This paper is only available as a PDF. To read, Please Download here.
Abstract
objective: To review (1) the clinical epidemiology of bleeding during anticoagulant therapy
with heparin or warfarin, (2) data useful in estimating the risk for bleeding in individual
patients, and (3) the efficacy of methods for its prevention.
methods: Relevant literature was identified by a computerized search of the Medline database
and by review of the bibliographies of original and review articles. Studies were
classified according to their design. Estimates of the risk for bleeding during anticoagulant
therapy, compared with the risk without therapy, were obtained from randomized trials.
Estimates of the frequency of bleeding during the course of anticoagulant therapy
and information about risk factors for bleeding were obtained primarily from longitudinal
studies of inception cohorts of patients followed from the start of therapy.
main results: The average daily frequencies of fatal, major, and major or minor bleeding during
heparin therapy were 0.05%, 0.8%, and 2.0%, respectively; these frequencies are approximately
twice those expected without heparin therapy. The average annual frequencies of fatal,
major, and major or minor bleeding during warfarin therapy were 0.6%, 3.0%, and 9.6%,
respectively; these frequencies are approximately five times those expected without
warfarin therapy. The risk for anticoagulant-related bleeding is highest at the start
of therapy: during warfarin therapy, the risk for major bleeding during the first
month of therapy is approximately 10 times the risk after the first year of therapy.
An individual patient's risk for major anticoagulant-related bleeding can be estimated
on the basis of specific risk factors such as the intensity of the anticoagulant effect
achieved and the presence of serious comorbid diseases, especially cerebrovascular,
kidney, heart, and liver disease; older age and concurrent medicines may also be independent
risk factors. Major bleeding most often affects the gastrointestinal tract, soft tissues,
and urinary tract. Diagnostic evaluation of gastrointestinal bleeding and gross hematuria
leads to identification of previously unknown lesions in approximately one-third of
cases, even when the prothrombin time is elevated. Intracranial bleeding is rare,
but it is frequently fatal. The frequency of bleeding during warfarin therapy is reduced
by less intense therapy achieving a prothrombin time with an International Normalized
Ratio of 2.0 to 3.0, which is efficacious for most indications.
conclusion: Anticoagulant-related bleeding is common and often serious. The risk for bleeding
can be estimated in an individual patient, giving the primary physician a quantitative
basis for weighing the risks and benefits of therapy and for optimizing patient management.
The frequency of anticoagulant-related bleeding is reduced by less intense warfarin
therapy. Future studies should evaluate new approaches to management that may further
reduce complications while maintaining efficacy.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The American Journal of MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Placebocontrolled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation.Lancet. 1989; 1: 175-179
- Stroke prevention in atrial fibrillation study: final results.Circulation. 1991; 84: 527-539
- The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.N Engl J Med. 1990; 323: 1505-1511
- Canadian Atrial Fibrillation Anticoagulation (CAFA) Study.J Am Coll Cardiol. 1991; 18: 349-355
- The effect of warfarin on mortality and reinfarction after myocardial infarction.N Engl J Med. 1990; 323: 147-152
- Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery.BMJ. 1987; 295: 1309-1312
- Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery.N Engl J Med. 1988; 318: 1162-1173
- Rules of evidence and clinical recommendations on the use of antithrombotic agents.Chest. 1989; 95: 2S-4S
- Hemorrhagic complications of long-term anticoagulant therapy.Chest. 1989; 95 (Suppl): 26S-36S
- The bleeding severity index: validation and comparison to other methods for classifying bleeding complications of medical therapy.J Clin Epidemiol. 1989; 42: 711-718
