Elsevier

The American Journal of Medicine

Volume 119, Issue 8, August 2006, Pages 707.e11-707.e16
The American Journal of Medicine

AJM Online
Clinical research study
Paradoxical Rebound Platelet Activation After Painkillers Cessation: Missing Risk for Vascular Events?

https://doi.org/10.1016/j.amjmed.2005.11.007Get rights and content

Abstract

Background

Several reliable reports strongly indicate that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors is associated with an increased risk of cardiovascular events. Considering the key role of platelets in coronary atherosclerosis and the fact that antiplatelet therapy with aspirin (and more recently, clopidogrel) has been associated with reduced vascular mortality, we sought to determine the effect of therapy and withdrawal of NSAIDs and COX-2 inhibitors on platelet activity.

Methods

Platelet characteristics from 34 aspirin-naive volunteers who were receiving NSAIDs and COX-2 inhibitors were compared with 138 drug-free controls. Platelets were assessed twice at baseline (at least 1 month of NSAIDs and COX-2 inhibitors) and after a 14-day washout. We used adenosine diphosphate-induced conventional aggregometry, the point-of-care Ultegra analyzer (Ultegra Accumetrics, San Diego, Calif), and whole blood flow cytometry.

Results

Platelet activity during therapy with NSAIDs and COX-2 inhibitors was similar and unremarkable between groups. However, there was a highly significant increase of platelet activity as assessed by conventional aggregometry (P = .0003), Ultegra analyzer readings (P = .03), and expression of GPIIb/IIIa (P = .02), P-selectin (P = .03), and platelet endothelial cell adhesion molecule-1 (P = .001) after withdrawal from NSAIDs and COX-2 inhibitors.

Conclusions

These data suggest that drug cessation, rather than continuous therapy with NSAIDs and COX-2 inhibitors, may be associated with rebound platelet activation, which may predispose one to a higher risk of vascular events. This hypothesis requires intensive testing in crossover randomized studies and may justify more aggressive antiplatelet regimens in patients after discontinuation of therapy with NSAIDs and COX-2 inhibitors.

Section snippets

Subjects

Subjects were eligible if they met all of the following inclusion criteria: males and females 21 years and older; able to provide informed consent; documented history of vascular disease, or more than 2 of 8 risk factors for vascular disease (family history, sedentary lifestyle, diabetes mellitus, hypertension, morbid obesity, hypercholesterolemia, postmenopausal or surgically sterile females, current or recent smokers); and available and willing to return for follow-up tests. Subjects were

Results

A total of 180 volunteers were initially considered, but 8 participants had to be excluded from analysis because of clots in the samples (1 participant), baseline cell counts out of institutional limits (2 participants), use of aspirin (4 participants), and noncompliance (1 participant). The remaining 172 aspirin-naive subjects were considered evaluable and grouped into the dataset with complete aggregometry, analyzer, and receptor measures dependent on NSAID and COX-2 inhibitor use. The locked

Discussion

The data from the present retrospective analyses are the first to suggest that it is not immediate therapy with NSAIDs and COX-2 inhibitors, but rather withdrawal from these agents that is associated with a paradoxical increase of platelet activity. Despite the obvious limitations of this study, these findings may provide some insights into the existing and growing concern that NSAIDs and COX-2 inhibitors may be associated with worse clinical outcomes. Most important, if such vascular events

References (34)

  • T.J. Jerde et al.

    Celecoxib inhibits ureteral contractility and prostanoid release

    Urology

    (2005)
  • M.P. Diamond et al.

    Modulation of the expression of vascular endothelial growth factor in human fibroblasts

    Fertil Steril

    (2005)
  • J. Basivireddy et al.

    Indomethacin-induced renal damagerole of oxygen free radicals

    Biochem Pharmacol

    (2004)
  • D. Mukherjee et al.

    Risk of cardiovascular events associated with selective COX-2 inhibitors

    JAMA

    (2001)
  • G.A. FitzGerald

    Cardiovascular pharmacology of nonselective nonsteroidal anti-inflammatory drugs and coxibsclinical considerations

    Am J Cardiol

    (2002)
  • M.L. Capone et al.

    Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects

    Circulation

    (2004)
  • D.J. van Kraaij et al.

    A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers

    Br J Clin Pharmacol

    (2002)
  • G. Andrioli et al.

    Study on paradoxical effects of NSAIDs on platelet activation

    Inflammation

    (1997)
  • M.A. Buerkle et al.

    Selective inhibition of cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo

    Circulation

    (2004)
  • A.M. Blaicher et al.

    Effect of non-selective, non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 selective inhibitors on the PFA-100 closure time

    Anaesthesia

    (2004)
  • J. Van Ryn et al.

    Meloxicam does not affect the antiplatelet effect of aspirin in healthy male and female volunteers

    J Clin Pharmacol

    (2004)
  • G. Andrioli et al.

    Dual effects of diclofenac on human platelet adhesion in vitro

    Blood Coagul Fibrinolysis

    (1996)
  • N.A. Goldenberg et al.

    Brief communicationduration of platelet dysfunction after a 7-day course of ibuprofen

    Ann Intern Med

    (2005)
  • Z.M. Ruggeri

    New insights into the mechanisms of platelet adhesion and aggregation

    Semin Hematol

    (1994)
  • J.W. Smith et al.

    Rapid platelet-function assay. An automated and quantitative cartridge-based method

    Circulation

    (1999)
  • K.A. Ault

    Flow cytometric measurement of platelet function and reticulated platelets

    Ann New York Acad Sci

    (1993)
  • J. Hippisley-Cox et al.

    Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugspopulation based nested case-control analysis

    BMJ

    (2005)
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