Oral Vitamin K Versus Placebo to Correct Excessive Anticoagulation in Patients Receiving Warfarin
A Randomized Trial
- Mark A. Crowther, MD, MSc;
- Walter Ageno, MD;
- David Garcia, MD;
- Luqi Wang, PhD;
- Dan M. Witt, PharmD;
- Nathan P. Clark, PharmD;
- Mark D. Blostein, MD;
- Susan R. Kahn, MD, MSc;
- Sara K. Vesely, PhD;
- Sam Schulman, MD;
- Michael J. Kovacs, MD;
- Marc A. Rodger, MD, MSc;
- Phillip Wells, MD, MSc;
- David Anderson, MD, MSc;
- Jeffery Ginsberg, MD;
- Rita Selby, MD, MSc;
- Sergio Siragusa, MD;
- Mauro Silingardi, MD;
- Mary Beth Dowd, PharmD; and
- Clive Kearon, MD, PhD
- From McMaster University, Hamilton, Ontario, Canada; University of Insubria, Varese, Italy; University of New Mexico, Albuquerque, New Mexico; Kaiser Permanente, Denver, Colorado; McGill University, Montreal, Quebec, Canada; University of Western Ontario, London, Ontario, Canada; University of Ottawa, Ottawa, Ontario, Canada; Dalhousie University, Halifax, Nova Scotia, Canada; University of Toronto, Toronto, Ontario, Canada; University of Palermo, Palermo, Italy; Reggio Emilia Hospital, Reggio Emilia, Italy; and University of Oklahoma, Oklahoma City, Oklahoma.
Abstract
Background: Low-dose oral vitamin K decreases the international normalized ratio (INR) in overanticoagulated patients who receive warfarin therapy. Its effects on bleeding events are uncertain.
Objective: To see whether low-dose oral vitamin K reduces bleeding events over 90 days in patients with warfarin-associated coagulopathy.
Design: Multicenter, randomized, placebo-controlled trial. Randomization was computer-generated, and participants were allocated to trial groups by using sequentially numbered study drug containers. Patients, caregivers, and those who assessed outcomes were blinded to treatment assignment.
Setting: 14 anticoagulant therapy clinics in Canada, the United States, and Italy.
Patients: Nonbleeding patients with INR values of 4.5 to 10.0.
Intervention: Oral vitamin K, 1.25 mg (355 patients randomly assigned; 347 analyzed), or matching placebo (369 patients randomly assigned; 365 analyzed).
Measurements: Bleeding events (primary outcome), thromboembolism, and death (secondary outcomes).
Results: 56 patients (15.8%) in the vitamin K group and 60 patients (16.3%) in the placebo group had at least 1 bleeding complication (absolute difference, −0.5 percentage point [95% CI, −6.1 to 5.1 percentage points]); major bleeding events occurred in 9 patients (2.5%) in the vitamin K group and 4 patients (1.1%) in the placebo group (absolute difference, 1.5 percentage points [CI, −0.8 to 3.7 percentage points]). Thromboembolism occurred in 4 patients (1.1%) in the vitamin K group and 3 patients (0.8%) in the placebo group (absolute difference, 0.3 percentage point [CI, −1.4 to 2.0 percentage points]). Other adverse effects were not assessed. The day after treatment, the INR had decreased by a mean of 1.4 in the placebo group and 2.8 in the vitamin K group (P < 0.001).
Limitation: Patients who were actively bleeding were not included, and warfarin dosing after enrollment was not mandated or followed.
Conclusion: Low-dose oral vitamin K did not reduce bleeding in warfarin recipients with INRs of 4.5 to 10.0.
Funding: Canadian Institutes of Health Research and Italian Ministry of Universities and Research.
Article and Author Information
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Grant Support: By the Canadian Institutes of Health Research and the Italian Ministry of Universities.
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Potential Financial Conflicts of Interest: Employment: L. Wang (McMaster University). Consultancies: M.A. Crowther (Anton Pharmaceuticals).
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Reproducible Research Statement: Study protocol: Available from http://www.clinicaltrials.gov. Statistical code and data set: Available from Dr. Crowther (e-mail, crowthrm{at}mcmaster.ca) after approval by the steering committee.
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Requests for Single Reprints: Mark A. Crowther, MD, MSc, Division of Hematology and Thromboembolism, McMaster University Faculty of Health Sciences, Room L208, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada; e-mail, crowthrm{at}mcmaster.ca.
