Does Low Dose Oral Vitamin K Improve International Normalized Ratio (INR) Stability? - Full Text View

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Does Low Dose Oral Vitamin K Improve International Normalized Ratio (INR) Stability? (OVWAC VII)

This study is not yet open for participant recruitment.

Verified by St. Joseph's Healthcare, October 2009

First Received: October 5, 2009 No Changes Posted

Sponsor:	St. Joseph's Healthcare
Collaborators:	McMaster University University of Western Ontario, Canada
Information provided by:	St. Joseph's Healthcare
ClinicalTrials.gov Identifier:	NCT00990158

Purpose

Warfarin is highly effective for the prevention of both first and recurrent thrombotic events, however even minor excursions outside the reference INR range of 2.0 to 3.0 are associated with bleeding or thrombotic complications. The importance of maintaining the INR within the desired interval has led to the concept of "time in therapeutic range (TTR)" - the total proportion of time that the INR is between 2.0 and 3.0. The investigators propose a multicentre, double blind, randomized trial which will determine if 0.150 mg of oral vitamin K increases time in the therapeutic range for patients receiving warfarin.

Condition	Intervention	Phase
Coagulation Bleeding Thrombosis	Drug: Phytonadione (Vitamin K1) Drug: Placebo	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study
Official Title:	A Multicentre Study of Low Dose Oral Vitamin K for INR Control in Patients Receiving Warfarin

Resource links provided by NLM:

MedlinePlus related topics: Blood Thinners

Drug Information available for: Vitamin K1 Vitamin K Warfarin Phytonadione

U.S. FDA Resources

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

Primary Outcome Measures:

When compared with placebo does the addition of 150 micrograms of daily vitamin K to "usual warfarin therapy" improve anticoagulant control as measured by "time in the therapeutic range"? [ Time Frame: 7 Months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Does low dose Vitamin K (LDVK) increase the frequency of adverse clinical events, including thromboembolism and major and/or all bleeding? [ Time Frame: 7 Months ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	400
Study Start Date:	January 2010
Estimated Study Completion Date:	March 2012
Estimated Primary Completion Date:	January 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Low dose vitamin K + usual warfarin: Active Comparator Low dose oral vitamin K (0.150 mg orally once daily) + warfarin continuation with usual warfarin monitoring	Drug: Phytonadione (Vitamin K1) A daily dose of 150 micrograms of vitamin K medication given orally for a total of 7 months
Usual warfarin therapy + placebo: Placebo Comparator Patients continue usual warfarin and take one placebo per day	Drug: Placebo A daily dose of matching placebo medication given orally for a total of 7 months

Show Detailed Description

Eligibility

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

Criteria

Inclusion Criteria:

Warfarin therapy administered to a target INR of 2.0 to 3.0

Exclusion Criteria:

Out of range INR on day of screening - enrolment will only occur if the patient's INR on the day of screening is between 1.8 and 3.4 (inclusive) - if the INR is outside this range the patient will be re-screened when the INR is within this range.
Recent warfarin initiation - all patients must have received warfarin for a minimum of 3 months
Planned termination or extended temporary interruption of warfarin within 6 months or anticipated survival of less than 6 months
Known severe liver disease, known excess alcohol consumption , known malabsorption syndrome or inability to take oral medications
Use of medications known to interfere with warfarin and whose dose is likely to change over the course of the study (e.g. barbiturates, rifampin etc.)
Known allergy to vitamin K
Inability or unwillingness to follow study procedures or provide consent
Prior participation in this study, or participating in a competing study which may impact INR control

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00990158

Contacts

Contact: Mark A Crowther, MD	905 521 6024	crowthrm@mcmaster.ca
Contact: Luqi Wang, PhD	905 522 1155 ext 35948	wanglu@mcmaster.ca

Locations

Canada, Ontario
St. Joseph's Hospital
Hamilton, Ontario, Canada, L8N 4A6
London Health Sciences Centre
London, Ontario, Canada, N6A 4G5

Sponsors and Collaborators

St. Joseph's Healthcare

McMaster University

University of Western Ontario, Canada

Investigators

Principal Investigator:

Mark A Crowther, MD

McMaster University

More Information

Additional Information:

Oral Vitamin K for Warfarin Associated Coagulopathy study (OVWAC VI) This link exits the ClinicalTrials.gov site

A webinar describing results of our prior study may be found at this website This link exits the ClinicalTrials.gov site

Publications:

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G; American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):160S-198S.

