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Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R). Rationale for the Study and Protocol Design

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Abstract

Purpose

To assess whether glycoprotein IIb/IIIa inhibition using tirofiban in low risk patients undergoing percutaneous coronary intervention (PCI) may reduce the risk of periprocedural myocardial infarction compared to standard care in poor responders to aspirin and/or clopidogrel.

Methods

We will enroll patients at ten European sites or more to participate in the Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel (3T/2R) study with a pre-specified sample size of 240 patients out of 1,100 or more who will undergo screening. The primary outcome measure is troponin I or T elevation ratio at least three times the upper limit of normal within 48 h after completion of the PCI.

Conclusion

The results of 3T/2R study will evaluate whether tailored intensification of anti-platelet treatment based on poor individual response to oral anti-platelet agents may modulate the risk of periprocedural myocardial infarction during PCI. Our findings attempt at unraveling a new era of individualized anti-platelet treatment through the use of point-of-care assessment.

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References

  1. Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986;315:983–9.

    PubMed  CAS  Google Scholar 

  2. Keating FK, Whitaker DA, Kabbani SS, Ricci MA, Sobel BE, Schneider DJ. Relation of augmented platelet reactivity to the magnitude of distribution of atherosclerosis. Am J Cardiol 2004;94:725–8.

    Article  PubMed  Google Scholar 

  3. Massberg S, Schulz C, Gawaz M. Role of platelets in the pathophysiology of acute coronary syndrome. Semin Vasc Med 2003;3:147–62.

    Article  PubMed  Google Scholar 

  4. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004;292:1867–74.

    Article  PubMed  CAS  Google Scholar 

  5. Sun JZ, Maguire D. How to prevent perioperative myocardial injury: the conundrum continues. Am Heart J 2007;154:1021–8.

    Article  PubMed  Google Scholar 

  6. Hamdalla H, Steinhubl SR. Oral antiplatelet therapy for percutaneous coronary revascularization. Catheter Cardiovasc Interv 2007;69:637–42.

    Article  PubMed  Google Scholar 

  7. Angiolillo DJ. ADP receptor antagonism: what’s in the pipeline? Am J Cardiovasc Drugs 2007;7:423–32.

    Article  PubMed  CAS  Google Scholar 

  8. Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease. Circulation 2007;115:2196–207.

    Article  PubMed  Google Scholar 

  9. Angiolillo DJ, Alfonso F. Platelet function testing and cardiovascular outcomes: steps forward in identifying the best predictive measure. Thromb Haemost 2007;98:707–9.

    PubMed  CAS  Google Scholar 

  10. Angiolillo DJ, Bernardo E, Sabate M, et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007;50:1541–7.

    Article  PubMed  Google Scholar 

  11. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49:1505–16.

    Article  PubMed  CAS  Google Scholar 

  12. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in platelet aggregation following sustained aspirin and clopidogrel treatment in patients with coronary heart disease and influence of the 807 C/T polymorphism of the glycoprotein Ia gene. Am J Cardiol 2005;96:1095–9.

    Article  PubMed  CAS  Google Scholar 

  13. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007;50:1822–34.

    Article  PubMed  CAS  Google Scholar 

  14. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING study. J Am Coll Cardiol 2005;46:1820–6.

    Article  PubMed  CAS  Google Scholar 

  15. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST study. J Am Coll Cardiol 2005;46:1827–32.

    Article  PubMed  CAS  Google Scholar 

  16. Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA. Aspirin sensitivity: implications for patients with coronary artery disease. JAMA 2004;292:3017–23.

    Article  PubMed  CAS  Google Scholar 

  17. Eikelboom JW, Hankey GJ. Aspirin resistance: a new independent predictor of vascular events? J Am Coll Cardiol 2003;41:966–8.

    Article  PubMed  Google Scholar 

  18. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002;105:1650–5.

    Article  PubMed  CAS  Google Scholar 

  19. Grotemeyer KH, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non responder. A pilot-study including 180 post-stroke patients. Thromb Res 1993;71:397–403.

    Article  PubMed  CAS  Google Scholar 

  20. Grundmann K, Jaschonek K, Kleine B, Dichgans J, Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol 2003;250:63–6.

