Aspirin as an antithrombotic drug: from the aggregometer to clinical trials.
Aspirin inhibits thromboxane A2 and prostaglandin formation in platelets and prostaglandin I2 (prostacyclin) in vascular cells. It prevents platelet aggregation by irreversible acetylation of cyclooxygenase, a key enzyme in the arachidonic acid metabolism. Oral aspirin can be extensively hydrolyzed to inactive salicylate in the stomach and the liver (first-pass) before it enters the systemic circulation. Presystemic acetylation of platelets thus occurs during aspirin absorption, with a concomitant sparing of peripheral vascular cyclo-oxygenase, mainly exposed to salicylate. On the basis of its antiplatelet effect, aspirin has been assessed during the past two decades in patients with a history of myocardial infarction, stroke, transient ischemic attack or unstable angina. A meta-analysis of randomized controlled trials of long term aspirin treatment for secondary prevention of vascular disease indicated that aspirin (300-1500 mg daily) significantly reduced fatal and non-fatal vascular events. More recently aspirin (160 mg daily) produced a significant reduction in hospital vascular mortality and in non-fatal events in patients with suspected acute myocardial infarction. Combination of aspirin with streptokinase was significantly better than either drug alone. On the other hand two primary prevention trials of aspirin in healthy doctors did not show any modification of vascular mortality despite an overall reduction of non-fatal myocardial infarction. Resolution of some problems related to the mechanism of action of aspirin and to selection of trial populations will possibly increase the benefit/risk ratio of aspirin treatment for prevention of vascular disease.
de Gaetano
G
G
Istituto di Ricerche Farmacologiche Mario Negri, Imbaro, Italy.
D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D002561:Cerebrovascular Disorders / Q000517:prevention & control*; D006801:Humans; D015201:Meta-Analysis as Topic; D009203:Myocardial Infarction / Q000517:prevention & control; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic; D013927:Thrombosis / Q000517:prevention & control*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors
D010975:Platelet Aggregation Inhibitors; D011448:Prostaglandin Antagonists; D013928:Thromboxane A2; D001241:Aspirin