The major complication of anticoagulant therapy is

Transcription

1 Hemorrhagic Complications of Anticoagulant Treatment Mark N. Levine, MD, MSc, Chair; Gary Raskob, PhD; Seth Landefeld, MD; and Clive Kearon, MD, PhD, FCCP Abbreviations: ACCP American College of Chest Physicians; APTT activated partial thromboplastin time; ASA acetylsalicylic acid; ASPECT Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis; INR international normalized ratio; LMW low molecular weight; PT prothrombin time; SPAF Stroke Prevention in Atrial Fibrillation (CHEST 2001; 119:108S 121S) The major complication of anticoagulant therapy is bleeding. In this review, the incidence of hemorrhage in patients receiving oral anticoagulants or heparin and the clinical and laboratory risk factors that predispose to bleeding are discussed. The focus is on major bleeding and fatal bleeding. Details of the method used to select relevant articles can be found in the five previous symposia of the American College of Chest Physicians (ACCP). 1 5 Bleeding was classified as major if it was intracranial or retroperitoneal, if it led directly to death, or if it resulted in hospitalization or transfusion. 1,2 Although bleeding is the major side effect of anticoagulant therapy, it should not be considered in isolation of potential benefit, ie, reduction in thromboembolism. Oral Anticoagulants The major determinants of oral anticoagulant-induced bleeding are the intensity of the anticoagulant effect, patient characteristics, the concomitant use of drugs that interfere with hemostasis, and the length of therapy. Intensity of Anticoagulant Effect There is a strong relationship between the intensity of anticoagulant therapy and the risk of bleeding that has been reported in patients with deep vein thrombosis, 6 tissue heart valves, 7 and mechanical heart valves. 8,9 In randomized clinical trials for these indications, 6 9 the frequency of major bleeding in patients randomly assigned to less intense warfarin therapy (targeted international normalized ratio [INR] approximately 2.0 to 3.0) has been less than half the frequency in patients randomly assigned to more intense warfarin therapy (targeted INR 3.0). The intensity of anticoagulant effect is probably the most important risk factor for intracranial hemorrhage, independent of the indication for therapy, with the risk increasing dramatically with an INR Less intense warfarin therapy has also been administered to other groups of patients with very low rates of major bleeding. In five randomized trials in patients with atrial fibrillation, for example, the annual incidence of major bleeding averaged 1.3% in patients randomly assigned to less intense warfarin therapy (targeted INR Correspondence to: Mark N. Levine, MD, MSc, Clinical Research Institute, Faculty of Health Sciences, 2E5, McMaster University, 1200 Main St. W., Hamilton, Ontario, Canada L8N 3Z5 generally 2.0 to 3.0), compared with 1.0% in patients randomly assigned to treatment with placebo. 11 In patients with atrial fibrillation, an INR of 2.5 (range, 2.0 to 3.0) minimizes the risk of either hemorrhage or thromboembolism. 12,13 Very-low-intensity warfarin regimens (targeted INR 2.0) have been investigated and found to be safe in certain populations. In two randomized trials 14,15 in patients with malignancy, very-low-intensity warfarin therapy (warfarin, 1 mg/d, and warfarin, 1 mg/d for 6 weeks followed by adjustment to an INR of 1.3 to 1.9, respectively) did not increase the frequency of hemorrhage at all. Increased variation in anticoagulant effect, as indicated by variation in the INR, is associated with an increased frequency of hemorrhage independent of the mean INR. 16,17 This effect is probably attributable to increased frequency and degree of marked elevations in the INR. Patient Characteristics In many studies, especially those conducted before the era of less intense warfarin therapy, major bleeding was especially frequent in patients with ischemic cerebral vascular disease or venous thromboembolism. 1,2 Although the high frequency of hemorrhage was thought to be related to the high prevalence of comorbid conditions, it is likely that the high intensity of anticoagulation was a major contributor to bleeding in these early studies. In studies that have used less intense anticoagulation, low rates of warfarin-related bleeding have been observed in patients with ischemic cerebrovascular disease 12,18 or venous thromboembolism. 5,6 The risk of bleeding during warfarin therapy is probably also related to patient characteristics other than the indication for therapy. A number of studies have found that the frequency of bleeding during warfarin therapy is higher in older patients, although other studies 16,32 36 have not. Also, risk for intracranial hemorrhage may be increased among older patients, especially those 75 years when the INR is above therapeutic levels. 10,11,17,37 Past GI bleeding is a risk factor for bleeding during warfarin therapy. 20,38 In contrast, peptic ulcer disease alone, without past bleeding, has not been associated with an increased risk of bleeding. 20,21,39 Several comorbid diseases have been associated with bleeding during warfarin therapy 16 ; these include treated hypertension, 20,21,23,25,40 cerebrovascular disease, 17 serious heart disease, 17,22 renal insufficiency, 17 and malignancy. 41 Although many other patient characteristics have been associated with bleeding during warfarin therapy, the data supporting these findings are not compelling. For example, some studies 16,21,22,24,27 noted an increased frequency of bleeding among women treated with warfarin, but several others 21,23,26,33,34 have not. Although most experienced clinicians believe that either alcoholism or liver disease increases the risk of bleeding during long-term warfarin therapy, two studies 20,21 did not find such an association, whereas a large population-based study 41 did. Occult pathologic lesions may also precipitate warfarin- 108S Sixth ACCP Consensus Conference on Antithrombotic Therapy

