Oral Vitamin K for Warfarin Associated Coagulopathy

NCT00143715 | Completed Phase 3 DMC

• 1 other identifier: MCT-66693
• Study Type: interventional
• Target: 690
• Locations: 4 countries
• Sites: 15

Brief Summary

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.

Conditions

Coagulation; Bleeding; Thrombosis

Keywords

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

Outcome Measures

Primary Outcomes (1)

• The primary outcome measure is "all clinically overt bleeding"

  90 days

Secondary Outcomes (1)

• Secondary outcome measures are "all adjudication-confirmed major hemorrhage", "all adjudication-confirmed thrombotic events", "changes in INR values" and "cost effectiveness"

  90 days

Study Arms (2)

1

EXPERIMENTAL

Low dose oral vitamin K + warfarin cessation

Drug: Phytonadione (Vitamin K1)

2

PLACEBO COMPARATOR

Drug: Phytonadione (Vitamin K1)

Interventions

Phytonadione (Vitamin K1) DRUG

1.25 mg given orally

1; 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Currently receiving warfarin with a target INR of 2.0 to 3.5
• INR value \> 4.49 and drawn within last 24 hrs

You may not qualify if:

• 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

Sponsors & Collaborators

• St. Joseph's Healthcare Hamilton: lead
• McMaster University: collaborator

Study Sites (15)

Kaiser Permanente of Colorado Clinical Pharmacy

Westminster, Colorado, 80234, United States

Location

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, 87106, United States

Location

Queen Elizabeth II Health Health Sciences

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

Hamilton General Hospital

Hamilton, Ontario, L8L 2X2, Canada

Location

McMaster University

Hamilton, Ontario, L8N 3Z5, Canada

Location

St. Joseph's Hospital

Hamilton, Ontario, L8N 4A6, Canada

Location

Henderson Hospital

Hamilton, Ontario, L8V 1C3, Canada

Location

London Health Sciences Centre

London, Ontario, N6A 4G5, Canada

Location

The Ottawa Hospital Civic Campus

Ottawa, Ontario, K1Y 4E9, Canada

Location

Sunnybrook and Women's College Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

SMBD Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

AOU Policlinico di Palermo

Palermo, 90127, Italy

Location

Medicina I^- Centro Emostasi E Trombosi -Arcispedale S. Maria Nuova,

Reggio Emilia, 42100, Italy

Location

Dept. Internal Medicine, University of Insubria

Varese, 21100, Italy

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

Related Publications (22)

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• 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.

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• 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.

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  PMID: 10073841 BACKGROUND

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  PMID: 9657434 BACKGROUND

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  PMID: 11722425 BACKGROUND

• 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.

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• 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.

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  PMID: 10908494 BACKGROUND

MeSH Terms

Conditions

Thrombosis; Hemorrhage; Hemostatic Disorders

Interventions

Vitamin K 2

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Vitamin K; Naphthoquinones; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Phytol; Diterpenes; Terpenes; Quinones; Polycyclic Compounds

Study Officials

• Mark A Crowther, MD

  McMaster University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: August 31, 2005
• First Posted: September 2, 2005
• Study Start: September 1, 2004
• Primary Completion: October 1, 2006
• Study Completion: January 1, 2007
• Last Updated: July 20, 2011

Record last verified: 2011-07

Locations

US (2); IT (3); SG (1); CA (9)