Antithrombotic drugs for the secondary prevention of ischemic stroke

On the assumption that antithrombotic drugs are able to reduce the incidence of any vascular event independently of where it first occurs, they are used for the secondary prevention of arterial vascular disease in different locations. The Antiplatelet Trialists' Collaboration meta-analysis has shown that the net benefit of antiplatelet drugs in the prevention of stroke, acute myocardial infarction and vascular death is about the same for patients with prior stroke or prior myocardial infarction. Most of the trials included in the Antiplatelet Trialists' Collaboration meta-analysis used aspirin, which was shown to lower the risk of stroke, myocardial infarction, and vascular death in patients with a history of transient ischemic attack or stroke. Aspirin should be given to patients operated on for symptomatic carotid stenosis and should be considered for asymptomatic patients. In a comparative study ticlopidine (500 mg) vs aspirin (650 mg), ticlopidine reduced the relative risk of vascular events by 9% and of recurrent stroke by 21%. When clopidogrel (75 mg) was compared with aspirin (325 mg), a 7.3% relative risk reduction was seen in the stroke group (6431 patients) of the CAPRIE study; a reduction in hemorrhagic events, especially in gastrointestinal bleeding, was also seen. At variance with previous studies, the ESPS-2 showed an advantage when dipyridamole (400 mg) was added to aspirin (50 mg). Oral anticoagulants are more effective than aspirin in the prevention of cardioembolic stroke in patients with atrial fibrillation. The higher efficacy of indobufen with respect to aspirin in this particular setting needs confirmation. Inhibition of thrombosis may be one of the mechanisms explaining the effect of statins in reducing both stroke and cardiac events in high-risk patients.     

Aspirin and cerebral ischemic accidents

At the acute phase of cerebral infarction, two recent large studies found that the use of aspirin reduces both mortality and the risk of the recurrence of stroke. In primary prevention, aspirin nearly halves the risk of myocardial infarction but does not reduce that of stroke. Concerning the secondary prevention of atherothrombotic brain infarcts, aspirin has been the most extensively studied drug, and is efficient between 50 mg and 1.3 g. In spite of the efficacy of other antiplatelets in this indication--ticlopidine (500 mg), clopidogrel (75 mg) and dipyridamole (400 mg)--aspirin remains the most cost-effective, doses between 100 and 300 mg being the most widely used. Cardiac diseases with a high embolic risk require the use of oral anticoagulation. In nonvalvular atrial fibrillation, the choice of antithrombotic drugs depends on risk stratification: oral anticoagulants are indicated in high-risk subjects, whereas aspirin is recommended in low-risk subjects and when oral anticoagulants are contraindicated. Studies with associations of aspirin and other antiplatelets are required to increase the yield of this medication in high-risk subjects, in parallel with efforts to detect and to treat the vascular risk factors.     

Aspirin and other antiplatelet drugs in the prophylaxis of thrombosis

Aspirin is of proven value as an antithrombotic drug. In unstable angina it reduces the risk of death and myocardial infarction by half. After a myocardial infarction it reduces the risk of death by about 10% and of coronary incidence (coronary death or definite myocardial infarction) by about 25%. These effects appear to be additive with those of beta-blocking drugs. Aspirin also reduces the risk of occlusion of aortocoronary saphenous vein grafts by about half. In transient cerebral ischaemia, aspirin may reduce the risk of stroke and death by 50%. In most clinical trials to date the daily dose of aspirin ranges from 325 mg to 1400 mg. Interest in very low doses of aspirin (less than 60 mg daily) is considerable but has yet to be translated into proven clinical benefit. Dipyridamole has not been shown to be effective as an antithrombotic when used alone. Its antiplatelet action ex vivo may be enhanced by combination with aspirin but clinical trials have shown relatively little advantage of the combination over aspirin alone. Sulphinpyrazone has not become established as a first line antithrombotic drug. Epoprostenol is useful in extracorporeal circulations to prevent platelet consumption and possibly in severe inoperable peripheral vascular disease.     

Antithrombotic secondary prevention after stroke

Opinion statement In patients with transient ischemic attack (TIA) or ischemic stroke of noncardiac origin, antiplatelet drugs are able to decrease the risk of stroke by 11% to 15%, and decrease the risk of stroke, myocardial infarction (MI), and vascular death by 15% to 22%. Aspirin leads to a moderate but significant reduction of stroke, MI, and vascular death in patients with TIA and ischemic stroke. Low doses are as effective as high doses, but are better tolerated in terms of gastrointestinal side effects. The recommended aspirin dose, therefore, is between 50 and 325 mg. Bleeding complications are not dose-dependent, and also occur with the lowest doses. The combination of aspirin (25 mg twice daily) with slow-release dipyridamole (200 mg twice daily) is superior compared with aspirin alone for stroke prevention. Ticlopidine is effective in secondary stroke prevention in patients with TIA and stroke. For some end points, it is superior to aspirin. Due to its side-effect profile (neutropenia, thrombotic thrombocytopenic purpura [TTP]), ticlopidine should be given to patients who are intolerant of aspirin. Prospective trials have not indicated whether ticlopidine is suggested for patients who have recurrent cerebrovascular events while on aspirin. Clopidogrel has a better safety profile than ticlopidine. Although not investigated in patients with TIA, clopidogrel should also be effective in these patients assuming the same pathophysiology than in patients with stroke. Clopidogrel is second-line treatment in patients intolerant for aspirin, and first-line treatment for patients with stroke and peripheral arterial disease or MI. A frequent clinical problem is patients who are already on aspirin because of coronary heart disease or a prior cerebral ischemic event, and then suffer a first or recurrent TIA or stroke. No single clinical trial has investigated this problem. Therefore, recommendations are not evidence-based. Possible strategies include the following: continue aspirin, add dipyridamole, add clopidogrel, switch to ticlopidine or clopidogrel, or switch to anticoagulation with an International Normalized Ratio (INR) of 2.0 to 3.0. The combination of low-dose warfarin and aspirin was never studied in the secondary prevention of stroke. In patients with a cardiac source of embolism, anticoagulation is recommended with an INR of 2.0 to 3.0. At the present time, anticoagulation with an INR between 3.0 and 4.5 cannot be recommended for patients with noncardiac TIA or stroke. Anticoagulation with an INR between 3.0 and 4.5 carries a high bleeding risk. Whether anticoagulation with lower INR is safe and effective is not yet known. Treatment of vascular risk factors should also be performed in secondary stroke prevention.     

Clinical trials evaluating platelet-modifying drugs in patients with atherosclerotic cardiovascular disease and thrombosis

Aspirin has been convincingly shown to reduce stroke and death in men with transient ischemic attacks (it may possibly be beneficial to women also), myocardial infarction and death in patients with unstable angina, thromboembolic complications associated with artificial heart valves in patients receiving oral anticoagulants (although gastrointestinal bleeding is prohibitive with this combination), and thrombotic occlusion of silicone rubber arteriovenous cannulae in uremic patients undergoing hemodialysis. In addition, aspirin may possibly decrease occlusion of saphenous vein aortocoronary grafts and venous thrombosis in men after hip replacement, although these reports require confirmation. Aspirin is ineffective in the secondary prevention of stroke and has unproven benefit in the secondary prevention of myocardial infarction. Dipyridamole in combination with oral anticoagulation decreases the thromboembolic complications associated with mechanical heart valves. The combination of aspirin and dipyridamole prevents both early and late occlusion of saphenous vein aortocoronary bypass grafts and protects renal function in patients with membranoproliferative glomerulonephritis. The relative importance of combining aspirin and dipyridamole compared with either agent used singly remains to be established. Sulfinpyrazone reduces the thrombotic occlusion of arteriovenous cannulae and early occlusion of saphenous vein aortocoronary grafts. The reported benefit in the secondary prevention of myocardial infarction is controversial.     

Platelet inhibitor agents in cardiovascular disease: an update

Platelets interact with the coagulation and fibrinolytic systems in the maintenance of hemostasis. However, these physiologic mechanisms may become pathologic, requiring prevention and treatment. In this review, the following clinical developments are analyzed: 1) the role of platelets in thrombogenesis; 2) the pharmacology of platelet inhibitory agents; and, most important, 3) the results of recent randomized trials of platelet inhibitor agents in different cardiovascular disorders. Aspirin reduces mortality and infarction rates in unstable angina and significantly decreases vascular mortality in acute myocardial infarction. Platelet inhibitors decrease mortality and recurrent cardiovascular events in the chronic phase after myocardial infarction. They also decrease vein graft occlusion rates after coronary bypass surgery. Although platelet inhibitors are beneficial in preventing acute vessel occlusion during coronary angioplasty, they are ineffective in preventing chronic restenosis. Antiplatelet agents, combined with warfarin, reduce thromboembolic events in patients with a mechanical prosthesis. Platelet inhibitors are also effective in secondary prevention of vascular events in patients with cerebrovascular disease. Finally, the use of aspirin for primary prevention of cardiovascular disease is still evolving, particularly in individuals at high risk. In conclusion, platelet inhibitors are effective in patients with a variety of cardiovascular disorders. The best studied, most inexpensive and least toxic agent is aspirin at a daily dose of 160 to 325 mg. Studies using new platelet inhibitor agents with different mechanisms of action are currently underway.     

