatonfüred and Heart and Vascular Centre, Semmelweis University, Budapest, Hungary

,

Fabian Stimpfle

⁴Department of Cardiology and Cardiovascular Disease, University Hospital Tübingen, University of Tübingen, Tübingen, Germany

,

Julia Hromek

²Department of Cardiology and Angiology II, University Heart Centre Freiburg, University of Freiburg, Bad Krozingen, Germany

,

Anja Vogelgesang

³Department of Cardiology and Pneumology, Heart Centre, Georg-August-University Göttingen, Göttingen, Germany

,

Martin Hadamitzky

⁷Department of Radiology, Deutsches Herzzentrum München, Technical University of Munich, München, Germany

,

Dirk Sibbing^*

¹Department of Cardiology, LMU München, Munich, Germany

⁵DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

,

Tobias Geisler^*

⁴Department of Cardiology and Cardiovascular Disease, University Hospital Tübingen, University of Tübingen, Tübingen, Germany

› Author Affiliations

Abstract

Background Phenotype-guided de-escalation (PGDE) of P2Y₁₂-inhibitor treatment with an early switch from prasugrel to clopidogrel was identified as an effective alternative treatment strategy in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). The Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Genotyping Substudy aimed to investigate whether CYP2C19 genotypes correlate with on-treatment platelet reactivity (PR) in ACS patients treated with clopidogrel or prasugrel and thus might be useful for guidance of early de-escalation of anti-platelet treatment.

Methods and Results A total of 603 ACS consecutive patients were enrolled in four centres (23.1% of the overall TROPICAL-ACS population). Rapid genotyping (Spartan RX) for CYP2C19*2, *3 and *17 alleles was performed. Associations between PR and the primary and secondary endpoints of the TROPICAL-ACS trial and CYP2C19*2 and CYP2C19*17 carrier status were evaluated.

For the PGDE group, the on-clopidogrel PR significantly differed across CYP2C19*2 (p < 0.001) and CYP2C19*17 genotypes (p = 0.05). Control group patients were not related (p = 0.90, p = 0.74) to on-prasugrel PR. For high PR versus non-high PR patients within the PGDE group, significant differences were observed for the rate of CYP2C19*2 allele carriers (43% vs. 28%, p = 0.007).

Conclusion CYP2C19*2 and CYP2C19*17 carrier status correlates with PR in ACS patients treated with clopidogrel and thus might be useful for pre-selecting patients who will and who may not be suitable for PGDE of anti-platelet treatment. Regarding phenotype-guided treatment, we did not observe added benefit of genotyping to predict ischaemic and bleeding risk in patients who underwent a PGDE approach.

Clinical Trial Registration URL: https//www.clinicaltrials.gov. Unique Identifier: NCT: 01959451.

Keywords

acute coronary syndrome - genotyping - platelets - thrombosis - bleeding - cytochrome P450 (CYP) 2C19