    Article  PubMed  CAS  Google Scholar 

  21. Mueller MR, Salat A, Stangl P, et al. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost 1997;78:1003–7.

    PubMed  CAS  Google Scholar 

  22. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003;41:961–5.

    Article  PubMed  CAS  Google Scholar 

  23. Chopra V, Marmur JD, Cavusoglu E. The role of clopidogrel in the management of patients with ischemic heart disease. Cardiovasc Drugs Ther 2003;17:467–77.

    Article  PubMed  CAS  Google Scholar 

  24. 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;107:2908–13.

    Article  PubMed  Google Scholar 

  25. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003;89:783–7.

    PubMed  CAS  Google Scholar 

  26. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005;45:246–51.

    Article  PubMed  CAS  Google Scholar 

  27. Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes. Thromb Haemost 2007;97:282–7.

    PubMed  CAS  Google Scholar 

  28. Hochholzer W, Trenk D, Bestehorn HP, 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;48:1742–50.

    Article  PubMed  CAS  Google Scholar 

  29. Hochholzer W, Trenk D, Frundi D, et al. 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 2005;111:2560–4.

    Article  PubMed  CAS  Google Scholar 

  30. Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312–7.

    Article  PubMed  CAS  Google Scholar 

  31. Marcucci R, Gori AM, Paniccia R, et al. Residual platelet reactivity is associated with clinical and laboratory characteristics in patients with ischemic heart disease undergoing PCI on dual antiplatelet therapy. Atherosclerosis 2007;195:e217–23.

    Article  PubMed  CAS  Google Scholar 

  32. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–5.

    Article  PubMed  CAS  Google Scholar 

  33. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006;47:27–33.

    Article  PubMed  CAS  Google Scholar 

  34. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention. Am J Cardiol 2006;97:38–43.

    Article  PubMed  CAS  Google Scholar 

  35. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232–8.

    Article  PubMed  CAS  Google Scholar 

  36. Okamatsu K, Takano M, Sakai S, et al. Elevated troponin T levels and lesion characteristics in non-ST-elevation acute coronary syndromes. Circulation 2004;109:465–70.

    Article  PubMed  CAS  Google Scholar 

  37. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR—REACT 2 randomized trial. JAMA 2006;295:1531–8.

    Article  PubMed  CAS  Google Scholar 

  38. Valgimigli M, Percoco G, Barbieri D, et al. The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the ADVANCE trial. J Am Coll Cardiol 2004;44:14–9.

    Article  PubMed  CAS  Google Scholar 

  39. Angiolillo DJ, Costa MA, Shoemaker SB, et al. Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment. Am J Cardiol 2008;101:440–5.

    Article  PubMed  CAS  Google Scholar 

  40. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 2005;115:101–8.

    Article  PubMed  CAS  Google Scholar 

  41. von Beckerath N, Pogatsa-Murray G, Wieczorek A, Sibbing D, Schomig A, Kastrati A. Correlation of a new point-of-care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness. Thromb Haemost 2006;95:910–1.

    Google Scholar 

  42. van Werkum JW, van der Stelt CA, Seesing TH, Hackeng CM, ten Berg JM. A head-to-head comparison between the VerifyNow P2Y12 assay and light transmittance aggregometry for monitoring the individual platelet response to clopidogrel in patients undergoing elective percutaneous coronary intervention. J Thromb Haemost 2006;4:2516–8.

    Article  PubMed  Google Scholar 

  43. Valgimigli M, Campo G, Percoco G, et al. Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: the MULTISTRATEGY randomized trial. Jama 2008;299:1788–99.

    Article  PubMed  CAS  Google Scholar 

  44. Valgimigli M, Percoco G, Cicchitelli G, et al. High-dose bolus tirofiban and sirolimus eluting stent versus abiciximab and bare metal stent in acute myocardial infarction (STRATEGY) study—protocol design and demography of the first 100 patients. Cardiovasc Drugs Ther 2004;18:225–30.

