The major complication of anticoagulant therapy is

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1 Hemorrhagic Complications of Anticoagulant Treatment Mark N. Levine, M.D., M.Sc., Chainnan jack Hirsh, M.D., F.C.C.P. Seth Landefeld, M.D. Gary Raskob, M.Sc. 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 published reports are classified into one of five categories based on the strength of the study design, and whenever possible, conclusions are based on results of randomized control trials. 1 2 Hemorrhage 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 All other bleeding episodes were classified as minor. The details of bleeding events and definition of bleeding varied considerably between studies. Details of the methodology used to select relevant articles can be found in our reviews in the two previous symposia of the American College of Chest Physicians. 1 2 Since these previous reviews, important new information has emerged from randomized trials on the relationship between intensity of oral anticoagulant therapy and hemorrhage and on the risk of hemorrhage in patients receiving oral anticoagulants for atrial fibrillation. In this review, we include a section on heparin-associated bleeding that was not included in the previous reviews. 1 2 Although bleeding is considered the major side effect of anticoagulant therapy, it should not be considered in isolation of potential benefit, ie, reduction in thrombosis. ORAL ANTICOAGULANTS The major determinants of oral anticoagulant-induced bleeding are the intensity of the anticoagulant effect, patient characteristics, the use of drugs that interfere with hemostasis, and the length of therapy. Relationship Between Intensity of Anticoagulant Therapy and Hemorrhage The intensity of the anticoagulant response to warfarin is influenced by the dose of warfarin, the patient's vitamin K intake, interindividual variability in anticoagulant response to a given dosage, and other factors that alter the pharmacokinetics and pharmacodynamics of warfarin, of which the most important are concomitant medication and liver function. 352$ 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, tissue heart valves, and mechanical heart valves. In patients with venous thrombosis, Hull and colleagues 3 reported a strong relationship between the intensity of warfarin treatment and the risk of bleeding (level I). The patients randomized to receive less intense warfarin (targeted international normalized ratio [INR] = 2.) had significantly less bleeding (4 percent 22 percent) than those receiving more intense therapy (targeted INR = 2.5 to 4.5). In the 13 patients who bled, the INR was greater than 3.. In a trial reported by Turpie et al, 4 patients with tissue heart valves were randomized to either standard intensity warfarin (INR 2.5 to 4.) or less intense warfarin (INR 2. to 2.5) (level I). The rate of clinically important bleeding over three months was reduced from 14 percent in the standard intensity group to 6 percent in the low intensity group without loss of antithrombotic efficacy. In a reported trial by Saour et al, 5 patients with prosthetic heart valves were randomized to either moderate intensity warfarin (targeted INR 2.65) or high-intensity warfarin (targeted INR 9.) (level I). Bleeding was more common in the higher-intensity group. Of the 122 patients randomized to the moderate intensity, 4 experienced major bleeding and 22 experienced minor bleeding. In the 125 patients who received the higher-intensity warfarin, there were 9 major bleeds (of which 2 were fatal intracranial) and 44 minor bleeds. The difference in total and minor bleeding between groups was statistically significant. It is important to note, however, that the targeted intensity of the higher-intensity arm in this trial is much higher than the currently recommended intensity. In a trial recently reported by Altman et al, 6 patients with mechanical valves received either acenocoumarol (INR 3. to 4.5) or acenocourmarol (INR 2. to 2.99) (level I). All patients received concurrent aspirin and dipyridamole. There was a statistically significant reduction in bleeding in patients who received the less intense therapy: 21 percent 4 percent. Hemorrhagic Complications (Lavine et al)

2 Finally, results from the recent Boston randomized trial indicate that lower-dose oral anticoagulants (INR 1.5 to 2. 7) can be administered safely in patients with atrial fibrillation. 7 Relationship Between Risk of Bleeding and lhtient Characteristics Major bleeding is especially likely in patients with ischemic cerebral vascular disease and venous thromboembolism, possibly owing to the higher prevalence of associated risk factors in these conditions. 