Full Text

References

References
1 Amsterdam EA, Wenger NK, Brindis RG. , et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 64 (24) e139-e228
2 Roffi M, Patrono C, Collet JP. , et al; ESC Scientific Document Group. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37 (03) 267-315
3 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
4 Zettler ME, Peterson ED, McCoy LA. , et al; TRANSLATE-ACS Investigators. Switching of adenosine diphosphate receptor inhibitor after hospital discharge among myocardial infarction patients: insights from the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) observational study. Am Heart J 2017; 183: 62-68
5 De Luca L, D'Ascenzo F, Musumeci G. , et al. Incidence and outcome of switching of oral platelet P2Y12 receptor inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention: the SCOPE registry. EuroIntervention 2017; 13 (04) 459-466
6 Motovska Z, Hlinomaz O, Miklik R. , et al; PRAGUE-18 Study Group. Prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: multicenter randomized PRAGUE-18 study. Circulation 2016; 134 (21) 1603-1612
7 Déry JP, Mehta SR, Fisher HN. , et al; Canadian Observational AntiPlatelet sTudy (COAPT) Investigators. Baseline characteristics, adenosine diphosphate receptor inhibitor treatment patterns, and in-hospital outcomes of myocardial infarction patients undergoing percutaneous coronary intervention in the prospective Canadian Observational AntiPlatelet sTudy (COAPT). Am Heart J 2016; 181: 26-34
8 Angiolillo DJ, Rollini F, Storey RF. , et al. International expert consensus on switching platelet P2Y₁₂ receptor-inhibiting therapies. Circulation 2017; 136 (20) 1955-1975
9 Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107 (23) 2908-2913
10 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 (16) 1821-1830
11 Sibbing D, Stegherr J, Latz W. , et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30 (08) 916-922
12 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 (08) 849-857
13 Mega JL, Close SL, Wiviott SD. , et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360 (04) 354-362
14 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 (9660): 309-317
15 Simon T, Verstuyft C, Mary-Krause M. , et al; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360 (04) 363-375
16 Scott SA, Sangkuhl K, Stein CM. , et al; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 2013; 94 (03) 317-323
17 Cavallari LH. Personalizing antiplatelet prescribing using genetics for patients undergoing percutaneous coronary intervention. Expert Rev Cardiovasc Ther 2017; 15 (08) 581-589
18 Sibbing D, Koch W, Gebhard D. , et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010; 121 (04) 512-518
19 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
20 Zabalza M, Subirana I, Sala J. , et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart 2012; 98 (02) 100-108
21 Li Y, Tang HL, Hu YF, Xie HG. The gain-of-function variant allele CYP2C19*17: a double-edged sword between thrombosis and bleeding in clopidogrel-treated patients. J Thromb Haemost 2012; 10 (02) 199-206
22 Giusti B, Gori AM, Marcucci R. , et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 2009; 103 (06) 806-811
23 Trenk D, Hochholzer W, Fromm MF. , et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51 (20) 1925-1934
24 Hulot JS, Collet JP, Silvain J. , et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 2010; 56 (02) 134-143
25 Sorich MJ, Rowland A, McKinnon RA, Wiese MD. CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. Circ Cardiovasc Genet 2014; 7 (06) 895-902
26 Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ 2011; 343: d4588
27 Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA 2011; 306 (24) 2704-2714
28 Jang JS, Cho KI, Jin HY. , et al. Meta-analysis of cytochrome P450 2C19 polymorphism and risk of adverse clinical outcomes among coronary artery disease patients of different ethnic groups treated with clopidogrel. Am J Cardiol 2012; 110 (04) 502-508
29 Liu YP, Hao PP, Zhang MX. , et al. Association of genetic variants in CYP2C19 and adverse clinical outcomes after treatment with clopidogrel: an updated meta-analysis. Thromb Res 2011; 128 (06) 593-594
30 Viviani Anselmi C, Briguori C, Roncarati R. , et al. Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in predicting clinical outcome following drug-eluting stent implantation in patients with stable coronary artery disease. JACC Cardiovasc Interv 2013; 6 (11) 1166-1175
31 Cresci S, Depta JP, Lenzini PA. , et al. Cytochrome p450 gene variants, race, and mortality among clopidogrel-treated patients after acute myocardial infarction. Circ Cardiovasc Genet 2014; 7 (03) 277-286
32 Stimpfle F, Geisler T. Impact of tailored anti-P2Y12 therapies in acute coronary syndromes. Pharmacogenomics 2015; 16 (05) 493-499
33 Cavallari LH, Franchi F, Rollini F. , et al. Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention. J Transl Med 2018; 16 (01) 92
