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Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study

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Abstract

Background

Recently we have demonstrated a dose-dependent improvement of endothelial function after administration of a single loading dose of clopidogrel in patients with coronary artery disease (CAD). We therefore hypothesized that chronic therapy with clopidogrel may improve endothelial function in patients with CAD.

Methods

In a double-blind, randomized, monocentric study 120 patients with established CAD were randomized to one of the following treatment arms: clopidogrel 75 mg q.d., acetylsalicylic acid (ASA) 100 mg q.d., or a combination of ASA and clopidogrel. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitroglycerin-mediated dilation (NMD) of the brachial artery were determined before and after 28 days of treatment. The effect of clopidogrel was monitored in vitro by ADP-induced platelet aggregation in platelet-rich plasma. Effects of treatment on platelet superoxide production were measured by lucigenin-enhanced chemiluminescence in washed platelets. C-reactive protein, RANTES and monocyte chemoattractant protein-1 were determined as inflammatory markers. The study was registered as ISRCTN34097747.

Results

Treatment groups were comparable regarding age, gender, cardiovascular risk factor distribution and concomitant medication. FMD [median (IQR) ASA, +0.8 (−2.0; 2.7); ASA + clopidogrel, ±0 (−2.0; 2.9); clopidogrel, +1.0 (−1.1; 2.4); P = n.s.], NMD, platelet superoxide production or inflammatory markers remained unchanged in all treatment groups.

Conclusion

We conclude that the beneficial effects of short-term effects of clopidogrel on endothelial function of patients with CAD are abolished after long-term clopidogrel treatment.

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Acknowledgments

We are indebted to Mr. Fresenius from the GCP pharmacy of the Johannes Gutenberg-University Medical Center for the accurate preparation of the blinded study drug. We acknowledge the excellent technical assistance of Mrs. K. Havliczek and Mrs. H. Seiler. This study was financially supported by Bristol-Myers Squibb.

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Authors and Affiliations

  1. Department of Medicine II, Mainz University Medical Center, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany

    Mir Abolfazl Ostad, Eva Nick, Vitor Paixao-Gatinho, Boris Schnorbus, Robert Schiewe, Thomas Munzel & Ascan Warnholtz

  2. Department of Clinical Chemistry, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Peter Tschentscher

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  1. Mir Abolfazl Ostad
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  2. Eva Nick
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  3. Vitor Paixao-Gatinho
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  4. Boris Schnorbus
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  5. Robert Schiewe
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  6. Peter Tschentscher
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  7. Thomas Munzel
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  8. Ascan Warnholtz
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Correspondence to Ascan Warnholtz.

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Ostad, M.A., Nick, E., Paixao-Gatinho, V. et al. Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study. Clin Res Cardiol 100, 29–36 (2011). https://doi.org/10.1007/s00392-010-0199-6

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  • DOI: https://doi.org/10.1007/s00392-010-0199-6

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