Loading search results
A Multicentre, Multinational Study of Oral Vitamin K for the Treatment of Warfarin Associated Coagulopathy
Sponsor study identifier
Secondary identifiers
interventional
690
4 countries
15
Study Start
September 2004
Date type not reportedThis date has not been verified as actual or estimated.
Primary Completion
October 2006
Actual (reported)Study Completion
January 2007
Actual (reported)Excessive prolongation of the international normalized ratio (INR) occurs frequently in patients taking warfarin; in fact, about one in six INR values is above the desired range. Excessive prolongation of the INR is clinically important because the risk of bleeding approximately doubles for each one point increase in the INR beyond the usual therapeutic range. Thus, treatment strategies which rapidly and reliably lower an excessively prolonged INR into the desired range have the potential to reduce bleeding. When taken by patients with INR values between 4.5 and 10, a small dose of oral vitamin K (1 mg to 2.5mg) reduces the INR into the desired INR range in about 75% of cases within 24 hours of its administration. If warfarin is simply withheld, and no vitamin K is given, about 25% of patients will have an INR in the desired range at 24 hours. However, vitamin K is rarely given to such patients. In a recent survey carried out by our group, less than 20% of such patients would have been given low dose oral vitamin K by a group of physicians who regularly supervise warfarin therapy. The most common treatment for excessive prolongation of the INR is to simply withhold warfarin and allow the INR to fall into the therapeutic range. Although this strategy is effective its safety has never been adequately examined. In fact, recent evidence suggests that patients with INR values of more than 6.0 who are treated with simple warfarin withdrawal have a risk of major bleeding of 4% in the two weeks after they develop their prolonged INR. When asked why they did not give oral vitamin K to a non-bleeding patient who has an excessively prolonged INR, physicians generally give one of three reasons: (1)They are not convinced that oral vitamin K reduces bleeding. (2) They are concerned that oral vitamin K may cause thrombosis. (3) In contrast with simply withholding warfarin, giving oral vitamin K requires a patient to visit the physician, and the physician must have a supply of vitamin K. The investigators hypothesize that the routine practice of not administering oral vitamin K to patients with excessively prolonged INR values is causing patients to have major, life-threatening and fatal bleeds. To convince physicians that oral vitamin K should be administered to all non-bleeding patients with INR values of more than 4.5, the investigators propose a study which the investigators anticipate will demonstrate that oral vitamin K reduces bleeding, does not cause thrombosis, and can be administered at home without direct physician supervision. To accomplish these goals, the investigators propose a multinational, double-blind, placebo-controlled trial. The investigators will randomize patients with INR values between 4.5 and 10.0 to receive 1.25 mg of oral vitamin K or placebo and follow them for bleeding and thrombosis. Patients with INR values of more than 10.0 will receive a single 1.25 mg dose of oral vitamin K. Successful completion of this study will establish a treatment standard supported by clinical data which will, in turn, change the way that patients taking warfarin who present with an excessively prolonged INR are treated.
Registry-reported information. Elapsed time and enrollment totals alone do not measure study progress or recruitment pace.
January 2007
Actual (reported)Click on a node to explore related trials.
Dates and qualifiers reported by the registry. Estimated dates do not confirm that a milestone has occurred.
September 2004
Date type not reportedThis date has not been verified as actual or estimated.
August 31, 2005
Actual (reported)September 2, 2005
Actual (reported)October 2006
Actual (reported)January 2007
Actual (reported)The primary outcome measure is "all clinically overt bleeding"
90 days
Secondary outcome measures are "all adjudication-confirmed major hemorrhage", "all adjudication-confirmed thrombotic events", "changes in INR values" and "cost effectiveness"
90 days
Low dose oral vitamin K + warfarin cessation
Kaiser Permanente of Colorado Clinical Pharmacy
Westminster, Colorado, 80234, United States
University of New Mexico Health Sciences Center
Albuquerque, New Mexico, 87106, United States
Queen Elizabeth II Health Health Sciences
Halifax, Nova Scotia, B3H 2Y9, Canada
Hamilton General Hospital
Hamilton, Ontario, L8L 2X2, Canada
McMaster University
Hamilton, Ontario, L8N 3Z5, Canada
St. Joseph's Hospital
Hamilton, Ontario, L8N 4A6, Canada
Henderson Hospital
Hamilton, Ontario, L8V 1C3, Canada
Chan KB, Man-Son-Hing M, Molnar FJ, Laupacis A. How well is the clinical importance of study results reported? An assessment of randomized controlled trials. CMAJ. 2001 Oct 30;165(9):1197-202.
Man-Son-Hing M, Laupacis A, O'Rourke K, Molnar FJ, Mahon J, Chan KB, Wells G. Determination of the clinical importance of study results. J Gen Intern Med. 2002 Jun;17(6):469-76. doi: 10.1046/j.1525-1497.2002.11111.x.
Mark A Crowther, MD
McMaster University
690 participants (actual enrollment reported by the registry).
First Submitted
August 31, 2005
First Posted
September 2, 2005
Study Start
September 2004
Date type not reportedThis date has not been verified as actual or estimated.
Contact the study team to confirm eligibility.