Oake N, Jennings A, Forster AJ, Fergusson D, Doucette S, van Walraven C. Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. CMAJ. 2008 Jul 29;179(3):235-44. Review.

Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med. 2007 Jan 22;167(2):117-24. Review.

Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002 Jan 16;287(3):337-44.

Verhovsek M, Motlagh B, Crowther MA, Kennedy C, Dolovich L, Campbell G, Wang L, Papaioannou A. Quality of anticoagulation and use of warfarin-interacting medications in long-term care: a chart review. BMC Geriatr. 2008 Jul 3;8:13.

Schmitt L, Speckman J, Ansell J. Quality assessment of anticoagulation dose management: comparative evaluation of measures of time-in-therapeutic range. J Thromb Thrombolysis. 2003 Jun;15(3):213-6.

Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993 Mar 1;69(3):236-9.

Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004 Jul 3;329(7456):15-9.

Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007 Jul 9;167(13):1414-9.

Sconce EA, Avery PJ, Wynne HA, Kamali F. Vitamin K epoxide reductase complex subunit 1 (VKORC1 ) polymorphism influences the anticoagulation response subsequent to vitamin K intake: a pilot study. J Thromb Haemost. 2008 Jul;6(7):1226-8. Epub 2008 Jul 1. No abstract available.

Sconce E, Khan T, Mason J, Noble F, Wynne H, Kamali F. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb Haemost. 2005 May;93(5):872-5.

Khan T, Wynne H, Wood P, Torrance A, Hankey C, Avery P, Kesteven P, Kamali F. Dietary vitamin K influences intra-individual variability in anticoagulant response to warfarin. Br J Haematol. 2004 Feb;124(3):348-54.

Cushman M, Booth SL, Possidente CJ, Davidson KW, Sadowski JA, Bovill EG. The association of vitamin K status with warfarin sensitivity at the onset of treatment. Br J Haematol. 2001 Mar;112(3):572-7.

Reese AM, Farnett LE, Lyons RM, Patel B, Morgan L, Bussey HI. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy. 2005 Dec;25(12):1746-51.

Booth SL, Charnley JM, Sadowski JA, Saltzman E, Bovill EG, Cushman M. Dietary vitamin K1 and stability of oral anticoagulation: proposal of a diet with constant vitamin K1 content. Thromb Haemost. 1997 Mar;77(3):504-9. Review.

Bovill EG, Fung M, Cushman M. Vitamin K and oral anticoagulation: thought for food. Am J Med. 2004 May 15;116(10):711-3. No abstract available.

Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood. 2007 Mar 15;109(6):2419-23. Epub 2006 Nov 16.

Rombouts EK, Rosendaal FR, Van Der Meer FJ. Daily vitamin K supplementation improves anticoagulant stability. J Thromb Haemost. 2007 Oct;5(10):2043-8. Epub 2007 Jul 31.

de Assis MC, Rabelo ER, Avila CW, Polanczyk CA, Rohde LE. Improved Oral Anticoagulation After a Dietary Vitamin K-Guided Strategy: A Randomized Controlled Trial. Circulation 2009 Sep 22;120(12):1115-22.

Schurgers LJ, Shearer MJ, Hamulyák K, Stöcklin E, Vermeer C. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood. 2004 Nov 1;104(9):2682-9. Epub 2004 Jul 1.

Ford SK, Misita CP, Shilliday BB, Malone RM, Moore CG, Moll S. Prospective study of supplemental vitamin K therapy in patients on oral anticoagulants with unstable international normalized ratios. J Thromb Thrombolysis. 2007 Aug;24(1):23-7. Epub 2007 Feb 24.

