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J Am Coll Cardiol, 2008; 51:1404-1411, doi:10.1016/j.jacc.2007.12.044 (Published online 29 March 2008).
© 2008 by the American College of Cardiology Foundation
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EXPEDITED PUBLICATIONS: LATE-BREAKING CLINICAL TRIAL

Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance

A Multicenter Randomized Prospective Study

Laurent Bonello, MD*,*, Laurence Camoin-Jau, MD, PhD{dagger}, Stéphane Arques, MD{ddagger}, Christian Boyer, MD§, Dimitri Panagides, MD, PhD||, Olivier Wittenberg, MD, Marie-Claude Simeoni, MD#, Paul Barragan, MD**, Françoise Dignat-George, MD, PhD{dagger} and Franck Paganelli, MD, PhD*

* Service de Cardiologie, Hôpital Universitaire Nord, Marseille, France
{dagger} Laboratoire d'Hématologie, Unité INSERM UMRS 608, Hôpital de la Conception, Marseille, France
{ddagger} Service de Cardiologie, Hôpital d'Aubagne, Aubagne, France
§ Service de Cardiologie, Clinique Clairval, Marseille, France
|| Service de Cardiologie, Clinique Bouchard, Marseille, France
Service de Cardiologie, Hôpital Privé Beauregard, Marseille, France
# Laboratoire de Statistique, Faculté de la Timone, Marseille, France
** Service de Cardiologie, Polyclinique les Fleurs, Ollioules, France

Manuscript received October 11, 2007; revised manuscript received November 28, 2007, accepted December 17, 2007.

* Reprint requests and correspondence: Dr. Laurent Bonello, Département de Cardiologie, Hôpital Universitaire Nord, Chemin des Bourrely, 13015, Marseille, France (Email: laurentbonello{at}yahoo.fr).

Objectives: This study evaluates the clinical impact of adjusting the loading dose of clopidogrel according to vasodilator-stimulated phosphoprotein (VASP) index in patients with clopidogrel resistance undergoing percutaneous coronary intervention (PCI).

Background: Clopidogrel resistance plays a key role in ischemic recurrence after PCI. In vitro tests of clopidogrel resistance can accurately predict major adverse cardiac events after PCI.

Methods: In this prospective, randomized, multicenter study, clopidogrel resistance was defined as a VASP index of more than 50% after a 600-mg loading dose. Patients with clopidogrel resistance undergoing coronary stenting were randomized to a control group or to the VASP-guided group, in which patients received additional bolus clopidogrel to decrease the VASP index below 50%.

Results: A total of 162 patients were included. The control (n = 84) and VASP-guided groups (n = 78) had similar demographic, clinical, and biological characteristics. In the VASP-guided group, dose adjustment was efficient in 67 patients (86%) and VASP index was significantly decreased (from 69.3 ± 10 to 37.6 ± 13.8; p < 0.001). Eight major adverse cardiac events (5%) were recorded during the 1-month follow-up, with a significantly lower rate in the VASP-guided group compared with the control group (0% vs. 10%; p = 0.007). There was no difference in the rate of major and minor bleeding (5% vs. 4%; p = 1).

Conclusions: This is the first study to suggest that adjusting the clopidogrel loading dose according to platelet monitoring using the VASP index is safe and may significantly improve the clinical outcome after PCI in patients with clopidogrel resistance despite a first 600-mg loading dose.

Abbreviations and Acronyms
  ADP = adenosine diphosphate
  MACE = major adverse cardiac events
  MFI = mean fluorescence intensity
  NSTEMI = non–ST-segment elevation myocardial infarction
  PCI = percutaneous coronary intervention
  PGE1 = prostaglandin E1
  TIMI = Thrombolysis In Myocardial Infarction
  VASP = vasodilator-stimulated phosphoprotein


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Will Measuring Vasodilator-Stimulated Phosphoprotein Phosphorylation Help Us Optimize the Loading Dose of Clopidogrel?
Neal S. Kleiman
J. Am. Coll. Cardiol. 2008 51: 1412-1414. [Full Text] [PDF]



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Eur. Heart J., July 2, 2009; 30(14): 1753 - 1763.
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F. Van de Werf
New antithrombotic agents: are they needed and what can they offer to patients with a non-ST-elevation acute coronary syndrome?
Eur. Heart J., July 2, 2009; 30(14): 1695 - 1702.
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M. Valgimigli, G. Campo, N. de Cesare, E. Meliga, P. Vranckx, A. Furgieri, D. J. Angiolillo, M. Sabate, M. Hamon, A. Repetto, et al.
Intensifying Platelet Inhibition With Tirofiban in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing Elective Coronary Intervention: Results From the Double-Blind, Prospective, Randomized Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel Study
Circulation, June 30, 2009; 119(25): 3215 - 3222.
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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 2, 2009; 53(22): 2080 - 2097.
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A. Prasad and D. R Holmes
Update on dual antiplatelet therapy for percutaneous coronary intervention
Heart, June 1, 2009; 95(11): 861 - 865.
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M. J. Price
Bedside Evaluation of Thienopyridine Antiplatelet Therapy
Circulation, May 19, 2009; 119(19): 2625 - 2632.
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D. Tousoulis, A. Briasoulis, S. S Dhamrait, C. Antoniades, and C. Stefanadis
Effective platelet inhibition by aspirin and clopidogrel: where are we now?
Heart, May 1, 2009; 95(10): 850 - 858.
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M. S. SABATINE
Novel antiplatelet strategies in acute coronary syndromes
Cleveland Clinic Journal of Medicine, April 1, 2009; 76(Suppl_1): S8 - S15.
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D. L. BHATT, K. KOTTKE-MARCHANT, J. H. ALEXANDER, W. F. PEACOCK, and M. S. SABATINE
Platelet response in practice: Applying new insights and tools for testing and treatment
Cleveland Clinic Journal of Medicine, April 1, 2009; 76(Suppl_1): S24 - S32.
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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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P. M. Kang, M. Ruel, and F. W. Sellke
Highlights from the 2008 American Heart Association scientific session.
J. Thorac. Cardiovasc. Surg., March 1, 2009; 137(3): 791 - 794.
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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.
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R. Marcucci, A. M. Gori, R. Paniccia, B. Giusti, S. Valente, C. Giglioli, P. Buonamici, D. Antoniucci, R. Abbate, and G. F. Gensini
Cardiovascular Death and Nonfatal Myocardial Infarction in Acute Coronary Syndrome Patients Receiving Coronary Stenting Are Predicted by Residual Platelet Reactivity to ADP Detected by a Point-of-Care Assay: A 12-Month Follow-Up
Circulation, January 20, 2009; 119(2): 237 - 242.
[Abstract] [Full Text] [PDF]

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D. Varon and G. Spectre
Antiplatelet agents
Hematology, January 1, 2009; 2009(1): 267 - 272.
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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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P. Gladding, M. Webster, I. Zeng, H. Farrell, J. Stewart, P. Ruygrok, J. Ormiston, S. El-Jack, G. Armstrong, P. Kay, et al.
The Antiplatelet Effect of Higher Loading and Maintenance Dose Regimens of Clopidogrel: The PRINC (Plavix Response in Coronary Intervention) Trial
J. Am. Coll. Cardiol. Intv., December 1, 2008; 1(6): 612 - 619.
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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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B. Aleil, L. Jacquemin, F. De Poli, M. Zaehringer, J.-P. Collet, G. Montalescot, J.-P. Cazenave, M.-C. Dickele, J.-P. Monassier, and C. Gachet
Clopidogrel 150 mg/day to Overcome Low Responsiveness in Patients Undergoing Elective Percutaneous Coronary Intervention: Results From the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) Randomized Study
J. Am. Coll. Cardiol. Intv., December 1, 2008; 1(6): 631 - 638.
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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.
[Abstract] [Full Text] [PDF]

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D. L. Bhatt
Resisting the Temptation to Oversimplify Antiplatelet Resistance
J. Am. Coll. Cardiol. Intv., December 1, 2008; 1(6): 660 - 662.
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J. M. Siller-Matula, I. Lang, G. Christ, and B. Jilma
Calcium-Channel Blockers Reduce the Antiplatelet Effect of Clopidogrel
J. Am. Coll. Cardiol., November 4, 2008; 52(19): 1557 - 1563.
[Abstract] [Full Text] [PDF]

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D. Aradi, A. Vorobcsuk, and A. Komocsi
Optimizing Clopidogrel Therapy Before Stent Implantation: Should Clinical Setting Be Taken Into Account?
J. Am. Coll. Cardiol., October 14, 2008; 52(16): 1349 - 1349.
[Full Text] [PDF]

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L. Bonello, L. Camoin-Jau, A. Stephane, P. Barragan, F. Dignat-George, and F. Paganelli
Reply
J. Am. Coll. Cardiol., October 14, 2008; 52(16): 1349 - 1350.
[Full Text] [PDF]

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R. P. Giugliano and E. Braunwald
The Year in Non-ST-Segment Elevation Acute Coronary Syndrome
J. Am. Coll. Cardiol., September 23, 2008; 52(13): 1095 - 1103.
[Full Text] [PDF]

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M. Gilard, J.-C. Cornily, and J. Boschat
Reply
J. Am. Coll. Cardiol., September 16, 2008; 52(12): 1039 - 1039.
[Full Text] [PDF]

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D. O. Williams and J. D. Abbott
What to Do With Patients Receiving Long-Term Clopidogrel: Reload or Relax?
Circulation, September 16, 2008; 118(12): 1219 - 1222.
[Full Text] [PDF]

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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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T. Cuisset, C. Frere, J. Quilici, M. C. Alessi, and J. L. Bonnet
Adjusting Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Index: On Time, Too Early, or Too Late?
J. Am. Coll. Cardiol., August 26, 2008; 52(9): 790 - 791.
[Full Text] [PDF]

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L. Bonello, L. Camoin-Jau, S. Arques, P. Barragan, F. Dignat-George, and F. Paganelli
Reply
J. Am. Coll. Cardiol., August 26, 2008; 52(9): 791 - 792.
[Full Text] [PDF]

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Can Adjustment of Clopidogrel Dosing Reduce Ischemic Events After Stent Implantation?
Journal Watch Cardiology, May 14, 2008; 2008(514): 7 - 7.
[Full Text]

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N. S. Kleiman
Will Measuring Vasodilator-Stimulated Phosphoprotein Phosphorylation Help Us Optimize the Loading Dose of Clopidogrel?
J. Am. Coll. Cardiol., April 8, 2008; 51(14): 1412 - 1414.
[Full Text] [PDF]


 
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