Hemorrhagic Complications of Anticoagulant Treatment

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) major complication of anticoagulant therapy is T hebleeding. 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 ⬎ 4.0.10 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 108S

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 trials14,15 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 disease12,18 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 studies17–31 have found that the frequency of bleeding during warfarin therapy is higher in older patients, although other studies16,32–36 have not. Also, risk for intracranial hemorrhage may be increased among older patients, especially those ⱖ 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 therapy16; 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 studies16,21,22,24,27 noted an increased frequency of bleeding among women treated with warfarin, but several others21,23,26,33,34 have not. Although most experienced clinicians believe that either alcoholism or liver disease increases the risk of bleeding during long-term warfarin therapy, two studies20,21 did not find such an association, whereas a large population-based study41 did. Occult pathologic lesions may also precipitate warfarinSixth ACCP Consensus Conference on Antithrombotic Therapy

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.42– 44 In a large randomized trial42 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 trial43 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 studies16,20,21,28 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 studies33,45,46 have supported this observation, although some32,40 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 ⱖ 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 al38 identified four independent risk factors for bleeding: age ⱖ 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 al30 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,48 –52 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,53–55 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 studies48 –55 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 4.5.56 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

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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 al8 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,65 380 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,66 205 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 al63 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 al58 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 al67 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-analyses79,81 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 study71 (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 ⱖ 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 ⱖ 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 ⬎ 3.0.71 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 Saour et al8 Turpie et al63 Altman et al64 Acar et al65 Pengo et al66

Treatment

Patients, No.

Major, No. (%)

Fatal, No. (%)

Major, %/yr

Fatal, %/yr

Warfarin INR 2.65 Warfarin INR 9.0 Warfarin INR 3.0–4.5 plus placebo Warfarin INR 3.0–4.5 plus ASA, 100 mg Acenocoumarol INR 2.0–3.0 plus ASA, 100 mg Acenocoumarol INR 2.0–3.0 plus ASA, 650 mg Acenocoumarol INR 2.0–3.0 Acenocoumarol INR 3.0–4.5 Warfarin INR 2.5–3.5 Warfarin INR 3.5–4.5

122 125 184 186 207 202 188 192 104 101

4 (3.2)* 9 (7.2) 19 (10.3) 24 (12.9) 15 (7.2) 19 (9.4) 13 (6.9) 19 (10.0) 4 (3.8)* 11 (11.0)

0 2 (1.6) 4 (2.2) 3 (1.6) 2 (1.0) 1 (0.5) 1 (0.5) 1 (0.5) 0 1 (1.0)

— — 5.2 4.1 3.6 5.1 4.0 5.6 1.2* 3.8

— — 0.7 0.9 — — 0.24 0.24 — —

*p ⬍ 0.05. 110S

Sixth ACCP Consensus Conference on Antithrombotic Therapy

Table 2—Atrial Fibrillation* Bleeding† Source Petersen et al70

SPAF69

Boston68 Connolly et al73 SPAF II71

European18

Ezekowitz et al72 SPAF III74 Morocutti et al76 Gullov et al77

Pengo et al75 Hellemons et al78

Treatment

Patients, No.

Major

Fatal

Warfarin ASA (75 mg) Placebo Warfarin ASA (325 mg) Placebo Warfarin No treatment Warfarin Placebo Warfarin ⱕ 75 yr ASA ⱕ 75 yr Warfarin ⬎ 75 yr ASA ⬎ 75 yr Warfarin Placebo ASA (300 mg) Warfarin Placebo Warfarin plus ASA (325 mg) Warfarin Warfarin Indobufen Warfarin Warfarin (1.25 mg) Warfarin plus aspirin (1.25 mg and 300 mg) Aspirin (300 mg) Warfarin Warfarin (1.25 mg) Phenprocoumon/acenocoumarol Phenprocoumon/acenocoumarol Aspirin (150 mg)

335 336 336 201 192 195 212 208 187 191 358 357 197 188 225 230 404 260 265 521 523 454 462 170 167 171 169 153 150 131 122 141