2 related bleeding. In one study, patients who bled with the prothrombin time (PT) in the therapeutic range were more likely to have an underlying pathologic lesion as the cause of bleeding than patients whose bleeding occurred when the PT was elevated above the therapeutic range. 19 Nevertheless, pathologic lesions were found to be associated with GI or genitourinary bleeding frequently enough in patients who were overanticoagulated to suggest that investigation of such patients is prudent. Concomitant Drugs Concomitant use of aspirin has been associated with a higher frequency of bleeding even in patients treated with low-intensity warfarin therapy In a large randomized trial 42 comparing the combination of low-dose warfarin therapy and aspirin, 80 mg/d, to aspirin, 160 mg/d, in patients with a history of myocardial infarction, the frequency of spontaneous major hemorrhage during the first year of therapy was increased to 1.4% in patients treated with warfarin, 3 mg (INR 2.0), and aspirin, 80 mg/d, compared with 0.7% in patients treated with aspirin, 160 mg/d (p 0.01). In a large trial 43 of primary prevention in persons at high risk for ischemic heart disease, the rate of hemorrhagic stroke was 0.09%/yr in those treated with low-dose warfarin (targeted INR 1.5) plus acetylsalicylic acid (ASA), 75 mg/d; 0.01%/yr with low-dose warfarin alone; 0.02%/yr with ASA alone; and none in the placebo group. The corresponding numbers of major extracranial bleeds were 7, 8, 5, and 1, respectively. Risk of Bleeding and the Length of Anticoagulant Therapy For an individual patient, the cumulative risk of bleeding is directly related to the length of anticoagulant therapy. Four studies 16,20,21,28 reported higher frequencies of bleeding early in the course of therapy. In one of these studies, for example, the frequency of major bleeding decreased from 3.0% during the first month of outpatient warfarin therapy to 0.8%/mo during the rest of the first year of therapy and to 0.3%/mo thereafter. 20 Other descriptive studies 33,45,46 have supported this observation, although some 32,40 have not. Estimating Bleeding Risk Models have been developed for estimating the risk for major bleeding during oral anticoagulant therapy. These models are based on the identification of independent risk factors for warfarin-related bleeding, such as a history of stroke, history of GI bleeding, age 65 years, and higher levels of anticoagulation. 16,24,27,28,30,38,47 Such prediction rules can be useful in clinical practice because although physicians estimates of risk for anticoagulant-related bleeding are reasonably accurate during hospitalization, they are inaccurate during long-term outpatient therapy. 38,47 Two prediction models have been developed and validated in outpatients treated with warfarin. Beyth et al 38 identified four independent risk factors for bleeding: age 65 years, history of GI bleeding, history of stroke, and one or more of four specific comorbid conditions. This model was validated in another cohort of patients treated in another city; the cumulative incidence of major bleeding at 48 months was 53% in high-risk patients (three or four risk factors), 12% in middle-risk patients (one or two risk factors), and 3% in low-risk patients (no risk factors). Kuijer et al 30 recently developed another prediction model based on age, gender, and the presence of malignancy. In patients classified at high, middle, and low risk, the frequency of major bleeding was 7%, 4%, and 1%, respectively after 3 months of therapy. Risk of Hemorrhage and Clinical Disorders Ischemic Cerebral Vascular Disease: Randomized trials compared oral anticoagulant therapy with a nontreatment group, a very-low-dose anticoagulant group, 53,54 or an antiplatelet group, 55,56 following an acute episode of ischemic cerebrovascular disease (for details see Fourth ACCP Consensus Conference on Antithrombotic Therapy). 4 In all but two of these studies, the intensity of anticoagulation was high (middle of PT target corresponded to an INR of 4). Oral anticoagulant therapy was associated with increased bleeding in all of these studies, with a frequency of major bleeding (usually intracerebral) varying from 2 to 13% during a mean duration of follow-up of 6 to 30 months. In prior studies, 11,17,18,57 previous stroke has not been identified as a risk factor for intracerebral bleeding in orally anticoagulated patients with atrial fibrillation (INR 1.4 to 4.5; see chapter on Antithrombotic Therapy in Atrial Fibrillation ). The high frequency of bleeding observed in the early studies of anticoagulation noted above is likely related to many factors, including the high intensities of anticoagulation, unsuspected initial intracerebral hemorrhage (pre-ct era), suboptimal control of concomitant hypertension, and initiation of anticoagulation in the setting of acute cerebral ischemia. In the Stroke Prevention in Reversible Ischemia Trial, 1,316 patients with a transient ischemia attack or minor ischemic stroke were randomized to aspirin, 30 mg/d, or warfarin therapy at a targeted INR of 3.0 to There was a statistically significant increase in major bleeding associated with warfarin: 53 major bleeding complications (8.1%; 27 intracranial, 17 fatal) vs 6 major bleeding complications with aspirin (0.9%; 3 intracranial, 1 fatal) during a mean follow-up period of 14 months. The bleeding incidence increased by a factor of 1.4 for each 0.5-U increase of the INR. Prosthetic Heart Valves In our previous reviews of bleeding rates in patients receiving long-term oral anticoagulant therapy for prosthetic heart valves, a number of trials that were reported in the 1970s and 1980s were considered. 3,4,58 62 The targeted intensity of oral anticoagulant therapy was derived retrospectively based on our best guess of the reagents used to perform the PT. The total rates of major bleeding were between 0% and 6.8%, and the addition of aspirin to warfarin increased the risk of minor bleeding. CHEST / 119 / 1/ JANUARY, 2001 SUPPLEMENT 109S

3 Since 1990, six randomized trials have evaluated longterm oral anticoagulant therapy in patients with mechanical heart valves. 8,9,63 66 The rates of major bleeding were reported in five of these trials (Table 1). In three trials, different intensities of oral anticoagulants were compared. 8,65,66 Saour et al 8 randomized patients to either moderate-intensity warfarin therapy (targeted INR 2.65) or very-high-intensity warfarin therapy (targeted INR, 9.0). The rate of major bleeding in the former treatment arm was 3.2% compared with 7.2% in the latter arm. This difference was statistically significant. In the trial conducted by Acar et al, patients were randomized to treatment with acenocoumarol at a targeted INR of 2.0 to 3.0 or the same medication at a targeted INR of 3.0 to 4.5. The rate of major bleeding in the lower-intensity group was 6.9% compared with 10% in the higherintensity group. This difference was not statistically significant. In a trial conducted by Pengo and colleagues, patients were randomized to treatment with either warfarin or acenocoumarol at a targeted INR of 2.5 to 3.5 or the same medications at a targeted INR of 3.5 to 4.5. The rate of major bleeding was 3.8% in the former group compared with 11% in the latter group. This difference was statistically significant. In a double-blind trial, Turpie et al 63 compared warfarin (INR 3.0 to 4.5) with warfarin plus aspirin, 100 mg. The rate of major bleeding was 10.3% in the warfarin alone group compared with 12.9% in the warfarin plus aspirin group. Altman et al 58 compared two different doses of aspirin (100 mg/d vs 650 mg/d) in patients receiving acenocoumarol at an INR of 2.0 to 3.0. The rate of bleeding in the lower-dose aspirin group was 7.2% compared with 9.4% in the higher-dose group. The annual bleeding rates (percentage per year) were reported in several trials (Table 1). These rates of major bleeding were between 1.2%/yr and 5.6%/yr. Cannegieter et al 67 reported the results of a retrospective study in 1,608 patients who received oral anticoagulant therapy for mechanical heart valves. The rate of intracranial and spinal bleeding was 0.57%/yr, and the rate of major extracranial bleeding was 2.1%/yr. Atrial Fibrillation The efficacy of warfarin in preventing stroke in patients with nonvalvular atrial fibrillation has been consistently demonstrated in a number of randomized clinical trials and in meta-analyses. 17,18,57,68 81 Overall, the rates of warfarin-related bleeding in these studies have been low (Table 2). In two meta-analyses 79,81 of 12 trials of warfarin for stroke prevention, warfarin increased the odds of major bleeding (odds ratio of 1.90 and relative risk of 2.4, respectively); the absolute risk increase was 0.3%/yr. 79 Although intracranial bleeding was more frequent in patients treated with warfarin in these trials (0.3%/yr vs 0.1%/yr in patients not treated with warfarin or aspirin), the absolute difference was small and overwhelmed by the substantial reduction in the frequency of stroke. One study 71 (Stroke Prevention in Atrial Fibrillation [SPAF] II) raised concern that the risk for warfarin-related bleeding, especially intracranial hemorrhage, may be increased substantially in patients 75 years old. The rate of major bleeding while receiving warfarin was 2.3%/yr, compared with 1.1%/yr for patients receiving aspirin, 325 mg/d. However, the rate of major warfarin-related bleeding was 4.2%/yr in patients 75 years old, compared with 1.7%/yr in younger patients; the rates for intracranial bleeding were 1.8%/yr and 0.6%/yr, respectively. The reason why these rates are substantially higher than those observed in the other clinical trials of warfarin in patients with atrial fibrillation is likely related to the intensity of anticoagulant therapy: virtually all intracranial hemorrhages in SPAF II, as in the other clinical trials, were associated with an INR In contrast, in the SPAF III trial (targeted INR 2.0 to 3.0), the mean age was 71 years and the rate of intracranial hemorrhage was 0.5%/yr. 74 There have been two trials evaluating a fixed low dose of warfarin (1.5 mg/d). 75,77 These trials were stopped early because of the SPAF III trial results that demonstrated that low-intensity warfarin therapy (ie, INR 1.5) was insufficient for stroke prevention. 74 The rates of major bleeding were low in these studies (Table 2). Table 1 Prosthetic Heart Valves Bleeding Source Treatment Patients, No. Major, No. (%) Fatal, No. (%) Major, %/yr Fatal, %/yr Saour et al 8 Warfarin INR (3.2)* 0 Warfarin INR (7.2) 2 (1.6) Turpie et al 63 Warfarin INR plus placebo (10.3) 4 (2.2) Warfarin INR plus ASA, 100 mg (12.9) 3 (1.6) Altman et al 64 Acenocoumarol INR plus ASA, 100 mg (7.2) 2 (1.0) 3.6 Acenocoumarol INR plus ASA, 650 mg (9.4) 1 (0.5) 5.1 Acar et al 65 Acenocoumarol INR (6.9) 1 (0.5) Acenocoumarol INR (10.0) 1 (0.5) Pengo et al 66 Warfarin INR (3.8)* 0 1.2* Warfarin INR (11.0) 1 (1.0) 3.8 *p S Sixth ACCP Consensus Conference on Antithrombotic Therapy

