European Heart Journal Advance Access originally published online on March 16, 2008
European Heart Journal 2008 29(8):957-958; doi:10.1093/eurheartj/ehn091
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Resistance to what, does it matter? How do we study it?
Department of Cardiology, Mayo Clinic, 200 First St S.W., Rochester, MN 55905, USA
* Corresponding author. Tel: +1 507 255 2504, Fax: +1 507 255 2550, Email: dholmes{at}mayo.edu
This editorial refers to ‘Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation’
by M.J. Price et al., on page 992
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehn046 
The importance of platelets and thrombosis in the pathophysiology of acute ischaemic coronary syndromes has been well appreciated. This information has formed the backbone of the guidelines on both sides of the Atlantic that patients with acute as well as chronic coronary artery disease be treated with aspirin as a long-term strategy of care. While the specific dosage schedule may vary, aspirin treatment remains a Class I indication.1 Increasingly, adherence to this as well as other guidelines is a measure of quality of care.
The issue of platelet function and thrombosis has become more complicated in the era of stent-based percutaneous coronary intervention (PCI);2–4 this is a particular issue regarding the problem of stent thrombosis, a subject which has attracted tremendous scientific, lay press, and patient as well as regulatory interest.
This interest has been stimulated by several factors:5,6 (i) stent placement is the procedure of choice for PCI revascularizations; (ii) stent thrombosis is a significant problem for a very small percentage of patients undergoing PCI, but, when it occurs, it can have catastrophic implications for the patient, with death or myocardial infarction occurring in 50–60% of patients;1,5,6 (iii) drug-eluting stents were introduced to prevent restenosis but were found to be susceptible to stent thrombosis again at a low to very low frequency rate; (iv) recent data have indicated that stent thrombosis occurs with both bare metal and drug-eluting stents.5
After the importance of antiplatelet regimens in patients undergoing PCI was recognized,7 there was rapid adoption of dual antiplatelet strategies in patients treated with stents; this included initially aspirin and Ticlopidine, but then was switched to aspirin and clopidogrel because of an improved safety profile with the latter.
Uncertainties remained concerning the duration of therapy as well as the specific regimen to be used. This importance was emphasized by early reports with drug-eluting stents that discontinuation of dual antiplatelet therapy could be associated with stent thrombosis. It again must be remembered that stent thrombosis may also occur with bare metal stents.5 Finally, it was recognized that some patients even when on antiplatelet strategies developed stent thrombosis. This has led to the concept first of aspirin resistance and now clopidogrel resistance. The issues of resistance to aspirin or in this case clopidogrel resistance are multiple and complex.9–15 Questions include:
- The definition of resistance—is it a dichotomous variable or, like many biological processes, a linear variable which has an increasing hazard ratio of an event with increasing resistance.
- How is resistance measured? This is of crucial importance if the measurement techniques have a great bearing on the definition of the incidence of resistance.
- What is the confounding effect of variable drugs?
- When should resistance be assessed and in whom?
- Perhaps most important is the link between definition and measurement of resistance and a physiological event such as stent thrombosis in a drug-eluting stent. This latter issue is compounded by the fact that the number of adverse events is low. There may be multiple other factors involved, such as adequacy of deployment technique and overlapped stents, as well as the specific segment to be stented. The ability to predict an individual at risk and the ability to develop alternative strategies is incredibly important in this regard.
Despite these issues, in this initial foray, Price et al.16 have documented that by using a point-of-care assay, post-treatment reactivity of platelets in patients on clopidogrel is associated with increased event rates. This study serves the purpose of stimulating more and larger efforts to study the issue of clopidogrel platelet reactivity by developing either new regimens of the same drug or new drugs which have different, more predictable, and more powerful effects on platelet function, such as prasugrel. It still must be remembered that optimizing the initial implant of any stent is the cornerstone to improving patient safety and outcome.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
References
- Fraker TD Jr, Fihn SD, 2002 Chronic Stable Angina Writing Committee. J Am Coll Cardiol—Givvons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB Jr, Gardin JM, O'Rourke RA, Williams SV, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW, eds. (2007) 50. American College of Cardiology; American Heart Association. 2264–2274. 2007 Chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines writing group to update the 2002 Guidelines for the management of patients with chronic stable angina.
[Free Full Text] - Holmes DR Jr, Kereiakes DJ, Laskey WK, Colombo A, Ellis SG, Henry TD, Popma JJ, Serruys PW, Kimura T, Williams DO, Windecker S, Krucoff MW. Thrombosis and drug-eluting stents: an objective appraisal. J Am Coll Cardiol (2007) 50:109–118.
[Abstract/Free Full Text] - Holmes DR Jr. Antiplatelet therapy after percutaneous coronary intervention (PCI). Cerebrovasc Dis (2006) 21((suppl 1)):25–34.[CrossRef][Medline]
- Grines CL, Bonow RO, Casey DR Jr., Gardner TJ, Lockhart PB, Noliterno DJ, O'Gara P, Whitlow P. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation (2007) 115:813–818. American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, American Dental Association, American College of Physicians.
[Abstract/Free Full Text] - Doyle B Jr., Rihal CS, O'Sullivan CJ, Lennon RJ, Wiste HJ, Bell M, Bresnahan J, Holmes DR Jr. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation (2007) 116:2363–2365.
[Free Full Text] - Spertus JA, Kettelkamp R, Vance C, Decker C, Jones PG, Rumsfeld JS, Messenger JC, Khanal S, Peterson ED, Bach RG, Krumholz HM, Cohen DJ. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation (2006) 113:2803–2809.
[Abstract/Free Full Text] - Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med (1998) 339:1665–1671.
[Abstract/Free Full Text] - Malinin A, Pokov A, Swaim L, Kotob M, Serebruany V. Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel. Methods Find Exp Clin Pharmacol (2006) 28:315–322.[CrossRef][Web of Science][Medline]
- Malinin A, Pokov A, Spergling M, Defranco A, Schwartz K, Schwartz D, Mahmud E, Atar D, Serebruany V. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12® rapid analyzer: The VERIfy Thrombosis risk Assessment (VERITAS) study. Thromb Res (2007) 119:277–284.[CrossRef][Web of Science][Medline]
- Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Commeau P, Comet B, Lafont A, Camoin L, Walter U, Eigenthaler M. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv (2003) 59:295–302.[CrossRef][Web of Science][Medline]
- Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, DeLao T, Bray PF, Kleiman NS. 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.
[Abstract/Free Full Text] - Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation (2004) 109:3171–3175.
[Abstract/Free Full Text] - 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) 45:246–251.
[Abstract/Free Full Text] - 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) 107:2908–2913.
[Abstract/Free Full Text] - Paniccia R, Antonucci E, Gori AM, Marcucci R, Giglioli C, Antoniucci D, Gensini GF, Abbate R, Prisco D. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost (2007) 5:1839–1847.[CrossRef][Web of Science][Medline]
- Price MJ, Edemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, Ernst A, Sawhney NS, Schatz RA, Teirstein PS. 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. First published on February 10, 2008. doi:10.1093/eurheartj/ehn046.
[Abstract/Free Full Text]
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- Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation
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EHJ 2008 29: 992-1000.[Abstract] [FREE Full Text]
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