‡ ‡ ‡ 1.7/yr 0.9/yr 1.2/yr 8 (3.8) 8 (3.8) 5 (2.7) 1 (0.5) 1.7/yr 0.9/yr 4.2/yr§ 1.6/yr 13 (5.8) 3 (1.3) 6 (1.5) 6 (2.3) 4 (1.5) 13 (2.4/yr) 12 (2.1/yr) 6 (1.3) 1 (0.2) 1.1/yr 0.8/yr 0.3/yr 1.4/yr 2.6/yr 1.0/yr 0.5/yr 1.4/yr 1.4/yr

1 (0.3) 0 0 ‡ ‡ ‡ 1 (0.5) 1 (0.5) 2 (1.1) 0 ‡ ‡ ‡ ‡ 3 (1.3) 1 (0.4) 2 (0.5) 0 1 (0.4) 3 (0.6/yr) 2 (0.4/yr) 1 (0.2) 0 0.3/yr 0 0 0.3/yr ‡ ‡ ‡ ‡ ‡

Targeted INR 2.8–4.2

2.0–3.5

1.5–2.7 2.0–3.0 2.0–4.5

2.5–4.0

1.4–2.8 1.2–1.5 2.0–3.0 2.0–3.5 — 2.0–3.0 — — — 2.0–3.0 — 2.5–3.5 1.1–1.6 —

*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 ⬍ 0.04.

Ischemic Heart Disease There are 10 published randomized trials of long-term oral anticoagulant therapy in patients with acute myocardial infarction42,82–92 (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 al82 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 Study42 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

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Table 3—Ischemic Heart Disease* Bleeding † Source Sixty-plus83,84 EPSIM85 Breddin et al86

Treatment Acenocoumarin Placebo Oral anticoagulants‡ ASA (500 mg tid) Phenprocoumon, ASA (500 mg tid) Placebo

Meuwissen et al87

Phenprocoumon Placebo

Loeliger et al88

Phenprocoumon Placebo Dicumarol No treatment Dicumarol Placebo Warfarin Placebo Nicoumalone/phenprocoumon Placebo Warfarin 3 mg plus ASA 80 mg Warfarin 1 mg plus ASA 80 mg ASA 160 mg

Bjerkelund89,90 Harvald et al91 Smith et al82 ASPECT92 CARS42

Patients, No. 439 439 652 651 320 317 309 68 70 128 122 138 139 145 170 607 607 1,700 1,704 3,382 2,082 3,393

Major

Fatal

18 (4.1) 1 (0.2) 21 (3.2) 5 (0.8) NR NR NR 0

6 (1.4) 1 (0.2) 8 (1.2) 4 (0.6) 0 0 0 0

0 1 (0.8) 1 (0.8) 20 (14.5) 5 (3.6) 28 (19.3) 0 13 (2.1) 0 73 (4.3)§ 19 (1.1) 75 (2.2%) 42 (1.7%) 57 (1.5%)

0 0 1 (0.8) 4 (2.9) 1 (0.7) 1 (0.7) 0 3 (0.5) 0 11 (0.6)§ 0 NR NR NR

Targeted INR 2.2–5.0

2.0–5.0

1.9–5.0

2.0–5.0 1.3–2.1 1.5–2.1 2.8–4.8 2.8–4.8 1.2㛳 1.0㛳 1.0㛳

*Sixty-plus ⫽ Sixty-Plus Reinfarction Study Research Group; EPSIM ⫽ Enqueˆte 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. §⬍ 0.01. 㛳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 Yusuf93 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 112S

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 trials94 –99 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 studies95–97 than in the more recent trials (ie, INR 2.0 to 3.0).6,97–99 The higher-intensity Sixth ACCP Consensus Conference on Antithrombotic Therapy

Table 4 —Venous Thromboembolism* Bleeding (approximately 3 mo)† Source

Treatment

Patients, No.

