This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (381)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Social Bookmarking   What's this?

An Analysis of Risk Factors

Felix J. M. van der Meer, MD; Frits R. Rosendaal, MD, PhD; Jan P. Vandenbroucke, MD, PhD; Ernest Briët, MD, PhD

Arch Intern Med. 1993;153(13):1557-1562.

Abstract
Background
Insufficient data are available about the safety of oral anticoagulant therapy. The specialized organization of thrombosis services in the Netherlands can provide important information on the bleeding risk and various risk factors for bleeding in patients receiving oral anticoagulant therapy.

Methods
In a follow-up study over a 12-month period beginning in January 1988 on all patients treated by the Leiden Thrombosis Service, the frequency of bleeding complications was assessed. A Poisson regression model was used to assess the relative contribution to the bleeding risk of age, sex, target zone (intensity of anticoagulant effect aimed at), achieved intensity of anticoagulant therapy (International Normalized Ratio), and the type of coumarin derivative used.

Results
Six thousand eight hundred fourteen patients experienced 1003 bleeding complications (16.5 per 100 treatment-years), 162 of which were major bleeds (2.7 per 100 treatment-years). Bleeding increased significantly with age (32% increase for all bleeding, 46% for major bleeding for every 10-year increase in age in comparison with age <40 years). Women had more minor bleeding complications than men, whereas both sexes experienced major bleeding in an equal frequency. There was no influence of target zone, while every one-point increase in International Normalized Ratio gave 42% more major bleeding (54% more regarding all bleeding). Use of acenocoumarol resulted in fewer bleeds (26% less regarding all bleeding and 46% less regarding major bleeding) than use of phenprocoumon.

Conclusions
The risk of anticoagulant therapy in a routine, real-life situation is similar as in the setting of several well-organized clinical trials. The risk of bleeding complications rises significantly with age and with the achieved intensity of anticoagulation, and is dependent on the type of coumarin derivative that is used.

(Arch Intern Med. 1993;153:1557-1562)

Author Affiliations
From the Hemostasis and Thrombosis Research Center, Department of Hematology (Drs van der Meer, Rosendaal, and Briët), and the Department of Clinical Epidemiology (Drs Rosendaal and Vandenbroucke), University Hospital Leiden (the Netherlands).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Epidemiology of Subtherapeutic Anticoagulation in the United States
Rose et al.
Circ Cardiovasc Qual Outcomes 2009;2:591-597.
ABSTRACT | FULL TEXT  

Should Patient Characteristics Influence Target Anticoagulation Intensity for Stroke Prevention in Nonvalvular Atrial Fibrillation?: The ATRIA Study
Singer et al.
Circ Cardiovasc Qual Outcomes 2009;2:297-304.
ABSTRACT | FULL TEXT  

Evaluation of Effectiveness of a Computerized Notification System for Reporting Critical Values
Piva et al.
Am J Clin Pathol 2009;131:432-441.
ABSTRACT | FULL TEXT  

Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis
Oake et al.
CMAJ 2008;179:235-244.
ABSTRACT | FULL TEXT  

Pharmacology and Management of the Vitamin K Antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Ansell et al.
Chest 2008;133:160S-198S.
ABSTRACT | FULL TEXT  

Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Schulman et al.
Chest 2008;133:257S-298S.
ABSTRACT | FULL TEXT  

Antithrombotic Therapy in Atrial Fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Singer et al.
Chest 2008;133:546S-592S.
ABSTRACT | FULL TEXT  

CYP4F2 genetic variant alters required warfarin dose
Caldwell et al.
Blood 2008;111:4106-4112.
ABSTRACT | FULL TEXT  

Major Hemorrhage and Tolerability of Warfarin in the First Year of Therapy Among Elderly Patients With Atrial Fibrillation
Hylek et al.
Circulation 2007;115:2689-2696.
ABSTRACT | FULL TEXT  

Influence of decision aids on patient preferences for anticoagulant therapy: a randomized trial
Holbrook et al.
CMAJ 2007;176:1583-1587.
ABSTRACT | FULL TEXT  

Development of a contemporary bleeding risk model for elderly warfarin recipients.
Shireman et al.
Chest 2006;130:1390-1396.
ABSTRACT | FULL TEXT  

Postanalytical External Quality Assessment of Warfarin Monitoring in Primary Healthcare
Kristoffersen et al.
Clin. Chem. 2006;52:1871-1878.
ABSTRACT | FULL TEXT  