- The impact of long-term warfarin therapy on quality of life: evidence from a randomized trial.Arch Intern Med. 1991; 151: 1944-1949
- Optimal therapeutic range for oral anticoagulant therapy.Chest. 1989; 95 (Suppl): 5S-11S
- Reliance on prothrombin time ratios causes significant errors in anticoagulation therapy.Arch Intern Med. 1992; 152: 278-282
- “Therapeutic range” for oral anticoagulant therapy.Chest. 1986; 89: 11S-15S
- Aspirin, heparin, or both to treat acute unstable angina.N Engl J Med. 1988; 319: 1105-1111
- Prediction of bleeding during heparin therapy.JAMA. 1980; 244: 1209-1212
- Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy.Am J Med. 1987; 82: 703-713
- Hemorrhagic complications of anticoagulant therapy.Arch Intern Med. 1974; 133: 386-392
- Long-term anticoagulant therapy after myocardial infarction.Lancet. 1962; 2: 626-630
- A double-blind trial of long-term anticoagulant treatment after myocardial infarction.Acta Med Scand. 1967; 182: 549-566
- An evaluation of anticoagulant therapy in the treatment of cerebrovascular disease: report of the Veterans Administration Cooperative Study of Atherosclerosis.Neurology. 1961; 11: 132-138
- Long-term anticoagulant therapy in patients with cerebral infarction.Acta Med Scand. 1965; 178 (Suppl): 7-55
- Anticoagulant therapy: five years experience with the patient with an established cerebrovascular accident.Arch Neurol. 1963; 8: 209-214
- Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves.J Thorac Cardiovasc Surg. 1976; 72: 127-129
- Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement.Lancet. 1988; 1: 1242-1245
- Trial of different intensities of anticoagulation in patients with prosthetic heart valves.N Engl J Med. 1990; 322: 428-432
- Therapeutic level in long-term anticoagulant therapy after myocardial infarction: its relation to recurrent infarction and sudden death.Am J Cardiol. 1963; 1: 158-163
- Double blind trial of long-term anticoagulant treatment after myocardial infarction.Acta Med Scand. 1969; 186: 361-368
- Home prothrombin time monitoring after the initiation of warfarin therapy: a randomized, prospective study.Ann Intern Med. 1989; 111: 730-737
- Randomized prospective trial comparing the native prothrombin antigen with the prothrombin time for monitoring oral anticoagulant therapy.Blood. 1990; 75: 344-349
- Low-dose heparin therapy in the long-term management of venous thromboembolism.Am J Med. 1979; 67: 553-556
- Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.N Engl J Med. 1979; 301: 855-858
- Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis.N Engl J Med. 1982; 306: 189-194
- Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.N Engl J Med. 1982; 307: 1676-1681
- Heparin for five days as compared with ten days in the initial treatment of proximal venous thrombosis.N Engl J Med. 1990; 322: 1260-1264
- Duration of warfarin anticoagulant therapy and the probabilities of recurrent thromboembolism and hemorrhage.Am J Med. 1986; 81: 255-259
- Prothrombin time ratio and other factors associated with bleeding in patients treated with warfarin.J Clin Epidemiol. 1989; 42: 759-764
- 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: 1537-1541
- Hematological complications with the St. Jude valve and reduced-dose coumadin.Ann Thorac Surg. 1989; 48: 280-283
- An audit of anticoagulation and endocarditis prophylaxis after heart valve surgery.N Z Med J. 1991; 104: 85-88
- Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy.Am J Med. 1989; 87: 144-152
- The cause of bleeding during anticoagulant treatment.Acta Med Scand. 1965; 178: 129-131
- Subdural haematoma associated with long term oral anticoagulation.Br J Neurosurg. 1988; 2: 351-356
- Anticoagulant-related intracerebral hemorrhage.Neurology. 1985; 35: 943-948
- The risk of intracerebral hemorrhage during oral anticoagulant treatment: a population study.Ann Neurol. 1984; 16: 553-558
- Anticoagulationrelated intracranial extracerebral haemorrhage.J Neurol Neurosurg Psychiatry. 1989; 52: 829-837
- Intracerebral hematomas during anticoagulant treatment.Stroke. 1990; 21: 726-730
- Heparin in the treatment of thromboembolic stroke.Ann N Y Acad Sci. 1989; 556: 406-415
- Immediate anticoagulation of embolic stroke: a randomized trial.Stroke. 1983; 14: 668-676
