Oral Vitamin K for Warfarin Associated Coagulopathy

This study has been completed.
Sponsor:
Collaborator:
McMaster University
Information provided by:
St. Joseph's Healthcare Hamilton
ClinicalTrials.gov Identifier:
NCT00143715
First received: August 31, 2005
Last updated: July 19, 2011
Last verified: July 2011
  Purpose

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 Intervention Phase
Coagulation
Bleeding
Thrombosis
Drug: Phytonadione (Vitamin K1)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicentre, Multinational Study of Oral Vitamin K for the Treatment of Warfarin Associated Coagulopathy

Resource links provided by NLM:


Further study details as provided by St. Joseph's Healthcare Hamilton:

Primary Outcome Measures:
  • The primary outcome measure is "all clinically overt bleeding" [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Enrollment: 690
Study Start Date: September 2004
Study Completion Date: January 2007
Primary Completion Date: October 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Low dose oral vitamin K + warfarin cessation
Drug: Phytonadione (Vitamin K1)
1.25 mg given orally
Placebo Comparator: 2 Drug: Phytonadione (Vitamin K1)
1.25 mg given orally

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00143715

Locations
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
McMaster University
Hamilton, Ontario, Canada, L8N 3Z5
Hamilton General Hospital
Hamilton, Ontario, Canada, L8L 2X2
Henderson Hospital
Hamilton, Ontario, Canada, L8V 1C3
St. Joseph's Hospital
Hamilton, Ontario, Canada, L8N 4A6
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
Sponsors and Collaborators
St. Joseph's Healthcare Hamilton
McMaster University
Investigators
Principal Investigator: Mark A Crowther, MD McMaster University
  More Information

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
Study First Received: August 31, 2005
Last Updated: July 19, 2011
Health Authority: Canada: Health Canada

Keywords provided by St. Joseph's Healthcare Hamilton:
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

Additional relevant MeSH terms:
Blood Coagulation Disorders
Hemostatic Disorders
Hemorrhage
Thrombosis
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Hemorrhagic Disorders
Pathologic Processes
Embolism and Thrombosis
Vitamin K 1
Vitamin K
Vitamins
Warfarin
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants
Hematologic Agents
Therapeutic Uses
Anticoagulants

ClinicalTrials.gov processed this record on July 26, 2014