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| ID | Type | Description | Link |
|---|---|---|---|
| HSM # 11-00577 |
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The purpose of this study is to determine the importance of genetic differences on individuals' response to warfarin in a group of healthy subjects. Warfarin is also known by the "trade name" Coumadin and is in a class of medications called anticoagulants or "blood thinners." Warfarin works by reducing the blood's ability to make clots. It is used to stop blood clots from forming or growing larger in your blood and blood vessels. Warfarin is prescribed for many conditions, including for people with certain types of irregular heartbeat, people with replacement or mechanical heart valves, people who have suffered a heart attack, people who have had orthopedic surgery, or who have a history of having blood clots. Warfarin is used to prevent or treat deep vein thrombosis (swelling and blood clot in a vein), pulmonary embolism (a blood clot in the lung), and strokes (a blood clot in the brain). Researchers have found that certain genes may affect how a person's body will break down or react to warfarin. If genetic information can help doctors better determine the best dose of warfarin before it is first given, this may help the doctors get patients to the correct levels of blood thinning and thereby reduce the risk of bleeding or the risk of developing a blood clot. The expectation of this study is that this information will ultimately improve warfarin therapy while lessening the risks associated with dosing errors. This study is considered investigational because the subjects are healthy and not being prescribed warfarin for clinical care.
Warfarin is a highly effective oral anticoagulant that is increasingly prescribed in the United States. It has a narrow therapeutic window, however, that represents an inherent limitation, such that insufficient and excessive levels of anticoagulation are associated with elevated risks of thrombosis and bleeding particularly frequent early in the initial dose-finding phase of therapy. Typically, anticoagulation is achieved through empiric dosing and titration with consideration of certain variables and frequent assessment of the international normalized ratio (INR). Despite these precautions, conventional dosing strategies are associated with therapeutic levels of anticoagulation only about half the time on treatment. Recently, genetic variants, specifically variations in the CYP2C9 and VKORC1 genes, have been identified that affect warfarin dose requirements, prompting the expectation that gene-based dosing strategies may maximize therapeutic efficacy while minimizing the risks associated with dosing errors. While the association between variation in these genes and differences in warfarin dose requirements has been identified, the specific contribution of allelic variation to the response to warfarin administration has not been thoroughly identified. The investigators therefore seek to assess the impact of allelic variation on warfarin dose-response relationships in a group of healthy subjects. The investigators hypothesize that genetic variation in the CYP2C9 and VKORC1 enzymes will result in differences in the warfarin dose-response relationships when accounting for non-genetic factors that can affect the pharmacokinetics of warfarin and its effect on coagulation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Warfarin | Experimental | Healthy subjects age 18-74 with no medical indication for warfarin therapy, who are free of medications and co-morbid medical conditions with the potential to interfere with warfarin metabolism, and who are willing to follow a fixed vitamin K diet (men 120 micrograms/day, women 90 micrograms/day) are included. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Warfarin | Drug | Enrolled subjects on a fixed vitamin K diet followed a standard warfarin dosing algorithm with daily point-of-care INR checks to goal INR ≥ 2 for two consecutive days, then to baseline INR≤1.2 off warfarin. Genotyping for common and rare polymorphisms in CYP2C9, VKORC1, and CYP4F2 performed at study entry and unblinded at completion. Plasma Vitamin K and S-warfarin levels are obtained at goal INR ≥ 2 and study exit (INR ≤1.2 off warfarin). |
| Measure | Description | Time Frame |
|---|---|---|
| Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | To assess the effect of genotype variants (CYP2C9 and VKORC1 -1639 G>A) on the anticoagulant response to warfarin, the primary outcome was the cumulative dose required to achieve an INR value in the usual clinical therapeutic range (>2.0) for two consecutive days. | average of 2 - 13 days |
| Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) | Subjects were also grouped into four categories based on CYP2C9 and VKORC1 genotype profile: Group 1 (CYP2C9 wild-type and VKORC1 wild-type), Group 2 (CYP2C9 wild-type and VKORC1 variant), Group 3 (CYP2C9 variant and VKORC1 wild-type), and Group 4 (CYP2C9 variant and VKORC1 variant). Median cumulative warfarin dose requirement was determined for each genotype category. | 2-30 days |
| Measure | Description | Time Frame |
|---|---|---|
| Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status | To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin. | average of 2 - 30 days |
| Explained Variation in Combined Therapeutic Warfarin Dose Models |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jonathan L Halperin, MD | Icahn School of Medicine at Mount Sinai | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mount Sinai School of Medicine | New York | New York | 10029 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17620536 | 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. | |
| 12742309 | Background | Hirsh J, Fuster V, Ansell J, Halperin JL; American Heart Association/American College of Cardiology Foundation. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol. 2003 May 7;41(9):1633-52. doi: 10.1016/s0735-1097(03)00416-9. No abstract available. |
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Subjects were educated regarding vitamin K restricted diet. Each maintained a food intake log and refrained from medications or alcohol for one week. Only subjects adhering to the prescribed diet and avoiding medications that could potentially interfere with warfarin metabolism qualified for the dose-response testing phase.
