Aspirin: benefit and risk in thromboprophylaxis

Aspirin is often perceived either as a harmless panacea or as a useless poison which causes endless, needless trouble. We have carefully reviewed the literature on all aspects of aspirin and find that neither view is justified. Regular use of even low-dose aspirin (150 mg/day or less) may lead to clinically-important adverse events, particularly haemorrhage. The risk of such an event is considerably outweighed by the benefit for patients with a significant risk of a thromboembolic event. For individuals without a clear risk of thrombosis or thromboembolism, the balance is more even: indiscriminate aspirin-taking is to be discouraged.     

The relationship between zinc, copper and lipid metabolic indicators in adults

With the completion of the major carotid endarterectomy trials the indications for this procedure can be defined. The procedure, if done by experienced teams, has been shown to improve the chance of stroke free survival in symptomatic and asymptomatic patients with a high-grade stenosis of the internal carotid artery. In asymptomatic patients the risk reduction gained by prophylactic carotid endarterectomy may be small in relation to the risk of coincident factors particularly coronary artery disease. The benefit gained by carotid endarterectomy depends closely on the risk of the procedure itself, and a single little flaw during the management can annulate the benefit of the operation in asymptomatic patients. There are still considerable controversies with regard to peri-operative management and surgical technique, e.g., the necessity of routine pre-operative arteriography has recently been questioned. Quality control programmes become a requirement with the publication of performance standards for carotid endarterectomy. According to a consensus of the American Heart Association, the surgical morbidity/mortality must be less than 6% for symptomatic carotid lesions and less than 3% for asymptomatic lesions. The present review discusses the steps of the pre-operative work-up, the procedure itself and the post-operative management with the aim to identify accepted safety standards as well as areas of uncertainty.     

Secondary prevention of arteriosclerosis

Secondary prevention of arteriosclerosis tries to inhibit progression of the atherosclerotic process. Therapeutic measures focus on modification of cardiovascular risk factors and antithrombotic treatment. Hypercholesterolemia is the main risk factor for coronary artery disease. The risk of a coronary event is correlated to the plasma cholesterol level. Lowering plasma cholesterol results in reduction of vascular morbidity and mortality. Cigarette smoking is the predominant risk factor for peripheral arterial occlusive disease (PAOD). Smoking cessation reduces progression of PAOD and lowers cardiovascular morbidity and mortality. The preventive effect of antihypertensive therapy in hypertensive patients is most pronounced for cerebrovascular events. Antihypertensive measures improve prognosis after stroke and myocardial infarction. The increased cardiovascular risk in diabetics is in part explained by hyperglycemia and hyperinsulinemia, but also depends on coexisting dyslipidemia and hypertension. Intensive treatment of elevated blood glucose levels, dyslipidemia and hypertension are important preventive measures. Aspirin is highly effective in secondary prevention of vascular events. For the coronary arteries, low-dose aspirin is well established. Whether low-dose aspirin is equally effective for reducing progression of arteriosclerosis in the cerebrovascular and in the peripheral vessels is questionable. Ticlopidine serves as an alternative to aspirin; however, neutropenia may occur, which requires supervision of the patient.     

Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials

CONTEXT: Aspirin has been widely used to prevent myocardial infarction and ischemic stroke but some studies have suggested it increases risk of hemorrhagic stroke. OBJECTIVE: To estimate the risk of hemorrhagic stroke associated with aspirin treatment. DATA SOURCES: Studies were retrieved using MEDLINE (search terms, aspirin, cerebrovascular disorders, and stroke), bibliographies of the articles retrieved, and the authors' reference files. STUDY SELECTION: All trials published in English-language journals before July 1997 in which participants were randomized to aspirin or a control treatment for at least 1 month and in which the incidence of stroke subtype was reported. DATA EXTRACTION: Information on country of origin, sample size, duration, study design, aspirin dosage, participant characteristics, and outcomes was abstracted independently by 2 authors who used a standardized protocol. DATA SYNTHESIS: Data from 16 trials with 55462 participants and 108 hemorrhagic stroke cases were analyzed. The mean dosage of aspirin was 273 mg/d and mean duration of treatment was 37 months. Aspirin use was associated with an absolute risk reduction in myocardial infarction of 137 events per 10000 persons (95% confidence interval [CI], 107-167; P<.001) and in ischemic stroke, a reduction of 39 events per 10000 persons (95% CI, 17-61; P<.001). However, aspirin treatment was also associated with an absolute risk increase in hemorrhagic stroke of 12 events per 10000 persons (95% CI, 5-20; P<.001). This risk did not differ by participant or study design characteristics. CONCLUSIONS: These results indicate that aspirin therapy increases the risk of hemorrhagic stroke. However, the overall benefit of aspirin use on myocardial infarction and ischemic stroke may outweigh its adverse effects on risk of hemorrhagic stroke in most populations.     