1 2 In venous thromboembolism, these comorbid conditions (cancer, recent surgery, and paraplegia) predispose the patient to thrombosis. In cerebrovascular disease, major bleeding is usually intracerebral, possibly because of associated hypertension or the vascular disease per se. The risk of bleeding during warfarin therapy is probably also related to patient characteristics other than the indication for therapy. Results of observational studies (level IV) suggest that the risk of bleeding is related to age, history of past bleeding, and specific comorbid conditions. However, the presence of such factors should not be considered as contraindications to anticoagulant therapy, but clinical judgment may need to be used in certain situations. Several studies have found that the frequency of bleeding during warfarin therapy is higher in older patients, s- 15 although some other studies disagree The only two studies of large inception cohorts 9 1 found an increased bleeding risk in older patients, with a relative risk for major bleeding of 3.2 for patients aged 65 years or older in one study. 9 Past gastrointestinal bleeding is also an indicator of increased risk of bleeding during warfarin therapy. 9 In contrast, peptic ulcer disease alone, without past bleeding, has not been associated with an increased risk of bleeding Several comorbid diseases have been associated with bleeding during warfarin therapy; these include treated hypertension, cerebrovascular disease, 9 serious heart disease, 9 11 and renal insufficiency. 9 Although many other patient characteristics have been associated with bleeding during warfarin therapy, the data supporting these findings are not compelling. For example, a few studies have noticed an increased frequency of bleeding among women treated with warfarin, although most have not Although most experienced clinicians believe that either alcoholism or liver disease increases the risk of bleeding during long-term warfarin therapy, two recent studies did not find such an association However, these negative findings may reflect the infrequency with which such patients are treated with warfarin and, perhaps, inaccurate documentation of alcoholism in medical records. Two recent observational studies1 21 reported higher frequencies of warfarin-related bleeding in patients with atrial fibrillation than would be expected on the basis of results from randomized trials; this contrast may reflect differences in the intensity of anticoagulant effect or in the frequency of other risk factors for bleeding. Independent risk factors for bleeding during longterm warfarin therapy were recently identified: 9 22 age 65 years or older, history of past gastrointestinal bleeding, stroke (present or past), atrial fibrillatidn, and one or more of three specific co morbid conditions (recent myocardial infarction, renal insufficiency, or severe anemia). Hypertension was not associated with increased risk for bleeding after controlling for these risk factors. In addition, there was a suggestion that patients who bled with the prothrombin time (IT) in the therapeutic range were subsequently found to have an underlying pathologic lesion as the cause of bleeding. These studies suggest that the yield of finding an underlying occult bleeding source is higher if the bleed occurs when the INR is within the therapeutic range. However, it would seem prudent Table l - lschemic Cerebrovascular Disease Bleeding Patient Targeted Study Treatment No. Total(%) Major(%) Fatal(%) INR Baker"' /dicurnarol (39.7)* 1 (12.8) 4 (5.1) 5.6 No Rx 77 5 (6.5) 3 (3.9) l (1.3) Baker"', Fisher'" Dicurnarol (39.3)* 18 (8.) 12 (5.4) (4.6) 2 (.9) Enger and Boyesen"' Phenylindanedione 52 1 (19.2)* 4 (7.7) 3 (5.8) l 48 Hill et al 31 Phenindione (high) (21.1)* 5 (7.) 5 (7.) Phenindione (low) 71 1 (1.4) 1 (1.4) McDowell et al'" (17.9)* 2 (2.1) 2 (2.1) No Rx 15 1 (1.) 1 (1.) 1 (1.) Olsson et al (11.8) 2 (2.9) 2 (2.9) ASA + dipyridarnole 67 3 (4.5) *p<.1 CHEST I 12 I 4 I OCTOBER, 1992 I Supplement 353S

3 to investigate the cause of overt gastrointestinal and genitourinary bleeding. 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. It is likely, however, that the risk of bleeding varies during the course of anticoagulant therapy. Two recent studies reported higher frequencies of bleeding early in the course of therapy. 9 1 In one of these studies, for example, the frequency of major bleeding decreased from 3. percent during the first month of outpatient warfarin therapy to.8 percent per month during the rest of the first year of therapy and to.3 percent per month thereafter. 9 Other descriptive studies have supported this observation, although some have not Risk of Hemorrhage and Clinical Disorders lschemic Cerebral Vascular Disease: There have been six randomized trials conducted which compared oral anticoagulant treatment with either a nontreatment group, a very low dose anticoagulant group, or an antiplatelet group (Table 1). In all cases, there was increased bleeding associated with the oral anticoagulant treatment. The risk of bleeding in the anticoagulant group was impressive and ranged from 11.8 to 39 percent. The risk of major bleeding (most commonly intracerebral) was also high, being greater than 7 percent in four out of the six studies. 2.5, Fatal hemorrhage ranged from 2 to 7 percent. 