Role of platelet inhibitor therapy in myocardial infarction

Summary Atherosclerotic plaque disruption is the predominant pathogenetic mechanism underlying the acute coronary syndromes. Plaque rupture leads to the exposure of collagen and vessel media, resulting in platelet and clotting activation, and occlusive thrombus formation. While drugs that interfere with platelet activation and function have been available for years, more powerful agents with novel mechanisms of action are being developed. Of the available platelet inhibitor drugs, only aspirin, sulfinpyrazone, and dipyridamole have undergone extensive clinical testing in patients with cardiovascular disease. More recently ticlopidine, a new and potent platelet inhibitor, has been successfully tested in patients with coronary and vascular disease.In acute myocardial infaction, aspirin significantly reduces cardiovascular mortality and reinfarction. Furthermore, the combination of aspirin and a thrombolytic agent produces maximal benefit. A role for heparin in the prevention of early mortality and reinfaction is emerging. This drug is effective for the prevention of left ventricular thrombosis in patients with anterior myocardial infarction.In the secondary prevention of reinfarction and cardiovascular mortality, available data support the use of a platelet inhibitor. Trials have shown that aspirin is as effective alone as in combination with dipyridamole, and is probably more effective than sulfinpyrazone. Long-term anticoagulant therapy also appears to be beneficial, but is associated with a high cost, need for extensive monitoring, and potential for hemorrhagic side effects.The role of aspirin in primary prevention is controversial. It may be indicated for patients at high risk for coronary disease in whom the benefit of therapy may outweigh the potential risk of cerebral bleeding.Coronary atherosclerotic plaque rupture, associated with thrombus formation, is fundamental to the development of acute myocardial infarction. Based on this concept, the role of antithrombotic therapy for the prevention or treatment of ischemic events in patients with coronary artery disease has stimulated enormous interest among clinicians and basic investigators. In this review we will examine: a) the pathogenesis of coronary thrombosis, b) the pharmacology of plateletinhibitor agents, and c) their role in the management of patients with acute myocardial infarction and in primary and secondary prevention of cardiovascular disease.Platelets interact with both the coagulation and fibrinolytic systems in the pathogenesis of thrombosis. While the purpose of this review is to discuss the role of platelets and platelet inhibitors in coronary disease, the use of anticoagulant or thrombolytic agents will be analyzed briefly when pertinent.     

Antiplatelet therapy in the treatment of cerebrovascular disease

Aspirin and the new agent ticlopidine have been the most thoroughly evaluated of the platelet-antiaggregating drugs used for the prevention of stroke and other vascular events. Numerous trials have shown aspirin to be effective in reducing the risk of myocardial infarction (MI), recurrent transient ischemic attacks, stroke, and vascular death in men at high risk for these events. Primary prevention trials have shown that aspirin reduces the risk of MI in healthy men over 50 years of age but does not reduce the risk of stroke. Two large, multicenter trials have shown that ticlopidine is effective in reducing the risk of fatal and nonfatal stroke in both men and women. Ticlopidine may also be effective in reducing the risk of recurrent stroke in patients who have had a completed thromboembolic stroke.     

Aspirin and dipyridamole and their limitations in the therapy of coronary artery disease

We have reviewed some of the voluminous literature on the effects of aspirin combined with dipyridamole on coronary thrombosis. There is clear evidence that aspirin is partially effective in preventing platelet aggregation and subsequent thrombosis in experimental constricted and damaged coronary arteries of dogs. Clinical studies show a clear reduction in myocardial infarction in male human subjects who are given aspirin as therapy for unstable angina, or as prophylaxis in asymptomatic individuals. In many studies aspirin and dipyridamole have been combined and are effective. We have not found dipyridamole to be effective in the dog with coronary artery constriction and find no substantial evidence that it is effective in preventing myocardial infarction in man. Until definitive studies show that combining dipyridamole with aspirin is more effective than aspirin alone, we do not recommend its use for prevention of coronary thrombosis.     

