Oral Vitamin K Versus Placebo to Correct Excessive Anticoagulation in Patients Receiving Warfarin

A Randomized Trial

  1. Mark A. Crowther, MD, MSc;
  2. Walter Ageno, MD;
  3. David Garcia, MD;
  4. Luqi Wang, PhD;
  5. Dan M. Witt, PharmD;
  6. Nathan P. Clark, PharmD;
  7. Mark D. Blostein, MD;
  8. Susan R. Kahn, MD, MSc;
  9. Sara K. Vesely, PhD;
  10. Sam Schulman, MD;
  11. Michael J. Kovacs, MD;
  12. Marc A. Rodger, MD, MSc;
  13. Phillip Wells, MD, MSc;
  14. David Anderson, MD, MSc;
  15. Jeffery Ginsberg, MD;
  16. Rita Selby, MD, MSc;
  17. Sergio Siragusa, MD;
  18. Mauro Silingardi, MD;
  19. Mary Beth Dowd, PharmD; and
  20. Clive Kearon, MD, PhD
  1. 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

    • Grant Support: By the Canadian Institutes of Health Research and the Italian Ministry of Universities.

    • Potential Financial Conflicts of Interest: Employment: L. Wang (McMaster University). Consultancies: M.A. Crowther (Anton Pharmaceuticals).

    • 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.

    • 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.

    • 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.

    • Dr. Ageno: Department of Internal Medicine, Universita Degli Studi Dell'Insubria-Varese, Via Speroni 5, Varese, Italy 21100.

    • Dr. Garcia: University of New Mexico, 5th Ambulatory Care Center, 2211 Lomas Boulevard NE, Albuquerque, NM 87131.

    • Dr. Wang: St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8S 2G9, Canada.

    • Drs. Witt, Clark, and Dowd: Kaiser Permanente Colorado Region, 280 Exempla Circle, Lafayette, CO 80026.

    • Dr. Blostein: McGill University, 3755 Côte Sainte-Catherine, Montreal, Quebec M3T 1E2, Canada.

    • Dr. Kahn: Jewish General Hospital 3755 Côte Sainte-Catherine, A-127, Montreal, Quebec H3T 1E2, Canada.

    • Dr. Vesely: The University of Oklahoma, Health Sciences Centre, P.O. Box 26901, Oklahoma City, OK 73126-0901.

    • Dr. Schulman: McMaster University, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

    • Dr. Kovacs: Hematology Division, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada.

    • Dr. Rodger: The Ottawa Hospital, 1812, Ebox 201, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.

    • Dr. Wells: The Ottawa Hospital, Civic Site, Suite F649, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.

    • Dr. Anderson: Dalhousie University, Halifax, Nova Scotia B3H 3J5, Canada.

    • Dr. Ginsberg: McMaster University, 1200 Main Street West, HSC 3X28, Hamilton, Ontario L8N 3Z5, Canada.

    • Dr. Selby: Sunnybrook Health Sciences Centre, Room 0675a, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.

    • Dr. Siragusa: Cattedra ed U.O. di Ematologia con trapianto, Azienda Ospedaliera Universitaria Policlinico P. Giaccone, via del Vespro 127, I-90127 Palermo, Italy.

    • Dr. Silingardi: Arcispedale S. Maria Nuova, Azienda Ospedaliera, Viale Risorgimento 80, 42100 Reggio Emilia, Italy.

    • Dr. Kearon: McMaster University, Henderson General Hospital, 711 Concession Street, 40 Wing, Ground Floor, Room 115, Hamilton, Ontario L8V 1C3, Canada.

    • Author Contributions: Conception and design: M.A. Crowther, W. Ageno, D. Garcia, S. Schulman, P. Wells, J. Ginsberg, R. Selby, C. Kearon.

    • 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.

    • Drafting of the article: M.A. Crowther, W. Ageno, D.M. Witt, N.P. Clark, P. Wells, D. Anderson.

    • 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.

    • 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.

    • 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.

    • Statistical expertise: M.A. Crowther, L. Wang, S.K. Vesely, M.A. Rodger.

    • Obtaining of funding: M.A. Crowther, W. Ageno, M.J. Kovacs, M.A. Rodger, P. Wells, R. Selby.

    • Administrative, technical, or logistic support: M.A. Crowther, D. Garcia, S.R. Kahn, M.B. Dowd.

    • Collection and assembly of data: M.A. Crowther, L. Wang, D.M. Witt, N.P. Clark, S. Siragusa, M.B. Dowd.

    • ClinicalTrials.gov registration number: NCT00143715.

    Responses to this article

    • Oral Vitamin-K for high INR: Did we really get the answer?
      • Mahmoud A Moawad and
      • Alan Brush, Ida Goreburg & Cheryl Warner
      Ann Intern Med published online October 26, 2009
    • Vitamin K for warfarin coagulopathy
      • Mark A Crowther and
      • David Garcia
      Ann Intern Med published online October 26, 2009
    • Letter In Response To Crowther Et Al., Annals Of Internal Medicine, 150, 2009, 293-300
      • Mark W Swaim and
      • B Gail Macik
      Ann Intern Med published online October 26, 2009
    • Let's Keep Our Eye on the Ball
      • Ayad Jindeel and
      • Harbor-UCLA Medical Center
      Ann Intern Med published online October 26, 2009
    • Vitamin K to correct excessive anticoagulation
      • P Dileep Kumar
      Ann Intern Med published online October 26, 2009
    • The clinical use of Vitamin K
      • Yu Han and
      • Liu Hong and Jianhua Qiu
      Ann Intern Med published online October 26, 2009
    • Vitamin K: to give or not to give?
      • Vittorio Pengo and
      • Gentian Denas, Seena Padayattil
      Ann Intern Med published online October 26, 2009
    • Oral Vitamin K: ACCP Guidelines still apply
      • Robert C Pendleton and
      • Sara Vazquez
      Ann Intern Med published online October 26, 2009
    • Oral Vitamin K Versus Placebo to Correct Excessive Anticoagulation in Patients Receiving Warfarin
      • Ahmad Kaako
      Ann Intern Med published online October 26, 2009

    Summary for Patients

    • Summaries for Patients:Is Vitamin K Helpful for People Who Have Taken Too Much Warfarin? Ann Intern Med March 3, 2009 150:I-25; doi:10.1059/0003-4819-150-5-200903030-00001
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