'Prosthetic Heart Valves: There have been eight randomized trials oflong-term oral anticoagulant therapy in patients with prosthetic heart valves In five trials, oral anticoagulant therapy was compared to a combination of oral anticoagulants and antiplatelet agents,33-38 and in three trials, different intensities of oral anticoagulants were compared4-6 (Table 2). The frequency of bleeding ranged from 1.2 to 42.4 percent in the patients treated with anticoagulant alone. Major bleeding ranged from to 6.8 percent. There were no fatal bleeds in two studies, 4 37 but fatal bleeding was as high as 4.1 percent in another, 35 with most fatal bleeds being intracerebral. In three of four studies, there was a significantly greater frequency of bleeding when aspirin was added to warf arin, whereas in two trials, the addition of dipyridamole was not associated with an increased risk of bleeding In one of these studies, the targeted intensity (INR 2.6 to 7.5) may have contributed to this bleeding. 34 Most of the bleeding episodes during combined treatment with anticoagulant and aspirin were gastrointestinal. In a recent double-blind trial, Turpie et al 38 randomized patients with prosthetic heart valves to warfarin (INR 3. to 4.5) plus placebo or warfarin (same INR) plus aspirin 1 mg daily. Forty-eight of 184 placebo patients (26.1 percent) experienced bleeding compared to 72 of 186 aspirin patients (38. 7 percent). This difference was statistically significant. The rates of major bleeding were 1.3 percent and 12.9 percent, respectively. Saour et al 5 recently reported the results of a trial in which patients with mechanical valves were ran- Table 2-Prosthetic Heart Valves Bleeding Patient Targeted Study Treatment No. Total(%) Major(%) Fatal(%) INR Altman et al 33 Acenocoumarin + ASA (5 mg) 57 7 (12.3) 1 (1.7) 1 (1.7) Acenocoumarin 65 7 (1.7) 1 (1.5) 1 (1.5) Chesebro et al,. + ASA (25 mg bid) (13.5)* 2 (11.8) 3 (1.8) dipyridamole 18 7 (3.9) 4 (2.2) t (4.9) 4 (2.2) 3 (1.6) Dale et al"' "" + ASA (5 mg bid) (2.)* 12 (16.) 1 (1.3) (8.2) 5 (6.8) 3 (4.1) Sullivan et al 37 + dipyridamole 79 3 (3.7) 2 (2.5) 2 (2.5) + placebo 84 1 (1.2) Turpie et al (13.9)* 5 (4.6) (less intense) 12 6 (5.9) Saour et al' (more intense) (42.4)* 9 (7.2)* 2 (1.6) 9. (less intense) (21.3) 4 (3.2) 2.65 Altman et aj Acenocoumarin (more intense) 48 1 (2.8)* ASA (66 mg) + dipyridamole Acenocoumarin (less intense) 51 2 (3.9) ASA (66 mg) + dipyridamole Turpie et al"" + placebo (26.1) 19 (1.3) 4 (2.2) ASA (loomg) (38.7)* 24 (12.9) 3 (1.6) *p<.5. tnonrandomized <.'Oncurrent control. 354S Hemorrhagic Complications (Levine et al)

4 domized to either moderate intensity warfarin (targeted INR 2.65) or very high intensity warfarin (targeted INR 9.). 5 The rate of major bleeding in the former treatment arm was 3.2 percent compared to 7.2 percent in the latter arm. In a trial reported recently by Altman and colleagues, 6 patients with mechanical valves were randomly allocated to more intense or less intense oral anticoagulant therapy; acenocoumarol targeted INR 3. to 4.5, acenocoumarol targeted INR 2. to 2.9, respectively. All patients also received aspirin, 33 mg twice daily, and dipyridamole, 75 mg twice daily. Ten patients (21 percent) in the more intense group bled, compared to two patients in the less intense group (4 percent), p<.5. Although there was less bleeding associated with the lower intensity anticoagulant therapy, the effect of intensity alone on bleeding is confounded by the concurrent aspirin and dipyridamole. In three of the trials in patients with heart valves, a less intense anticoagulant regimen was studied, INR approximately 2. to 2.5.<H; In all of these trials, the less intense regimen was associated with less bleeding, but no loss of antithrombotic efficacy. The recommended therapeutic range in North America for patients receiving oral anticoagulant therapy for mechanical valves has been an INR of 3. to These three trials raise the question of whether the intensity of anticoagulant therapy for mechanical heart valves can be lowered to a therapeutic range similar to venous thromboembolic disease. 2 3 Atrial Fibrillation: There have been four randomized trials published recently examining patients with atrial fibrillation who received long-term oral anticoagulant therapy (Table 3). In the study reported by Peterson et al, 39 patients with chronic nonrheumatic atrial fibrillation were randomized to either warfarin (335 patients), aspirin, 75 mg once daily (336 patients), or placebo (336 patients). The targeted therapeutic range was an INR of 2.8 to 4.2. Five patients receiving warfarin had thromboembolic complications, compared with 2 patients receiving aspirin, and 21 receiving placebo. There were 21 warfarin patients (6.3 percent) who experienced nonfatal bleeding events, and one warfarin patient had a fatal intracerebral hemorrhage.two patients receiving aspirin and none receiving placebo experienced bleeding. In the trial reported by the Stroke Prevention in Atrial Fibrillation Study Group, patients with atrial fibrillation not related to rheumatic or prosthetic valvular heart disease were randomized to either warfarin at a targeted INR of 2. to 3.5 (21 patients), aspirin, 325 mg daily (192 patients), or placebo (195 patients). 