4 Table 2 Atrial Fibrillation* Source Treatment Patients, No. Major Bleeding Fatal Targeted INR Petersen et al 70 Warfarin (0.3) ASA (75 mg) Placebo SPAF 69 Warfarin /yr ASA (325 mg) /yr Placebo /yr Boston 68 Warfarin (3.8) 1 (0.5) No treatment (3.8) 1 (0.5) Connolly et al 73 Warfarin (2.7) 2 (1.1) Placebo (0.5) 0 SPAF II 71 Warfarin 75 yr /yr ASA 75 yr /yr Warfarin 75 yr /yr ASA 75 yr /yr European 18 Warfarin (5.8) 3 (1.3) Placebo (1.3) 1 (0.4) ASA (300 mg) (1.5) 2 (0.5) Ezekowitz et al 72 Warfarin (2.3) Placebo (1.5) 1 (0.4) SPAF III 74 Warfarin plus ASA (325 mg) (2.4/yr) 3 (0.6/yr) Warfarin (2.1/yr) 2 (0.4/yr) Morocutti et al 76 Warfarin (1.3) 1 (0.2) Indobufen (0.2) 0 Gullov et al 77 Warfarin /yr 0.3/yr Warfarin (1.25 mg) /yr 0 Warfarin plus aspirin (1.25 mg and 300 mg) /yr 0 Aspirin (300 mg) /yr 0.3/yr Pengo et al 75 Warfarin /yr Warfarin (1.25 mg) /yr Hellemons et al 78 Phenprocoumon/acenocoumarol /yr Phenprocoumon/acenocoumarol /yr Aspirin (150 mg) /yr *Boston The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators; European The European Atrial Fibrillation Trial Study Group. Data presented as No. (%), %/yr, or No. (%/yr). Not reported in publications. p Ischemic Heart Disease There are 10 published randomized trials of long-term oral anticoagulant therapy in patients with acute myocardial infarction 42,82 92 (Table 3). In seven of these trials, 82 84,87 92 anticoagulant therapy was compared with placebo or control treatment; in the eighth, 85 anticoagulant therapy was compared with aspirin; in the ninth, 86 anticoagulant therapy was compared with aspirin or placebo; and in the 10th, 42 fixed low doses of warfarin (1 mg or 3 mg) combined with aspirin were compared with aspirin alone. The frequency of major bleeding ranged from 0 to 10% and fatal bleeding ranged from 0 to 2.9%. Smith et al 82 reported the results of a randomized trial that renewed interest in the long-term use of oral anticoagulants after myocardial infarction. The targeted INR was 2.8 to 4.8. Five patients in the warfarin group (0.8%) had intracranial hemorrhages, and three of these were fatal. Eight warfarin-treated patients (1.3%) experienced major extracranial bleeds. There were no major bleeds in the placebo group. In a trial conducted by the Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) investigators, patients who had sustained a myocardial infarction were randomized to either oral anticoagulant therapy at a targeted INR of 2.8 to 4.8 or placebo treatment. 92 The mean follow-up period was 37 months. Seventy-three patients (4.3%) in the anticoagulant group experienced major bleeding compared with 19 placebo-treated patients (1.1%). Three extracranial bleeds in the anticoagulant group were fatal; all were GI in origin. Cerebral hemorrhage was more common in patients who had been treated with anticoagulants (17 cases; 1%), 8 of which were fatal, compared with 2 cases in placebotreated patients, none of which were fatal. The rate of major bleeding in the anticoagulant-treated group was 1.5%/yr compared with 0.2%/yr in the placebo-treated group. This difference was statistically significant. The Coumadin-Aspirin Reinfarction Study 42 compared long-term treatment using fixed low doses of warfarin (1 mg or 3 mg) combined with aspirin, 80 mg, to treatment CHEST / 119 / 1/ JANUARY, 2001 SUPPLEMENT 111S

5 Table 3 Ischemic Heart Disease* Bleeding Source Treatment Patients, No. Major Fatal Targeted INR Sixty-plus 83,84 Acenocoumarin (4.1) 6 (1.4) Placebo (0.2) 1 (0.2) EPSIM 85 Oral anticoagulants (3.2) 8 (1.2) ASA (500 mg tid) (0.8) 4 (0.6) Breddin et al 86 Phenprocoumon, ASA (500 mg tid) 320 NR Placebo 317 NR NR 0 Meuwissen et al 87 Phenprocoumon Placebo Loeliger et al 88 Phenprocoumon (0.8) Placebo (0.8) 1 (0.8) Bjerkelund 89,90 Dicumarol (14.5) 4 (2.9) No treatment (3.6) 1 (0.7) Harvald et al 91 Dicumarol (19.3) 1 (0.7) Placebo Smith et al 82 Warfarin (2.1) 3 (0.5) Placebo ASPECT 92 Nicoumalone/phenprocoumon 1, (4.3) 11 (0.6) Placebo 1, (1.1) 0 CARS 42 Warfarin 3 mg plus ASA 80 mg 3, (2.2%) NR 1.2 Warfarin 1 mg plus ASA 80 mg 2, (1.7%) NR 1.0 ASA 160 mg 3, (1.5%) NR 1.0 *Sixty-plus Sixty-Plus Reinfarction Study Research Group; EPSIM Enquête de Prevention Secondaire de L Infarctus du Myocarde. CARS Coumadin Aspirin Reinfarction Study; NR not reported. Data are presented as No. (%). A number of different oral anticoagulants Median INR at 6 months of treatment. Warfarin was administered as a fixed dose (1 mg or 3 mg). with aspirin alone (160 mg) using a randomized doubleblind study design. The median follow-up period was 14 months. The median INR values 4 weeks and 6 months after beginning treatment were 1.3 and 1.2, respectively, for patients given warfarin, 3 mg, and 1.0 at both times for patients given either warfarin, 1 mg, or aspirin, 160 mg, alone. Major hemorrhages, including those related to invasive procedures, occurred in 75 patients (2.0%) given warfarin, 3 mg, with aspirin, 80 mg; 42 patients (1.7%) given warfarin, 1 mg, with aspirin, 80 mg; and 57 patients (1.5%) given aspirin alone. For spontaneous major hemorrhage (not procedure related), 1-year life table estimates were 1.4% in the warfarin, 3 mg, plus aspirin group; 1.0% in the warfarin, 1 mg, plus aspirin group; and 0.74% in the aspirin-alone group. Three additional trials, Veterans Administration trial, ASPECT2, and Warfarin Re-Infarction Study (WARIS) 2, are evaluating different intensities of warfarin combined with aspirin vs aspirin alone for long-term treatment of patients with myocardial infarction; the results of these trials should become available within the next year. Anand and Yusuf 93 have conducted a meta-analysis of trials evaluating oral anticoagulant therapy in patients with coronary artery disease. Trials were stratified based on the intensity of oral anticoagulant therapy and on the use of aspirin. There appeared to be a relationship between the intensity of oral anticoagulant therapy and major bleeding. For trials of high-intensity therapy (INR 2.8 to 4.8), although there was a reduction in mortality and thromboembolic complications, there was a sixfold increase in major bleeding (from 0.7 to 4.6%). For moderate-intensity therapy (INR 2 to 3) vs control, there was a reduction in myocardial infarction and stroke, but major bleeding was increased eightfold (from 0 to 7.5%). For moderateintensity to high-intensity therapy vs aspirin, there was a 2.4-fold increase in major bleeding (from 1.0 to 3.7%). For low-intensity oral anticoagulant therapy (INR 2.0) and aspirin vs aspirin alone, there was no significant reduction in mortality, myocardial infarction, or stroke, but major bleeding increased by 1.3-fold (from 1.8 to 2.3%). Venous Thromboembolism There have been six randomized trials in patients with venous thromboembolism in which oral anticoagulant therapy was compared with various subcutaneous heparin regimens, usually over a 3-month period (Table 4). In a seventh study, 6 two intensities of oral anticoagulation were compared following initial heparin therapy (Table 4). A higher intensity of oral anticoagulation (ie, INR 2.6 to 4.4) was evaluated in the earlier studies than in the more recent trials (ie, INR 2.0 to 3.0). 6,97 99 The higher-intensity 112S Sixth ACCP Consensus Conference on Antithrombotic Therapy

