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Several human genes affect how medications are metabolized by the body. It is believed that knowledge of variations of these genes can help health care providers better manage an anticoagulation medicine called warfarin (Coumadin®)and as a result decrease patient problems with bleeding or the development of blood clots. This study was designed to evaluate if genetic testing can improve warfarin initiation better than usual care.
This study was completed in 2008 and was published. Consult the citation link for more details.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pharmacogenetic-based warfarin dosing | Experimental | Pharmacogenetic-based warfarin dosing: Warfarin dosing based on formula that incorporates genetic testing results. NOTE: Standard of care for elective knee and hip replacement at our institution is to receive post-operative warfarin thromboprophylaxis. Administration of warfarin was not specific to this study, nor was the duration of prophylaxis, however, warfarin dosing was influenced by the study arm, as noted above. |
|
| Standard of care (control) | Active Comparator | Control or "usual care" warfarin dosing NOTE: Standard of care ("usual care") for elective knee and hip replacement at our institution is to receive post-operative warfarin thromboprophylaxis. Administration of warfarin was not specific to this study, nor was the duration of prophylaxis, however, warfarin dosing was influenced by the study arm, as noted above. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pharmacogenetic-based warfarin dosing | Genetic | Prior to elective joint replacement surgery a blood sample is collected for genetic information(genotyping)which was used for calculating warfarin doses for patients randomized to the cytochrome arm. Outcomes in terms of efficacy, safety, and management of warfarin were compared between this group and the group in which warfarin doses are determined per usual care. NOTE: Standard of care for elective knee and hip replacement at our institution is to receive post-operative warfarin thromboprophylaxis. Administration of warfarin was not specific to this study, nor was the duration of prophylaxis, however, warfarin dosing was influenced by the study arm as noted above. |
| Measure | Description | Time Frame |
|---|---|---|
| The Number of Participants With Adverse Events Associated With Warfarin Anticoagulation Following Total Hip and Total Knee Replacement | Adverse events were defined as
| 90 days post surgery |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Determinations in Therapuetic Range (INR 1.8-2.9) | Patient response to warfarin was evaluated based on the international normalized ratio (INR), calculated from a prothrombin time blood test. When the INR value was between 1.8 and 2.9, the patient was considered to be "therapeutic." The proportion of INR determinations that fell within the therapeutic range (INR between 1.8-2.9) was calculated, per arm, based on total number of INR determinations that were made during treatment with warfarin. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gwen McMillin, PhD | ARUP Laboratories | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Utah Health Care | Salt Lake City | Utah | 84132 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20386359 | Result | McMillin GA, Melis R, Wilson A, Strong MB, Wanner NA, Vinik RG, Peters CL, Pendleton RC. Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study. Ther Drug Monit. 2010 Jun;32(3):338-45. doi: 10.1097/FTD.0b013e3181d925bb. |
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Exclusion Criteria:
Patients planning total hip or knee replacement surgery at the University of Utah Hospital, will be approached about participation in the study by Dr Chris Peters, MD or assigned orthopedic staff at the pre-operative office visit at the University of Utah Orthopaedic Center. Patients were enrolled from 9/27/06 - 10/2/08
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| ID | Title | Description |
|---|---|---|
| FG000 | 2 Genotype Arm | The initial dose of warfarin will be corrected by the AC services team to account for variant genotypes, according to the following: Sqrt (Dose) = 0.628 - 0.0135(Age) - 0.240(CYP2C9*2) - 0.370 (CYP2C9*3) - 0.241(VKORC1) + 0.0162(Height) Age: input age in years CYP2C9: input 0, 1, or 2 based on the number of variant alleles VKORC1: input 1 for GG, 2 for GA, and 3 for AA Height: input height in centimeters Patients in this study group will be managed by designated AC services physicians, different from those in managing patients in the Control Arm of this study. Dosing adjustments will be made based on post-surgical INR values obtained initially on POD#2 daily during hospital stay, and 2 times weekly, or as needed, thereafter. |
| FG001 | 1 Control Arm | This is a two-armed parallel study with randomized assignment designed to test the hypothesis that selection of the initial warfarin dose based on CYP2C9 and VKORC1 genotypes will improve warfarin pharmacotherapy outcomes. Initial dose of warfarin will be given as per standard protocol for the Control Arm. Briefly, 3 or 5 mg warfarin will be administered on the day of surgery (post-operative day zero, POD#0) and the subsequent day. Patients in this study group will be managed by designated AC services physicians. Dosing adjustments will be made based on post-surgical INR values obtained initially on POD#2, daily during hospital stay, and 2 times weekly, or as needed, thereafter. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Genotype-Based Dosing Arm | Initial warfarin dose calculated according to published Sconce algorithm |
| BG001 | Control Arm | Standard of care dosing |
| 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 | The Number of Participants With Adverse Events Associated With Warfarin Anticoagulation Following Total Hip and Total Knee Replacement | Adverse events were defined as
| Posted | Number | participants | 90 days post surgery |
|
Adverse events were recorded and investigated as they occurred, throughout the study period.
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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 | 2 Genotype Arm | The initial dose of warfarin will be corrected by the AC services team to account for variant genotypes, according to the following: Sqrt (Dose) = 0.628 - 0.0135(Age) - 0.240(CYP2C9*2) - 0.370 (CYP2C9*3) - 0.241(VKORC1) + 0.0162(Height) Age: input age in years CYP2C9: input 0, 1, or 2 based on the number of variant alleles VKORC1: input 1 for GG, 2 for GA, and 3 for AA Height: input height in centimeters Patients in this study group will be managed by designated AC services physicians, different from those in managing patients in the Control Arm of this study. Dosing adjustments will be made based on post-surgical INR values obtained initially on POD#2 daily during hospital stay, and 2 times weekly, or as needed, thereafter. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Venous thromboembolic event or bleed | Vascular disorders | VTE | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Minor bleed | Vascular disorders | Systematic Assessment | Minor bleeds did not require hospitalization |
Limited by the fact that INR was used to adjust dose at the third dose, which may not have allowed enough time for steady-state concentrations of warfarin to be achieved, nor for the genotype-based dosing to be adequately studied.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Gwen McMillin/Principal Investigator | University of Utah | 801-583-2787 | 2671 | gwen.mcmillin@aruplab.com |
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| ID | Term |
|---|---|
| D054556 | Venous Thromboembolism |
| D006470 | Hemorrhage |
| ID | Term |
|---|---|
| D013923 | Thromboembolism |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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|
| Usual care warfarin dosing | Other | For patients in arm 2, the control group, warfarin dosing is per usual care. Outcomes in terms of safety, efficacy, and warfarin management was compared to that of patients in the other arm, who receive warfarin dosing based on genotyping. NOTE: Standard of care for elective knee and hip replacement at our institution is to receive post-operative warfarin thromboprophylaxis. Administration of warfarin was not specific to this study, nor was the duration of prophylaxis, however, warfarin dosing was influenced by the study arm as noted above. |
|
| 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
| Percentage of Determinations Subtherapeutic (INR<1.8) | Patient response to warfarin was evaluated based on the international normalized ratio (INR), calculated from a prothrombin time blood test. When the INR value was less than 1.8, the patient was considered to be "subtherapeutic." The proportion of INR determination that were subtherapeutic was caluculated, per arm, based on the total number of INR determinations that were made during treatment with warfarin. | 2 weeks (knee arthroplasty) or 4 weeks (hop arthroplasty) |
| Percentage of Determinations Supratherapeutic (INR>2.9) | Patient response to warfarin was evaluated based on the international normalized ratio (INR), calculated from a prothrombin time blood test. When the INR value was greater than 2.9, the patient was considered to be "supratherapeutic." The proportion of INR determinations that were supratherapeutic was calculated, per arm, based on total number of INR determinations that were made during treatment with warfarin. | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
| Withdrawal by Subject |
|
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 1 Control Arm | This is a two-armed parallel study with randomized assignment designed to test the hypothesis that selection of the initial warfarin dose based on CYP2C9 and VKORC1 genotypes will improve warfarin pharmacotherapy outcomes. Initial dose of warfarin will be given as per standard protocol for the Control Arm. Briefly, 3 or 5 mg warfarin will be administered on the day of surgery (post-operative day zero, POD#0) and the subsequent day. Patients in this study group will be managed by designated AC services physicians. Dosing adjustments will be made based on post-surgical INR values obtained initially on POD#2, daily during hospital stay, and 2 times weekly, or as needed, thereafter. |
|
|
| Secondary | Percentage of Determinations in Therapuetic Range (INR 1.8-2.9) | Patient response to warfarin was evaluated based on the international normalized ratio (INR), calculated from a prothrombin time blood test. When the INR value was between 1.8 and 2.9, the patient was considered to be "therapeutic." The proportion of INR determinations that fell within the therapeutic range (INR between 1.8-2.9) was calculated, per arm, based on total number of INR determinations that were made during treatment with warfarin. | Determinations were assessed cumulatively throughout the study period, per patient, per arm. The total number of determinations was 804 for the genotype arm and 780 for the control arm | Posted | Number | percentage of therapeutic INR values | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
