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J Am Coll Cardiol, 2007; 49:2312-2317, doi:10.1016/j.jacc.2007.01.094 (Published online 1 June 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

Impact of Platelet Reactivity After Clopidogrel Administration on Drug-Eluting Stent Thrombosis

Piergiovanni Buonamici, MD, Rossella Marcucci, MD, Angela Migliorini, MD, Gian Franco Gensini, MD, Alberto Santini, MD, Rita Paniccia, MD, Guia Moschi, MD, Anna Maria Gori, MD, Rosanna Abbate, MD and David Antoniucci, MD*

Department of Cardiology, Careggi Hospital, Florence, Italy

Manuscript received January 2, 2007; revised manuscript received January 26, 2007, accepted January 28, 2007.

* Reprint requests and correspondence: Dr. David Antoniucci, Division of Cardiology, Careggi Hospital, Viale Pieraccini, I-50134, Florence, Italy. (Email: david.antoniucci{at}virgilio.it).

Objectives: We sought to determine whether nonresponsiveness to clopidogrel as revealed by high in vitro post-treatment platelet reactivity is predictive of drug-eluting stent (DES) thrombosis.

Background: No data exist about the impact of nonresponsiveness to clopidogrel on the risk of DES thrombosis.

Methods: We conducted a prospective observational cohort study from July 2005 to August 2006 in an academic hospital. A total of 804 patients who had successful sirolimus- or paclitaxel-eluting stent implantation were assessed for post-treatment platelet reactivity after a loading dose of 600 mg of clopidogrel. Patients with platelet aggregation by 10 µmol adenosine 5'-diphosphate ≥70% were defined as nonresponders. All patients received chronic dual antiplatelet treatment (aspirin 325 mg and clopidogrel 75 mg daily) for 6 months. The primary end point was the incidence of definite/probable early, subacute, and late stent thrombosis at 6-month follow-up.

Results: The incidence of 6-month definite/probable stent thrombosis was 3.1%. All stent thromboses were subacute or late. Of 804 patients, 105 (13%) were not responsive to clopidogrel. The incidence of stent thrombosis was 8.6% in nonresponders and 2.3% in responders (p < 0.001). By multivariate analysis, the predictors of stent thrombosis were as follows: nonresponsiveness to clopidogrel (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.32 to 7.16; p = 0.009), left ventricular ejection fraction (HR 0.95, 95% CI 0.92 to 0.98; p = 0.001), total stent length (HR 1.01, 95% CI 1.00 to 1.02; p = 0.010), and ST-segment elevation acute myocardial infarction (HR 2.41, 95% CI 1.04 to 5.63; p = 0.041).

Conclusions: Nonresponsiveness to clopidogrel is a strong independent predictor of stent thrombosis in patients receiving sirolimus- or paclitaxel-eluting stents.

Abbreviations and Acronyms
  ADP = adenosine 5'-diphosphate
  AMI = acute myocardial infarction
  CI = confidence interval
  DES = drug-eluting stent(s)
  HR = hazard ratio
  LVEF = left ventricular ejection fraction


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J. Am. Coll. Cardiol., March 31, 2009; 53(13): 1101 - 1109.
[Abstract] [Full Text] [PDF]