- Risk of intracranial hemorrhage in glioma patients receiving anticoagulant therapy for venous thromboembolism.J Neurosurg. 1987; 66: 357-358
- Infective endocarditis.in: Braunwald E Heart disease. WB Saunders, Philadelphia1988: 1093-1134
- The use of anticoagulants in bacterial endocarditis.Postgrad Med J. 1974; 50: 312-313
- The significance of hemorrhage during the treatment of patients with coumarin anticoagulants.Acta Med Scand. 1958; 162: 1-62
- Determinants of the response to oral anticoagulant drugs in man.Pharmacol Rev. 1970; 22: 35-96
- Massive hemorrhage complicating age-related macular degeneration: clinicopathologic correlation and role of anticoagulants.Ophthalmology. 1986; 93: 1581-1592
- Massive intraocular hemorrhage associated with anticoagulation and age-related macular degeneration.Graefe's Arch Clin Exp Ophthalmol. 1988; 226: 59-64
- Anticoagulants and cataract surgery.J Cataract Refract Surg. 1988; 14: 569-571
- A bleeding risk index for estimating the probability of major bleeding in hospitalized patients starting anticoagulant therapy.Am J Med. 1990; 89: 569-578
- Haemorrhagic complications of heparin therapy.Lancet. 1977; 1: 1133-1134
- Experiences with long-term anticoagulant treatment.Lancet. 1959; 2: 489-491
- The performance of clinics for outpatient control of anticoagulation.J R Coll Physicians Lond. 1987; 21: 42-45
- Long-term anticoagulant therapy.JAMA. 1963; 186: 914-916
- A 7-year analysis of hemorrhage in patients in long-term anticoagulant treatment.Br Heart J. 1979; 42: 128-132
- Haemorrhagic and thromboembolic complications in patients with atrial fibrillation on anticoagulant prophylaxis.J Intern Med. 1989; 225: 137-142
- Anticoagulant therapy after acute myocardial infarction.JAMA. 1972; 222: 541-548
- Anticoagulants in acute myocardial infarction.JAMA. 1973; 225: 724-729
- Assessment of short term anticoagulant administration after cardiac infarction.BMJ. 1969; 1: 335-342
- Sodium heparin vs sodium warfarin in acute myocardial infarction.in: Conclusions based on study of 798 cases at 13 hospitals. 29th ed. JAMA. 189. 1964: 555-562
- Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism.Lancet. 1986; 2: 1294-1296
- Management of heparin therapy: controlled prospective trial.N Engl J Med. 1975; 292: 1046-1050
- Randomized prospective trial of continuous vs intermittent heparin therapy.JAMA. 1976; 236: 1365-1367
- Heparin therapy: a randomized prospective study.Am Heart J. 1979; 97: 155-158
- Heparin therapy in venous thromboembolism.Am J Med. 1981; 70: 808-816
- Heparin treatment of deep vein thrombosis: effects and complications after continuous or intermittent heparin administration.Acta Med Scand. 1981; 210: 357-361
- Heparin.N Engl J Med. 1991; 324: 1565-1574
- An objective study of alternative methods of heparin administration.Thromb Res. 1980; 18: 177-187
- Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomised trial.BMJ (Clin Res). 1987; 294: 1189-1192
- Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.N Engl J Med. 1986; 315: 1109-1114
- Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis.Ann Intern Med. 1987; 107: 441-445
- Subcutaneous sodium heparin versus intravenous sodium heparin in the treatment of deep vein thrombosis.in: Proceedings of the 6th International Meeting of the Danubian League Against Thrombosis and Haemorrhagic Disorders, Vienna, Austria, May 31 to June 31989: 389-393 (cited in Hommes DW, et al; see [101])
- Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis.in: A randomized clinical trial. 29th ed. Thromb Haemost. 64. 1990: 222-226
- Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis: a meta-analysis.Ann Intern Med. 1992; 116: 279-284
- Control of heparin therapy.BMJ. 1979; 4: 139-141
- A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time.N Engl J Med. 1972; 287: 324-327
- Heparin therapy for thromboembolic disorders: a prospective evaluation of 134 cases monitored by the activated coagulation time.JAMA. 1983; 250: 1413-1416
- Heparin therapy for deep venous thrombosis.Am J Surg. 1980; 140: 836-840
- Heparin assays and bleeding complications in treatment of deep venous thrombosis with particular reference to retroperitoneal bleeding.Thromb Haemost. 1985; 53: 278-281
- Control and complications of intermittent heparin therapy.Surg Gynecol Obstet. 1977; 145: 338-342
- Comparison of the native prothrombin antigen and the prothrombin time for monitoring oral anticoagulant therapy.Blood. 1984; 64: 445-451
- Hemorrhage during long-term anticoagulant drug therapy. Part I. Intracranial hemorrhage.Calif Med. 1966; 104: 6-10
- Efficacy and toxicity of heparin in relation to age and sex.N Engl J Med. 1968; 279: 284-286
- Complications of intravenous administration of heparin in elderly women.JAMA. 1970; 213: 1303-1306
- Risk of complications during intravenous heparin therapy.West J Med. 1982; 136: 189-197
- Risks of longterm oral anticoagulant therapy in elderly patients after myocardial infarction.Lancet. 1982; 1: 64-68
- Anticoagulant drugs in the elderly: the risks usually outweigh the benefits.BMJ. 1988; 2: 1261-1263
- Problems associated with long-term anticoagulant therapy.Circulation. 1962; 25: 311-317
- Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients.J Intern Med. 1991; 229: 351-355
- Management of anticoagulation in outpatients: experience with an anticoagulation service in a municipal hospital setting.Arch Intern Med. 1977; 137: 197-202
- Age-related risks of long-term oral anticoagulant therapy.Arch Intern Med. 1988; 148: 1733-1736
- Heparin therapy in thromboembolic disease.Lancet. 1966; 1: 621-623
- Use of bishydroxycoumarin (Dicumarol®) in the presence of impaired renal function.JAMA. 1952; 148: 839-841
- Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement.Am Heart J. 1980; 99: 746-751
- Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions.Am J Med. 1989; 87: 153-159
- Significance of occult gastrointestinal bleeding during anticoagulation therapy.Am J Med. 1987; 83: 269-272
- Gastrointestinal bleeding in patients receiving long-term anticoagulant therapy.Am J Med. 1988; 84: 683-690
- Management of oral anticoagulant therapy: experience with an anticoagulation clinic.Arch Intern Med. 1984; 144: 1966-1968
- Acute gastrointestinal bleeding in anticoagulated patients: a prospective evaluation.Am J Gastroenterol. 1989; 84: 10-12
- Clinical significance of hematuria in patients on anticoagulant therapy.J Urol. 1987; 137: 923-925
- Patient self-management of oral anticoagulation guided by capillary (fingerstick) whole blood prothrombin times.Arch Intern Med. 1989; 149: 2509-2511
- Guideline-based consultation to prevent anticoagulant-related bleeding: a randomized, controlled trial in a teaching hospital.Ann Intern Med. 1992; 116: 829-837
- Long term anticoagulation with low molecular weight heparin in outpatients with side effects on oral anticoagulants.Nouv Rev Fr Hematol. 1989; 31: 363-369
- Hemostatic effect of tranexamic acid mouthwash in anticoagulant-treated patients undergoing oral surgery.N Engl J Med. 1989; 320: 840-843
- Usefulness of heparin in initial management of patients with recent transient ischemic attacks.Arch Neurol. 1985; 42: 960-962
- Heparin therapy for recent transient focal cerebral ischemia.Mayo Clin Proc. 1987; 62: 1101-1106
- Anticoagulant therapy in cerebral infarction: report on cooperative study.Neurology. 1962; 12: 823-835
- Anticoagulant therapy in cerebral thrombosis and cerebral embolism.Neurology. 1961; 11: 119-131
- Secondary prevention of myocardial infarction: a comparison of acetylsalicylic acid, placebo and phenprocoumon.Haemostasis. 1980; 9: 325-344
- The effect of long-term treatment with dicumarol in myocardial infarction.Acta Med Scand. 1957; 158 (Suppl): 1-212
- Warfarin sodium in prevention of deep venous thrombosis and pulmonary embolism in patients with fractured neck of femur.Lancet. 1976; 2: 869-872
- Anticoagulant prophylaxis, thromboembolism and mortality in elderly patients with hip fractures.Acta Chin Scand. 1966; 131: 16-29
- Relation of hemorrhage and thrombosis to prothrombin during treatment with coumarin-type anticoagulation.N Engl J Med. 1958; 259: 266-271
- Complications of long-term anticoagulation.Ann Neurol. 1988; 23: 570-574
- Haemorrhagic and thromboembolic complications versus intensity of treatment of venous thromboembolism with oral anticoagulants.Acta Med Scand. 1988; 224: 425-430
- Cerebrovascular disease: trial of longterm anticoagulant therapy.BMJ. 1962; 2: 1003-1006
Article info
Publication history
Accepted:
January 5,
1993
Received:
July 29,
1992
Identification
Copyright
© 1993 Published by Elsevier Inc.