6 Table 4 Venous Thromboembolism* Bleeding (approximately 3 mo) Source Treatment Patients, No. Major Fatal Bynum and Wilson 94 Warfarin (INR ) 24 4 (16.7) 0 Heparin (5,000 U sc bid) Hull et al 95 Warfarin (INR ) 33 4 (12.1) 0 Heparin (5,000 U sc bid) Hull et al 96 Warfarin (INR ) 53 3 (5.7) 0 Heparin (approx. 10,000 U sc bid) Hull et al 6 Warfarin (INR ) 49 2 (4.1) 0 Warfarin (approx. 2.2) 47 2 (4.3) 0 Pini et al 97 Warfarin (INR 2.7) (12.8) 0 Enoxaparin (4,000 IU sc qd) 93 3 (3.2) 0 Das et al 98 Warfarin (INR ) Dalteparin (5,000 IU sc qd) Lopaciuk et al 99 Acenocoumarol (INR ) 95 2 (2.1) 0 Nadroparin (85 IU/kg sc qd) 98 1 (1.0) 0 *sc subcutaneous; approx. approximately. Data are presented as No. (%). regimens were consistently associated with more total bleeding than the comparison arms, with a similar trend for major bleeding (Table 4). In the study by Hull et al 6 that compared two intensities of oral anticoagulation, the frequency of total bleeding was also substantially lower with the less intense regimen (4% vs 22%), without being associated with a loss of antithrombotic efficacy. In two studies that compared less intense oral anticoagulation with low-molecular-weight (LMW) heparin preparations (administered at lower-than-conventional doses), minor bleeding occurred more frequently with warfarin, but the frequency of major bleeding did not differ. Two large ongoing studies are comparing LMW heparin and warfarin (INR 2.0 to 3.0) for the maintenance phase of treatment of a first episode of deep vein thrombosis (Long-term Innohep Treatment Evaluation [LITE] study) or venous thromboembolism which has occurred in association with cancer (Comparison of Low Molecular Weight Heparin vs Oral Anticoagulant Therapy in Cancer [CLOT] study). The results of randomized trials in which patients with venous thromboembolism were treated with less intense oral anticoagulation (not part of primary comparison) following initial treatment with either unfractionated or LMW heparin confirm a low frequency of major bleeding of 3% during 3 months of therapy Three randomized trials have compared a short duration (4 weeks 113,114 or 6 weeks 115 ) with a medium duration (3 months 113,114 or 6 months 115 ) of less intense oral anticoagulation for the treatment of venous thromboembolism. Following the initial phase of treatment during which all patients were treated with anticoagulant medication, major bleeding occurred very infrequently without convincing evidence of less bleeding with the shorter duration of therapy Two additional randomized trials have evaluated long-term oral anticoagulation for the prevention of recurrent venous thromboembolism following an acute episode. 116,117 Schulman et al 116 randomized patients to regimens of either 6 months or 4 years of anticoagulation (INR 2.0 to 2.85) following a second episode of venous thromboembolism. Major bleeding occurred more frequently in patients who were treated with long-term anticoagulation (2.4%/yr vs 0.7%/yr). Kearon et al 117 randomized patients with a first episode of idiopathic venous thromboembolism to remain on a regimen of warfarin (INR 2.0 to 3.0) or to receive placebo for an additional 2 years following an initial 3 months of anticoagulation. Major bleeding occurred more frequently in patients who continued to receive anticoagulants (4.3%/yr vs 0%/yr). In the two studies combined, the case-fatality ratio of major bleeding in patients receiving anticoagulant medication was 15% (2 of 13 patients). There are a number of ongoing randomized trials evaluating various intensities of long-term oral anticoagulation for the prevention of recurrent venous thromboembolism in well-defined populations (eg, idiopathic thrombosis). More recently, Agnelli et al 118 randomized patients with idiopathic deep vein thrombosis to discontinue treatment with oral anticoagulants after 3 months or to continue receiving therapy (INR 2.0 to 3.0) for an additional 9 months having completed an initial 3 months of treatment. Major bleeding occurred in 3% of patients during the additional 9 months of therapy compared to no episodes in those who discontinued anticoagulant therapy. Summary of Rates of Intracranial Hemorrhage Rates of intracranial hemorrhage during long-term oral anticoagulant therapy are presented in Table 5. These data clearly indicate that the rate of intracranial hemorrhage increases with an increasing intensity of anticoagulant effect, and that this is particularly relevant in patients 75 CHEST / 119 / 1/ JANUARY, 2001 SUPPLEMENT 113S

7 Table 5 Intracranial Hemorrhage During Long-term Oral Anticoagulant Therapy* Source Patients Therapy INR ICH, %/yr Fihn et al 16 Atrial fibrillation (n 1,236) Control 0.1 Fihn et al 16 Atrial fibrillation (n 1,225) Warfarin yr (n 223) 0.3 SPAF II 37,71 Atrial fibrillation (n 555) Warfarin yr (n 358) yr (n 197) 1.8 SPAF III 81 Atrial fibrillation (n 523) Warfarin SPIRIT 56 Cerebral ischemia (n 651) Phenprocoumon Turpie et al 63 Prosthetic valves (n 184) Warfarin Pengo et al 66 Prosthetic valves (n 104) Warfarin Acar et al 65 Prosthetic valves (n 188) Acenocoumarol *ICH intracranial hemorrhage; SPIRIT The Stroke Prevention in Reversible Ischemia Trial. Targeted INR 3.0 in the majority of trials. years of age. In a case-control study, the risk of intracerebral hemorrhage doubled for each increase of approximately 1 in the INR. 119 Heparin Heparin is usually given in low doses by subcutaneous injection to prevent venous thrombosis (prophylactic heparin), in higher doses to treat patients with acute venous thromboembolism or with acute coronary syndromes (therapeutic heparin), and in very high doses in patients during open heart surgery. In this chapter, we will discuss only bleeding associated with therapeutic heparin. Heparin has the potential to induce bleeding by inhibiting blood coagulation, by impairing platelet function, 120 and by increasing capillary permeability. 121 Heparin can also produce thrombocytopenia, but this is rarely an important cause of bleeding. Risk of Bleeding Associated With Therapeutic Heparin Administration Venous Thromboembolism: The incidence of bleeding during heparin therapy has been reported from randomized trials that have compared continuous IV heparin with intermittent IV heparin, IV heparin with subcutaneous heparin, continuous IV heparin for 7 to 10 days with a shorter course (4 to 5 days), 100,101 and continuous IV heparin and oral anticoagulants compared with oral anticoagulants alone. 103 Data on the risk of bleeding are also Table 6 LMW Heparin vs Unfractionated Heparin for the Treatment of Venous Thromboembolism* Source Regimens Major Bleeding Fatal Bleeding Prandoni et al 133 Nadroparin sc bid (weight-adjusted) 1/85 (1) 0/85 IV heparin APTT ratio 1.5 to 2.0 3/85 (4) 0/85 Hull et al 134 Tinzaparin, 175 Xa U/kg sc qd 1/213 (0.5) 0/213 IV heparin APTT ratio 1.5 to /219 (5.0) 2/219 (0.9) Lopaciuk et al 136 Nadroparin, 92 Xa U/kg sc bid 0/74 0/74 SC heparin APTT ratio 1.5 to 2.5 1/72 (1) 0/72 Simonneau et al 135 Enoxaparin, 1 mg/kg sc bid 0/67 0/67 IV heparin APTT ratio 1.5 to 2.5 0/67 0/67 Lindmarker et al 137 Dalteparin, 200 Xa U/kg sc qd 0/101 0/101 IV heparin APTT ratio 1.5 to 3.0 0/103 0/101 Fiessinger et al 138 Dalteparin, 200 Xa U/kg sc qd 0/127 0/127 IV heparin APTT ratio 1.5 to 3.0 2/133 (2) 0/133 Levine et al 106 Enoxaparin, 1 mg/kg sc bid 5/247(2) 2/247 (0.8) IV heparin APTT 60 to 85 s 3/253 (1) 0/253 Koopman et al 107 Nadroparin sc bid (weight-adjusted) 1/202 (0.5) 0/202 IV heparin APTT ratio 1.5 to 2.0 4/198 (2) 2/198 (1) Columbus 108 Reviparin, 3,500 to 6,300 Xa U sc bid (weight-adjusted) 16/510 (3) 0/510 IV heparin APTT ratio 1.5 to /511 (2) 2/511 (0.4) Simonneau et al 109 Tinzaparin, 175 Xa U/kg sc qd 0/304 0/304 IV heparin APTT ratio 2.0 to 3.0 1/308 (0.3) 1/308 (0.3) *Data are presented as No./patient (%) or No./patients. Columbus Columbus Investigators; see Table 4 for other abbreviations. Double blind. Home treatment. Pulmonary embolism. 114S Sixth ACCP Consensus Conference on Antithrombotic Therapy

