Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A prospective randomized evaluation of a pharmacogenomic approach to antiplatelet therapy among patients with ST-elevation myocardial infarction: the RAPID STEMI study

The Pharmacogenomics Journal volume 16, pages 71–78 (2016)Cite this article

Subjects

Abstract

Treatment of carriers of the CYP2C19*2 allele and ABCB1 TT genotype with clopidogrel is associated with increased ischemic complications after percutaneous coronary intervention (PCI). We sought to evaluate a pharmacogenomic strategy among patients undergoing PCI for ST-elevation myocardial infarction (STEMI), by performing a randomized trial, enrolling 102 patients. Point-of-care genetic testing for CYP2C19*2, ABCB1 TT and CYP2C19*17 was performed with carriers of either the CYP2C19*2 allele or ABCB1 TT genotype randomly assigned to a strategy of prasugrel 10 mg daily or an augmented dosing strategy of clopidogrel (150 mg daily for 6 days then 75 mg daily). The primary end point was the proportion of at-risk carriers exhibiting high on-treatment platelet reactivity (HPR), a marker associated with increased adverse cardiovascular events, after 1 month. Fifty-nine subjects (57.8%) were identified as carriers of at least one at-risk variant. Treatment with prasugrel significantly reduced HPR compared with clopidogrel by P2Y12 reaction unit (PRU) thresholds of >234 (0 vs 24.1%, P=0.0046) and PRU>208 (3.3 vs 34.5%, P=0.0025). The sensitivity of point-of-care testing was 100% (95% CI 88.0–100), 100% (86.3–100) and 96.9% (82.0–99.8) and specificity was 97.0% (88.5–99.5), 97.1% (89.0–99.5) and 98.5% (90.9–99.9) for identifying CYP2C19*2, ABCB1 TT and CYP2C19*17, respectively. Logistic regression confirmed carriers as a strong predictor of HPR (OR=6.58, 95% CI 1.24–34.92; P=0.03). We confirmed that concurrent identification of three separate genetic variants in patients with STEMI receiving PCI is feasible at the bedside. Among carriers of at-risk genotypes, treatment with prasugrel was superior to an augmented dosing strategy of clopidogrel in reducing HPR.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607–1621.

    Article  CAS  PubMed  Google Scholar 

  2. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005; 294: 1224–1232.

    Article  CAS  PubMed  Google Scholar 

  3. Kushner FG, Hand M, Smith SC Jr, King SB III, Anderson JL, Antman EM et al. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009; 120: 2271–2306.

    Article  PubMed  Google Scholar 

  4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494–502.

    Article  CAS  PubMed  Google Scholar 

  5. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527–533.

    Article  CAS  PubMed  Google Scholar 

  6. Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010; 376: 14233–14243.

    Article  Google Scholar 

  7. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49: 1505–1516.

    Article  CAS  PubMed  Google Scholar 

  8. Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992–1000.

    Article  PubMed  Google Scholar 

  9. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–2015.

    Article  CAS  PubMed  Google Scholar 

  10. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045–1057.

    Article  CAS  PubMed  Google Scholar 

  11. So DY, Roberts JD . Overcoming obstacles in pharmacogenomic strategies for antiplatelet drugs: are we RAPID enough? Pharmacogenomics 2012; 13: 1105–1108.

    Article  CAS  PubMed  Google Scholar 

  12. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354–362.

    Article  CAS  PubMed  Google Scholar 

  13. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363–375.

    Article  CAS  PubMed  Google Scholar 

  15. Xie HG . Genetic variations of S-mephenytoin 4'-hydroxylase (CYP2C19) in the Chinese population. Life Sci 2000; 66: L175–L181.

    Article  Google Scholar 

  16. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cayla G, Hulot JS, O'Connor SA, Pathak A, Scott SA, Gruel Y et al. Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA 2011; 306: 1765–1774.

    Article  CAS  PubMed  Google Scholar 

  18. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J 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: 512–518.

    Article  CAS  PubMed  Google Scholar 

  19. Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M 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.

    Article  CAS  PubMed  Google Scholar 

  20. Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011; 124: 1132–1137.

    Article  PubMed  Google Scholar 

  21. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919–933.

    Article  CAS  PubMed  Google Scholar 

  22. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344–2351.

    Article  PubMed  Google Scholar 

  23. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011; 305: 1097–1105.

    Article  CAS  PubMed  Google Scholar 

  24. Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360: 753–764.

    Article  CAS  PubMed  Google Scholar 

  25. Stanulla M, Schaeffeler E, Flohr T, Cario G, Schrauder A, Zimmermann M et al. Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 2005; 293: 1485–1489.

    Article  CAS  PubMed  Google Scholar 

  26. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O 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: 134–143.

    Article  CAS  PubMed  Google Scholar 

  27. Pare G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704–1714.

    Article  CAS  PubMed  Google Scholar 

  28. 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: 2704–2714.

