Aspirin ======= þ Permanant platelet inhibition: - effect is irreversible for life of platelet, which is 8-10 days - daily platelet turnover is 10-15% þ ASA antithrombic dosage. - One oral dose of 100 mg completely suppresses biosynthesis of thromboxane A2 within one hour - Repeated administration of 30-50 mg daily eventually has same effect but takes 7-10 days to achieve. [Patrono C. N Engl J Med 1994;330:1287.] þ ASA anticoagulant effect. - "It is sometimes forgotten that in addition to its antiplatelet effects, chronic salicylate toxicity can deplete prothrombin as well and result in prolongation of the PT with resultant bleeding" (H Louzon, M.D.) [Goldsweig HG Kapusta M Schwartz J J Rheumatol Bleeding, salicylates, and prolonged prothrombin time: three case reports and a review of the literature. J Rheumatol 1976 Mar;3(1):37-42.] Fourteen cases of ASA induced hypoprothrombinemic bleeding, including three patients reported by the authors, are reviewed. Predisposing factors toward bleeding include malnutrition and malabsorption syndrome. Although the bleeding is usually benign, it may be serious on occasion. The importance of this rarely considered cause of ASA associated bleeding lies in the fact that it is readily corrected with Vitamin K. þ after MI - randomized trial of ASA 160 mg enteric coated daily vs placebo in suspected MI (75% male): vascular deaths in 9.4% (804) of treated group, 11.8% (1016) in placebo group, of 8600 patients. Major bleeding in 31 in ASA group and 33 in placebo group. Confirmed hemorrhagic stroke in 5 in ASA group and 2 in placebo group. [ISIS-2 Collaborative Group, Lancet 1988;2:349.] - "As I thought about the problem of trying to determine if earlier treatment with ASA would be beneficial I remembered the results of ISSIS-2 . This was the only study (that I am aware of) that looked at ASA vs placebo as a function of time (the arm with NO thrombolysis)." -------------------------------------------------- Hours Vascular deaths/Patients %Reduction ASA Placebo -------------------------------------------------- 0-1 34/356 43/358 20.5 2 80/953 103/955 22.2 3 109/1243 149/1243 26.9 4 109/1181 138/1178 21.2 0-4 332/3733 433/3734 23.3 5-12 366/3633 451/3636 18.8 13-24 106/1221 132/1230 19.8 5-24 472/4854 583/4866 18.8 -------------------------------------------------- "I have calculated and added the last column of numbers which expresses the mortality reduction of ASA compared to placebo. It is easy to see that within the first 5 hours there does not appear to be any advantage of earlier treatment. Beyond 5 hours the mortality advantage is reduced but I did not perform a chi-squared statistic to check for significance compared to the < = 5 hour interval (23.3% vs. 18.8%)." "Another tidbit from this study is the observation that, although very low (80 mg) doses of ASA are effective for secondary prevention, it takes several days for these levels to achieve antiplatelet effects. At a dose of 160 mg or greater the effect is more immediate. Unfortunately I did not copy the list of references that detail the pharmcokinteics of oral ASA." --H. Louzon, M.D. þ unstable angina - double-blind controlled trial of 796 men (untable angina or non-Q MI) with 75 mg ASA/day vs. placebo: MI in 17 of ASA group and 38 in placebo group; one year later, total of 78 in ASA group and 145 in placebo group had died of MI. [The RISC Group. Lancet 1990;336:827.] [Wallentin LC et al. J Am Coll Cardiol 1991;18:1587.] þ prevention - double-blind trial in more than 22,000 male US physicians compared 325 mg of ASA daily with placebo. After 5 years, MI in 139 of ASA group and and 239 of placebo group. Hemorrhagic CVA in 23 of ASA group and 12 of placebo group. [Physicians' Health Study Research Group, N Engl J Med 1989;321:129.] Relative risk of hemorrhagic CVA vs. MI might be more in women (also in low-risk men?) Trials of 40-75 mg daily now in progress. þ GI side effects - lower doses and enteric coating decreas GI side effects [Hawthorne AB et al. Br J Clin Pharmacol 1991;32:77.]