Major

Fatal

Bynum and Wilson94

Warfarin (INR 2.6–4.4) Heparin (5,000 U sc bid) Warfarin (INR 2.6–4.4) Heparin (5,000 U sc bid) Warfarin (INR 2.6–4.4) Heparin (approx. 10,000 U sc bid) Warfarin (INR 2.6–4.5) Warfarin (approx. 2.2) Warfarin (INR 2.7) Enoxaparin (4,000 IU sc qd) Warfarin (INR 2.0–3.0) Dalteparin (5,000 IU sc qd) Acenocoumarol (INR 2.0–3.0) Nadroparin (85 IU/kg sc qd)

24 24 33 35 53 53 49 47 94 93 55 50 95 98

4 (16.7) 0 4 (12.1) 0 3 (5.7) 0 2 (4.1) 2 (4.3) 12 (12.8) 3 (3.2) 0 0 2 (2.1) 1 (1.0)

0 0 0 0 0 0 0 0 0 0 0 0 0 0

Hull et al95 Hull et al96 Hull et al6 Pini et al97 Das et al98 Lopaciuk et al99

*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 al6 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 studies97–98 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 ⱕ 3% during 3 months of therapy.100 –112 Three randomized trials have compared a short duration (4 weeks113,114 or 6 weeks115) with a medium duration (3 months113,114 or 6 months115) 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.113–115 Two additional randomized trials have evaluated long-term oral anticoagulation for the prevention of recurrent venous thromboembolism follow-

ing an acute episode.116,117 Schulman et al116 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 al117 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 al118 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

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Table 5—Intracranial Hemorrhage During Long-term Oral Anticoagulant Therapy* Source

Patients

Therapy

Atrial fibrillation (n ⫽ 1,236) Atrial fibrillation (n ⫽ 1,225) ⬎ 75 yr (n ⫽ 223) Atrial fibrillation (n ⫽ 555) ⱕ 75 yr (n ⫽ 358) ⬎ 75 yr (n ⫽ 197) Atrial fibrillation (n ⫽ 523) Cerebral ischemia (n ⫽ 651) Prosthetic valves (n ⫽ 184) Prosthetic valves (n ⫽ 104) Prosthetic valves (n ⫽ 188)

Fihn et al Fihn et al16 16

SPAF II37,71

SPAF III81 SPIRIT56 Turpie et al63 Pengo et al66 Acar et al65

INR

Control Warfarin

⬍ 3.0†

Warfarin

2.0–4.5

Warfarin Phenprocoumon Warfarin Warfarin Acenocoumarol

2.0–3.0 3.0–4.5 3.0–4.5 2.5–3.5 2.0–3.0

ICH, %/yr 0.1 0.3 0.3 0.9 0.5 1.8 0.5 3.7 1.4 0.3 0.2

*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,122–127 IV heparin with subcutaneous heparin,128 –131 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 Prandoni et al

133

Hull et al134† Lopaciuk et al136 Simonneau et al135 Lindmarker et al137 Fiessinger et al138 Levine et al106‡ Koopman et al107‡ Columbus108‡ Simonneau et al109§

Regimens

Major Bleeding

Fatal Bleeding

Nadroparin sc bid (weight-adjusted) IV heparin APTT ratio 1.5 to 2.0 Tinzaparin, 175 Xa U/kg sc qd IV heparin APTT ratio 1.5 to 2.5 Nadroparin, 92 Xa U/kg sc bid SC heparin APTT ratio 1.5 to 2.5 Enoxaparin, 1 mg/kg sc bid IV heparin APTT ratio 1.5 to 2.5 Dalteparin, 200 Xa U/kg sc qd IV heparin APTT ratio 1.5 to 3.0 Dalteparin, 200 Xa U/kg sc qd IV heparin APTT ratio 1.5 to 3.0 Enoxaparin, 1 mg/kg sc bid IV heparin APTT 60 to 85 s Nadroparin sc bid (weight-adjusted) IV heparin APTT ratio 1.5 to 2.0 Reviparin, 3,500 to 6,300 Xa U sc bid (weight-adjusted) IV heparin APTT ratio 1.5 to 2.5 Tinzaparin, 175 Xa U/kg sc qd IV heparin APTT ratio 2.0 to 3.0