Thirty-five subjects responded to email and printed solicitations advertised at Mount Sinai Medical Center for the study, and five were excluded due to medication conflicts, unwillingness to take warfarin, and medical conditions precluding participation. Dates of recruitment spanned 04/2009 - 05/2012.
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| ID | Title | Description |
|---|---|---|
| FG000 | Warfarin | Healthy subjects age 18-74 with no medical indication for warfarin therapy, who are free of medications and co-morbid medical conditions with the potential to interfere with warfarin metabolism, and who are willing to follow a fixed vitamin K diet (men 120 micrograms/day, women 90 micrograms/day) are included. Warfarin : Enrolled subjects on a fixed vitamin K diet followed a standard warfarin dosing algorithm with daily point-of-care INR checks to goal INR ≥ 2 for two consecutive days, then to baseline INR≤1.2 off warfarin. Genotyping for common and rare polymorphisms in CYP2C9, VKORC1, and CYP4F2 performed at study entry and unblinded at completion. Plasma Vitamin K and S-warfarin levels are obtained at goal INR ≥ 2 and study exit (INR ≤1.2 off warfarin). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Warfarin | Healthy subjects age 18-74 with no medical indication for warfarin therapy, who are free of medications and co-morbid medical conditions with the potential to interfere with warfarin metabolism, and who are willing to follow a fixed vitamin K diet (men 120 micrograms/day, women 90 micrograms/day) are included. Warfarin : Enrolled subjects on a fixed vitamin K diet followed a standard warfarin dosing algorithm with daily point-of-care INR checks to goal INR ≥ 2 for two consecutive days, then to baseline INR≤1.2 off warfarin. Genotyping for common and rare polymorphisms in CYP2C9, VKORC1, and CYP4F2 performed at study entry and unblinded at completion. Plasma Vitamin K and S-warfarin levels are obtained at goal INR ≥ 2 and study exit (INR ≤1.2 off warfarin). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | To assess the effect of genotype variants (CYP2C9 and VKORC1 -1639 G>A) on the anticoagulant response to warfarin, the primary outcome was the cumulative dose required to achieve an INR value in the usual clinical therapeutic range (>2.0) for two consecutive days. | Of the 35 subjects enrolled, 30 were included in the study as listed above. | Posted | Median | Inter-Quartile Range | milligrams | average of 2 - 13 days |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Warfarin | Enrolled subjects on a fixed vitamin K diet followed a standard warfarin dosing algorithm with daily point-of-care INR checks to goal INR ≥ 2 for two consecutive days, then to baseline INR≤1.2 off warfarin. Genotyping for common and rare polymorphisms in CYP2C9, VKORC1, and CYP4F2 performed at study entry and unblinded at completion. Plasma Vitamin K and S-warfarin levels are obtained at goal INR ≥ 2 and study exit (INR ≤1.2 off warfarin). |
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Small number of subjects, which prevented detection of modest effects; relied on self-reported race and self-reported adherance to vitamin K restricted diet without objective markers such as ancestry informative markers and serum vitamin k levels.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Daniella Kadian-Dodov | Mount Sinai School of Medicine | (212) 241-9454 | daniella.kadian-dodov@mssm.edu |
Not provided
| ID | Term |
|---|---|
| D014859 | Warfarin |
| D000925 | Anticoagulants |
| ID | Term |
|---|---|
| D015110 | 4-Hydroxycoumarins |
| D003374 | Coumarins |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 |
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|
|