8 Table 7 Risk of Intracranial and Major Extracranial Bleeding (14 d) for Subcutaneous Heparin in Acute Ischemic Stroke* Bleeding Treatments Patients, No. Total Intracranial Extracranial Fatal Heparin, 12,500 U bid plus 2, (3.1) 42 (1.7) 33 (1.4) 10 (0.4) ASA, 300 mg qd Heparin, 5,000 U bid plus 2, (1.6) 19 (0.8) 20 (0.8) 9 (0.4) ASA, 300 mg qd Heparin, 12,500 U bid 2, (3.2) 43 (1.8) 33 (1.4) 12 (0.5) Heparin, 5,000 U bid 2, (1.1) 16 (0.7) 10 (0.4) 9 (0.4) ASA, 300 mg qd 4, (1.0) 26 (0.5) 23 (0.5) 13 (0.3) Control 4, (0.6) 15 (0.3) 14 (0.3) 5 (0.1) *Data are presented as No. (%) unless otherwise indicated. Data taken from International Stroke Trial. 142 available from randomized trials comparing continuous IV heparin given on a weight-adjusted basis, with a standard clinical approach (5,000-U bolus, 1,000 U/h), 132 for continuous IV heparin monitored using either the activated partial thromboplastin time (APTT) or a heparin assay, 104 and IV heparin compared with subcutaneous LMW heparin , The bleeding outcomes from clinical trials comparing LMW heparin with unfractionated heparin treatment for venous thromboembolism are shown in Table 6. For IV unfractionated heparin, the rates of major bleeding range from 0 to 7% and the rates of fatal bleeding range from 0 to 2%. For LMW heparin, the rates of major bleeding range from 0 to 3% and fatal bleeding from 0 to 0.8%. These data and results of meta-analyses 111,112 support the inference that LMW heparin does not result in an increased risk of major bleeding compared with unfractionated heparin. A recent meta-analysis 112 identified three sources of variation in the rates of major bleeding for studies comparing LMW heparin with IV unfractionated heparin. These included the type of LMW heparin, whether or not the patient received some anticoagulation before enrollment in the trial, and whether treatment was given on an inpatient or outpatient basis. Further studies are required to determine if there are intrinsic differences between LMW heparin preparations in the risk of major bleeding or whether variation found by meta-analysis is due to differences in the regimens (dose and/or frequency of administration), differences in patient populations, or may have occurred by chance. Table 8 LMW Heparin vs Unfractionated Heparin for Acute Ischemic Coronary Syndromes* Study Regimens* Treatment Duration, d Patients, No. Major Bleeding Fatal Bleeding Gurfinkel et al 147 ASA alone IV heparin APTT ratio (2.9) 0 Nadroparin 214 U/kg sc bid FRISC Placebo sc bid (0.5) 1 (0.1) Dalteparin 120 U/kg sc bid (0.8) 0 Placebo sc qd (0.3) 0 Dalteparin 7,500 U sc qd (0.3) 0 Klein et al 149 IV heparin APTT ratio (1.0) NR Dalteparin 120 U/kg sc bid (1.1) NR Placebo sc qd (0.4) NR Dalteparin 7500 u sc qd (0.5) NR TIMI 11A Enoxaparin 1.25 mg/kg sc q12h (6.5) NR Enoxaparin 1.0 mg/kg sc q12h (1.9) NR Cohen et al 150 IV heparin APTT ratio 55 to 85s 2 8 1, (6.8) NR Enoxaparin 1.0 mg/kg sc q12h 2 8 1, (6.3) NR FRISC II Placebo sc bid 3 mo 1, (1.5) NR Dalteparin 120 U/kg sc bid 3 mo 1, (3.2) NR Antman et al 153 IV heparin APTT ratio 1.5 to hospital 1, (1.0) 4 (0.2) Enoxaparin 1.0 mg/kg sc q12h 8 hospital 1, (1.5) 4 (0.2) Placebo sc q12h 43 1, (1.5) Enoxaparin 40 mg or 60 mg sc qd 43 1, (2.9) *Data are presented as No. (%) unless otherwise indicated. FRISC Fragmin During Instability in Coronary Artery Disease Study; TIMI The Thrombosis in Myocardial Infarction Trial Investigation; see Tables 3, 4 for other abbreviations. CHEST / 119 / 1/ JANUARY, 2001 SUPPLEMENT 115S