4 Recruitment to the trial was stopped after 588 patients had been recruited to the study because active therapy with either warfarin or aspirin significantly reduced the risk of thromboembolic events compared to placebo alone. The mean follow-up was 1.13 years. Hemorrhagic events requiring hospital admission, blood transfusion, or surgery occurred at a rate of 1. 7 percent per year in the warfarin group; intracranial hemorrhage occurred at a rate of.9 percent per year, and cerebral hemorrhage at a rate of.4 percent per year. In patients who received placebo, the rate of total bleeding was 1.2 percent per year with.2 percent per year having intracranial bleeds. In a trial recently reported from Boston, 42 patients with nonrheumatic atrial fibrillation were randomized to either low dose warfarin therapy (targeted INR 1.5 to 2. 7) (212 patients) or no treatment (28 patients). 7 In this study, bleeding was considered major if it was fatal, intracerebral, or associated with a transfusion of greater than 4 U of erythrocytes. There were two major bleeds in the warfarin group (one intracerebral and one gastrointestinal), compared to one in the control group (intrapulmonary hemorrhage); one bleed in each group was fatal. In addition, six patients receiving warfarin experienced bleeding episodes leading to hospitalization or transfusion com- Table 3-Nonrheumatic Atrial Fibrillation Bleeding Patient Targeted Study Treatment No. Total(%) Major(%) Fatal(%) INR Peterson et al"" (6.3)-t- NR 1 (.3) ASA(75mg) (.6) NR 3.16 NR SPAF.. 21 NR 1.7%/year NR ASA(325mg) 192 NR.9%/year NR 195 NR 1.2%/year NR Boston (18.8) 8 (3.8) 1 (.5) No Rx (1.6) 8 (3.8) 1 (.5) CAFA" (18.2) 5 (2.7) 2 (1.1) (9.9) 1 (.5) NR =not reported in publications. tp<.5. CHEST I 12 I 4 I OCTOBER, 1992 I Supplement 355$

5 Study Sixty-plus"' " EPSIM group.., Breddin et al"' Meuwissen et al 47 Loeliger et al.. Bjerkelund et al 49 " Harvald et al" Smith et al" Treatment Acenocoumarin Oral anticoagulants* ASA (5 mg tid) Phenprocoumon ASA (5 mg tid) Phenprocoumon Phenprocoumon Dicumarol No Rx Dicumarol *A number of different oral anticoagulants. tp<.1. :j:nr =not reported. Table 4-lschemic Heart Disease Patient No > pared to seven control patients. Thirty-two patients receiving warfarin had minor bleeds compared to 14 control patients. The rate of major bleeding for the warfarin gorup was 1. 6 per 1 patient years compared to 1.8 per 1 patient years for the control patients. In the Canadian Atrial Fibrillation Anticoagulation Study, patients with nonrheumatic atrial fibrillation were randomly allocated to receive either warfarin, targeted INR 2. to 3., or placebo. The mean follow-up was 15.2 months. Major bleeding occurred in five patients receiving warfarin compared to one placebo-treated patient. The annual rate of fatal or major bleeding was 2.5 percent in the warfarin group and.5 percent in the placebo group. Minor bleeding occurred in 16 percent of warfarin-treated patients and 9.4 percent of placebo-treated patients. The rate of fatal bleeding was approximately.2 per 1 patient years in both groups. Total(%) Bleeding Major(%) 74 (17.)t 18 (4.1) 6 (1.4) 1 (.2) 14 (16.)t 21 (3.2) 3.5 (5.4) 5 (.8) 12 (3.8) NR:j: 9 (2.8) NR:j: NR:j: 7 (1.3)t 17 (13.3)t (.8) 7 (5.7) 1 (.8) 32 (23.2)t 2 (14.5) 9 (6.5) 5 (3.6) 53 (36.5)t 28 (19.3) 8 (4.7) 52 (8.6) 13 (2.1) 25 (4.1) Fatal(%) 6 (1.4) 1 (.2) 8 (1.2) 4 (.6) 1 (.8) 4 (2.9) 1 (.7) 1 (.7) 3 (.5) Targeted INR l lschemic Heart Disease: There are eight published randomized trials oflong-term oral anticoagulant therapy in patients with acute myocardial infarction (Table 4). In six of these, anticoagulant therapy was compared with placebo or control; in the seventh, anticoagulant therapy was compared with aspirin, 45 and in the eighth, anticoagulant therapy was compared with aspirin or placebo. 46 Anticoagulant therapy was associated with an increased risk of bleeding ranging from 3.8 to 36.5 percent. The frequency of major bleeding ranged from to 1 percent, and fatal bleeding ranged from to 2.9 percent. Recently, Smith et al 42 reported the results of a randomized trial of oral anticoagulant therapy in patients with acute myocardial infarction which renewed interest in the long-term use of oral anticoagulants after myocardial infarction. A total of 1,214 such patients were randomized to either warfarin (67 Table 5-Venous Thromboembolism Study Bynum and Wilson"' Hull et al" Hull et al" Hull et aj 3 Hull et al"'' Hull et al"' *Low dose subcutaneous heparin. t Adjusted dose subcutaneous heparin. :j:p<.1. Treatment Heparin* Heparin* Heparint (less intense) (less intense) (less intense) Patient No. Total(%) 24 9 (37.5):1: 24 1 (4.2) 33 7 (21.2):1: (17.):j: 53 1 (1.9) (22.4):1: 47 2 (4.3) Bleeding Targeted Major(%) Fatal(%) INR ) (12.1) (5.7) (4.1) (4.3) (2.) $ Hemontlagic Complications (l.bvine et al)