    Article  PubMed  CAS  Google Scholar 

  45. Valgimigli M, Percoco G, Malagutti P, et al. Tirofiban and sirolimus-eluting stent vs abciximab and bare-metal stent for acute myocardial infarction: a randomized trial. Jama 2005;293:2109–17.

    Article  PubMed  Google Scholar 

  46. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116:2634–53.

    Article  PubMed  Google Scholar 

  47. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76:142–54.

    PubMed  CAS  Google Scholar 

  48. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344–51.

    Article  PubMed  Google Scholar 

  49. Balian V, Galli M, Marcassa C, et al. Intracoronary ST-segment shift soon after elective percutaneous coronary intervention accurately predicts periprocedural myocardial injury. Circulation 2006;114:1948–54.

    Article  PubMed  Google Scholar 

  50. Mulukutla SR, Marroquin OC, Smith C, et al. Effect of statin therapy prior to elective percutaneous coronary intervention on frequency of periprocedural myocardial injury. Am J Cardiol 2004;94:1363–6.

    Article  PubMed  CAS  Google Scholar 

  51. Briguori C, Colombo A, Airoldi F, et al. Statin administration before percutaneous coronary intervention: impact on periprocedural myocardial infarction. Eur Heart J 2004;25:1822–8.

    Article  PubMed  CAS  Google Scholar 

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Conflicts of interests

This study was co-supported by an unrestricted grant from Merck, USA and IROKO Pharmaceuticals, USA.

Author information

Authors and Affiliations

  1. University of Ferrara, Cardiovascular Institute, Arcispedale S. Anna Hospital, Corso Giovecca 203, 44100, Ferrara, Italy

    Marco Valgimigli, Gianluca Campo, Fabrizio Ferrari & Roberto Ferrari

  2. Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS, Gussago (BS), Italy

    Marco Valgimigli & Roberto Ferrari

  3. Policlinico S. Marco, Zingonia (BG), Italy

    Nicoletta de Cesare

  4. Virga Jesseziekenhuis, Hasselt, Belgium

    Pascal Vranckx

  5. University Hospital of Caen, Normandy, France

    Martial Hamon

  6. Division of Cardiology, College of Medicine, University of Florida, Jacksonville, FL, USA

    Dominick J. Angiolillo

  7. Interventional Cardiology Unit, Cardiology Department, Saint Paul University Hospital, Barcelona, Spain

    Manel Sabatè

  8. Department of Medical and Surgical Cardiology, Villa Maria Cecilia Hospital, Cotignola (RA), Italy

    Alessandro Furgieri

  9. Department of Cardiology, Guglielmo da Saliceto Hospital, Piacenza, Italy

    Carlo Tumscitz

  10. Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy

    Alessandra Repetto

  11. Cardiovascular Intervention Laboratory, San Giovanni Bosco Hospital, Turin, Italy

    Salvatore Colangelo

  12. Unit of Cardiology, Azienda Ospedaliera S. Giovanni Battista, Turin, Italy

    Emanuele Meliga

  13. Cardiology, Lagosanto Hospital, Opium Valley, Lagosanto, Italy

    Moh’d Kubbajeh & Gianfranco Percoco

  14. Medical Statistics Unit, University of Brescia, Brescia, Italy

    Giovanni Parrinello

Authors
  1. Marco Valgimigli
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  2. Gianluca Campo
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  3. Nicoletta de Cesare
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  5. Martial Hamon
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  6. Dominick J. Angiolillo
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  7. Manel Sabatè
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  8. Fabrizio Ferrari
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  9. Alessandro Furgieri
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  10. Carlo Tumscitz
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  11. Alessandra Repetto
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  12. Salvatore Colangelo
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  13. Emanuele Meliga
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  14. Moh’d Kubbajeh
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  15. Giovanni Parrinello
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  16. Gianfranco Percoco
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  17. Roberto Ferrari
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Corresponding author

Correspondence to Marco Valgimigli.

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Valgimigli, M., Campo, G., de Cesare, N. et al. Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R). Rationale for the Study and Protocol Design. Cardiovasc Drugs Ther 22, 313–320 (2008). https://doi.org/10.1007/s10557-008-6121-z

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  • DOI: https://doi.org/10.1007/s10557-008-6121-z

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