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D. Sibbing, S. Braun, T. Morath, J. Mehilli, W. Vogt, A. Schomig, A. Kastrati, and N. von Beckerath
Platelet Reactivity After Clopidogrel Treatment Assessed With Point-of-Care Analysis and Early Drug-Eluting Stent Thrombosis
J. Am. Coll. Cardiol., March 10, 2009; 53(10): 849 - 856.
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E. Mahla, M. J. Antonino, U. S. Tantry, and P. A. Gurbel
Point-of-Care Platelet Function Analysis: Ready for Prime Time?
J. Am. Coll. Cardiol., March 10, 2009; 53(10): 857 - 859.
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P. A. Gurbel, K. P. Bliden, J. F. Saucedo, T. A. Suarez, J. DiChiara, M. J. Antonino, E. Mahla, A. Singla, W. R. Herzog, A. K. Bassi, et al.
Bivalirudin and Clopidogrel With and Without Eptifibatide for Elective Stenting: Effects on Platelet Function, Thrombelastographic Indexes, and Their Relation to Periprocedural Infarction: Results of the CLEAR PLATELETS-2 (Clopidogrel With Eptifibatide to Arrest the Reactivity of Platelets) Study
J. Am. Coll. Cardiol., February 24, 2009; 53(8): 648 - 657.
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W. Kuliczkowski, A. Witkowski, L. Polonski, C. Watala, K. Filipiak, A. Budaj, J. Golanski, D. Sitkiewicz, J. Pregowski, J. Gorski, et al.
Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology
Eur. Heart J., February 2, 2009; 30(4): 426 - 435.
[Abstract] [Full Text] [PDF]

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J. P. Chen, L. V. Crisco, R. Jabara, and S. B. King III
Late Angiographic Stent Thrombosis: The LAST Straw for Drug-Eluting Stents?
Angiology, January 1, 2009; 59(6): 667 - 675.
[Abstract] [PDF]

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F. Burzotta, A. Parma, C. Pristipino, A. Manzoli, F. Belloni, G. Sardella, S. Rigattieri, A. Danesi, P. Mazzarotto, F. Summaria, et al.
Angiographic and clinical outcome of invasively managed patients with thrombosed coronary bare metal or drug-eluting stents: the OPTIMIST study
Eur. Heart J., December 2, 2008; 29(24): 3011 - 3021.
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L. Ang and E. Mahmud
Monitoring oral antiplatelet therapy: is it justified?
Therapeutic Advances in Cardiovascular Disease, December 1, 2008; 2(6): 485 - 496.
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A. K. Chhatriwalla and D. L. Bhatt
Should dual antiplatelet therapy after drug-eluting stents be continued for more than 1 year?: Dual Antiplatelet Therapy After Drug-Eluting Stents Should Be Continued for More Than One Year and Preferably Indefinitely
Circ Cardiovasc Interv, December 1, 2008; 1(3): 217 - 225.
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A. Colombo and R. T. Gerber
Should dual antiplatelet therapy after drug-eluting stents be continued for more than 1 year?: Dual Antiplatelet Therapy After Drug-Eluting Stents Should Not Be Continued for More Than 1 Year and Preferably Indefinitely
Circ Cardiovasc Interv, December 1, 2008; 1(3): 226 - 232.
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N. S. Kleiman
Searching for the Ceiling: New Reflections on the Disposition and Metabolism of Clopidogrel
J. Am. Coll. Cardiol. Intv., December 1, 2008; 1(6): 628 - 630.
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T. Cuisset, C. Frere, J. Quilici, P.-E. Morange, J.-P. Mouret, L. Bali, P.-J. Moro, M. Lambert, M.-C. Alessi, and J. L. Bonnet
Glycoprotein IIb/IIIa Inhibitors Improve Outcome After Coronary Stenting in Clopidogrel Nonresponders: A Prospective, Randomized Study
J. Am. Coll. Cardiol. Intv., December 1, 2008; 1(6): 649 - 653.
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G. De Luca
Adjunctive antithrombotic therapy during primary percutaneous coronary intervention
Eur. Heart J. Suppl., December 1, 2008; 10(suppl_J): J2 - J14.
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N. S. Kleiman
Clopidogrel and Calcium-Channel Antagonists: Another Drug-Drug Interaction for the Ever-Wary Clinician?
J. Am. Coll. Cardiol., November 4, 2008; 52(19): 1564 - 1566.
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S. A. Murphy, E. M. Antman, S. D. Wiviott, G. Weerakkody, G. Morocutti, K. Huber, J. Lopez-Sendon, C. H. McCabe, E. Braunwald, and for the TRITON-TIMI 38 Investigators
Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial
Eur. Heart J., October 2, 2008; 29(20): 2473 - 2479.
[Abstract] [Full Text] [PDF]