9 As previously noted, three small studies 6,97,98 found that intermediate-dose heparin therapy (unfractionated or LMW) was associated with less total bleeding, and either the same or a lesser frequency of major bleeding (about 1%) than oral anticoagulation (INR 2.0 to 3.0), when each was administered for 3 months following an episode of deep vein thrombosis (Table 4). In an additional randomized, controlled trial 139 that compared unfractionated heparin, 10,000 U, and dalteparin, 5,000 IU, with each administered subcutaneously twice daily for 3 months following acute venous thromboembolism, there was no difference in the frequency of total bleeding and no episodes of major bleeding in either group. Ischemic Cerebral Vascular Disease: Seventeen studies have evaluated heparin regimens (unfractionated or LMW) for the treatment of acute ischemic stroke. The findings of the first 16 of these studies, which evaluated various heparin regimens in an aggregate of only 1,800 patients, were inconclusive in terms of both efficacy and risk of bleeding (for review of the first 15 trials, see Sandercock et al 140 and Kay et al. 141 The recently completed International Stroke Trial, 142 which randomized 19,000 patients with acute ischemic stroke to treatment with aspirin, 300 mg, subcutaneous heparin, 5,000 U bid or 12,500 U bid, both, or neither has provided reliable estimates of the risks and benefits associated with each of these interventions (Table 7). Heparin was associated with a dose-dependent increase of both intracranial and extracranial bleeding that, at the higher dose, more than offset the antithrombotic benefit. Patients who had the highest risk of recurrent ischemic stroke also had the highest risk of intracerebral bleeding. For example, in patients who presented with acute ischemic stroke associated with atrial fibrillation, the frequency of hemorrhagic stroke after 14 days was 2.1% (32 of 1,557) in patients treated with heparin (either dose) compared with 0.4% (7 of 1,612 patients) in those who were not treated with heparin, with no difference between the two groups in terms of the combined end point of recurrent ischemic or hemorrhagic stroke. The Trial of ORG10172 in Acute Stroke Treatment study 143 randomized 1,281 patients with acute ischemic stroke to a 7-day course of IV danaparoid sodium or placebo treatment. There was a statistically significant increase in major bleeding associated with danaparoid; 5.2% (2.4% intracranial) vs 1.8% (0.8% intracranial) within 10 days of randomization. Ischemic Coronary Syndromes: There have been two trials 144,145 in which patients with ischemic coronary artery disease were randomized to treatment with heparin or no heparin, one trial 144 in which heparin was compared with aspirin, and one trial 146 in which high-dose heparin therapy was compared with a lower dose of heparin. The results of these trials have shown that heparin administered alone in patients with coronary artery disease (without concurrent thrombolytic therapy) is not associated with an increased risk of major bleeding. 4 LMW heparin has been compared with a no-treatment control or IV unfractionated heparin in several trials in patients with unstable coronary artery disease. The bleeding outcomes from these clinical trials are shown in Table 8. For IV unfractionated heparin, the rates of major bleeding range from 0 to 6.3% during the initial 8 days of treatment, and from 0.3 to 3.2% during the long-term treatment phase between approximately 1 week and 3 months. For several of the trials, explicit data for the incidence of fatal bleeding were not reported. The data in Table 8 support the inference that LMW heparin does not result in an increased risk of major bleeding compared with IV unfractionated heparin. The absolute rates of major bleeding were higher in more recent trials than were observed in the initial large trials 148,149 of LMW heparin. This is probably due to inclusion in the more recent studies of patients who undergo cardiac catheterization or coronary bypass surgery; much of the major bleeding in these trials was associated with invasive vascular procedures or coronary bypass surgery. In contrast, the earlier studies 148,149 excluded patients for whom catheterization, angioplasty, or coronary bypass surgery were planned. Relationship Between Risk of Bleeding and Heparin Dose/Response Since the anticoagulant response to heparin (measured by a test of blood coagulation, eg, the APTT) is influenced by the heparin dose, it was not possible from reported studies to separate the effects of these two variables (dose and laboratory response) on hemorrhagic rates. To our knowledge, there have been no randomized trials in patients with established venous thromboembolism directly comparing different doses of heparin. In a study 154 evaluating prophylaxis in patients with recent-onset traumatic spinal cord injuries, the incidence of bleeding was significantly greater in patients randomized to receive heparin adjusted to maintain the APTT at 1.5 times control than compared with heparin, 5,000 U bid. The mean dose of heparin for the adjusted-dose regimen was 13,200 U bid. Bleeding occurred in seven adjusted-dose patients compared with none in the fixed-dose group. Subgroup analysis of randomized trials and prospective cohort studies provide suggestive evidence for an association between the incidence of bleeding and the anticoagulant response. (See previous ACCP conferences on antithrombotic therapy. 1 5 ) Although none of the studies were designed to compare the effects on bleeding of either different doses of heparin or different levels of heparin response, there is a suggestion that bleeding is more likely to occur when an in vitro test of coagulation is prolonged excessively, but this evidence is by no means definitive. In addition, there is good evidence that serious bleeding during heparin treatment can occur when the anticoagulant response is in the therapeutic range. Finally, the results of the Global Use of Strategies to Open Occluded Coronary Arteries IIa study 155 and the Thrombolysis in Myocardial Infarction 9A study 156 in patients with ischemic coronary syndromes indicated that a 20% increase in the IV heparin dose 1,000 U/h that was used in the Global Use of Strategies to Open Occluded Coronary Arteries I study increased the risk of intracranial bleeding when combined with thrombolytic therapy. 116S Sixth ACCP Consensus Conference on Antithrombotic Therapy

10 Relationship Between Risk of Bleeding and Method of Administering Heparin The evidence for a relationship between the risk of bleeding and the method of administering heparin comes from six randomized trials, in which heparin was either administered by continuous IV infusion or intermittent IV injection, and five randomized trials, in which heparin was either administered by continuous infusion or twice daily subcutaneous injection (see Fourth ACCP Consensus Conference on Antithrombotic Therapy). 4 In summary, there was an increased rate of major bleeding with intermittent IV heparin compared with continuous IV infusion. No difference in major bleeding was detected between continuous IV heparin and subcutaneous heparin. Relationship Between the Risk of Bleeding and Patient Risk Factors There is good evidence that comorbid conditions, particularly recent surgery or trauma, are very important risk factors for heparin-induced bleeding. 26,102,125 This association was demonstrated in the study by Hull and associates 102 in patients with proximal vein thrombosis. Patients without clinical risk factors for bleeding were treated with a starting dose of heparin, 40,000 U, by continuous infusion, while those with well-recognized risk factors for bleeding (recent surgery, trauma) received a starting dose of 30,000 U. Bleeding occurred in 1 of 88 patients (1.1%) who received 40,000 U initially and 12 of 111 patients (10.8%) who received 30,000 U. The concomitant use of aspirin was identified as a risk factor in early retrospective studies. 157 The association of aspirin ingestion with heparin-induced bleeding was confirmed by Sethi and associates 158 in their study in patients undergoing aortocoronary bypass surgery. In this study, the preoperative use of aspirin caused excessive operative bleeding in patients who receive very high doses of heparin as part of the routine for bypass procedures. Although the concomitant use of aspirin is associated with heparin-induced bleeding, this combination is used frequently in the initial treatment of acute coronary artery syndromes without serious bleeding. The risk of heparinassociated bleeding increases with concomitant thrombolytic therapy 4 or glycoprotein IIb/IIIa antagonists. 159,160 Renal failure and patient gender have also been implicated as risk factors for heparin-induced bleeding. 161,162 The reported association with female gender has not been consistent among studies and remains in question. Other studies 161,163 have reported that older patients had a higher risk of heparin-induced bleeding. In an analysis of a randomized trial, age predicted for major bleeding and age 70 years were associated with a clinically important increased risk of major bleeding. 164 Summary Bleeding is the major complication of anticoagulant therapy. The criteria for defining the severity of bleeding varied considerably between studies, accounting in part for the variation in the rates of bleeding reported. Since the last review, there have been several meta-analyses published on the rates of major bleeding in trials of anticoagulants for atrial fibrillation and ischemic heart disease. The major determinants of oral anticoagulantinduced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that low-intensity oral anticoagulant therapy (targeted INR of 2.5; range, 2.0 to 3.0) is associated with a lower risk of bleeding than therapy targeted at a higher intensity. Lower-intensity regimens (INR 2.0) are associated with an even smaller increase in major bleeding. In terms of treatment decision making for anticoagulant therapy, bleeding risk cannot be considered alone, ie, the potential decrease in thromboembolism must be balanced against the potential increased bleeding risk. The risk of bleeding associated with IV heparin in patients with acute venous thromboembolism is 3% in recent trials. There is some evidence to suggest that this bleeding risk increases with the heparin dosage and age ( 70 years). LMW heparin is not associated with increased major bleeding compared with standard heparin in acute venous thromboembolism. Standard heparin and LMW heparin are not associated with an increase in major bleeding in ischemic coronary syndromes, but are associated with an increase in major bleeding in ischemic stroke. References 1 Levine MN, Raskob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest 1986; 89(suppl): 15S 25S 2 Levine MN, Raskob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest 1989; 95(suppl): 26S 35S 3 Levine MN, Hirsh J, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest 1992; 102(suppl):352S 363S 4 Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest 1995; 108(suppl):276S 290S 5 Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest 1998; 114: Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982; 307: Turpie AGG, Gunstensen J, Hirsh J, et al. Randomized comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988; 1: Saour JN, Sieck JO, Mamo LAR, et al. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990; 322: Altman R, Rouvier J, Gurfinkel E. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. J Thorac Cardiovasc Surg 1991; 101: Hylek E, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation CHEST / 119 / 1/ JANUARY, 2001 SUPPLEMENT 117S

