Bleeding, Venous Thromboembolism
Conditions
Keywords
Genotyping, Warfarin dosing, arthroplasty
Brief summary
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.
Detailed description
This study was completed in 2008 and was published. Consult the citation link for more details.
Interventions
GENETICPharmacogenetic-based warfarin dosing
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.
OTHERUsual care warfarin dosing
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.
Sponsors
Gwen McMillin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants were otherwise healthy adults (≥ 18 years of age) who were planning total hip or knee replacement or revision surgery at the University of Utah Hospital, and scheduled a pre-operative office visit at the University of Utah Orthopaedic Center.
Exclusion criteria
* Blood transfusion in previous two weeks * Participant is already taking warfarin * Pre-operative INR \> 4.0 * Pre-operative bilirubin \> 2.4 mg/dL * Current active cancer diagnosis with ongoing treatment * Concomitant medications known to exert a major interaction with warfarin such as septra, metronidazole, tramadol, amiodarone, ciprofloxacin, or cimetidine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Adverse Events Associated With Warfarin Anticoagulation Following Total Hip and Total Knee Replacement | 90 days post surgery | Adverse events were defined as 1. Major bleeding: fatal bleeding, bleeding into a critical organ, bleeding that requires hospital admission 2. Minor bleeding: clinically overt bleeding not meeting criteria for major bleeding 3. Symptomatic deep vein thrombosis (DVT) 4. Pulmonary embolism (PE) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Determinations in Therapuetic Range (INR 1.8-2.9) | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) | 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. |
| Percentage of Determinations Subtherapeutic (INR<1.8) | 2 weeks (knee arthroplasty) or 4 weeks (hop arthroplasty) | 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. |
| Percentage of Determinations Supratherapeutic (INR>2.9) | 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) | 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. |
Countries
United States
Participant flow
Recruitment details
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
Pre-assignment details
Exclusion Criteria: 1. Blood transfusion in previous two weeks 2. Participant is already taking warfarin 3. Pre-operative INR \> 4.0 4. Pre-operative bilirubin \> 2.4 mg/dL 5. Current active cancer diagnosis with ongoing treatment 6. Concomitant medications known to exert a major interaction with warfarin
Participants by arm
| Arm | Count |
|---|---|
| Genotype-Based Dosing Arm Initial warfarin dose calculated according to published Sconce algorithm | 114 |
| Control Arm Standard of care dosing | 115 |
| Total | 229 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 3 | 9 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Control Arm | Genotype-Based Dosing Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 35 Participants | 36 Participants | 71 Participants |
| Age, Categorical Between 18 and 65 years | 80 Participants | 78 Participants | 158 Participants |
| Age, Continuous | 59.25 years STANDARD_DEVIATION 12.83 | 58.18 years STANDARD_DEVIATION 12.14 | 58.75 years STANDARD_DEVIATION 12.49 |
| Region of Enrollment United States | 115 participants | 114 participants | 229 participants |
| Sex: Female, Male Female | 72 Participants | 68 Participants | 140 Participants |
| Sex: Female, Male Male | 43 Participants | 46 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 114 | 6 / 115 |
| serious Total, serious adverse events | 2 / 114 | 4 / 115 |
Outcome results
Primary
The Number of Participants With Adverse Events Associated With Warfarin Anticoagulation Following Total Hip and Total Knee Replacement
Adverse events were defined as 1. Major bleeding: fatal bleeding, bleeding into a critical organ, bleeding that requires hospital admission 2. Minor bleeding: clinically overt bleeding not meeting criteria for major bleeding 3. Symptomatic deep vein thrombosis (DVT) 4. Pulmonary embolism (PE)
Time frame: 90 days post surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 Genotype Arm | The Number of Participants With Adverse Events Associated With Warfarin Anticoagulation Following Total Hip and Total Knee Replacement | 2 participants |
| 1 Control Arm | The Number of Participants With Adverse Events Associated With Warfarin Anticoagulation Following Total Hip and Total Knee Replacement | 4 participants |
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.
Time frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty)
Population: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 Genotype Arm | Percentage of Determinations in Therapuetic Range (INR 1.8-2.9) | 43.3 percentage of therapeutic INR values |
| 1 Control Arm | Percentage of Determinations in Therapuetic Range (INR 1.8-2.9) | 44.9 percentage of therapeutic INR values |
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.
Time frame: 2 weeks (knee arthroplasty) or 4 weeks (hop arthroplasty)
Population: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 Genotype Arm | Percentage of Determinations Subtherapeutic (INR<1.8) | 48.0 percentage of deteminations |
| 1 Control Arm | Percentage of Determinations Subtherapeutic (INR<1.8) | 47.1 percentage of deteminations |
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.
Time frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty)
Population: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 Genotype Arm | Percentage of Determinations Supratherapeutic (INR>2.9) | 8.7 percentage of determinations |
| 1 Control Arm | Percentage of Determinations Supratherapeutic (INR>2.9) | 8.0 percentage of determinations |
Post Hoc
Mean Number of Dose Adjustments
The average number of dose adjustments made per patient, per arm, during the study period was calculated
Time frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2 Genotype Arm | Mean Number of Dose Adjustments | 8.4 doses | Standard Deviation 2.18 |
| 1 Control Arm | Mean Number of Dose Adjustments | 7.0 doses | Standard Deviation 2.48 |
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.
Time frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2 Genotype Arm | Mean Number of Doses Before First Dose Adjustment | 3.1 doses | Standard Deviation 1.1 |
| 1 Control Arm | Mean Number of Doses Before First Dose Adjustment | 3.6 doses | Standard Deviation 1.3 |
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.
Time frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2 Genotype Arm | Mean Number of Doses Before the First Supratherapeutic INR | 5.4 doses administered | Standard Deviation 2.1 |
| 1 Control Arm | Mean Number of Doses Before the First Supratherapeutic INR | 4.8 doses administered | Standard Deviation 1.9 |
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.
Time frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2 Genotype Arm | Mean Number of Doses Required for the First Therapeutic INR | 3.9 doses | Standard Deviation 1.3 |
| 1 Control Arm | Mean Number of Doses Required for the First Therapeutic INR | 3.4 doses | Standard Deviation 1.1 |
Post Hoc
Percent of Patients With Dose Adjustments
The percent of patients that required a dose adjustment during the study period was calculated.
Time frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 Genotype Arm | Percent of Patients With Dose Adjustments | 83.5 percentage of patients |
| 1 Control Arm | Percent of Patients With Dose Adjustments | 78.0 percentage of patients |