6 Table 6-Hemorrhage During Therapy Indication No. of Patients Major Bleed{%) Fatal Bleed{%) Ischemic cerebrovascular Prosthetic mechanical heart valves Atrial fibrillation Ischemic heart Venous thromboembolism More intense { Less intense , (7.) 38 (4.1) 37 {4.) 11 {4.) 13 {8.1) 6 {I. 7) 28 (4.8) 11 {1.2) 3 {.3) 22 (.9) patients) or placebo (67 patients). The targeted INR was 2.8 to 4.8. Five patients in the warfarin group (.8 percent) had intracranial hemorrhages and three of these were fatal. Eight warfarin-treated patients experienced major extracranial bleeds. There were no major nor fatal bleeds in the placebo group. Minor bleeding occurred in 52 of the warfarin-treated patients compared to 25 placebo-treated patients. \knous Thromboembolism: There have been four randomized trials which have evaluated bleeding during oral anticoagulant therapy in patients with venous thromboembolism (Table 5). In all of these studies, the dose of warfarin in one group was adjusted to maintain the PT ratio at an INR of approximately 4.5, while the other group was treated less intensively. In two of the studies, the group receiving less intense (nonwarfarin) therapy received low dose unfractionated subcutaneous heparin (5, U subcutaneously twice daily);s 2 53 in the third trial, the comparison group received adjusted dose subcutaneous standard heparin; 54 and in the fourth trial, the dose of warfarin was adjusted to an INR of approximately In all four studies, total bleeding (both major and minor) was significantly greater in the group receiving more intense anticoagulation therapy. Bleeding in patients receiving the more intense warfarin varied from 17 to 37.5 percent, and major bleeding varied from 4.1 to percent. In patients receiving less intense warfarin, major bleeding occurred in 4 percent. There were no fatal bleeds during long-term warfarin therapy in any of the trials. Summary of Bleeding Risks Bleeding rates (pooled rates) during long-term anticoagulation therapy are substantial with standard high intensity therapy and are lower with low intensity therapy (INR 2. to 3.). For major bleeding, the rates ranged from 2.4 to 8.1 percent; and for fatal bleeding, to 4.8 percent (Table 6). The highest bleeding rates were seen in patients with cerebrovascular disease and venous thromboembolism. It is important to note that the pooled rates consist of individual rates from trials of higher and lower intensity anticoagulant therapy. Annual bleeding rates (percent per year) are presented in Table 7 for prosthetic heart valves and in Table 8 for nonrheumatic atrial fibrillation. The average frequency of bleeding in patients receiving warfarin alone has varied from 1.8 percent per year to 14 percent per year (median, 5. 7 percent per year). In these patients, the frequency of major bleeding has varied from.8 percent per year to 4.1 percent per year (median, 1. 7 percent per year), and the frequency of fatal bleeding has varied from.2 percent per year to 2.3 percent per year (median.8 percent per year). Thus, average annual risks of total, major, and fatal bleeding can be estimated to be 6, 2, and.8 percent, respectively. HEPARIN Heparin is usually given in low doses by subcutaneous injection to prevent venous thrombosis (prophylactic heparin), in higher doses to treat patients with Table 7 - Prosthetic Heart Valves Bleeding, %/yr Study Altman et al 33 Chesebro et al"' Dale et al Altman et al Turpie et al"" *Patients also received ASA plus dipyridamole. Treatment Acenocoumarin + ASA {5 mg) Acenocoumarin + ASA (25 mg bid) + dipyridamole + ASA (5 mg bid) Acenocoumarin* (more intense) Acenocoumarin* {less intense) +ASA {1 mg) + placebo Total Major Fatal CHEST I 12 I 4 I OCTOBER, 1992 I Supplement 3575

7 Table 8-Nonrheumatic Atrial Fibrillation Study Petersen et al'" SPAP' Boston' CAFA' 1 *NR =not reported in publication. Treatment ASA (75mg) ASA (325 mg) No RX Bleeding, %/yr Tbtal Major Fatal 3.1 NR*.2.3 NR* NR* NR* 1.7 NR* NR*.9 NR* NR* 1.2 NR* acute venous thromboembolism or with acute coronary syndromes (therapeutic heparin), and in very high doses in patients during open heart surgery. Bleeding occurs much more frequently when heparin is given in large doses therapeutically than when it is administered in small doses prophylactically. Heparin has the potential to induce bleeding by inhibiting blood coagulation, by impairing platelet function, and by increasing capillary permeability. The major mechanism for bleeding is likely to be through its anticoagulant action. Heparin interacts with platelets and prolongs the bleeding time in man Table 9-Risk of Bleeding Associated With Therapeutic Heparin Study Salzman et al" Glazier and Corwell"' Mani et al"" \Vilson and Lampman"" Fagher and Lundh 1 Wilson et al"" Bentley et al" 1 Andersson et al"' Hull et al"' Doyle et al 66 Pini et al *Five fatal bleeds in all studies combined. tp<.5. Method of Administration Continuous VS intermittent Continuous intermittent Continuous VS intermittent Continuous VS intermittent Continuous intermittent Continuous intermittent Subcutaneous continuous Subcutaneous VS continuous Subcutaneous continuous Subcutaneous continuous Subcutaneous continuous Patient No Major* 24-h Hemorrhage Heparin Dose, No(%) u (1.) 24,48 t 6 (8.3) 31,74 25,488 t 7 (33.) 32,88 6 (I.15.) 33,74 4 (11.) 29,861 2 (5.) 27,695 4 (1.) 37,15 3 (2.) 37,371 4 (3.8) 41,38 3 (8.) 28,44 5 (17.) 43,57 2 (4.) 36,998 4 (8.) 36,814 2 (2.7) 35, 2 (2.8) 31,5 2 (3.5) 32,317 2 (3.4) 29,674 4 (7.8) 29,18 2 (3.8) 29,26 5 (3.6) 33,8 9 (6.8) 31,7 358S Hemorrhagic Complications (Levine et al)