Auricular fibrillation, systemic embolism and anticoagulant treatment

The risk of arterial embolism, specially cerebral, in patients with mitral stenosis associated atrial fibrillation is seventeen fold greater than that of the general population and five fold greater than that of non rheumatic atrial fibrillation. The usefulness of oral anticoagulant therapy in patients with atrial fibrillation and mitral stenosis is clear. In patients with non rheumatic atrial fibrillation, the controversy about its usefulness has been cleared with five recent reports showing a significant benefit or oral anticoagulation. We believe that these results may be applied to the routine management of these patients provided an adequate patient selection, consideration of contraindications and the use of a low anticoagulation range. Aspirin effectiveness in these patients is unsettled. One study showed benefits of 375 mg/day in patients younger than 75 years. The embolic risk in patients with atrial fibrillation must be stratified. High risk patients require the use of oral anticoagulation with an INR range between 3 and 4.5; those with medium risk require an INR between 2 and 3 and in some, aspirin use may be an alternative. When electrical cardioversion is indicated, oral anticoagulation must be used when atrial fibrillation has lasted for more than two days. In these cases, it is advisable to postpone cardioversion for three weeks after oral coagulation has started and to maintain this treatment for 3 or 4 additional weeks after cardioversion.     

Salutary effects of aspirin in coronary artery disease are not limited to its platelet inhibitory effects

Aspirin is widely used in the treatment and prevention of coronary artery disease (CAD). However, other platelet inhibitory agents, which inhibit platelet activation, have not been found to be effective or as effective as aspirin. The discrepancy between the efficacy of these compounds and aspirin suggests that the therapeutic efficacy of aspirin may not be limited to its platelet inhibitory effect. In this review, the basis for a unique place for aspirin in the therapy of patients with CAD is discussed. The author believes that the nonplatelet-mediated effects of aspirin could be more important than the platelet inhibitory effect, or at least may complement the platelet inhibitory effects of aspirin in patients with acute myocardial ischemia and in others undergoing intracoronary procedures.     

Low-dose aspirin therapy is associated with few side effects but does not prevent hepatic artery thrombosis in liver transplant recipients

Hepatic artery thrombosis occurs in 4% to 10% of adult patients and in up to 26% of children undergoing liver transplantation. Aspirin has been used to prevent this complication but may increase procedure-related and gastrointestinal bleeding. The aim of this study was to assess the efficacy and safety of low-dose aspirin in the prophylaxis of hepatic artery thrombosis. The histories of 529 patients who survived liver transplantation between September 1988 and December 1993 were reviewed retrospectively. The routine clinical practice followed until 1992 was to initiate oral aspirin therapy on the first postoperative day (81 mg daily in adults and 40 mg daily in children) as prophylaxis for vascular thrombosis. This was done in 354 patients. Aspirin was not administered to the remaining 175 patients. Hepatic artery thrombosis occurred in 13 patients treated with aspirin (3.7%) and in 7 patients not treated with aspirin (4.0%) (P = .85). Recipient age of younger than 2 years and low donor liver weight were the only factors that predisposed the patients to hepatic artery thrombosis. A total of 1,651 percutaneous liver biopsies were performed in this series, with 1,111 performed in patients treated with aspirin. Significant bleeding after liver biopsy occurred in 12 patients treated with aspirin (1.1%) and in 3 patients not treated with aspirin (0.6%) (P = .29). Gastrointestinal bleeding occurred in 66 patients treated with aspirin (18.9%) and in 23 patients not treated with aspirin (12.8%) (P = .08). Low-dose aspirin therapy is not shown to be effective in preventing hepatic artery thrombosis after liver transplantation. Although aspirin does not produce a statistically significant increase in the risk of bleeding after liver biopsy, there is a trend toward an increased incidence of gastrointestinal bleeding.     

Abciximab. An updated review of its use in ischaemic heart disease

Abciximab is a glycoprotein IIb/IIIa receptor antagonist that has proven to be of significant clinical value in improving patient outcome after percutaneous coronary revascularisation. Primarily, the drug inhibits platelet aggregation, but it may also have anticoagulant activity and other beneficial effects, such as inhibiting migration and promoting apoptosis of smooth muscle cells. Large well designed studies have found administration of abciximab (as an adjunct to heparin and aspirin) during percutaneous coronary revascularisation to significantly reduce the incidence of ischaemic complications occurring in the 30 days after the procedure. Significant benefit, particularly on the incidence of myocardial infarction, was still evident after 6 months in 2 of 4 major trials. Abciximab provides particular benefit in patients with unstable angina or myocardial infarction who are undergoing percutaneous coronary revascularisation. The benefits of the drug are additive to those achieved with coronary stenting. Very preliminary data suggest that abciximab may improve coronary blood flow after myocardial infarction and allow reperfusion to be achieved with reduced thrombolytic doses. Caution is required to minimise the risk of bleeding complications with the use of abciximab in combination with heparin and aspirin. Careful patient selection, use of an appropriate heparin regimen, early vascular sheath removal and meticulous femoral artery access site care are recommended. Thrombocytopenia can occur with abciximab treatment, but severe cases are uncommon (< 2% of patients) and can be treated with platelet transfusions. The high acquisition cost of abciximab may be partly or fully offset by the costs averted by the reduced incidence of ischaemic complications and need for urgent and/or repeat revascularisation in high risk patients who receive the drug. However, if bleeding complications occur, this adds to treatment costs. Cost effectiveness analyses generally support the use of abciximab in high risk patients. CONCLUSIONS: Abciximab can be recommended for the prevention of acute ischaemic events in most patients undergoing percutaneous coronary revascularisation, but careful patient selection and strict adherence to the recommended treatment protocol are required to reduce the risk of bleeding complications and thrombocytopenia. Its use in high risk patients is largely supported by pharmacoeconomic data. Further pharmacoeconomic information is needed to establish the drug as a standard of care for all patient groups. The indications for abciximab are likely to expand as more data on its use in acute coronary syndromes become available.     

Antiplatelet therapy. Aspirin, ticlopidine/clopidogrel, and anti-integrin agents

Aspirin is the most widely employed antithrombotic agent in use today and has a proven role in the prevention and acute management of atherosclerosis-associated arterial thrombotic events. More recently developed antiplatelet agents have been found to have specific prophylactic roles associated with percutaneous coronary intervention and other clinical settings. This article outlines pharmacologic considerations and current clinical knowledge relevant to the use of aspirin, ticlopidine, clopidogrel, and the GPIIbIIIa antagonists in the management of thrombotic disorders.     

Effect of various antithrombotic regimens (aspirin, aspirin plus dipyridamole, anticoagulants) on the functional status of patients and grafts one year after coronary artery bypass grafting

From 1987 until 1991 a large prospective randomized multicentre study was performed in The Netherlands, Germany and Switzerland entitled CABADAS (Prevention of Coronary Artery Bypass graft occlusion by Aspirin, Dipyridamole, and Acenocoumarol/Phenprocoumon Study). The aim of CABADAS was to evaluate the relative efficacy of (1) aspirin, (2) aspirin plus dipyridamole, and (3) oral anticoagulants in the prevention of vein graft occlusion during the first year after aortocoronary bypass surgery. No significant difference was observed in the incidence of graft occlusion among the three treatment groups. In a subgroup of 127 CABADAS patients, studied in the Academic Medical Centre in Amsterdam, the relationship between treatment and clinical status (i.e. symptoms of angina pectoris and exercise capacity) was assessed, and the relationship between treatment and functional status of the vein grafts was determined by means of thallium-201 exercise scintigraphy. There were no differences in symptoms among the three treatment groups in the 127 patients studied. There were no significant differences either among the treatment groups, as regards exercise capacity and the number or intensity of perfusion defects, in the 81 patients who underwent thallium-201 exercise scintigraphy. The three antithrombotic treatment regimens had a similar effect on the clinical status of patients and on the functional status of venous bypass grafts one year after coronary bypass surgery. This finding underscores the CABADAS results in that aspirin may be the preferred treatment option in patients following venous bypass surgery.     