    Article  CAS  PubMed  Google Scholar 

  29. Mega JL, Topol EJ, Sabatine MS . CYP2C19 genotype and cardiovascular events. JAMA 2012; 307: 1482–1483.

    Article  CAS  PubMed  Google Scholar 

  30. Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J 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.

    Article  CAS  PubMed  Google Scholar 

  31. Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol 2012; 59: 1928–1937.

    Article  CAS  PubMed  Google Scholar 

  32. Price MJ, Berger PB, Angiolillo DJ, Teirstein PS, Tanguay JF, Kandzari DE et al. Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial. Am Heart J 2009; 157: 818–824.

    Article  CAS  PubMed  Google Scholar 

  33. Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Muller U et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012; 59: 2159–2164.

    Article  CAS  PubMed  Google Scholar 

  34. Collet JP, Cuisset T, Range G, Cayla G, Elhadad S, Pouillot C et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367: 2100–2109.

    Article  CAS  PubMed  Google Scholar 

  35. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723–731.

    Article  CAS  PubMed  Google Scholar 

  36. Steg PG, James S, Harrington RA, Ardissino D, Becker RC, Cannon CP et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation 2010; 122: 2131–2141.

    Article  PubMed  Google Scholar 

  37. Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013; 382: 614–623.

    Article  PubMed  Google Scholar 

  38. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ et al. 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: 2261–2273.

    Article  CAS  PubMed  Google Scholar 

  39. O'Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: e78–e140.

    Article  PubMed  Google Scholar 

  40. Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, Borger MA et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569–2619.

    Article  CAS  PubMed  Google Scholar 

  41. Mega JL, Hochholzer W, Frelinger AL III, Kluk MJ, Angiolillo DJ, Kereiakes DJ et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011; 306: 2221–2228.

    Article  CAS  PubMed  Google Scholar 

  42. Sardella G, Calcagno S, Mancone M, Palmirotta R, Lucisano L, Canali E et al. Pharmacodynamic effect of switching therapy in patients with high on-treatment platelet reactivity and genotype variation with high clopidogrel dose versus prasugrel: the RESET GENE trial. Circ Cardiovasc Interv 2012; 5: 698–704.

    Article  CAS  PubMed  Google Scholar 

  43. Saucedo JF, Angiolillo DJ, DeRaad R, Frelinger AL III, Gurbel PA, Costigan TM et al. Decrease in high on-treatment platelet reactivity (HPR) prevalence on switching from clopidogrel to prasugrel: insights from the switching anti-platelet (SWAP) study. Thromb Haemost 2013; 109: 347–355.

    Article  CAS  PubMed  Google Scholar 

  44. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011; 90: 328–332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312–2317.

    Article  CAS  PubMed  Google Scholar 

  46. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827–1832.

    Article  CAS  PubMed  Google Scholar 

  47. Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742–1750.

    Article  CAS  PubMed  Google Scholar 

  48. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171–3175.

    Article  CAS  PubMed  Google Scholar 

  49. Geisler T, Langer H, Wydymus M, Gohring K, Zurn C, Bigalke B et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420–2425.

    Article  CAS  PubMed  Google Scholar 

  50. Alexopoulos D, Dimitropoulos G, Davlouros P, Xanthopoulou I, Kassimis G, Stavrou EF 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: 403–410.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Lyne Stuewe, Cheryl Charlebois, Colleen Chilton and Nitan Garg for their invaluable assistance in conducting the study. DYFS was supported by grants from the Heart and Stroke Foundation of Ontario and the Canadian Institutes of Health Research. The RAPID STEMI study was funded by unrestricted grants from Spartan Biosciences, Inc and the Canadian Institutes of Health Research (FRN 115129).

Author information

Authors and Affiliations

  1. Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    D Y F So, M Labinaz, M R Le May, C Glover, A J Dick, M Froeschl, J-F Marquis, M H Gollob, L Tran, B Hibbert & J D Roberts

  2. Cardiovascular Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    G A Wells & J Bernick

  3. Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    R McPherson

Authors
  1. D Y F So
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G A Wells
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R McPherson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Labinaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M R Le May
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Glover
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A J Dick
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Froeschl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J-F Marquis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M H Gollob
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J Bernick
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. B Hibbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J D Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

On behalf of the CAPITAL investigators

Corresponding author

Correspondence to D Y F So.

Ethics declarations

Competing interests

Dr. So holds a physician initiated grant supported by the Canadian Institute of Health Research and Eli Lilly, Canada.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

So, D., Wells, G., McPherson, R. et al. A prospective randomized evaluation of a pharmacogenomic approach to antiplatelet therapy among patients with ST-elevation myocardial infarction: the RAPID STEMI study. Pharmacogenomics J 16, 71–78 (2016). https://doi.org/10.1038/tpj.2015.17

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.17

This article is cited by

Search

Advanced search

Quick links