drugset / Trial / NCT00990158
Does Low Dose Oral Vitamin K Improve International Normalized Ratio (INR) Stability?
Phase 3
Completed
235 enrolled
St. Joseph's Healthcare Hamilton
McMaster University · collabUniversity of Western Ontario, Canada · collab
RandomizedParallel-groupQuadruple-blindTreatment
Summary
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.
Timeline
- Start
- 2010-07
- Primary completion
- 2014-04
- Completion
- 2014-04
Publications
- Background 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.
- Background 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.
- Background 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. doi: 10.1001/archinte.167.2.117.
- Background 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. doi: 10.1001/jama.287.3.337.
- Background 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.
- Background 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. doi: 10.1023/B:THRO.0000011377.78585.63.
- Background Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993 Mar 1;69(3):236-9.
- Background 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. doi: 10.1136/bmj.329.7456.15.
- Background 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. doi: 10.1001/archinte.167.13.1414.
- Background 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. No abstract available.
- Background 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. doi: 10.1160/TH04-12-0773.
- Background 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. doi: 10.1046/j.1365-2141.2003.04787.x.
- Background 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. doi: 10.1046/j.1365-2141.2001.02635.x.
- Background 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. doi: 10.1592/phco.2005.25.12.1746.
- Background 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.
- Background Bovill EG, Fung M, Cushman M. Vitamin K and oral anticoagulation: thought for food. Am J Med. 2004 May 15;116(10):711-3. doi: 10.1016/j.amjmed.2004.02.020. No abstract available.
- Background 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. doi: 10.1182/blood-2006-09-049262. Epub 2006 Nov 16.
- Background Rombouts EK, Rosendaal FR, Van Der Meer FJ. Daily vitamin K supplementation improves anticoagulant stability. J Thromb Haemost. 2007 Oct;5(10):2043-8. doi: 10.1111/j.1538-7836.2007.02715.x. Epub 2007 Jul 31.
- Background 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.
- Background Schurgers LJ, Shearer MJ, Hamulyak K, Stocklin 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. doi: 10.1182/blood-2004-04-1525. Epub 2004 Jul 1.
- Background 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. doi: 10.1007/s11239-007-0014-z. Epub 2007 Feb 24.
- Background 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.
- Background 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. doi: 10.1007/s11239-007-0022-z. Epub 2007 Mar 23.
- Background 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. doi: 10.1016/j.athoracsur.2007.03.014.
- Background 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.
- Background 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. doi: 10.1016/j.jacc.2005.05.022. No abstract available.
- Background 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.
- Background 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. doi: 10.1016/j.thromres.2004.03.004.
- Background 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. doi: 10.1023/B:THRO.0000014597.87575.e9.
- Background 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.
- Background 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. doi: 10.1097/00001721-200201000-00007.
- Background 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. doi: 10.1016/S0140-6736(00)03125-1.
- Background 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.
- Background 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.
- Background Carlquist JF, Horne BD, Muhlestein JB, Lappe 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. doi: 10.1007/s11239-006-9030-7.
- Background 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.
- Background Proportion Difference Power / Sample Size Calculation. 8-7-2008.
- Boonyawat K, Wang L, Lazo-Langner A, Kovacs MJ, Yeo E, Schnurr T, Schulman S, Crowther MA. The effect of low-dose oral vitamin K supplementation on INR stability in patients receiving warfarin. A randomised trial. Thromb Haemost. 2016 Aug 30;116(3):480-5. doi: 10.1160/TH16-04-0320. Epub 2016 Jun 23.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Comparator | Vitamin K | Unknown | 0.15 mg | Oral |