Reversible regulation of SHP-1 tyrosine phosphatase activity by oxidation

BACKGROUND AND PURPOSE: Randomized clinical trials testing aspirin in relatively low-risk, middle-aged people have consistently shown small increases in stroke associated with aspirin use. We analyzed the relationship between the regular use of aspirin and incident ischemic and hemorrhagic stroke among people aged 65 years or older participating in the Cardiovascular Health Study. METHODS: We conducted a multivariate analysis of incident stroke rates in a prospectively assessed, observational cohort of 5011 elderly people followed for a mean of 4.2 years. RESULTS: Participants had a mean age of 72 years, and 58% were women. Twenty-three percent used aspirin frequently, and 17% used aspirin infrequently at study entry. Frequent aspirin use was associated with an increased rate of ischemic stroke compared with nonusers (relative risk= 1.6; 95% confidence interval [CI], 1.2 to 2.2; P=0.001). After adjustment for other stroke risk factors, women who used aspirin frequently or infrequently at study entry had a 1.8-fold (95% CI, 1.2 to 2.8) and 1.6-fold (95% CI, 0.9 to 3.0) increased risk of ischemic stroke, respectively (P<0.01, test for trend), compared with nonusers. In men, aspirin use was not statistically significantly associated with stroke risk. Findings were similar when aspirin use in the years before the incident stroke was used in the modeling. Aspirin use at entry was also associated with a 4-fold (95% CI, 1.6 to 10.0) increase in risk of hemorrhagic stroke for both infrequent and frequent users of aspirin (P=0.003). CONCLUSIONS: Aspirin use was associated with increased risks of ischemic stroke in women and hemorrhagic stroke overall in this elderly cohort, after adjustment for other stroke predictors. The possibility exists of confounding by reasons for aspirin use rather than cause and effect. Whether regular aspirin use increases stroke risk for elderly people without cardiovascular disease can only be determined by randomized clinical trials.     

Aspirin in essential thrombocythemia: status quo and quo vadis

Aspirin has a well established role in the prevention of arterial thrombosis. Discussion on the efficacy and safety of aspirin in the treatment and prophylaxis of thrombosis in essential thrombocythemia (ET) has become an important issue. The rationale for its use in ET comes from the observation that arterial thrombosis and platelet-mediated microcirculatory disturbances are the major causes of morbidity and mortality in ET. Experimental data have shown persistently elevated levels of thromboxane A2 (TXA2) in ET patients probably reflecting an enhanced in vivo platelet activation. Increased TXA2 biosynthesis and platelet activation in vivo in ET are selectively suppressed by repeated low doses of aspirin. ET-related symptoms such as erythromelalgia, transient neurologic and ocular disturbances are sensitive to aspirin. However, the benefit of low-dose aspirin is still uncertain in the primary prevention of thrombosis in ET. Furthermore, aspirin may unmask a latent bleeding diathesis frequently present in ET which may result in severe hemorrhagic complications. Thus, aspirin is contraindicated in ET patients with a bleeding history or a very high platelet count (> 1500 x 10(9)/L) leading to the acquisition of von Willebrand factor deficiency. If indicated, aspirin is presently used in the widely accepted low-dose regimen of 100 mg daily. However, an optimal effective dose has not yet been established. To further evaluate the efficacy and safety of aspirin in ET, prospective clinical trials are needed.     

Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study

BACKGROUND: Despite the efficacy of warfarin sodium therapy for stroke prevention in atrial fibrillation, many physicians hesitate to prescribe it to elderly patients because of the risk for bleeding complications and because of inconvenience for the patients. METHODS: The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study was a randomized, controlled trial examining the following therapies: warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; and aspirin, 300 mg/d. These were compared with adjusted-dose warfarin therapy (international normalized ratio of prothrombin time [INR], 2.0-3.0). Stroke or a systemic thromboembolic event was the primary outcome event. Transient ischemic attack, acute myocardial infarction, and death were secondary events. Data were handled as survival data, and risk factors were identified using the Cox proportional hazards model. The trial was scheduled for 6 years from May 1, 1993, but due to scientific evidence of inefficiency of low-intensity warfarin plus aspirin therapy from another study, our trial was prematurely terminated on October 2, 1996. RESULTS: We included 677 patients (median age, 74 years). The cumulative primary event rate after 1 year was 5.8% in patients receiving minidose warfarin; 7.2%, warfarin plus aspirin; 3.6%, aspirin; and 2.8%, adjusted-dose warfarin (P = .67). After 3 years, no difference among the groups was seen. Major bleeding events were rare. CONCLUSIONS: Although the difference was insignificant, adjusted-dose warfarin seemed superior to minidose warfarin and to warfarin plus aspirin after 1 year of treatment. The results do not justify a change in the current recommendation of adjusted-dose warfarin (INR, 2.0-3.0) for stroke prevention in atrial fibrillation.     

Evaluation of platelet function and tissue plasminogen activator activity in ischemic heart disease depending on concurrence with hyperlipoproteinemia and aspirin therapy

Platelet activation, impairment of fibrinolysis and dyslipidemia are important factors in the pathogenesis and progression of ischemic heart disease. Aspirin therapy will reduce platelet activation both by its negative effect on platelet aggregation (SPA) and by inhibition of granule release which liberates such mediators as platelet factor 4 (PF4) and plasminogen activator inhibitor 1 (PAI-1). The present study was performed in 57 patients with ischemic heart disease (IHD), divided into groups depending on coexistent hyperlipoproteinemia (HLP) and aspirin treatment. The control group included 21 healthy individuals, matched for age and sex. Parameters of hemostasis (SPA, PF4, PAI-1) and concentration of lipid fractions (TC, TG, LDL, HDL) were measured in plasma. Increased PF4 levels were found in all groups with IHD, irrespective of hyperlipoproteinemia or aspirin treatment. Enhanced SPA and higher PAI-1 were limited to group IHD-HLP without aspirin. Highest PAI-1 activities were observed after stimulation of platelets in vitro. In conclusion, patients with IHD and hyperlipoproteinemia presented most pronounced platelet activation and impairment of fibrinolysis. Aspirin had a beneficial effect on these changes. Lower activities of PAI-1, in patients treated with aspirin, can be ascribed to its reduced release from platelets. Aspirin did not satisfactorily reduce the level of PF4, although it strongly inhibited SPA.     

Low- versus high-dose aspirin in prevention of ischemic stroke

Aspirin is the most extensively studied drug for the prevention of ischemic vascular disease. Meta-analyses confirm that aspirin is effective in prevention of ischemic events, including stroke. Recently, there has been considerable discussion about the best dose of aspirin to prevent stroke. Several studies tested aspirin in a daily dose of 975 mg or more alone or in combination with another drug, most commonly dipyridamole, and noted that aspirin was effective. Successively lower doses of aspirin were tested and recent studies demonstrate that low doses (< 100 mg/day) are effective. Only one study, enrolling patients with transient ischemic attack or minor stroke, has examined aspirin in a daily dose of approximately 325 mg. Side effects of aspirin are dose related; gastrointestinal bleeding and epigastric pain are less with low doses. Available data cannot confirm that low doses (< 100 mg/day) of aspirin are either more or less effective than larger (975 mg/day) doses. A direct comparison of the usefulness of low doses (< 100 mg/day) or large doses (approximately 1,000 mg/day) in patients at high risk of stroke is needed. Until the results of such a study are known, the better safety profile of low doses favors aspirin in a daily dose of 100 mg or less.     

Aspirin use in middle-aged men with cardiovascular disease: are opportunities being missed?