Clopidogrel versus ticlopidine after intracoronary stent placement

OBJECTIVES

The study compared the safety and efficacy of ticlopidine with clopidogrel in patients receiving coronary stents.

BACKGROUND

Stent thrombosis is reduced when ticlopidine is administered with aspirin. Clopidogrel is similar to ticlopidine in chemical structure and function but has fewer side effects; few data are available about its use in stent patients.

METHODS

We compared 30-day event rates in 500 consecutive coronary stent patients treated with aspirin and clopidogrel (300 mg loading dose immediately prior to stent placement, and 75 mg/day for 14 days) to 827 consecutive stent patients treated with aspirin and ticlopidine (500 mg loading dose and 250 mg twice daily for 14 days).

RESULTS

Patients treated with clopidogrel had more adverse clinical characteristics including older age, more severe angina, and more frequent infarction within the prior 24 h. Nonetheless, mortality was 0.4% in clopidogrel patients versus 1.1% in ticlopidine patients; nonfatal myocardial infarction occurred in 0% versus 0.5%, stent thrombosis in 0.2% versus 0.7%, bypass surgery or repeat angioplasty in 0.4% versus 0.5%, and any event occurred in 0.8% versus 1.6% of patients, respectively (p = NS). Based on the observed 30-day event rate of 1.6% with ticlopidine, the statistical power of the study was 43% to detect an even rate of 0.5% with clopidogrel, and 75% to detect an event rate with of 4% with clopidogrel, with a p value of 0.05.

CONCLUSIONS

These data indicate that clopidogrel can be safely substituted for ticlopidine in patients receiving coronary stents.     

Optimal platelet inhibition therapy in unstable angina pectoris and after coronary interventions

ASPIRIN AND HEPARIN: In several studies aspirin has been found to be very effective in unstable angina pectoris reducing fatal and non-fatal myocardial infarction by 50-70%. Unfortunately the optimal dose of aspirin is still an open question. Whereas heparin alone shows only a weak effectiveness the combination of aspirin and heparin is superior to aspirin alone and is still the basis of antithrombotic therapy in unstable angina. TICLOPIDINE AND CLOPIDOGREL: Experience with thienopyridine derivatives in unstable angina is limited. Ticlopidine has been found to be superior to aspirin alone. Data with the combination of clopidogrel and aspirin should be available soon. THERAPEUTIC RECOMMENDATION AFTER CORONARY INTERVENTION: Both, ticlopidine and clopidogrel have been found to be very effective in preventing coronary-stent thrombosis when combined with aspirin. Meanwhile ticlopidine has been widely substituted by clopidogrel due to the better safety profile of the latter one. 75 mg clopidogrel daily combined with aspirin is recommended for at least 4 weeks after coronary stenting.     

缺血性卒中二级预防中的抗血小板治疗

抗血小板治疗是缺血性卒中二级预防的重要措施之一。在缺血性卒中二级预防中,阿司匹林仍然是最常用的抗血小板药。氯吡格雷的疗效优于阿司匹林,但因其价格昂贵,目前仅在阿司匹林不能耐受或阿司匹林无效者中使用。联合用药只推荐缓释型双嘧达莫加小剂量阿司匹林。     

缺血性卒中二级预防中的抗血小板治疗

抗血小板治疗是缺血性卒中二级预防的重要措施之一。在缺血性卒中二级预防中，阿司匹林仍然是最常用的抗血小板药。氯吡格雷的疗效优于阿司匹林，但因其价格昂贵，目前仅在阿司匹林不能耐受或阿司匹林无效者中使用。联合用药只推荐缓释型双嘧达莫加小剂量阿司匹林。     

Heparin in the treatment and secondary prevention of myocardial infarction. A critical review of the main trials]

The aim of this article is to assess the therapeutic value of standard heparin in the acute phase and secondary prevention of myocardial infarction. Only clinical trials with an adequate methodology have been analysed. In patients having undergone thrombolytic therapy associated with aspirin, heparin slightly reduces the mortality but only during the period of its administration. In a metaanalysis of approximately twenty clinical trials of patients not receiving thrombolytic or aspirin therapy, heparin was associated with a significant reduction of deep vein thrombosis, pulmonary embolism, recurrent myocardial infarction and cerebrovascular accidents. In the context of secondary prevention of myocardial infarction, the administration of a moderate dose of subcutaneous heparin resulted in a beneficial effect on morbidity and mortality in one published trial. The use of low molecular weight heparins for the prevention of coronary thrombosis merits attention because of the pharmacological and pharmacokinetic properties of these products.     