34 Sibbing D, Aradi D, Jacobshagen C. , et al; TROPICAL-ACS Investigators. A randomised trial on platelet function-guided de-escalation of antiplatelet treatment in ACS patients undergoing PCI. Rationale and design of the Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Trial. Thromb Haemost 2017; 117 (01) 188-195
35 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
36 Aradi D, Kirtane A, Bonello L. , et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015; 36 (27) 1762-1771
37 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 (9827): 1705-1711
38 Tantry US, Bonello L, Aradi D. , et al; Working Group on On-Treatment Platelet Reactivity. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013; 62 (24) 2261-2273
39 Thygesen K, Alpert JS, Jaffe AS. , et al; Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction; Authors/Task Force Members Chairpersons; Biomarker Subcommittee; ECG Subcommittee; Imaging Subcommittee; Classification Subcommittee; Intervention Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; ESC Committee for Practice Guidelines (CPG); Document Reviewers. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60 (16) 1581-1598
40 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
41 Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 2009; 169 (04) 505-514
42 Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol 2016; 13 (01) 11-27
43 Cuisset T, Deharo P, Quilici J. , et al. 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
44 Sherwood MW, Wiviott SD, Peng SA. , et al. Early clopidogrel versus prasugrel use among contemporary STEMI and NSTEMI patients in the US: insights from the National Cardiovascular Data Registry. J Am Heart Assoc 2014; 3 (02) e000849
45 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 (01) 16-22
46 Wirth F, Zahra G, Xuereb RG, Barbara C, Fenech A, Azzopardi LM. Comparison of a rapid point-of-care and two laboratory-based CYP2C19*2 genotyping assays for personalisation of antiplatelet therapy. Int J Clin Pharm 2016; 38 (02) 414-420
47 Erlinge D, James S, Duvvuru S. , et al. Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease. Thromb Haemost 2014; 111 (05) 943-950
48 Weitzel KW, Elsey AR, Langaee TY. , et al. Clinical pharmacogenetics implementation: approaches, successes, and challenges. Am J Med Genet C Semin Med Genet 2014; 166C (01) 56-67
49 Shuldiner AR, Palmer K, Pakyz RE. , et al. Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program. Am J Med Genet C Semin Med Genet 2014; 166C (01) 76-84
50 Peterson JF, Field JR, Unertl KM. , et al. Physician response to implementation of genotype-tailored antiplatelet therapy. Clin Pharmacol Ther 2016; 100 (01) 67-74
51 Lee JA, Lee CR, Reed BN. , et al. Implementation and evaluation of a CYP2C19 genotype-guided antiplatelet therapy algorithm in high-risk coronary artery disease patients. Pharmacogenomics 2015; 16 (04) 303-313
52 Harada S, Zhou Y, Duncan S. , et al. Precision medicine at the University of Alabama at Birmingham: laying the foundational processes through implementation of genotype-guided antiplatelet therapy. Clin Pharmacol Ther 2017; 102 (03) 493-501
53 Cavallari LH, Lee CR, Beitelshees AL. , et al. IGNITE Network. Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv 2018; 11 (02) 181-191
54 Cavallari LH, Beitelshees AL, Blake KV. , et al; The IGNITE Pharmacogenetics Working Group. The IGNITE Pharmacogenetics Working Group: an opportunity for building evidence with pharmacogenetic implementation in a real-world setting. Clin Transl Sci 2017; 10 (03) 143-146
55 Empey PE, Stevenson JM, Tuteja S. , et al; IGNITE Network. Multi-site investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy. Clin Pharmacol Ther 2017;
56 Holmes Jr DR, Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2010; 56 (04) 321-341
57 Mega JL, Close SL, Wiviott SD. , et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119 (19) 2553-2560
58 Hochholzer W, Trenk D, Fromm MF. , et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 2010; 55 (22) 2427-2434
59 Alexopoulos D, Dimitropoulos G, Davlouros P. , et al. Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping. JACC Cardiovasc Interv 2011; 4 (04) 403-410
60 Collet JP, Hulot JS, Anzaha G. , et al; CLOVIS-2 Investigators. High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2). JACC Cardiovasc Interv 2011; 4 (04) 392-402
61 Pereira NL, Sargent DJ, Farkouh ME, Rihal CS. Genotype-based clinical trials in cardiovascular disease. Nat Rev Cardiol 2015; 12 (08) 475-487
62 Collet JP, Hulot JS, Cuisset T. , et al; ARCTIC investigators. Genetic and platelet function testing of antiplatelet therapy for percutaneous coronary intervention: the ARCTIC-GENE study. Eur J Clin Pharmacol 2015; 71 (11) 1315-1324
63 Sibbing D, Gross L. CYP2C19 genotyping in percutaneous coronary intervention-treated patients: ready for prime time?. JACC Cardiovasc Interv 2018; 11 (02) 192-194
64 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 (17) 1869-1877
65 Price MJ, Angiolillo DJ. Pharmacogenomic testing to select antiplatelet therapy. J Am Coll Cardiol 2018; 71 (17) 1878-1881