Paradoxical Rebound Platelet Activation After Painkillers Cessation: Missing Risk for Vascular Events?

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.