The proportion of variance (R^2) explained by each predictor was calculated using multivariate regression analysis and adjusted for age, gender and reported race, with outcome values logarithmically transformed. The study was powered to detect R^2 > 20%, and significance was accepted at p<0.05. |
| average of 2 - 30 days |
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| 19228618 | Background | International Warfarin Pharmacogenetics Consortium; Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009 Feb 19;360(8):753-64. doi: 10.1056/NEJMoa0809329. |
| 20203262 | Background | Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MT, Chen CH, Motsinger-Reif A, Sagreiya H, Liu N, Wu AH, Gage BF, Jorgensen A, Pirmohamed M, Shin JG, Suarez-Kurtz G, Kimmel SE, Johnson JA, Klein TE, Wagner MJ; International Warfarin Pharmacogenetics Consortium. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood. 2010 May 6;115(18):3827-34. doi: 10.1182/blood-2009-12-255992. Epub 2010 Mar 4. |
| 18240910 | Background | Wu AH. Use of genetic and nongenetic factors in warfarin dosing algorithms. Pharmacogenomics. 2007 Jul;8(7):851-61. doi: 10.2217/14622416.8.7.851. |
| 20128861 | Background | Lubitz SA, Scott SA, Rothlauf EB, Agarwal A, Peter I, Doheny D, Van Der Zee S, Jaremko M, Yoo C, Desnick RJ, Halperin JL. Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population. J Thromb Haemost. 2010 May;8(5):1018-26. doi: 10.1111/j.1538-7836.2010.03792.x. Epub 2010 Feb 2. |
| 21272753 | Background | Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol. 2011 Feb 1;57(5):612-8. doi: 10.1016/j.jacc.2010.08.643. |
| 17989110 | Background | Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, Kahn SF, May HT, Samuelson KM, Muhlestein JB, Carlquist JF; Couma-Gen Investigators. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007 Nov 27;116(22):2563-70. doi: 10.1161/CIRCULATIONAHA.107.737312. Epub 2007 Nov 7. |
| 19842940 | Background | van Schie RM, Wadelius MI, Kamali F, Daly AK, Manolopoulos VG, de Boer A, Barallon R, Verhoef TI, Kirchheiner J, Haschke-Becher E, Briz M, Rosendaal FR, Redekop WK, Pirmohamed M, Maitland van der Zee AH. Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics. 2009 Oct;10(10):1687-95. doi: 10.2217/pgs.09.125. |
| 21083927 | Background | French B, Joo J, Geller NL, Kimmel SE, Rosenberg Y, Anderson JL, Gage BF, Johnson JA, Ellenberg JH; COAG (Clarification of Optimal Anticoagulation through Genetics) Investigators. Statistical design of personalized medicine interventions: the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. Trials. 2010 Nov 17;11:108. doi: 10.1186/1745-6215-11-108. |
| 21423021 | Background | Burmester JK, Berg RL, Yale SH, Rottscheit CM, Glurich IE, Schmelzer JR, Caldwell MD. A randomized controlled trial of genotype-based Coumadin initiation. Genet Med. 2011 Jun;13(6):509-18. doi: 10.1097/GIM.0b013e31820ad77d. |
| 21725053 | Background | Gong IY, Tirona RG, Schwarz UI, Crown N, Dresser GK, Larue S, Langlois N, Lazo-Langner A, Zou G, Roden DM, Stein CM, Rodger M, Carrier M, Forgie M, Wells PS, Kim RB. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood. 2011 Sep 15;118(11):3163-71. doi: 10.1182/blood-2011-03-345173. Epub 2011 Jul 1. |
| 19663669 | Background | Scott SA, Jaremko M, Lubitz SA, Kornreich R, Halperin JL, Desnick RJ. CYP2C9*8 is prevalent among African-Americans: implications for pharmacogenetic dosing. Pharmacogenomics. 2009 Aug;10(8):1243-55. doi: 10.2217/pgs.09.71. |
| 20504253 | Background | Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics. 2010 Jun;11(6):781-91. doi: 10.2217/pgs.10.49. |
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| 19874474 | Background | Ferder NS, Eby CS, Deych E, Harris JK, Ridker PM, Milligan PE, Goldhaber SZ, King CR, Giri T, McLeod HL, Glynn RJ, Gage BF. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost. 2010 Jan;8(1):95-100. doi: 10.1111/j.1538-7836.2009.03677.x. Epub 2009 Oct 30. |