BACKGROUND: Since the 1980s, clinical trial evidence has supported aspirin use in the secondary prevention of cardiovascular disease (CVD). AIM: To explore aspirin use among British men with known CVD in a population-based study. METHOD: Longitudinal study (British Regional Heart Study), in which subjects have been followed up for cardiovascular morbidity and mortality since 1978-1980. Aspirin use was assessed by questionnaires to study participants in November 1992 (Q92); cardiovascular diagnoses are based on general practice notifications to October 1992. A total of 5751 men aged 52-73 years (87% of survivors) completed questions on aspirin use. RESULTS: Overall, 547 men (9.5%) were taking aspirin daily, of whom 321 (59%) had documented CVD. Among men with pre-existing disease, 153 out of 345 (44%) men with myocardial infarction, 42 out of 109 (39%) with stroke, and 75 out of 247 (29%) with angina were taking aspirin daily. Among men with angina (54% versus 26%) or myocardial infarction (59% versus 42%), those who had undergone coronary artery bypass surgery (CABG) or angioplasty were more likely to be receiving aspirin. Higher rates of aspirin use were also found in those whose last major event occurred after January 1990 (47% versus 34%). There was no association between aspirin use and social class or region of residence. CONCLUSION: Despite strong evidence of its effectiveness, many patients with established CVD were not receiving aspirin. Daily aspirin treatment was less likely in men with less recent major CVD events and in those who had not received invasive treatment.     

Aspirin for primary prevention of cardiovascular events

OBJECTIVE: The use of aspirin for primary prevention of cardiovascular events in the general population is controversial. The purpose of this study was to create a versatile model to evaluate the effects of aspirin in the primary prevention of cardiovascular events in patients with different risk profiles. DESIGN: A Markov decision-analytic model evaluated the expected length and quality of life for the cohort's next 10 years as measured by quality-adjusted survival for the options of taking or not taking aspirin. SETTING: Hypothetical model of patients in a primary care setting. PATIENTS: Several cohorts of patients with a range of risk profiles typically seen in a primary care setting were considered. Risk factors considered included gender, age, cholesterol levels, systolic blood pressure, smoking status, diabetes, and presence of left ventricular hypertrophy. The cohorts were followed for 10 years. Outcomes were myocardial infarction, stroke, gastrointestinal bleed, ulcer, and death. MAIN RESULTS: For the cases considered, the effects of aspirin varied according to the cohort's risk profile. By taking aspirin, the lowest-risk cohort would be the most harmed with a loss of 1.8 quality-adjusted life days by taking aspirin; the highest risk cohort would achieve the most benefit with a gain of 11.3 quality-adjusted life days. Results without quality adjustment favored taking aspirin in all the cohorts, with a gain of 0.73 to 8.04 days. The decision was extremely sensitive to variations in the utility of taking aspirin and to aspirin's effects on cardiovascular mortality. The model was robust to other probability and utility changes within reasonable parameters. CONCLUSIONS: The decision of whether to take aspirin as primary prevention for cardiovascular events depends on patient risk. It is a harmful intervention for patients with no risk factors, and it is beneficial in moderate and high-risk patients. The benefits of aspirin in this population are comparable to those of other widely accepted preventive strategies. It is especially dependent on the patient's risk profile, patient preferences for the adverse effects of aspirin, and on the level of beneficial effects of aspirin on cardiovascular-related mortality.     

Randomised comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina. Studio Epoorine Sottocutanea nell'Angina Instobile (SESAIR) Refrattorie Group

Intravenous heparin has been used in the control of myocardial ischaemia in patients with unstable angina. We set out to assess the efficacy of subcutaneous heparin in reducing myocardial ischaemia in patients with unstable angina. 343 of 399 patients with unstable angina were monitored for 24 h and 108 were refractory to conventional antianginal treatment and were entered into a randomised multicentre trial. 37 patients were assigned to heparin infusion (partial thromboplastin time 1.5-2 times baseline), 35 to subcutaneous heparin (adjusted dose with partial thromboplastin time 1.5-2 times baseline), and 36 to aspirin (325 mg daily). All had additional conventional antianginal therapy. After the run-in patients were monitored for 3 days. The primary endpoint was reduced myocardial ischaemia assessed by the number of anginal attacks, silent ischaemic episodes, and duration of ischaemia per day. At 1 week and 1 month we accounted for anginal attacks and other clinical events (myocardial infarction, revascularisation procedures, and death). Aspirin did not significantly affect the incidence of myocardial ischaemia. On the first 3 days, infused and subcutaneous heparin significantly decreased the frequency of angina (on average by 91% and 86%, respectively), episodes of silent ischaemia (by 56% and 46%), and the overall duration of ischaemia (66% and 61%) versus run-in day and aspirin (p < 0.001 for all variables). The favourable effects of heparin therapy remained evident during follow-up. Only minor bleeding complications occurred. Subcutaneous heparin is effective in the control of myocardial ischaemia in patients with unstable angina.