Antithrombotic treatment is strongly underused despite reducing overall mortality among high-risk elderly patients hospitalized with atrial fibrillation
Monte et al.
Eur Heart J 2006;27:2217-2223.
ABSTRACT | FULL TEXT  

Anticoagulation in patients with heart failure: who, when, and why?
Nair et al.
Eur Heart J Suppl 2006;8:E32-E38.
ABSTRACT | FULL TEXT  

Reducing warfarin medication interactions: an interrupted time series evaluation.
Feldstein et al.
Arch Intern Med 2006;166:1009-1015.
ABSTRACT | FULL TEXT  

Comparison of Bleeding in Patients With Nonvalvular Atrial Fibrillation Treated With Ximelagatran or Warfarin: Assessment of Incidence, Case-Fatality Rate, Time Course and Sites of Bleeding, and Risk Factors for Bleeding.
Douketis et al.
Arch Intern Med 2006;166:853-859.
ABSTRACT | FULL TEXT  

Early Postoperative Anticoagulation After Mechanical Valve Replacement: A Systematic Review
Kulik et al.
Ann. Thorac. Surg. 2006;81:770-781.
ABSTRACT | FULL TEXT  

The Belgian Improvement Study on Oral Anticoagulation Therapy: a randomized clinical trial
Claes et al.
Eur Heart J 2005;26:2159-2165.
ABSTRACT | FULL TEXT  

Recurrence Rate After a First Venous Thrombosis in Patients With Familial Thrombophilia
Vossen et al.
Arterioscler. Thromb. Vasc. Bio. 2005;25:1992-1997.
ABSTRACT | FULL TEXT  

Should a patient with primary intracerebral haemorrhage receive antiplatelet or anticoagulant therapy?
Wani et al.
BMJ 2005;331:439-442.
FULL TEXT  

Risks of Oral Anticoagulant Therapy With Increasing Age
Torn et al.
Arch Intern Med 2005;165:1527-1532.
ABSTRACT | FULL TEXT  

Warfarin Maintenance Dosing Patterns in Clinical Practice: Implications for Safer Anticoagulation in the Elderly Population
Garcia et al.
Chest 2005;127:2049-2056.
ABSTRACT | FULL TEXT  

Warfarin maintenance dosages in the very elderly
Singla and Morrill
Am J Health Syst Pharm 2005;62:1062-1066.
ABSTRACT | FULL TEXT  

A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin
D'Andrea et al.
Blood 2005;105:645-649.
ABSTRACT | FULL TEXT  

Advanced Age, Anticoagulation Intensity, and Risk for Intracranial Hemorrhage among Patients Taking Warfarin for Atrial Fibrillation
Fang et al.
ANN INTERN MED 2004;141:745-752.
ABSTRACT | FULL TEXT  

Warfarin reversal
Hanley
J. Clin. Pathol. 2004;57:1132-1139.
ABSTRACT | FULL TEXT  

Safety of Anticoagulation Therapy in Well-informed Older Patients
Kagansky et al.
Arch Intern Med 2004;164:2044-2050.
ABSTRACT | FULL TEXT  

The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Ansell et al.
Chest 2004;126:204S-233S.
ABSTRACT | FULL TEXT  

Hemorrhagic Complications of Anticoagulant Treatment: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Levine et al.
Chest 2004;126:287S-310S.
ABSTRACT | FULL TEXT  

Antithrombotic Therapy in Atrial Fibrillation: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Singer et al.
Chest 2004;126:429S-456S.
ABSTRACT | FULL TEXT  

Role of a Quantitative D-Dimer Assay in Determining the Need for CT Angiography of Acute Pulmonary Embolism
Abcarian et al.
Am. J. Roentgenol. 2004;182:1377-1381.
ABSTRACT | FULL TEXT  

Current Debates in Antiphospholipid Syndrome: The Acquired Antibody-Mediated Thrombophilia
Ozturk et al.
CLIN APPL THROMB HEMOST 2004;10:89-126.
ABSTRACT  

Lowering the Intensity of Oral Anticoagulant Therapy: Effects on the Risk of Hemorrhage and Thromboembolism
Torn et al.
Arch Intern Med 2004;164:668-673.
ABSTRACT | FULL TEXT  

Comparison of the Quality of Oral Anticoagulant Therapy Through Patient Self-management and Management by Specialized Anticoagulation Clinics in the Netherlands: A Randomized Clinical Trial
Gadisseur et al.
Arch Intern Med 2003;163:2639-2646.
ABSTRACT | FULL TEXT  

Effect of Intensity of Oral Anticoagulation on Stroke Severity and Mortality in Atrial Fibrillation
Hylek et al.
NEJM 2003;349:1019-1026.
ABSTRACT | FULL TEXT  

Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial
Wilson et al.
CMAJ 2003;169:293-298.
ABSTRACT | FULL TEXT  

Anticoagulant-Related Bleeding in Older Persons With Atrial Fibrillation: Physicians' Fears Often Unfounded
Man-Son-Hing and Laupacis
Arch Intern Med 2003;163:1580-1586.
ABSTRACT | FULL TEXT  

Diagnostic Strategies for Excluding Pulmonary Embolism in Clinical Outcome Studies: A Systematic Review
Kruip et al.
ANN INTERN MED 2003;138:941-951.
ABSTRACT | FULL TEXT  

Risk for Venous Thromboembolism in Carriers of the Factor V Leiden Mutation
Middeldorp et al.
ANN INTERN MED 2003;138:76-77.
FULL TEXT  

Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis
Prandoni et al.
Blood 2002;100:3484-3488.
ABSTRACT | FULL TEXT  

Association Between CYP2C9 Genetic Variants and Anticoagulation-Related Outcomes During Warfarin Therapy
Higashi et al.
JAMA 2002;287:1690-1698.
ABSTRACT | FULL TEXT  

Better anticoagulation control improves survival after valve replacement
Butchart et al.
J. Thorac. Cardiovasc. Surg. 2002;123:715-723.
ABSTRACT | FULL TEXT  

Balancing the Risks of Stroke and Upper Gastrointestinal Tract Bleeding in Older Patients With Atrial Fibrillation
Man-Son-Hing and Laupacis
Arch Intern Med 2002;162:541-550.
ABSTRACT | FULL TEXT  

Outcomes After Withholding Anticoagulation From Patients With Suspected Acute Pulmonary Embolism and Negative Computed Tomographic Findings: A Cohort Study
Swensen et al.
Mayo Clin Proc. 2002;77:130-138.
ABSTRACT  

Oral anticoagulation for cerebral ischemia of arterial origin: High initial bleeding risk
Torn, MD; et al.
Neurology 2001;57:1993-1999.
ABSTRACT | FULL TEXT  

Home management of anticoagulation
Voller et al.
Eur Heart J Suppl 2001;3:Q44-Q49.
ABSTRACT  

Prevalence and Quality of Warfarin Use for Patients With Atrial Fibrillation in the Long-term Care Setting
McCormick et al.
Arch Intern Med 2001;161:2458-2463.
ABSTRACT | FULL TEXT  

Evaluation of Risk Factors for Stroke/Embolism and of Complications Due to Anticoagulant Therapy in Atrial Fibrillation
Wehinger et al.
Stroke 2001;32:2246-2252.
ABSTRACT | FULL TEXT  

Prevention of post-discharge venous thromboembolism in patients with rheumatoid arthritis undergoing knee or hip arthroplasty: a continuing matter of debate
NURMOHAMED and DIJKMANS
Ann Rheum Dis 2001;60:905-907.
FULL TEXT  

Clinical Predictors of Prolonged Delay in Return of the International Normalized Ratio to within the Therapeutic Range after Excessive Anticoagulation with Warfarin
Hylek et al.
ANN INTERN MED 2001;135:393-400.
ABSTRACT | FULL TEXT  

A Prospective Study of Asymptomatic Carriers of the Factor V Leiden Mutation To Determine the Incidence of Venous Thromboembolism
Middeldorp et al.
ANN INTERN MED 2001;135:322-327.
ABSTRACT | FULL TEXT  

Anticoagulation in patients with thromboembolic disease
Tait
Thorax 2001;56:ii30-37.
FULL TEXT  

Vitamin K lowered the international normalised ratio into the therapeutic range in patients receiving warfarin
Schmitt
Evid. Based Med. 2001;6:115-115.
FULL TEXT  

Cost-effectiveness of screening and extended anticoagulation for carriers of both factor V Leiden and prothrombin G20210A
Marchetti et al.
QJM 2001;94:365-372.
ABSTRACT | FULL TEXT  

Strategies Incorporating Spiral CT for the Diagnosis of Acute Pulmonary Embolism : A Cost-effectiveness Analysis
Paterson and Schwartzman
Chest 2001;119:1791-1800.
ABSTRACT | FULL TEXT  

Thromboembolism in heart failure, old ideas and new challenges
Isnard and Komajda
Eur J Heart Fail 2001;3:265-269.
ABSTRACT | FULL TEXT  

Comparison of 3 and 6 Months of Oral Anticoagulant Therapy After a First Episode of Proximal Deep Vein Thrombosis or Pulmonary Embolism and Comparison of 6 and 12 Weeks of Therapy After Isolated Calf Deep Vein Thrombosis
Pinede et al.
Circulation 2001;103:2453-2460.
ABSTRACT | FULL TEXT  

Characteristics of patients with antiphospholipid syndrome with major bleeding after oral anticoagulant treatment
Castellino et al.
Ann Rheum Dis 2001;60:527-530.
ABSTRACT | FULL TEXT  

Lung Scintigraphy and Helical Computed Tomography for the Diagnosis of Pulmonary Embolism: A Meta-Analysis
van Beek et al.
CLIN APPL THROMB HEMOST 2001;7:87-92.
ABSTRACT  

Warfarin Therapy for an Octogenarian Who Has Atrial Fibrillation
Gage et al.
ANN INTERN MED 2001;134:465-474.
ABSTRACT | FULL TEXT  

How Safely and for How Long Can Warfarin Therapy Be Withheld in Prosthetic Heart Valve Patients Hospitalized With a Major Hemorrhage?
Ananthasubramaniam et al.
Chest 2001;119:478-484.
ABSTRACT | FULL TEXT  

Managing Oral Anticoagulant Therapy
Ansell et al.
Chest 2001;119 :22S-38S.
FULL TEXT  

Hemorrhagic Complications of Anticoagulant Treatment
Levine et al.
Chest 2001;119 :108S-121S.
FULL TEXT  

Antithrombotic Therapy in Atrial Fibrillation
Albers et al.
Chest 2001;119 :194S-206S.
FULL TEXT  

Antithrombotic Therapy in Patients With Mechanical and Biological Prosthetic Heart Valves
Stein et al.
Chest 2001;119 :220S-227S.
FULL TEXT  

Thromboembolism in heart failure: who should be treated?
Diet and Erdmann
Eur J Heart Fail 2000;2:355-363.
ABSTRACT | FULL TEXT  

A Multicomponent Intervention To Prevent Major Bleeding Complications in Older Patients Receiving Warfarin: A Randomized, Controlled Trial
Beyth et al.
ANN INTERN MED 2000;133:687-695.
ABSTRACT | FULL TEXT  

Incidence of Recurrent Thromboembolic and Bleeding Complications Among Patients With Venous Thromboembolism in Relation to Both Malignancy and Achieved International Normalized Ratio: A Retrospective Analysis
Hutten et al.
JCO 2000;18:3078-3083.
ABSTRACT | FULL TEXT  

Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment
Taube et al.
Blood 2000;96:1816-1819.
ABSTRACT | FULL TEXT  

Oral Anticoagulation Management in Primary Care With the Use of Computerized Decision Support and Near-Patient Testing: A Randomized, Controlled Trial
Fitzmaurice et al.
Arch Intern Med 2000;160:2343-2348.
ABSTRACT | FULL TEXT  

Analysis of risk factors involved in oral-anticoagulant-related intracranial haemorrhages
Berwaerts and Webster
QJM 2000;93:513-521.
ABSTRACT | FULL TEXT  

Prospective Study of the Outcomes of Ambulatory Patients With Excessive Warfarin Anticoagulation
Hylek et al.
Arch Intern Med 2000;160:1612-1617.
ABSTRACT | FULL TEXT  

Using anticoagulation or aspirin to prevent stroke
Ellis et al.
BMJ 2000;320:1008-1008.
FULL TEXT  

Advances in Therapy and the Management of Antithrombotic Drugs for Venous Thromboembolism
Ansell et al.
ASH Education Book 2000;2000:266-284.
ABSTRACT | FULL TEXT  

Time Course of Reversal of Anticoagulant Effect of Warfarin by Intravenous and Subcutaneous Phytonadione
Raj et al.
Arch Intern Med 1999;159:2721-2724.
ABSTRACT | FULL TEXT  

Are older patients with mechanical heart valves at increased risk?
Masters et al.
Ann. Thorac. Surg. 1999;68:2169-2172.
ABSTRACT | FULL TEXT  

Gene-Gene and Gene-Environment Interactions Determine Risk of Thrombosis in Families With Inherited Antithrombin Deficiency
van Boven et al.
Blood 1999;94:2590-2594.
ABSTRACT | FULL TEXT  

Risk of post-discharge venous thromboembolism in patients with rheumatoid arthritis undergoing knee or hip arthroplasty. Is prolonged thromboprophylaxis warranted or dangerous?
NURMOHAMED et al.
Ann Rheum Dis 1999;58:392-395.
FULL TEXT  

Choosing Antithrombotic Therapy for Elderly Patients With Atrial Fibrillation Who Are at Risk for Falls
Man-Son-Hing et al.
Arch Intern Med 1999;159:677-685.
ABSTRACT | FULL TEXT  

Prediction of the Risk of Bleeding During Anticoagulant Treatment for Venous Thromboembolism
Kuijer et al.
Arch Intern Med 1999;159:457-460.
ABSTRACT | FULL TEXT  

Fortnightly review: Anticoagulation in heart disease
Hardman and Cowie
BMJ 1999;318:238-244.
FULL TEXT  

Comparison of an Anticoagulation Clinic With Usual Medical Care: Anticoagulation Control, Patient Outcomes, and Health Care Costs
Chiquette et al.
Arch Intern Med 1998;158:1641-1647.
ABSTRACT | FULL TEXT  

Cost-Effectiveness of Preference-Based Antithrombotic Therapy for Patients With Nonvalvular Atrial Fibrillation
Gage et al.
Stroke 1998;29:1083-1091.
ABSTRACT | FULL TEXT  

Acetaminophen and Other Risk Factors for Excessive Warfarin Anticoagulation
Hylek et al.
JAMA 1998;279:657-662.
ABSTRACT | FULL TEXT  

The Clinical Course of Patients With Suspected Pulmonary Embolism
van Beek et al.
Arch Intern Med 1997;157:2593-2598.
ABSTRACT  

Biological variation of International Normalized Ratio for prothrombin times, and consequences in monitoring oral anticoagulant therapy: computer simulation of serial measurements with goal-setting for analytical quality
Kjeldsen et al.
Clin. Chem. 1997;43:2175-2182.
ABSTRACT | FULL TEXT  

Control of Warfarin Treatment and Problems with the International Normalized Ratio
Bussey and Chiquette
CLIN APPL THROMB HEMOST 1997;3:S16-S23.
 

Atrial Fibrillation and Stroke Prevention With Warfarin in the Long-term Care Setting
Gurwitz et al.
Arch Intern Med 1997;157:978-984.
ABSTRACT  

Mortality and Causes of Death in Families With the Factor V Leiden Mutation (Resistance to Activated Protein C)
Hille et al.
Blood 1997;89:1963-1967.
ABSTRACT | FULL TEXT  

Anticoagulation for Nonrheumatic Atrial Fibrillation
Hart et al.
NEJM 1997;336:441-442.
FULL TEXT  

Antiphospholipid antibody associated thrombosis: A consensus for treatment?
McCrae
Lupus 1996;5:560-570.
ABSTRACT  

Factor V Leiden: should we screen oral contraceptive users and pregnant women?
Vandenbroucke et al.
BMJ 1996;313:1127-1130.
FULL TEXT  

Capillary testing in an anticoagulant clinic: comparison of two methods
Donohue et al.
BMJ 1996;313:982-982.
FULL TEXT  

Case 22-1996- Cerebral Hemorrhage in a 69-Year-Old Woman Receiving Warfarin
Greenberg and Edgar
NEJM 1996;335:189-196.
FULL TEXT  

Bleeding During Antithrombotic Therapy in Patients With Atrial Fibrillation
The Stroke Prevention in Atrial Fibrillation Inves
Arch Intern Med 1996;156:409-416.
ABSTRACT  

Cost-effectiveness of Warfarin and Aspirin for Prophylaxis of Stroke in Patients With Nonvalvular Atrial Fibrillation
Gage et al.
JAMA 1995;274:1839-1845.
ABSTRACT  

Long-term Patient Self-management of Oral Anticoagulation
Ansell et al.
Arch Intern Med 1995;155:2185-2189.
ABSTRACT  

Oral Anticoagulants and Intracranial Hemorrhage : Facts and Hypotheses
Hart et al.
Stroke 1995;26:1471-1477.
ABSTRACT | FULL TEXT