| 19074728 | Background | Li C, Schwarz UI, Ritchie MD, Roden DM, Stein CM, Kurnik D. Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy. Blood. 2009 Apr 23;113(17):3925-30. doi: 10.1182/blood-2008-09-176859. Epub 2008 Dec 12. |
| 18322281 | Background | Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, Kim RB, Roden DM, Stein CM. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008 Mar 6;358(10):999-1008. doi: 10.1056/NEJMoa0708078. |
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| 21830957 | Background | Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10. |
| 17851566 | Background | Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. 2008 Mar;83(3):460-70. doi: 10.1038/sj.clpt.6100316. Epub 2007 Sep 12. |
| Background | FDA approves updated warfarin (Coumadin) prescribing information. Press release of the Food and Drug Administration, August 16, 2007. (Accessed December 22, 2011 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967.htm). |
| Background | FDA clears genetic lab test for warfarin sensitivity. Press release of the Food and Drug Administration, September 17, 2007. (Accessed December 22, 2011 at http://www.fda.gov/newsevents/newsroom/pressannouncements/2007/ucm108984.htm). |
| 20693186 | Background | Joo J, Geller NL, French B, Kimmel SE, Rosenberg Y, Ellenberg JH. Prospective alpha allocation in the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. Clin Trials. 2010 Oct;7(5):597-604. doi: 10.1177/1740774510381285. Epub 2010 Aug 6. |
| 24029542 | Derived | Kadian-Dodov DL, van der Zee SA, Scott SA, Peter I, Martis S, Doheny DO, Rothlauf EB, Lubitz SA, Desnick RJ, Halperin JL. Warfarin pharmacogenetics: a controlled dose-response study in healthy subjects. Vasc Med. 2013 Oct;18(5):290-7. doi: 10.1177/1358863X13503193. Epub 2013 Sep 12. |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 |
| VKORC1 -1639 G>A |
VKORC1 GG was defined as "wild-type"; VKORC1 G/A was defined as "single variant"; and VKORC1 A/A was defined as "double variant". |
|
|
| Secondary | Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status | To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin. | Of 35 subjects were enrolled, 30 were included as listed above. | Posted | Median | Inter-Quartile Range | milligrams | average of 2 - 30 days |
|
|
|
| Secondary | Explained Variation in Combined Therapeutic Warfarin Dose Models | The proportion of variance (R^2) explained by each predictor was calculated using multivariate regression analysis and adjusted for age, gender and reported race, with outcome values logarithmically transformed. The study was powered to detect R^2 > 20%, and significance was accepted at p<0.05. | Of the 35 subjects enrolled, 30 completed the study as described above. | Posted | Number | proportion of variance | average of 2 - 30 days |
|
|
|
| Primary | Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) | Subjects were also grouped into four categories based on CYP2C9 and VKORC1 genotype profile: Group 1 (CYP2C9 wild-type and VKORC1 wild-type), Group 2 (CYP2C9 wild-type and VKORC1 variant), Group 3 (CYP2C9 variant and VKORC1 wild-type), and Group 4 (CYP2C9 variant and VKORC1 variant). Median cumulative warfarin dose requirement was determined for each genotype category. | Of the 35 subjects enrolled, 30 were included in the study as above. | Posted | Median | Inter-Quartile Range | milligrams | 2-30 days |
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
Not provided
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| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006401 | Hematologic Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|
| Group 4 |
|