Oral Vitamin K for Warfarin Associated Coagulopathy
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| ClinicalTrials.gov Identifier: NCT00143715 |
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Recruitment Status :
Completed
First Posted : September 2, 2005
Last Update Posted : July 20, 2011
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Coagulation Bleeding Thrombosis | Drug: Phytonadione (Vitamin K1) | Phase 3 |
Show Detailed Description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 690 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Multicentre, Multinational Study of Oral Vitamin K for the Treatment of Warfarin Associated Coagulopathy |
| Study Start Date : | September 2004 |
| Actual Primary Completion Date : | October 2006 |
| Actual Study Completion Date : | January 2007 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: 1
Low dose oral vitamin K + warfarin cessation
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Drug: Phytonadione (Vitamin K1)
1.25 mg given orally |
| Placebo Comparator: 2 |
Drug: Phytonadione (Vitamin K1)
1.25 mg given orally |
- The primary outcome measure is "all clinically overt bleeding" [ Time Frame: 90 days ]
- Secondary outcome measures are "all adjudication-confirmed major hemorrhage", "all adjudication-confirmed thrombotic events", "changes in INR values" and "cost effectiveness" [ Time Frame: 90 days ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Currently receiving warfarin with a target INR of 2.0 to 3.5
- INR value > 4.49 and drawn within last 24 hrs
Exclusion Criteria:
- Elective discontinuation of warfarin
- Age < 18 years
- Life expectancy of less than 10 days
- Indication for the acute normalization of INR i.e. active major bleeding (bleeding into central nervous system, retroperitoneum or other critical area or any bleeding requiring transfusion), need for surgery, major non-orthopedic surgery within the last seven days, invasive diagnostic procedure, head injury or termination of warfarin
- Known Severe liver disease AST or ALT > 5 x normal, bilirubin > 50 umol/litre, known coagulopathy due to liver disease
- Recent (<1 month) history of major bleeding episode i.e. Hemorrhagic stroke, gastrointestinal bleed or other bleed requiring transfusion or admission to hospital
- Known bleeding disorder or thrombolytic therapy within 48 Hrs i.e. Hemophilia, disseminated intravascular coagulation
- Known allergy to vitamin K
- Inability to take oral medications
- Known significant thrombocytopenia i.e. Platelet count of < 50 x 10 9/litre
- Geographic inaccessibility/inability to have serial INR's performed
- Failure to obtain informed consent
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00143715
| United States, Colorado | |
| Kaiser Permanente of Colorado Clinical Pharmacy | |
| Westminster, Colorado, United States, 80234 | |
| United States, New Mexico | |
| University of New Mexico Health Sciences Center | |
| Albuquerque, New Mexico, United States, 87106 | |
| Canada, Nova Scotia | |
| Queen Elizabeth II Health Health Sciences | |
| Halifax, Nova Scotia, Canada, B3H 2Y9 | |
| Canada, Ontario | |
| Hamilton General Hospital | |
| Hamilton, Ontario, Canada, L8L 2X2 | |
| McMaster University | |
| Hamilton, Ontario, Canada, L8N 3Z5 | |
| St. Joseph's Hospital | |
| Hamilton, Ontario, Canada, L8N 4A6 | |
| Henderson Hospital | |
| Hamilton, Ontario, Canada, L8V 1C3 | |
| London Health Sciences Centre | |
| London, Ontario, Canada, N6A 4G5 | |
| The Ottawa Hospital Civic Campus | |
| Ottawa, Ontario, Canada, K1Y 4E9 | |
| Sunnybrook and Women's College Health Sciences Centre | |
| Toronto, Ontario, Canada, M4N 3M5 | |
| Canada, Quebec | |
| SMBD Jewish General Hospital | |
| Montreal, Quebec, Canada, H3T 1E2 | |
| Italy | |
| AOU Policlinico di Palermo | |
| Palermo, Italy, 90127 | |
| Medicina I^- Centro Emostasi E Trombosi -Arcispedale S. Maria Nuova, | |
| Reggio Emilia, Italy, 42100 | |
| Dept. Internal Medicine, University of Insubria | |
| Varese, Italy, 21100 | |
| Singapore | |
| Singapore General Hospital | |
| Singapore, Singapore, 169608 | |
| Principal Investigator: | Mark A Crowther, MD | McMaster University |
Additional Information:
Publications:
| Responsible Party: | Mark Crowther, St Joseph's Hospital and McMaster University |
| ClinicalTrials.gov Identifier: | NCT00143715 History of Changes |
| Other Study ID Numbers: |
MCT-66693 MCT-66693 |
| First Posted: | September 2, 2005 Key Record Dates |
| Last Update Posted: | July 20, 2011 |
| Last Verified: | July 2011 |
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Vitamin K1 (phytonadione) Randomized controlled trial Warfarin Coagulopathy |
Bleeding Thrombosis Warfarin associated coagulopathy defined as an INR of 4.5 and 10.0 (for entry into randomized tria) or greater than 10.0 (for entry into parallel cohort study Warfarin associated coagulopathy |
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Vitamins Vitamin K Vitamin K 1 Warfarin Thrombosis Hemostatic Disorders Blood Coagulation Disorders Hemorrhage Pathologic Processes Embolism and Thrombosis Vascular Diseases Cardiovascular Diseases |
Hematologic Diseases Hemorrhagic Disorders Micronutrients Nutrients Growth Substances Physiological Effects of Drugs Anticoagulants Antifibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action Hemostatics Coagulants |