CLINICAL TRIALS OF ANTITHROMBOTIC AGENTS IN UNSTABLE ANGINA

A Veterans Administration (VA) Cooperative Study (NEJM 309:396,1983) has demonstrated that a single daily administration of aspirin 324 mg in buffered solution, started within 51 hours of admission to the hospital, significantly reduced the 12-week incidence of acute myocardial infarction (MI) or death by 51% in men with unstable angina. These results have been substantially confirmed by a Canadian Multicenter Trial (NEJM 313:1369,1985) in patients of both sexes treated with aspirin 325 mg qid. The rate of death or acute MI wasfound to be 51% lower in the group treated with aspirin,after a mean follow-up period of 18 months. To put these figures into perspective, one should consider thatgiven a 12-14% event rate at one year treatment of 100 patients with aspirin will protect 6-7 from a non-fatal MI or cardiac death. Despite the surprisingly identical figures of risk reduction in the two trials, there are a number of important differences in design and in several patient- or drug-related variables that should be taken into account when comparing the two studies. Aspirin inhibits thromboxane TX)A2dependent platelet function by irreversibly acetylating platelet cyclooxygenase. Besides being a potent inducer of irreversible platelet aggregation, TXA2 alsoconstricts vascular smooth muscle including the human coronary artery. Thus, the beneficial effects of aspirinin unstable angina might be theoretically related to prevention of platelet aggregation and subsequent vascularocclusion and/or to prevention of coronary vasospasm. The latter possibility, however, is contradicted by thefailure of aspirin to prevent acute myocardial ischaemia due to coronary vasospasmin patients with variant angina(Circulation 66:702,1982) and by theunchanged incidence or severity of angina in the aspirin-treated patientsstudied by the VA Cooperative Study(NEJM 310:122,1984). Thus, suppressionof TXA2mediated plateletaggregation seems a more likely mechanism to account for the reportedbenefitof aspirin in the latter study. Thisinterpretation is further strengthened by the fact that these beneficial effects were demonstrated in association with a single daily administration of the drug. Given the short half-life (20-30 min) of intact acetylsalicylic acid in the human circulation,these results are consistent with permanent inactivation by aspirin of an enzyme or receptor that cannot be resynthesised to a critical level withinthe 24-hour interval between dosing. Acetylation of platelet cyclooxygenase might represent such an irreversible process, although the dose of aspirin used (324 mg) does not allow the exclusion of other acetylation processes because it is 8-10 timesin excess of the amount needed to inhibit fully platelet TXA2 productionduring chronic dosing (Circulation 72:1177,1985).Based on dose-response studies performed in healthy volunteers (FitzGerald et al., JCI 71:676,1983), the-doses of aspirin used in the two trials(324 and 1,300 mg, respectively) would equally and profoundly suppress vascular Prostacyclin (PGI2) production.It is thought that this eicosanoid modulates vascular endothelial as well as smooth muscle function,and it hasbeen shown to inhibit humanplatelet aggregation in response toall known stimuli (Moncada & Vane, NEJM300:1142,1979). The hypothesis thata selective sparing of vascular PGI2production by low-dose aspirin might enhance the antithrombotic effect of thedrugin unstable angina is currently bein tested in a prospective clinical study comparing 40 and 325 mg/day.If an appreciable proportion of acute Mis and deaths occurring in the aspirin-treated patients (6.4% in the VACooperative Study)are due to TXA2-independent platelet aggregationin a major epicardial coronary artery, as suggested by the post-mortemfindings of Falk (Circulation 71:699,1985) and Davies et al. (Circulation 73:418,1986), then a substantial sparingof endothelial cyclooxygenase in the immediate vicinity of a fissured plaque might favourably affect its evolution. The finding that low-dose aspirindoes not impair the fibrinolytic capacity of the vessel wall (de Gaetano et al., Biochem Pharmacol 35:3147,1986) provides additional support to this working hypothesis.