8 and in experimental animals.5.5 Heparin also increases vessel permeability to macromolecules in a doserelated manner. 56 Heparin can also produce thrombocytopenia, but this is rarely an important cause of bleeding. The risk of heparin-induced bleeding is influenced by the following four variables: the dose of heparin and the patient's anticoagulant response; the method of heparin administration; the patient's clinical condition; and the concomitant use of aspirin or thrombolytic agents. Risk of Bleeding Associated with Therapeutic Heparin Administration Venous Thromboembolisrn: The incidence of bleeding during heparin therapy has been reported from randomized trials which have compared continuous intravenous heparin with intermittent intravenous heparin 57.i; 2 and from trials which have compared intravenous heparin with subcutaneous heparin In these studies, the reported risk of major hemorrhage has varied from 1 to 33 percent (Table 9). The rates of major bleeding fron contemporary studies using heparin by continuous intravenous infusion or high dose subcutaneous injection are approximately 5 percent. Ischemic Coronary Syndromes: There have heen two trials in which patients with ischemic coronary artery disease were randomized to heparin or no heparin, one trial in which heparin was compared to aspirin, 611 and one trial in which high dose heparin was compared with a lower dose ofheparin. 7 Theroux et al 611 randomized 479 patients with unstable angina to either aspirin, heparin (5, U intravenous bolus followed by a continuous infusion of 1, U/h), aspirin plus heparin, or placebo. Coronary angiography was performed on the fourth day. There was a trend toward increased minor bleeding in patients who received heparin, especially at angiogram catheter-insertion sites, but this did not reach statistical significance. Two of 118 patients who received aspirin had major bleeding compared to 2 of 118 placebo patients. In the trial reported by Serneri et al, patients with unstable angina were randomized to either a heparin bolus of 5, U followed by a continuous infusion of 1, U/h, a heparin bolus of 6, U intravenously every 6 h, or aspirin. No bleeds were detected in any of the treatment groups, but the trial lacked sufficient power to detect a clinically important difference in bleeding between groups. Turpie et al 7 randomized 221 patients with acute myocardial infarction to either heparin, 12,5 U subcutaneously twice daily, or heparin, 5, U subcutaneously twice daily. Treatment lasted for a minimum of ten days. No statistically significant difference in bleeding was detected between treatment groups; there were six bleeds in the high dose heparin group compared to four bleeds in the low dose group. Thus, heparin administered alone in patients with coronary artery disease (without concurrent thrombolytic therapy) is not associated with an increased risk of major bleeding. The role of heparin as adjunctive therapy for coronary thrombolysis has been evaluated in a number of trials In the SCATI study, patients with myocardial infarction were randomized to either heparin, 2, U by intravenous bolus followed by 12,5 U subcutaneously twice daily, or no heparin. Most patients also received concurrent streptokinase. The rate of bleeding was 4.4 percent in the heparin group compared to.6 percent in the control group. This difference was statistically significant. Howe, er, all bleeds occurred in patients who received streptokinase. In the GISSI-2 study, over 12, patients with myocardial infarction were randomized to either streptokinase plus heparin (12,5 U subcutaneo11sly twice daily starting 12 h postlytic therapy), rtpa plus the same dose of heparin, streptokinase alone, or rtpa alone. 72 The number of patients who received heparin was 6, 175 compared to 6,26 who did not receive heparin. There was no difference detected in hemorrhagic strokes between patients who received and did not receive heparin. However, three were more major bleeds in the heparin-treated patients compared to the non-heparin-treated patients, respectively, and more minor bleeds in heparin-treated patients, , respectively. When the results of the GISSI centers and international centers were combined, no difference was detected in hemorrhagic strokes between heparin-treated and non-heparin-treated groups, but there was increased major bleeding in heparin-treated patients, 1 percent.5 percent. Bleich et al 74 randomized 83 patients with myocardial infarction to rtpa plus heparin (5, U bolus plus 1, U/h) or rtpa alone. Twelve percent of the heparin-treated patients experienced moderate or severe bleeding compared to only 2 percent of control patients. Topol et al7 5 randomized 134 patients with myocardial infarction to rtpa plus an immediate intravenous heparin bolus of 1, U or rtpa alone. Coronary angiography was performed at 6 to 9 min. Postangiography, patients in both treatment groups were treated with a continuous heparin infusion of 5 to 1, U/h. No difference was detected in bleeding between groups, 13 percent 18 percent, respectively. In a trial reported by Hsia et al, patients with myocardial infarction were randomized to either rtpa plus an intravenous heparin bolus of 5, U followed by an infusion of 1, U/h or rtpa plus aspirin. There were 18 bleeds in the heparin group compared to 15 CHEST I 12 I 4 I OCTOBER I Supplement 359$

9 in the aspirin group. This difference was not statistically significant. Thus, the addition of heparin to lytic therapy increases the risk of bleeding. However, there was not an increased risk of fatal hemorrhage. 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 dependent variables (dose and laboratory response) on hemorrhagic rates. There have been no randomized trials in patients with established venous thromboembolism directly comparing different doses of heparin, but if hemorrhagic rates are correlated with the 24-h dose of heparin (from the studies in Tuble 9), a significant relationship is observed between heparin dose and bleeding (correlation coefficient is.56). 17 In a study 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 to heparin, 5, U twice daily (level I). 78 The mean dose of heparin for the adjusted-dose regimen was 13,2 U twice daily. Bleeding occurred in seven adjusted-dose patients compared to none in the fixeddose 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. In the U rokinase Pulmonary Embolism Study, 79 bleeding occurred in 2 percent of the 3 patients whose whole blood clotting time was greater than 6 min, but in only 5 percent of the 19 patients whose whole blood clotting was less than 6 min (relative risk 4.) (level 3). Norman and Provan 8 reported 5 major bleeding episodes in ten patients whose APTT was prolonged to more than twice the upper limit of their therapeutic range for at least 5 percent of their assays, but in only 1 of 4 patients whose APTT remained in the therapeutic range (relative risk 2.) (level 4). Wilson and Lampman 81 described 8 nonsurgical patients receiving heparin monitored by the whole blood clotting time. Ten of 18 patients (56 percent) who received "excessive heparin" (defined by a greatly prolonged whole blood clotting time) bled, whereas bleeding occurred in only 16 percent of the patients who did not receive "excessive heparin" (relative risk 3.5) (level 4). Thus, although none of the studies was designed to compare the effects on bleeding of either different doses of heparin or different levels of heparin re- 38S sponse, 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. 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 intravenous infusion or intermittent intravenous injection, and five randomized trials in which heparin was either administered by continuous infusion or twice daily subcutaneous injection63-67 (Table 9). Meta-analysis of studies comparing continuous with intermittent intravenous heparin showed an average incidence of major bleeding of 6.8 percent in the continuous infusion group and 14.2 percent in the intermittent heparin group, an odds ratio of.4 (p=.1). Patients randomized to receive heparin by intermittent injection received a higher dose of heparin than those allocated to the continuous intravenous group. Therefore, the difference in bleeding between methods could be explained by differences in dose. A meta-analysis of the studies comparing continuous intravenous heparin with subcutaneous heparin revealed an incidence of bleeding of 4.4 percent and 4.3 percent, respectively, an odds ratio of 1.. Relationship Between the Risk of Bleeding and Itztient Risk Factors There is good evidence that comorbid conditions, particularly recent surgery or trauma, are very important risk factors for heparin-induced bleeding This association was demonstrated in the recent study by Hull and associates 82 in patients with proximal vein thrombosis. Patients without clinical risk factors for bleeding were treated with a starting dose of 4, U of heparin by continuous infusion, while those with well recognized risk factors for bleeding (recent surgery, trauma) received a starting dose of 3, U. Bleeding occurred in 1 of 88 patients (1 percent) who received 4, U and 12of111 patients (11 percent) who received 3, U. The concomitant use of aspirin was identified as a risk factor in early retrospective studies. 83 The association of aspirin ingestion with heparin-induced bleeding was confirmed by Sethi and associates 84 in their study in patients undergoing aortocoronary bypass surgery. In this study, the preoperative use of aspirin caused excessive operative bleeding in patients Hemonhaglc Complicatlol is (Levine et el)