Akute Koronarsyndrome – ein Update Teil I: Pathogenese und medikamentöse Therapie

BACKGROUND: Unstable angina accounts for more than one million hospital admissions annually. 6-8% of patients with this condition have non-fatal myocardial infarction or die within the first year after diagnosis. Recently, the term "acute coronary syndromes" has been used to describe the spectrum of conditions that includes unstable angina, non-Q-wave myocardial infarction (which generally presents without ST-segment elevation), and Q-wave myocardial infarction (which generally presents with ST-segment elevation). PATHOGENESIS: Disruption of a formed plaque is a complex pathologic process that is central to the initiation of the acute coronary syndromes. Local thrombosis occurring after plaque disruption results from complex interactions among the lipid core, smooth-muscle cells, macrophages, and collagen. TREATMENT: Multiple huge clinical trials confirmed that aspirin reduces the risk of death from cardiac causes and fatal and non-fatal myocardial infarction by about 50-70% in patients presenting with unstable angina. Ticlopidine may be substituted for aspirin in patients with hypersensitivity to aspirin or gastrointestinal intolerance. Clopidogrel acts similarly to ticlopidin but has fewer side effects than ticlopidine and has not been reported to cause neutropenia. High-risk patients with refractory unstable angina and elevated troponin levels may have substantial benefit of glycoptotein (GP) IIb/IIIa inhibition. Current practice guidelines support the use of the combination of unfractionated heparin and aspirin for the treatment of unstable angina. Clinical studies have demonstrated that the incidence of the composite end point of death, myocardial infarction, or recurrent angina was lower with enoxaparin than with unfractionated heparin. Beta-blockers, nitrates, and calcium-channel blockers are useful for antiischemic therapy in patients with acute coronary syndromes.     

Thrombolysis and antithrombotic therapy for coronary artery disease

Aspirin in a dose of 160 to 325 mg should be administered on day 1 of an acute MI and continued indefinitely on a daily basis. Thrombolytic therapy should be administered within 6 to 12 hours after the onset of an acute MI with ST segment elevation or with left bundle branch block. Primary coronary angioplasty when available should be used rather than thrombolytic therapy in the treatment of older persons with acute MI who are poor candidates for thrombolytic therapy. Intravenous heparin should be given in persons with acute MI undergoing primary coronary angioplasty or surgical coronary revascularization and in persons with acute MI at high risk for systemic embolization. Long-term oral warfarin should be given after MI for the secondary prevention of MI in post-MI persons unable to tolerate daily aspirin, in post-MI persons with persistent atrial fibrillation, and in post-MI persons with left ventricular thrombus. Platelet GP IIb/IIIa inhibitors should be administered along with aspirin and enoxaparin in the acute phase of management of persons with unstable angina pectoris or non-Q wave MI. Aspirin should be administered daily indefinitely to persons after MI, to persons with unstable angina pectoris, to persons with stable angina pectoris, and to persons undergoing coronary revascularization. Aspirin plus ticlopidine or aspirin plus clopidogrel should be used in persons undergoing coronary artery stenting. Platelet GP IIb/IIIa inhibitors should be used at the time of coronary angioplasty, coronary atherectomy, or coronary stenting. Aspirin, 160 to 325 mg daily, is recommended in older men and postmenopausal women who are at high risk for developing coronary events in addition to treating their coronary risk factors.     