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L. Ang, V. Palakodeti, A. Khalid, S. Tsimikas, Z. Idrees, P. Tran, P. Clopton, N. Zafar, G. Bromberg-Marin, S. Keramati, et al.
Elevated Plasma Fibrinogen and Diabetes Mellitus Are Associated With Lower Inhibition of Platelet Reactivity With Clopidogrel
J. Am. Coll. Cardiol., September 23, 2008; 52(13): 1052 - 1059.
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J.-P. Collet, J. Silvain, A. Landivier, M.-L. Tanguy, G. Cayla, A. Bellemain, N. Vignolles, S. Gallier, F. Beygui, A. Pena, et al.
Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose: The Reload With Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term With Dual Antiplatelet Therapy (RELOAD) Study
Circulation, September 16, 2008; 118(12): 1225 - 1233.
[Abstract] [Full Text] [PDF]

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A. Chieffo, S.-J. Park, E. Meliga, I. Sheiban, M. S. Lee, A. Latib, Y.-H. Kim, M. Valgimigli, D. Sillano, V. Magni, et al.
Late and very late stent thrombosis following drug-eluting stent implantation in unprotected left main coronary artery: a multicentre registry
Eur. Heart J., September 1, 2008; 29(17): 2108 - 2115.
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Y.-H. Jeong, I.-S. Kim, B.-R. Choi, C. H. Kwak, and J.-Y. Hwang
The optimal threshold of high post-treatment platelet reactivity could be defined by a point-of-care VerifyNow P2Y12 assay
Eur. Heart J., September 1, 2008; 29(17): 2186 - 2187.
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A. M. Gori, R. Marcucci, A. Migliorini, R. Valenti, G. Moschi, R. Paniccia, P. Buonamici, G. F. Gensini, R. Vergara, R. Abbate, et al.
Incidence and Clinical Impact of Dual Nonresponsiveness to Aspirin and Clopidogrel in Patients With Drug-Eluting Stents
J. Am. Coll. Cardiol., August 26, 2008; 52(9): 734 - 739.
[Abstract] [Full Text] [PDF]

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D. Trenk and F.-J. Neumann
Aspirin Resistance: An Underestimated Risk in Patients With Drug-Eluting Stents?
J. Am. Coll. Cardiol., August 26, 2008; 52(9): 740 - 742.
[Full Text] [PDF]

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D. R. Holmes Jr and D. O. Williams
Catheter-Based Treatment of Coronary Artery Disease: Past, Present, and Future
Circ Cardiovasc Interv, August 1, 2008; 1(1): 60 - 73.
[Abstract] [Full Text] [PDF]

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M. J. Price
New antiplatelet therapies in development
Am. J. Health Syst. Pharm., July 1, 2008; 65(13_Supplement_5): S11 - S15.
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S. R. Dixon, C. L. Grines, and W. W. O'Neill
The Year in Interventional Cardiology
J. Am. Coll. Cardiol., June 17, 2008; 51(24): 2355 - 2369.
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D. Sibbing, G. Busch, S. Braun, S. Jawansky, A. Schomig, A. Kastrati, I. Ott, and N. von Beckerath
Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention
Eur. Heart J., June 2, 2008; 29(12): 1504 - 1509.
[Abstract] [Full Text] [PDF]

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D. Trenk, W. Hochholzer, M. F. Fromm, L.-E. Chialda, A. Pahl, C. M. Valina, C. Stratz, P. Schmiebusch, H.-P. Bestehorn, H. J. Buttner, 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., May 20, 2008; 51(20): 1925 - 1934.
[Abstract] [Full Text] [PDF]

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J. A. Cairns and J. Eikelboom
Clopidogrel Resistance: More Grist for the Mill
J. Am. Coll. Cardiol., May 20, 2008; 51(20): 1935 - 1937.
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