1/85 (1) 3/85 (4) 1/213 (0.5) 11/219 (5.0) 0/74 1/72 (1) 0/67 0/67 0/101 0/103 0/127 2/133 (2) 5/247(2) 3/253 (1) 1/202 (0.5) 4/198 (2) 16/510 (3) 12/511 (2) 0/304 1/308 (0.3)

0/85 0/85 0/213 2/219 (0.9) 0/74 0/72 0/67 0/67 0/101 0/101 0/127 0/133 2/247 (0.8) 0/253 0/202 2/198 (1) 0/510 2/511 (0.4) 0/304 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

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 ASA, 300 mg qd Heparin, 5,000 U bid plus ASA, 300 mg qd Heparin, 12,500 U bid Heparin, 5,000 U bid ASA, 300 mg qd Control

2,430

75 (3.1)

42 (1.7)

33 (1.4)

10 (0.4)

2,431

39 (1.6)

19 (0.8)

20 (0.8)

9 (0.4)

2,426 2,429 4,858 4,859

76 (3.2) 26 (1.1) 49 (1.0) 29 (0.6)

43 (1.8) 16 (0.7) 26 (0.5) 15 (0.3)

33 (1.4) 10 (0.4) 23 (0.5) 14 (0.3)

12 (0.5) 9 (0.4) 13 (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.105–109,133–138 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-analyses111,112 support the inference that

LMW heparin does not result in an increased risk of major bleeding compared with unfractionated heparin. A recent meta-analysis112 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 Gurfinkel et al147

FRISC 1996148

Klein et al149

TIMI 11A 1997151 Cohen et al150 FRISC II 1999152 Antman et al153

Regimens* ASA alone IV heparin APTT ratio 2.0 Nadroparin 214 U/kg sc bid Placebo sc bid Dalteparin 120 U/kg sc bid Placebo sc qd Dalteparin 7,500 U sc qd IV heparin APTT ratio 1.5 Dalteparin 120 U/kg sc bid Placebo sc qd Dalteparin 7500 u sc qd Enoxaparin 1.25 mg/kg sc q12h Enoxaparin 1.0 mg/kg sc q12h IV heparin APTT ratio 55 to 85s Enoxaparin 1.0 mg/kg sc q12h Placebo sc bid Dalteparin 120 U/kg sc bid IV heparin APTT ratio 1.5 to 2.5 Enoxaparin 1.0 mg/kg sc q12h Placebo sc q12h Enoxaparin 40 mg or 60 mg sc qd

Treatment Duration, d

Patients, No.

Major Bleeding

Fatal Bleeding

5–7 5–7 5–7 0–6 0–6 6–45 6–45 0–6 0–6 6–45 6–45 14 14 2–8 2–8 3 mo 3 mo 8 hospital 8 hospital 43 43

73 70 68 760 746 614 619 731 751 565 567 321 309 1,564 1,607 1,056 1,049 1,957 1,953 1,185 1,179

0 2 (2.9) 0 4 (0.5) 6–(0.8) 2 (0.3) 2 (0.3) 7 (1.0) 8 (1.1) 2 (0.4) 3 (0.5) 21 (6.5) 6 (1.9) 107 (6.8) 102 (6.3) 16 (1.5) 34 (3.2) 19 (1.0) 29 (1.5) 18 (1.5) 34 (2.9)

0 0 0 1 (0.1) 0 0 0 NR NR NR NR NR NR NR NR NR NR 4 (0.2) 4 (0.2)

*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

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As previously noted, three small studies6,97,98 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 trial139 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 al140 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 study143 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 trials144,145 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 trial146 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 trials147–150 116S

in patients with unstable coronary artery disease. The bleeding outcomes from these clinical trials147–150 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 trials151–153 than were observed in the initial large trials148,149 of LMW heparin. This is probably due to inclusion in the more recent studies151–153 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 studies148,149 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 study154 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 study155 and the Thrombolysis in Myocardial Infarction 9A study156 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. Sixth ACCP Consensus Conference on Antithrombotic Therapy

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,122–127 in which heparin was either administered by continuous IV infusion or intermittent IV injection, and five randomized trials,128 –131 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 associates102 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 associates158 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 therapy4 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 studies161,163 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.

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