|
|
|
| Secondary | Percentage of Determinations Subtherapeutic (INR<1.8) | Patient response to warfarin was evaluated based on the international normalized ratio (INR), calculated from a prothrombin time blood test. When the INR value was less than 1.8, the patient was considered to be "subtherapeutic." The proportion of INR determination that were subtherapeutic was caluculated, per arm, based on the total number of INR determinations that were made during treatment with warfarin. | Determinations were assessed cumulatively throughout the study period, per patient, per arm. The total number of determinations was 804 for the genotype arm and 780 for the control arm | Posted | Number | percentage of deteminations | 2 weeks (knee arthroplasty) or 4 weeks (hop arthroplasty) |
|
|
|
| Secondary | Percentage of Determinations Supratherapeutic (INR>2.9) | Patient response to warfarin was evaluated based on the international normalized ratio (INR), calculated from a prothrombin time blood test. When the INR value was greater than 2.9, the patient was considered to be "supratherapeutic." The proportion of INR determinations that were supratherapeutic was calculated, per arm, based on total number of INR determinations that were made during treatment with warfarin. | Determinations were assessed cumulatively throughout the study period, per patient, per arm. The total number of determinations was 804 for the genotype arm and 780 for the control arm | Posted | Number | percentage of determinations | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
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|
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| Post-Hoc | Mean Number of Doses Before First Dose Adjustment | The number of consistent doses administered before the first dose adjustment was required was recorded, per patient. The average number of doses administered before the first dose adjustment is shown. | Posted | Mean | Standard Deviation | doses | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
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| Post-Hoc | Mean Number of Dose Adjustments | The average number of dose adjustments made per patient, per arm, during the study period was calculated | Posted | Mean | Standard Deviation | doses | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
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|
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| Post-Hoc | Percent of Patients With Dose Adjustments | The percent of patients that required a dose adjustment during the study period was calculated. | Posted | Number | percentage of patients | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
|
|
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| Post-Hoc | Mean Number of Doses Required for the First Therapeutic INR | The number of doses required to achieve a therapeutic INR (1.8-2.9) was determined per patient, per arm. The average was then calculated and is shown here. | Posted | Mean | Standard Deviation | doses | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
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| Post-Hoc | Mean Number of Doses Before the First Supratherapeutic INR | The number of warfarin doses administered before a patient INR exceeded the therapeutic range (>2.9) was recorded. The average was then calculated and is shown here. | Posted | Mean | Standard Deviation | doses administered | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) |
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|
|
| 2 |
| 114 |
| 1 |
| 114 |
| EG001 | 1 Control Arm | This is a two-armed parallel study with randomized assignment designed to test the hypothesis that selection of the initial warfarin dose based on CYP2C9 and VKORC1 genotypes will improve warfarin pharmacotherapy outcomes. Initial dose of warfarin will be given as per standard protocol for the Control Arm. Briefly, 3 or 5 mg warfarin will be administered on the day of surgery (post-operative day zero, POD#0) and the subsequent day. Patients in this study group will be managed by designated AC services physicians. Dosing adjustments will be made based on post-surgical INR values obtained initially on POD#2, daily during hospital stay, and 2 times weekly, or as needed, thereafter. | 4 | 115 | 6 | 115 |
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| D010335 |
| Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |