Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: The Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial

doi:10.1067/mhj.2003.109

American Heart Journal

Volume 145, Issue 2, February 2003, Pages 239-247

Presented at the American College of Cardiology 50th Annual Scientific Sessions, March 19, 2001, Orlando, Fla, and at the XXIII Congress of the European Society of Cardiology, September 4, 2001, Stockholm, Sweden.

https://doi.org/10.1067/mhj.2003.109 Get rights and content

Abstract

Background Despite the common practice of clopidogrel loading for coronary stenting, the time dependence and degree of platelet inhibition after this therapy are not well defined. We sought to establish an optimal clopidogrel dosing regimen for sustained platelet inhibition in stented patients. Methods and Results Platelets were assessed by conventional aggregation with 5 μmol/L adenosine diphosphate (ADP), 1 μg/mL collagen (COLL), and 750 μmol/L arachidonic acid; whole blood aggregation by 1 μg/mL collagen (WBA); shear-induced closure time (CT); contractile force (CF); and expression of 9 surface receptors by flow cytometry in 100 patients undergoing elective stent placement without glycoprotein (GP) IIb/IIIa receptor antagonists. Blood was obtained at baseline and serially over 5 days poststenting after different clopidogrel loading regimens: 300 mg 24 hours before (Group A), 12 hours before (Group B), 3 to 6 hours before (Group C), and 75 mg at the time of intervention (Group D). Before stenting, ADP, COLL, CT, and WBA were reduced by clopidogrel loading (P <.05). CF was not affected by clopidogrel. Before stenting, GP IIb/IIIa expression increased in groups A through C (P <.05), whereas PECAM-1 and CD107a were reduced (P <.05). At 2 hours and 2 days poststenting, platelets, in general, exhibited an increase in activity that was most inhibited by clopidogrel loading. Clopidogrel inhibited GP Ib, platelet/endothelial cell adhesion molecule-1, CD 107a, CD 151, and GP IIb/IIIa expression at day 5 poststenting. Conclusion A 300 mg clopidogrel load given 3 to 24 hours before stenting inhibits platelets at the time of the procedure and reduces poststent activity more than a 75 mg dose given at the time of the procedure. The inhibition of adhesive molecule expression may also contribute an antithrombotic effect. Poststent activation of platelets may warrant higher periprocedural dosing. (Am Heart J 2003;145:239-47.)

Section snippets

Study patients

The study was approved by the Sinai Hospital Investigational Review Board. One hundred patients undergoing elective coronary artery stenting were studied, and gave written informed consent. Exclusion criteria were bleeding diathesis, acute myocardial infarction within 48 hours, stroke within 3 months, drug or alcohol abuse, prothrombin time >1.5 times control, platelet count <100,000/mm³, hematocrit <25% or creatinine >4.0 mg/dL, enrollment in other investigational drug trials within one month,

Results

One hundred twenty-six consecutive patients were screened and underwent baseline angiography. Twenty-six patients did not undergo coronary stenting because of insignificant or nonrevascularizable coronary artery disease, or referral for coronary artery bypass grafting. There were twenty-five patients each in groups A through D. Clinical and interventional characteristics are shown in Table I.

. Clinical characteristics of subjects by treatment group

Empty Cell	Group A	Group B	Group C	Group D
Age (y)	70 ± 7	73 ± 8	65

Discussion

The importance of platelet-mediated thrombosis in stent occlusion and limited information on clopidogrel's effects on platelet activity before and after coronary stenting led to the design of our study. We addressed the time course of platelet inhibition by clopidogrel, the effects of a loading dose compared to the standard maintenance dose, and the effect on markers of activation present on the platelet surface. The major findings of this prospective study are 1) pretreatment with a loading

Conclusions

Loading with 300 mg clopidogrel 3 to 24 hours before stent implantation inhibits platelets before the onset of the procedure and reduces activation induced by stenting more than the administration of 75 mg at the time of the procedure. These findings would predict a superior clinical outcome in patients receiving a loading dose in the CREDO trial.

Although loading is associated with early increased GP IIb/IIIa expression, a reduction in the expression of other adhesive molecules and late

Acknowledgements

We thank the Cardiac Catheterization Laboratory staff at Sinai Hospital and Ms Janine Muldowney for their technical excellence and outstanding support of this trial.

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There remains concern that the antiplatelet effects of aspirin and clopidogrel vary between patients and poor responders may be at increased risk of adverse events. However, the optimal method of measuring aspirin and/or clopidogrel response remains unresolved. We compared three methods of measuring clopidogrel response recommended by a recent consensus statement for the European Society of Cardiology, and investigated a novel approach to measuring aspirin response in patients established on both aspirin and clopidogrel. In addition, we investigated whether any of these assays predict peri-procedural myocardial necrosis following percutaneous coronary intervention (PCI).
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The three methods of measuring response to clopidogrel identify different patients as poor responders. Poor response to clopidogrel assessed by VerifyNow P2Y12 predicts myocardial necrosis. Measurement of [TxB2]_S-P demonstrates a wide variation in aspirin response in patients taking dual antiplatelet therapy.
Impact of gene polymorphisms, platelet reactivity, and the SYNTAX score on 1-year clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention: The GEPRESS study
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Citation Excerpt :
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^☆: Supported by a grant from Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, New York, NY, and Scimed/Boston Scientific, Maple Grove, Minn.

^☆☆: Reprint requests: Paul A. Gurbel, MD, Sinai Center for Thrombosis Research, Hoffberger Building, Suite 56, 2401 W Belvedere Ave, Baltimore, MD 21215-5271.

^★: E-mail: [email protected]

^★★: 0002-8703/2003/$30.00 + 0

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Clinical Investigations: Interventional CardiologyOnset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: The Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial☆,☆☆,★,★★

Abstract

Section snippets

Study patients

Results

Discussion

Conclusions

Acknowledgements

Pharmacol Res

J Am Coll Cardiol

J Am Coll Cardiol

Am Heart J

J Biol Chem

J Biol Chem

Blood

Bioorg Med Chem

Specific impairment of human platelet P2Y (AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel

Arterioscler Thromb Vasc Biol

Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets: definition and detection of ticlopidine/clopidogrel effects

Thromb Haemost

A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary artery stents

N Engl J Med

A clinical trial comparing three antithrombotic-drug regimens after coronary artery-stenting. Stent Anticoagulation Restenosis Study Investigators

N Engl J Med

A randomized blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE)

Lancet

Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation

Circulation

A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents

Circulation

Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS)

Circulation

Clinical Investigations: Interventional Cardiology
Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: The Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial☆,☆☆,★,★★