London Health Sciences Centre
London, Ontario, N6A 4G5, Canada
The Ottawa Hospital Civic Campus
Ottawa, Ontario, K1Y 4E9, Canada
Sunnybrook and Women's College Health Sciences Centre
Toronto, Ontario, M4N 3M5, Canada
SMBD Jewish General Hospital
Montreal, Quebec, H3T 1E2, Canada
AOU Policlinico di Palermo
Palermo, 90127, Italy
Medicina I^- Centro Emostasi E Trombosi -Arcispedale S. Maria Nuova,
Reggio Emilia, 42100, Italy
Dept. Internal Medicine, University of Insubria
Varese, 21100, Italy
Singapore General Hospital
Singapore, 169608, Singapore
Anderson DR, O'Brien BJ, Levine MN, Roberts R, Wells PS, Hirsh J. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med. 1993 Dec 1;119(11):1105-12. doi: 10.7326/0003-4819-119-11-199312010-00008.
Lousberg TR, Witt DM, Beall DG, Carter BL, Malone DC. Evaluation of excessive anticoagulation in a group model health maintenance organization. Arch Intern Med. 1998 Mar 9;158(5):528-34. doi: 10.1001/archinte.158.5.528.
Libby EN, Garcia DA. A survey of oral vitamin K use by anticoagulation clinics. Arch Intern Med. 2002 Sep 9;162(16):1893-6. doi: 10.1001/archinte.162.16.1893.
Ageno W, Crowther M, Steidl L, Ultori C, Mera V, Dentali F, Squizzato A, Marchesi C, Venco A. Low dose oral vitamin K to reverse acenocoumarol-induced coagulopathy: a randomized controlled trial. Thromb Haemost. 2002 Jul;88(1):48-51.
Wilson SE, Watson HG, Crowther MA. Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review. CMAJ. 2004 Mar 2;170(5):821-4. doi: 10.1503/cmaj.1030478.
Raj G, Kumar R, McKinney WP. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med. 1999 Dec 13-27;159(22):2721-4. doi: 10.1001/archinte.159.22.2721.
Nee R, Doppenschmidt D, Donovan DJ, Andrews TC. Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation. Am J Cardiol. 1999 Jan 15;83(2):286-8, A6-7. doi: 10.1016/s0002-9149(98)00842-x.
Crowther MA, Julian J, McCarty D, Douketis J, Kovacs M, Biagoni L, Schnurr T, McGinnis J, Gent M, Hirsh J, Ginsberg J. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet. 2000 Nov 4;356(9241):1551-3. doi: 10.1016/S0140-6736(00)03125-1.
Crowther MA, Donovan D, Harrison L, McGinnis J, Ginsberg J. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost. 1998 Jun;79(6):1116-8.
Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol. 2001 Oct;115(1):145-9. doi: 10.1046/j.1365-2141.2001.03070.x.
Crowther MA, Douketis JD, Schnurr T, Steidl L, Mera V, Ultori C, Venco A, Ageno W. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Ann Intern Med. 2002 Aug 20;137(4):251-4. doi: 10.7326/0003-4819-137-4-200208200-00009.
Warkentin TE, Crowther MA. Reversing anticoagulants both old and new. Can J Anaesth. 2002 Jun-Jul;49(6):S11-25.
Hylek EM, Chang YC, Skates SJ, Hughes RA, Singer DE. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med. 2000 Jun 12;160(11):1612-7. doi: 10.1001/archinte.160.11.1612.
Landefeld CS, Rosenblatt MW, Goldman L. Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions. Am J Med. 1989 Aug;87(2):153-9. doi: 10.1016/s0002-9343(89)80690-4.
Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989 Aug;87(2):144-52. doi: 10.1016/s0002-9343(89)80689-8.
Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med. 1993 Sep;95(3):315-28. doi: 10.1016/0002-9343(93)90285-w.
Oden A, Fahlen M. Oral anticoagulation and risk of death: a medical record linkage study. BMJ. 2002 Nov 9;325(7372):1073-5. doi: 10.1136/bmj.325.7372.1073.
Hylek EM, Regan S, Go AS, Hughes RA, Singer DE, Skates SJ. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med. 2001 Sep 18;135(6):393-400. doi: 10.7326/0003-4819-135-6-200109180-00008.
Segal JB, McNamara RL, Miller MR, Powe NR, Goodman SN, Robinson KA, Bass EB. Anticoagulants or antiplatelet therapy for non-rheumatic atrial fibrillation and flutter. Cochrane Database Syst Rev. 2001;(1):CD001938. doi: 10.1002/14651858.CD001938.
Hutten BA, Prins MH. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Cochrane Database Syst Rev. 2000;(3):CD001367. doi: 10.1002/14651858.CD001367.
Primary Completion
October 2006
Actual (reported)Study Completion
January 2007
Actual (reported)Last Updated
July 20, 2011
Record last verified: 2011-07
Download the complete ClinicalTrials.gov record imported by Syfrah, including fields not shown in this page. The registry may contain a newer revision.
Source: ClinicalTrials.gov.
JSON downloads include source attribution and retrieval details alongside the unchanged original record or the separately normalized values.
Source retrieved: