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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00990158
First Posted: October 6, 2009
Last Update Posted: May 21, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
McMaster University
University of Western Ontario, Canada
Information provided by (Responsible Party):
Mark Crowther, St. Joseph's Healthcare Hamilton
  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 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicentre Study of Low Dose Oral Vitamin K for INR Control in Patients Receiving Warfarin

Resource links provided by NLM:


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

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 ]

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 ]

Enrollment: 235
Study Start Date: July 2010
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Low dose vitamin K + usual warfarin
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
Placebo Comparator: Usual warfarin therapy + placebo
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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
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
Information from the National Library of Medicine

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): NCT00990158


Locations
Canada, Ontario
Hamilton Health Sciences Centre
Hamilton, Ontario, Canada, L8L 2X2
St. Joseph's Hospital
Hamilton, Ontario, Canada, L8N 4A6
London Health Sciences Centre
London, Ontario, Canada, N6A 4G5
University Health Network, Toronto General Hospital
Toronto, Ontario, Canada, M5G 2C4
Sponsors and Collaborators
St. Joseph's Healthcare Hamilton
McMaster University
University of Western Ontario, Canada
Investigators
Principal Investigator: Mark A Crowther, MD McMaster University
  More Information

Additional Information:
Publications:
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. 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. doi: 10.1378/chest.08-0670.
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. doi: 10.1503/cmaj.080171. 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. doi: 10.1186/1471-2318-8-13.
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. doi: 10.1111/j.1538-7836.2008.03003.x. Epub 2008 Jul 1.
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.
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, 3 p following 1122. doi: 10.1161/CIRCULATIONAHA.109.849208. Epub 2009 Sep 8.
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.
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. doi: 10.1592/phco.28.8.960.
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. 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. doi: 10.1378/chest.08-0674.
Proportion Difference Power / Sample Size Calculation. 8-7-2008.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Mark Crowther, Vice President, Research, St. Joseph's Healthcare Hamilton
ClinicalTrials.gov Identifier: NCT00990158     History of Changes
Other Study ID Numbers: NA 6695
First Submitted: October 5, 2009
First Posted: October 6, 2009
Last Update Posted: May 21, 2015
Last Verified: December 2013

Keywords provided by Mark Crowther, St. Joseph's Healthcare Hamilton:
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:
Hemorrhage
Thrombosis
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Vitamins
Vitamin K
Vitamin K 1
Warfarin
Micronutrients
Growth Substances
Physiological Effects of Drugs
Anticoagulants
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants


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