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

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. 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. 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. 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.