11 after transient ischemic attack or minor stroke. Lancet 1993; 342: Hylek EM, Skates SJ, Sheehan MA, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335: Bern MM, Lokich JJ, Wallach SR, et al. Very low doses of warfarin can prevent thrombosis in central vein catheters: a randomized prospective trial. Ann Intern Med 1990; 112: Levine M, Hirsh J, Gent M, et al. Double-blind randomized trial of very low dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343: Fihn SD, McDonnel M, Martin D, et al. Risk factors for complications of chronic anticoagulation: a multicenter study: Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993; 118: The Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med 1996; 156: The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333: Landefeld CS, Rosenblatt MW, Goldman L. Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions. Am J Med 1989; 87: Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989; 87: Petitti D, Strom B, Melmon K. Duration of warfarin anticoagulation therapy and the probabilities or recurrent thromboembolism and hemorrhage. Am J Med 1986; 81: Peyman MA. The significance of hemorrhage during treatment of patients with coumarin anticoagulants. Acta Med Scand 1958; 162(suppl): Launbjerg J, Egeblad H, Heaf J, et al. Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1,010 treatment years in 551 outpatients. J Intern Med 1991; 229: Roos J, van Joost HE. The cause of bleeding during anticoagulant treatment. Acta Med Scand 1965; 178: Pollard JW, Hamilton MJ, Christensen NA, et al. Problems associated with long-term anticoagulant therapy. Circulation 1962; 25: Coon WW, Willis PW. Hemorrhagic complications of anticoagulant therapy. Arch Intern Med 1974; 133: van der Meer FJ, Rosendaal FR, Van Den Broucke JP, et al. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med 1993; 153: Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: Steffensen FH, Kristensen K, Ejlersen E, et al. Major hemorrhagic complications during oral anticoagulant therapy in a Danish population-based cohort. J Intern Med 1997; 242: Kuijer PM, Hutten BA, Prins MH, et al. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159: Hutten BA, Lensing AW, Kraaijenhagen RA, et al. Safety of treatment with oral anticoagulants in the elderly: a systematic review. Drugs Aging 1999; 14: Forfar JC. A 7-year analysis of hemorrhage in patients in long-term anticoagulant treatment. Br Heart J 1979; 42: McInnes GT, Helenglass G. The performance of clinics for outpatient control of anticoagulation. J R Coll Physicians Lond 1987; 21: Davis FB, Estruch MT, Samson-Corvera EB, et al. Management of anticoagulation in outpatients: experience with an anticoagulation service in a municipal hospital setting. Arch Intern Med 1977; 137: Gurwitz JH, Goldberg RJ, Holden A, et al. Age-related risks of long term oral anticoagulant therapy. Arch Intern Med 1988; 148: Schenk JF, Mörsdorf S, Pindur G, et al. Analysis and occurrence of adverse events with oral anticoagulant therapy. Semin Thromb Hemost 1999; 25: Albers GW. Atrial fibrillation and stroke: three new studies, three remaining questions. Arch Intern Med 1994; 154: Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting risk of major bleeding in outpatients treated with warfarin. Am J Med 1998; 105: Nelson PH, Moser KM, Stoner C, et al. Risk of complications during intravenous heparin therapy. West J Med 1982; 136: Lundstrom T, Ryden L. Hemorrhagic and thromboembolic complications in patients with atrial fibrillation on anticoagulant prophylaxis. J Intern Med 1989; 225: White RH, Beyth R, Zhou H, et al. Major bleeding after hospitalization for deep vein thrombosis. Am J Med 1999; 107: Coumadin Aspirin Reinfarction Study (CARS) Investigators. Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 1997; 350: Medical Research Council. The Medical Research Council s general practice research framework. Lancet 1998; 351: Blackshear JL, Baker VS, Holland A, et al. Fecal hemoglobin excretion in elderly patients with atrial fibrillation: combined aspirin and low-dose warfarin vs conventional warfarin therapy. Arch Intern Med 1996; 156: Fuller JA, Melb MB. Experiences with long-term anticoagulant treatment. Lancet 1959; 2: Mosley DH, Schatz IJ, Breneman GM, et al. Long-term anticoagulant therapy. JAMA 1963; 186: Landefeld CS, McGuire E, Rosenblatt MW. A bleeding risk index for estimating the probability of major bleeding in hospitalized patients starting anticoagulant therapy. Am J Med 1990; 89: Enger E, Boyesen S. Long-term anticoagulant therapy in patients with cerebral infarction. Acta Med Scand 1965; 178(suppl): McDowell F, McDevitt E, Wright IS. Anticoagulant therapy: five years experience with the patient with an established cerebrovascular accident. Arch Neurol 1963; 8: Baker RN. An evaluation of anticoagulant therapy in the treatment of cerebrovascular disease: report of the Veterans Administration Cooperative study of atherosclerosis. Neurology 1961; 11: Baker RN, Broward JA, Fang HC, et al. Anticoagulant therapy in cerebral infarction: report on cooperative study. Neurology 1962; 12: S Sixth ACCP Consensus Conference on Antithrombotic Therapy

12 52 Fisher CM. Anticoagulant therapy in cerebral thrombosis and cerebral embolism. Neurology 1961; 11: Hill AB, Marshall J, Shaw DA. A controlled clinical trial of long-term anticoagulant therapy in cerebrovascular disease. Q J Med 1960; 29: Hill AB, Marshall J, Shaw DA. Cerebrovascular disease: trial of long-term anticoagulant therapy. BMJ 1962; 53: Olsson JE, Brechter C, Backlund H, et al. Anticoagulant vs antiplatelet therapy as prophylactic against cerebral infarction in transient ischemic attacks. Stroke 1980; 11: The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997; 42: Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation. Arch Intern Med 1999; 159: Altman R, Boullon F, Rouvier J, et al. Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves. J Thorac Cardiovasc Surg 1976; 72: Chesebro JH, Fuster V, Elveback LR, et al. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol 1983; 51: Dale J, Myhre E, Loew D. Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement. Am Heart J 1980; 99: Dale J, Myhre E, Storstein O, et al. Prevention of arterial thromboembolism with acetylsalicylic acid: a controlled study in patients with aortic ball valves. Am Heart J 1977; 94: Sullivan JM, Harken DE, Gorlin R. Pharmacologic control of thromboembolic complications of cardiac-valve replacement. N Engl J Med 1971; 284: Turpie AGG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993; 329: Altman R, Rouvier J, Gurfinkel E, et al. Comparison of high dose with low dose aspirin in patients with mechanical heart valve replacement treated with oral anticoagulants. Circulation 1996; 94: Acar J, Iung B, Boissel JP, et al. AREVA: multicenter randomized comparison of low dose versus standard dose anticoagulation in patients with mechanical prosthetic heart valves. Circulation 1996; 94: Pengo V, Barbero F, Banzato A, et al. A comparison of a moderate with moderate-high intensity oral anticoagulant treatment in patients with mechanical heart valve prostheses. Thromb Haemost 1997; 77: Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990; 323: Special Report. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med 1990; 322: Petersen P, Boysan G, Godtfredsen J, et al. Placebocontrolled randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 1989; 1: Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with non-rheumatic atrial fibrillation. N Engl J Med 1992; 327: Connolly SJ, Laupacis A, Gent M, et al. Canadian atrial fibrillation anticoagulation study. J Am Coll Cardiol 1991; 18: Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: Pengo V, Zasso A, Barbero F et al. Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998; 82: Morocutti C, Amabile G, Fattapposta F, et al. Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation: SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Stroke 1997; 28: Gullov AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusteddose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158: Hellemons BS, Langenberg M, Lodder J, et al. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ 1999; 319: Segal JB, McNamara RL, Miller MR, et al. Prevention of thromboembolism in atrial fibrillation: a meta-analysis of trials of anticoagulants and antiplatelet drugs. J Gen Intern Med 2000;15: Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. JAMA 1999; 281: Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323: Sixty-Plus Reinfarction Study Research Group. A doubleblind trial to assess long-term anticoagulant therapy in elderly patients after myocardial infarction. Lancet 1980; 2: Sixty-Plus Reinfarction Study Research Group. Risks of long-term oral anticoagulant therapy in elderly patients after myocardial infarction. Lancet 1982; 1: EPSIM Research Group. A controlled comparison of aspirin and oral anticoagulants in prevention of death after myocardial infarction. N Engl J Med 1982; 307: Breddin K, Loew D, Lechner K, et al. Secondary prevention of myocardial infarction: a comparison of acetylsalicylic acid, placebo and phenprocoumon. Haemostasis 1980; 9: Meuwissen O, Vervoom AC, Cohen O, et al. Double blind trial of long term anticoagulant treatment after myocardial infarction. Acta Med Scand 1969; 186: Loeliger EA, Hensen A, Kroes F, et al. A double blind trial of long term anticoagulant treatment after myocardial infarction. Acta Med Scand 1967; 182: Bjerkelund CJ. The effect of long term treatment with dicumarol in myocardial infarction. Acta Med Scand 1957; 158(suppl):1 212 CHEST / 119 / 1/ JANUARY, 2001 SUPPLEMENT 119S

13 90 Bjerkelund CJ. Therapeutic level in long term anticoagulant therapy after myocardial infarction: its relation to recurrent infarction and sudden death. Am J Cardiol 1963; 1: Harvald B, Hilden T, Lund E. Long term anticoagulant therapy after myocardial infarction. Lancet 1962; 2: ASPECT Research Group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 1994; 343: Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA 1999; 282: Bynum LJ, Wilson JE. Low dose heparin therapy in the long term management of venous thromboembolism. Am J Med 1979; 67: Hull R, Delmore T, Genton E. Warfarin sodium versus low dose heparin in the long term treatment of venous thromboembolism. N Engl J Med 1979; 301: Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long term treatment of venous thrombosis. N Engl J Med 1982; 306: Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin: the prevention of recurrence after deep vein thrombosis. Thromb Haemost 1994; 72: Das SK, Cohen AT, Edmondson RA, et al. Low-molecularweight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996; 20: Lopaciuk S, Bielska-Falda H, Noszczyk W, et al. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis. Thromb Haemost 1999; 81: Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 18: Gallus AS, Jackaman J, Tillett J, et al. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; 2: Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322: Brandjes DPM, Heijboer H, Buller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327: Levine MN, Hirsh J, Gent M, et al. A randomized trial comparing the activated thromboplastin time with the heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994; 154: Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996; 100: Levine M, Gent M, Hirsh J, et al. A comparison of lowmolecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: The Columbus Investigators. Low molecular weight heparin is an effective and safe treatment for deep-vein thrombosis and pulmonary embolism. N Engl J Med 1997; 337: Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 337: Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 1998; 338: Dolovich LR, Ginsberg JS, Douketis JD, et al. A metaanalysis comparing low molecular weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000; 60: Gould MK, Dembitzer A, Doyle R, et al. Low molecular weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized controlled trials. Ann Intern Med 1999; 130: Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet 1992; 340: Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995; 74: Schulman S, Rhedin A-S, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: Schulman S, Granqvist S, Holmström M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336: Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: Agnelli G, Prandoni P, Santamaria MG, et al. Three months compared with one year of oral anticoagulant treatment after a first idiopathic deep vein thrombosis: the Warfarin Optimal Duration Italian Trial (WODIT) [abstract]. Thromb Haemost 1999; 82(suppl): Hylek EM, Heiman H, Skates SJ, et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998; 279: Fernandez F, Nguyen P, van Ryn J, et al. Hemorrhagic doses of heparin and other glycosaminoglycans induce a platelet defect. Thromb Res 1986; 43: Blajchman MA, Young E, Ofosu FA. Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits. Ann NY Acad Sci 1989; 556: Salzman EW, Deykin D, Shapiro RM, et al. Management of heparin therapy. N Engl J Med 1975; 292: Glazier RL, Corwell EB. Randomized prospective trial of continuous vs intermittent heparin therapy. JAMA 1976; 236: Mant MJ, O Brien BD, Thong KL, et al. Haemorrhagic complications of heparin therapy. Lancet 1977; 1: Wilson JR, Lampman J. Heparin therapy: a randomized prospective study. Am Heart J 1979; 97: Fagher B, Lundh B. Heparin treatment of deep vein thrombosis. Acta Med Scand 1981; 210: Wilson JE, Bynum LJ, Parkey RW. Heparin therapy in venous thromboembolism. Am J Med 1981; 70: Bentley PG, Kakkar VV, Scully MF, et al. An objective study of alternative methods of heparin administration. Thromb Res 1980; 18: Andersson G, Fagrell B, Holmgren K, et al. Subcutaneous administration of heparin: a randomized comparison with 120S Sixth ACCP Consensus Conference on Antithrombotic Therapy

14 intravenous administration of heparin to patients with deep vein thrombosis. Thromb Res 1982; 27: Doyle DJ, Turpie AGG, Hirsh J, et al. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Intern Med 1987; 107: Pini M, Pattacini C, Quintavalla R, et al. Subcutaneous vs intermittent heparin in the treatment of deep vein thrombosis: a randomized clinical trial. Thromb Haemost 1990; 64: Raschke RA, Reilly BM, Gguidry J, et al. The weight-based heparin nomogram compared with a standard care nomogram: a randomized controlled trial. Ann Intern Med 1993; 119: Prandoni P, Lensing AW, Buller HR, et al. Comparison of subcutaneous low molecular weight heparin with intravenous standard in proximal deep vein thrombosis. Lancet 1992; 339: Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low molecular weight heparin compared with continuous intravenous heparin in the treatment of proximal vein thrombosis. N Engl J Med 1992; 326: Simonneau G, Charbonnier B, Decousus H, et al. Subcutaneous low molecular weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993; 153: Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Thromb Haemost 1992; 68: Lindmarker P, Holmström M, Granqvist S, et al. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep venous thrombosis. Thromb Haemost 1994; 72: Fiessinger JN, Lopez-Fernandez M, Gatterer E, et al. One daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost 1996; 76: Monreal M, Lafoz E, Olive A, et al. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 1994; 71: Sandercock PAG, van der Belt A, Lindley R, et al. Antithrombotic therapy in acute ischemic stroke: an overview of the completed randomized trials. J Neurol Neurosurg Psychiatry 1993; 56: Kay R, Wong KS, Yu YL, et al. Low molecular weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995; 333: International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both or neither among 19,435 patients with acute ischemic stroke. Lancet 1997; 349: Publications Committee for the Trial of ORG10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG10172 (Danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 1998; 279: Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin or both to treat acute unstable angina? N Engl J Med 1988; 319: Seneri GGN, Roveli F, Gensini GF, et al. Effectiveness of low-dose heparin in prevention of myocardial reinfarction. Lancet 1987; 1: Turpie AGG, Robinson JG, Doyle DJ, et al. Comparison of high dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction. N Engl J Med 1989; 320: Gurfinkel E, Manos EJ, Mejail RI, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 1995; 26: Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group. Low molecular weight heparin during instability in coronary artery disease. Lancet 1996; 347: Klein W, Buchwald A, Hillis SE, et al. Comparison of low molecular weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: Fragmin in unstable coronary artery disease study. Circulation 1997; 96: Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low molecular weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997; 337: The Thrombolysis in Myocardial Infarction (TIMI) IIA Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI IIA. J Am Coll Cardiol 1997; 29: Fragmin and Fast Revascularization during Instability in Coronary artery disease (FRISC II) Investigators. Long term low molecular mass heparin in unstable coronary artery disease: FRISC II prospective randomized multicentre study. Lancet 1999; 354: Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non Q wave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) IIB Trial. Circulation 1999; 100: Green D, Lee MY, Ito VY, et al. Fixed vs adjusted-dose heparin in the prophylaxis of thromboembolism in spinal cord injury. JAMA 1988; 260: GUSTO IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994; 90: TIMI 9A Investigators. Hirudin in acute myocardial infarction. Circulation 1994; 90: Yett HS, Skillman JJ, Salzman EW. The hazards of heparin plus aspirin [letter]. N Engl J Med 1978; 298: Sethi GK, Copeland JG, Goldman S, et al. Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 1990; 15: EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in highrisk coronary angioplasty. N Engl J Med 1994; 330: EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: Jick H, Slone D, Borda IT, et al. Efficacy and toxicity of heparin in relation to age and sex. N Engl J Med 1968; 279: Levine MN, Hirsh J, Kelton JG. Heparin-induced bleeding. In: Lane DA, Lindahl U, eds. Heparin: chemical and biological properties clinical applications. London, UK: Edward Arnold, 1989; Basu D, Gallus A, Hirsh J, et al. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287: Campbell NR, Hull RD, Brant R, et al. Aging and heparinrelated bleeding. Arch Intern Med 1996; 156: CHEST / 119 / 1/ JANUARY, 2001 SUPPLEMENT 121S