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.
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.


CONCLUSIONS
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.
Ostad
Mir Abolfazl
MA
Department of Medicine II, Mainz University Medical Center, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany.
Nick
Eva
E
Paixao-Gatinho
Vitor
V
Schnorbus
Boris
B
Schiewe
Robert
R
Tschentscher
Peter
P
Munzel
Thomas
T
Warnholtz
Ascan
A
D000077144:Clopidogrel; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000453:epidemiology*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects*; D019317:Evidence-Based Medicine; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D018570:Risk Assessment; D012307:Risk Factors; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D014657:Vasculitis / Q000188:drug therapy* / Q000453:epidemiology*
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine