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Cited by 919Systemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis MechanismsVenous Thromboembolism Diagnosis and Management

A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome

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Crowther, Mark A., Ginsberg, Jeff S., Julian, Jim, Denburg, Judah, Hirsh, Jack, Douketis, James, Laskin, Carl, Fortin, Paul +11 more·2003·New England Journal of Medicine
DOI 10.1056/nejmoa035241
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Abstract

BACKGROUND: Many patients with the antiphospholipid antibody syndrome and recurrent thrombosis receive doses of warfarin adjusted to achieve an international normalized ratio (INR) of more than 3.0. However, there are no prospective data to support this approach to thromboprophylaxis. METHODS: We performed a randomized, double-blind trial in which patients with antiphospholipid antibodies and previous thrombosis were assigned to receive enough warfarin to achieve an INR of 2.0 to 3.0 (moderate intensity) or 3.1 to 4.0 (high intensity). Our objective was to show that high-intensity warfarin was more effective in preventing thrombosis than moderate-intensity warfarin. RESULTS: A total of 114 patients were enrolled in the study and followed for a mean of 2.7 years. Recurrent thrombosis occurred in 6 of 56 patients (10.7 percent) assigned to receive high-intensity warfarin and in 2 of 58 patients (3.4 percent) assigned to receive moderate-intensity warfarin (hazard ratio for the high-intensity group, 3.1; 95 percent confidence interval, 0.6 to 15.0). Major bleeding occurred in three patients assigned to receive high-intensity warfarin and four patients assigned to receive moderate-intensity warfarin (hazard ratio, 1.0; 95 percent confidence interval, 0.2 to 4.8). CONCLUSIONS: High-intensity warfarin was not superior to moderate-intensity warfarin for thromboprophylaxis in patients with antiphospholipid antibodies and previous thrombosis. The low rate of recurrent thrombosis among patients in whom the target INR was 2.0 to 3.0 suggests that moderate-intensity warfarin is appropriate for patients with the antiphospholipid antibody syndrome.

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  • In patients with antiphospholipid syndrome and first venous thrombosis, there is no additional benefit of a vitamin K antagonist target INR of 3-4 versus 2-3, based on an RCT and pooled data from five studies that included a majority with venous events.

    “Data from an RCT21 reporting exclusively on patients with venous events and pooled data from five studies that included a majority with venous events21–25 showed no additional benefit of a target INR of 3–4 vs INR of 2–3.”

    From EULAR recommendations for the management of antiphospholipid syndrome in adults (2019) · cites this paper as [21]

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  • In one trial that provided data specifically on patients with arterial thrombosis, there was no difference in recurrences between those treated to a target INR of 2-3 or INR of 3-4 but without statistical significance (HR 3.1 (0.3-30.0)), although the sample was small and achievement of a target INR of 3-4 was low.

    “In one trial that provided data specifically on patients with arterial thrombosis, there was no difference in recurrences between those treated to a target INR of 2–3 or INR of 3–4 but without statistical significance (HR 3.1 (0.3–30.0)), although the sample was small and the achievement of a target INR of 3–4 was low.21”

    From EULAR recommendations for the management of antiphospholipid syndrome in adults (2019) · cites this paper as [21]

  • Pooled data from two retrospective studies and two RCTs showed no statistically significant difference in thrombosis recurrences between vitamin K antagonist target INR 3-4 and INR 2-3 (relative risk 0.46 (0.06-3.52)).

    “Pooled data from two retrospective studies and two RCTs21–24 showed that there was no statistically significant difference in thrombosis recurrences between treatment with VKA with a target INR of 3–4 and treatment with INR of 2–3 (relative risk (RR) 0.46 (0.06–3.52)).”

    From EULAR recommendations for the management of antiphospholipid syndrome in adults (2019) · cites this paper as [21]

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Research works printed but not linked: 4

  1. Crowther MA, Ginsberg JS. Antiphos- pholipid antibody syndrome. In: Goldhaber SZ, Ridker PM, eds. Thrombosis and throm- boembolism. Vol. 44 of Fundamental and clinical cardiology. New York: Marcel Dek- ker, 2002:49-66.
  2. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GRV. The man- agement of thrombosis in the antiphospho- lipid-antibody syndrome. N Engl J Med 1995;332:993-7.
  3. Kearon C, Gent M, Hirsh J, et al. A com- parison of three months of anticoagulation with extended anticoagulation for a first ep- isode of idiopathic venous thromboembo- lism. N Engl J Med 1999;340:901-7. [
  4. Erra- tum, N Engl J Med 1999;341:298.]

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Authors
Crowther, M. A., Ginsberg, J. S., Julian, J., Denburg, J., Hirsh, J., Douketis, J., Laskin, C., Fortin, P., Anderson, D., Kearon, C., Clarke, A., Geerts, W., Forgie, M., Green, D., Costantini, L., Yacura, W., Wilson, S., Gent, M., & Kovacs, M. J.
Affiliations
  • McMaster University (CA)
  • University of Toronto (CA)
  • Dalhousie University (CA)
  • McGill University (CA)
  • University of Ottawa (CA)
  • Northwestern University (US)
  • Western University (CA)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2003-09-18
Volume
349
Issue
12
Pages
1133-1138
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa035241
OpenAlex
W2053081517
Cited by
919
References
10
Citations by year
2026: 8 · 2025: 21 · 2024: 31 · 2023: 24 · 2022: 23 · 2021: 32 · 2020: 34 · 2019: 37 · 2018: 38 · 2017: 28 · 2016: 37 · 2015: 42 · 2014: 35 · 2013: 34 · 2012: 47
FWCI
34.28
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Heart and Stroke Foundation of Canada
  • Arthritis Society
  • University of Toronto
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
Keywords
antiphospholipid syndrome, warfarin, recurrent thrombosis, thromboprophylaxis, international normalized ratio, anticoagulation intensity, major bleeding, antithrombotic therapy
MeSH terms
Adult, Aged, Aged, 80 and over, Anticoagulants, Double-Blind Method, Female, Follow-Up Studies, Hemorrhage, Humans, Male, Middle Aged, Myocardial Infarction, Pulmonary Embolism, Warfarin, Antiphospholipid Syndrome, Antibodies, Antiphospholipid, International Normalized Ratio, Venous Thrombosis, Stroke, Secondary Prevention

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