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Current Author Addresses: Dr. Crowther: Division of Hematology and Thromboembolism, McMaster University Faculty of Health Sciences, Room L208, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.
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Dr. Ageno: Department of Internal Medicine, Universita Degli Studi Dell'Insubria-Varese, Via Speroni 5, Varese, Italy 21100.
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Dr. Garcia: University of New Mexico, 5th Ambulatory Care Center, 2211 Lomas Boulevard NE, Albuquerque, NM 87131.
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Dr. Wang: St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8S 2G9, Canada.
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Drs. Witt, Clark, and Dowd: Kaiser Permanente Colorado Region, 280 Exempla Circle, Lafayette, CO 80026.
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Dr. Blostein: McGill University, 3755 Côte Sainte-Catherine, Montreal, Quebec M3T 1E2, Canada.
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Dr. Kahn: Jewish General Hospital 3755 Côte Sainte-Catherine, A-127, Montreal, Quebec H3T 1E2, Canada.
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Dr. Vesely: The University of Oklahoma, Health Sciences Centre, P.O. Box 26901, Oklahoma City, OK 73126-0901.
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Dr. Schulman: McMaster University, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
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Dr. Kovacs: Hematology Division, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada.
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Dr. Rodger: The Ottawa Hospital, 1812, Ebox 201, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.
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Dr. Wells: The Ottawa Hospital, Civic Site, Suite F649, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.
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Dr. Anderson: Dalhousie University, Halifax, Nova Scotia B3H 3J5, Canada.
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Dr. Ginsberg: McMaster University, 1200 Main Street West, HSC 3X28, Hamilton, Ontario L8N 3Z5, Canada.
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Dr. Selby: Sunnybrook Health Sciences Centre, Room 0675a, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
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Dr. Siragusa: Cattedra ed U.O. di Ematologia con trapianto, Azienda Ospedaliera Universitaria Policlinico P. Giaccone, via del Vespro 127, I-90127 Palermo, Italy.
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Dr. Silingardi: Arcispedale S. Maria Nuova, Azienda Ospedaliera, Viale Risorgimento 80, 42100 Reggio Emilia, Italy.
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Dr. Kearon: McMaster University, Henderson General Hospital, 711 Concession Street, 40 Wing, Ground Floor, Room 115, Hamilton, Ontario L8V 1C3, Canada.
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Author Contributions: Conception and design: M.A. Crowther, W. Ageno, D. Garcia, S. Schulman, P. Wells, J. Ginsberg, R. Selby, C. Kearon.
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Analysis and interpretation of the data: M.A. Crowther, W. Ageno, L. Wang, D.M. Witt, N.P. Clark, S.K. Vesely, S. Schulman, M.A. Rodger, D. Anderson.
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Drafting of the article: M.A. Crowther, W. Ageno, D.M. Witt, N.P. Clark, P. Wells, D. Anderson.
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Critical revision of the article for important intellectual content: M.A. Crowther, W. Ageno, D. Garcia, D.M. Witt, N.P. Clark, S.R. Kahn, S. Schulman, M.J. Kovacs, M.A. Rodger, P. Wells, D. Anderson, J. Ginsberg, R. Selby, S. Siragusa, C. Kearon.
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Final approval of the article: M.A. Crowther, W. Ageno, D. Garcia, M.D. Blostein, S.R. Kahn, S. Schulman, M.J. Kovacs, P. Wells, D. Anderson, J. Ginsberg, R. Selby, S. Siragusa, C. Kearon.
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Provision of study materials or patients: M.A. Crowther, W. Ageno, D. Garcia, D.M. Witt, N.P. Clark, M.D. Blostein, S.R. Kahn, S. Schulman, M.J. Kovacs, P. Wells, D. Anderson, J. Ginsberg, R. Selby, M. Silingardi, M.B. Dowd, C. Kearon.
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Statistical expertise: M.A. Crowther, L. Wang, S.K. Vesely, M.A. Rodger.
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Obtaining of funding: M.A. Crowther, W. Ageno, M.J. Kovacs, M.A. Rodger, P. Wells, R. Selby.
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Administrative, technical, or logistic support: M.A. Crowther, D. Garcia, S.R. Kahn, M.B. Dowd.
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Collection and assembly of data: M.A. Crowther, L. Wang, D.M. Witt, N.P. Clark, S. Siragusa, M.B. Dowd.
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ClinicalTrials.gov registration number: NCT00143715.
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