Crowther MA, Ageno W, Garcia D, Wang L, Witt DM, Clark NP, et al. Effectiveness of low dose oral vitamin K for patients with elevated INR values: results of a randomized trial examining clinical outcomes. Journal of Thrombosis & Haemostasis 5[S2], PS 219. 2008.

Woods K, Douketis JD, Kathirgamanathan K, Yi Q, Crowther MA. Low-dose oral vitamin K to normalize the international normalized ratio prior to surgery in patients who require temporary interruption of warfarin. J Thromb Thrombolysis. 2007 Oct;24(2):93-7. Epub 2007 Mar 23.

Whitlock RP, Crowther MA, Warkentin TE, Blackall MH, Farrokhyar F, Teoh KH. Warfarin cessation before cardiopulmonary bypass: lessons learned from a randomized controlled trial of oral vitamin K. Ann Thorac Surg. 2007 Jul;84(1):103-8.

Crowther MA, Ageno W, Schnurr T, Manfredi E, Kinnon K, Garcia D, Douketis JD. Oral vitamin K produces a normal INR within 24 hours of its administration in most patients discontinuing warfarin. Haematologica. 2005 Jan;90(1):137-9.

Ageno W, Garcia D, Silingardi M, Galli M, Crowther M. A randomized trial comparing 1 mg of oral vitamin K with no treatment in the management of warfarin-associated coagulopathy in patients with mechanical heart valves. J Am Coll Cardiol. 2005 Aug 16;46(4):732-3. No abstract available.

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. Review.

Gunther KE, Conway G, Leibach L, Crowther MA. Low-dose oral vitamin K is safe and effective for outpatient management of patients with an INR>10. Thromb Res. 2004;113(3-4):205-9.

Crowther MA, Wilson S. Vitamin K for the treatment of asymptomatic coagulopathy associated with oral anticoagulant therapy. J Thromb Thrombolysis. 2003 Aug-Oct;16(1-2):69-72. Review.

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.

Crowther MA, McDonald E, Johnston M, Cook D. Vitamin K deficiency and D-dimer levels in the intensive care unit: a prospective cohort study. Blood Coagul Fibrinolysis. 2002 Jan;13(1):49-52.

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.

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.

Clark NP, Witt DM, Delate T, Trapp M, Garcia D, Ageno W, Hylek EM, Crowther MA; Warfarin-Associated Research Projects and Other Endeavors Consortium. Thromboembolic consequences of subtherapeutic anticoagulation in patients stabilized on warfarin therapy: the low INR study. Pharmacotherapy. 2008 Aug;28(8):960-7.

Carlquist JF, Horne BD, Muhlestein JB, Lappé DL, Whiting BM, Kolek MJ, Clarke JL, James BC, Anderson JL. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis. 2006 Dec;22(3):191-7.

Schulman S, Beyth RJ, Kearon C, Levine MN; American College of Chest Physicians. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):257S-298S.

Responsible Party:	St Joseph's Hospital and McMaster University ( Mark Crowther )
Study ID Numbers:	NA 6695
Study First Received:	October 5, 2009
Last Updated:	October 5, 2009
ClinicalTrials.gov Identifier:	NCT00990158 History of Changes
Health Authority:	Canada: Health Canada

Keywords provided by St. Joseph's Healthcare:

Vitamin K1 (phytonadione)
Randomized controlled trial
Warfarin
Coagulopathy
Time in therapeutic range

Bleeding
Thrombosis
VKORC1 and CYP2C9 genotypes
Time INR in therapeutic range

Additional relevant MeSH terms:

Coagulants
Molecular Mechanisms of Pharmacological Action
Growth Substances
Hematologic Agents
Physiological Effects of Drugs
Vascular Diseases
Vitamin K 1
Hemostatics
Thrombosis

Pharmacologic Actions
Embolism and Thrombosis
Fibrin Modulating Agents
Antifibrinolytic Agents
Therapeutic Uses
Vitamins
Vitamin K
Cardiovascular Diseases
Micronutrients

ClinicalTrials.gov processed this record on February 08, 2010