Effects of Cyclooxygenases Inhibitors on Vasoactive Prostanoids and Thrombin Generation at the Site of Microvascular Injury in Healthy Men

Abstract

Objective-Balance between vasoactive prostanoids that contribute to homeostasis of the circulatory system can be affected by cyclooxygenases inhibitors. Results of a recent large clinical trial show that myocardial infarction was more frequent among patients with rheumatoid arthritis treated with the selective cyclooxygenase-2 inhibitor rofecoxib compared with those treated with naproxen. Whether this difference was attributable to deleterious cardiovascular effects of rofecoxib or cardioprotective effects of naproxen has not been determined. We tested the hypothesis that naproxen, contrary to rofecoxib, exerts antithrombotic effects. Methods and Results-Forty-five healthy men were randomized to receive a 7-day treatment with rofecoxib (50 mg/d), naproxen (1000 mg/d), aspirin (75 mg/d), or diclofenac (150 mg/d). Formation of thromboxane, prostacyclin, and thrombin in the bleeding-time blood at the site of standardized microvascular injury was assessed before and after treatment. Naproxen, like aspirin, caused significant reduction of both thromboxane and prostacyclin, whereas diclofenac depressed prostacyclin synthesis but had no effect on tromboxane formation. Naproxen and aspirin significantly suppressed thrombin generation. Diclofenac showed a similar tendency, which did not reach statistical significance. Rofecoxib had no effect on any variables measured. Conclusions-In healthy men, naproxen exerts an antithrombotic effect at least as potent as aspirin, whereas rofecoxib does not affect hemostatic balance. Key Words: myocardial infarction Ⅲ risk factors Ⅲ cyclooxygenase inhibitors Ⅲ prostaglandins Ⅲ thrombin T he discovery of 2 isoforms of cyclooxygenases (COX-1 and COX-2) led to the introduction of coxibs, selective COX-2 inhibitors, into therapy. 1 They proved to combine strong anti-inflammatory properties with fewer gastrointestinal side effects than traditional nonsteroidal antiinflammatory drugs (NSAIDs). 2,3 FitzGerald et al 4 drew attention to the effects of coxibs on the synthesis of the vasoactive eicosanoids. They demonstrated that coxibs diminished excretion of prostacyclin (PGI 2 ) metabolites into urine without affecting either excretion of thromboxane A2 (TXA 2 ) or platelet blood aggregability. These results suggested that PGI 2 is synthesized by COX-2 in endothelial cells and that its biosynthesis can be depressed by coxibs, leaving unopposed activity of COX-1 in platelets. The issue soon became of clinical relevance with the publication of the VIGOR trial, 2 which compared the selective COX-2 inhibitor rofecoxib with the traditional NSAID naproxen in patients with rheumatoid arthritis. Patients treated with rofecoxib showed an increase in incidence of myocardial infarction compared with the naproxen group. Meta-analysis of studies concerning cardiovascular safety of rofecoxib gave conflicting results. 5,6 Vane 7 saw 3 possible explanations for the VIGOR trial results: a chance effect, a prothrombotic effect of rofecoxib, or the aspirin-like, protective activity of naproxen. We undertook this...

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