Ticlopidine versus aspirin after myocardial infarction (STAMI) trial

OBJECTIVES: We sought to compare the efficacy of aspirin and ticlopidine in survivors of acute myocardial infarction (AMI) treated with thrombolysis. BACKGROUND: The role of ticlopidine in secondary prevention after AMI has not yet been explored. METHODS: Of 4,696 patients with AMI treated with thrombolysis who were screened, 261 died in the hospital (5.6%) and 1,470 were enrolled in this randomized, double-blind, multicenter trial and allocated to treatment with either aspirin (160 mg/day) or ticlopidine (500 mg/day). The most frequent reasons for exclusion were refusal to give informed consent, planned myocardial revascularization, risk of noncompliance with study procedures, need for anticoagulant therapy and contraindications to the study treatments. The primary end point was the first occurrence of any of the following events during the six-month follow-up: fatal and nonfatal AMI, fatal and nonfatal stroke, angina with objective evidence of myocardial ischemia, vascular death or death due to any other cause. RESULTS: The primary end point was recorded in 59 (8.0%) of the 736 aspirin-treated and 59 (8.0%) of the 734 ticlopidine-treated patients (p = 0.966). Vascular death was the first event in five patients taking aspirin and in six patients taking ticlopidine (0.7% vs. 0.8%; p = NS); nonfatal AMI in 18 and 8 (2.4% vs. 1.1%; p = 0.049); nonfatal stroke in 3 and 4 (0.4% vs. 0.5%; p = NS); and angina in 33 and 40 (4.5% vs. 5.4%; p = NS), respectively. The frequency of adverse reactions was not significantly different between the two groups. CONCLUSIONS: No difference was found between the ticlopidine and aspirin groups in the rate of the primary combined end point of death, recurrent AMI, stroke and angina.     

Documented subacute stent thrombosis within thirty days after stenting with sirolimus-eluting stent (Cypher) for acute myocardial infarction: a Japanese single center retrospective non-randomized study.

BACKGROUND: The incidence of subacute stent thrombosis (SAT) within 30 days after stenting with a sirolimus-eluting stent (Cypher) for acute myocardial infarction (AMI) was retrospectively compared to that with bare-metal stents (BMS). METHODS AND RESULTS: Among 559 lesions in 558 consecutive AMI from April 2003 to February 2006, the incidence of documented SAT after Cypher implantation (2/276 lesions, 0.72%) was almost the same as for BMS (2 cases, 0.71%). Aspirin (81-100 mg/day) plus ticlopidine (200 mg/day) were administered continuously after admission in all 4 cases. CONCLUSION: Documented SAT did not increase after stenting with Cypher for AMI under aspirin plus ticlopidine.     

Low molecular weight heparins and coronary artery disease

Coronary artery disease encompasses a wide spectrum of conditions including silent ischemia, exertional angina, unstable angina, and myocardial infarction. Acute coronary syndromes (unstable angina and myocardial infarction) are caused by the rupture of an atherosclerotic plaque, platelet activation, and fibrin deposition resulting in thrombosis. Aspirin and unfractionated heparin (UFH) have traditionally been the treatment of choice in patients with acute coronary syndromes; however, low molecular weight heparins (LMWHs) offer potential advantages over UFH. Available evidence indicates that LMWH is superior to UFH in reducing ischemic events or death in the acute phase of unstable angina or non-Q-wave myocardial infarction. Long-term therapy with lower doses of LMWH may not offer any advantage to aspirin in the prevention of coronary events or death. Major bleeding complications are similar for LMWH and UFH although minor bleeding complications are more common with LMWH, primarily due to injection-site hematomas. Finally, use of LMWH appears to be costeffective compared with UFH. The available evidence supports improved clinical outcomes, favorable safety profile, and cost savings associated with LMWH use in the management of unstable angina and non-Q-wave myocardial infarction and should be favored over UFH.     

Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on Instability in Coronary Artery Disease in Southeast Sweden

In this study, 796 men with unstable coronary artery disease (that is, unstable angina or non-Q wave myocardial infarction) were randomized to double-blind placebo-controlled treatment with aspirin (75 mg/day). The long-term efficacy was judged from the occurrence of myocardial infarction or death or severe angina necessitating referral to coronary angiography. The risk of myocardial infarction or death was reduced during aspirin treatment--after 1 year, the risk ratio was 0.52 (confidence interval 0.37 to 0.72). Severe angina necessitating referral to coronary angiography was less common during aspirin therapy--after 3 months, the risk ratio was 0.59 (0.42 to 0.84) and after 1 year 0.71 (0.56 to 0.91). The combined event rate of myocardial infarction or death or referral to coronary angiography was reduced; after 3 months, the risk ratio was 0.44 (0.30 to 0.66) and after 1 year 0.65 (0.54 to 0.79). The 75-mg aspirin dose was well tolerated and had a high level of patient compliance. Treatment with aspirin (75 mg/day) should be recommended to all men for greater than or equal to 3 months after an episode of unstable coronary artery disease. Long-term therapy should be considered if there are no contraindications or side effects.