10 who received 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 and is acceptable in patients with ischemic heart disease. Renal failure and patient gender have also been implicated as risk factors for heparin-induced bleeding The reported association with female gender has not been consistent among studies and remains in question. Other studies have reported that older patients had a higher risk of bleeding Risk of Bleeding Associated with Prophylactic Low Dose Subcutaneous Heparin Low dose heparin is an effective form of prophylaxis for venous thrombosis in surgical and medical patients. In evaluating the hemorrhagic risk of prophylactic heparin in surgical patients, it is particularly important to ensure that heparin is compared with a placebo control group (because surgery alone causes bleeding) to avoid potential bias in the assessment of bleeding. Collins et al 87 conducted an overview analysis of randomized trials of prophylactic subcutaneous heparin of 25 trials of heparin prophylaxis in patients undergoing thoracic, abdominal, or pelvic surgery. In many studies, reporting of bleeding was incomplete and inadequate. Heparin administration was associated with an increased risk of minor bleeding; an absolute increase of2 percent. There was no evidence of increased fatal bleeding with heparin. The risk of bleeding did not appear to depend on whether the heparin was administered at 8-hourly or 12-hourly intervals. Claggett and Reisch 88 also conducted an overview analysis of randomized trials of heparin prophylaxis in general surgery patients. Twenty-one trials were analyzed, four of which were double-blind. The overall incidence of major hemorrhage was identical (.33 percent) among heparin-treated and control patients. In the double-blind studies, the incidence of hemorrhage was 1.8 percent in heparin-treated patients and.8 percent in control patients. This difference was not statistically significant. However, there was a statistically significant difference in wound hematomas between groups, 6.3 percent for heparin patients compared to 4.1 percent in control patients. There have been four double-blind placebo control randomized trials evaluating heparin prophylaxis in patients undergoing surgery for fractured hip in which a total of 189 patients received heparin and 182 patients received placebo There were no fatal bleeds, and no difference was detected in postoperative wound hematoma, transfusion requirements, and postoperative hemoglobin drop between treatment groups. There have been three double-blind randomized control trials in patients undergoing surgery for elective hip replacement There was no statistically significant difference in major bleeds (level 2), but in two out of three studies, there was a significant increase in hemoglobin fall or transfusion requirement. Thus, there is no evidence that heparin prophylaxis leads to excessive, fatal, or major bleeding in hip surgery, although there is a suggestion that minor bleeding and total blood loss (measured by hemoglobin fall or transfusion requirement) is increased by heparin prophylaxis. RECOMMENDATIONS Bleeding is the major complication of anticoagulant therapy. Reporting of bleeding varied considerably between studies. Since the last review, new information on bleeding rates is available, particularly in patients receiving oral anticoagulants for atrial fibrillation and mechanical heart valves. The major determinants of oral anticoagulant-induced bleeding an! the intensity of the anticoagulant effect, underlying patient characteristics, the use of drugs which interfere with hemostasis, and the length of therapy. There is good evidence that lower intensity oral anticoagulant therapy, targeted INR 2. to 3., is associated with a lower risk of bleeding. In terms of treatment decisionmaking for anticoagulant therapy, bleeding risk cannot be considered alone, ie, the potential decrease in thrombosis must be balanced against the potential increased bleeding risk. The risk of bleeding associated with intravenous heparin in patients with acute venous thromboembolism is approximately 5 percent. There is some evidence to suggest that this bleeding risk increases with the heparin dose. Heparin administered alone in patients with coronary artery disease is not associated with an increased bleeding risk, but when given in association with thrombolytic.therapy, the risk of minor bleeding is increased. The risk of bleeding with prophylactic low dose subcutaneous heparin is not increased in patients undergoing general surgery, hut there is an increased risk of minor bleeding at the operative site in patients undergoing orthopedic surgery who receive low dose heparin prophylaxis. REFERENCES 1 Levine MN, Raskob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest 1986; 89(suppl):l Levine MN, Raskob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest 1989; 95{suppl): 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; 37: Turpie AGG, Gunstensen J, Hirsh J, et al. 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Prevention of venous thrornboernbolism in general surgical patients. Ann Surg 1988; 28:227-4 CHEST I 12 I 4 I OCTOBER, 1992 I Supplement 363S