Healthy
Conditions
Keywords
Genetic Determinants of Warfarin Dose Variability
Brief summary
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.
Detailed description
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.
Interventions
DRUGWarfarin
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).
Sponsors
Icahn School of Medicine at Mount Sinai
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy adult (\> 18 years old.) subjects not taking warfarin * Willing and able to grant written informed consent * Available in proximity to the Medical Center for the anticipated duration of data collection (approximately 3 weeks). * Pre-menopausal women required negative pregnancy test at study onset and willingness to abstain from sexual activity or use barrier contraception; oral contraceptives interfere with coumadin.
Exclusion criteria
* Daily prescribed medications including (1) a medication known to interact with warfarin, based on interactions listed in Micromedex as moderate or severe, and probable or definite (as of study start date, Appendix A) (2) aspirin or clopidogrel, which may increase bleeding risk in combination with warfarin. * Recent therapy (within two weeks) with a medication known to interact with warfarin based on medication interactions listed in Micromedex * History of thrombotic disorder requiring anticoagulant therapy * Thrombophilia or coagulopathy, by history or screening coagulation profile with INR or PTT level \> 2x the upper limit of normal * Family history of thrombophilia or coagulopathy; prisoners or wards of the state; scheduled elective surgery within one month * Active liver disease based on clinical history or serum transaminase levels \> 2x the upper limit of normal * Protein C or S Deficiency assessed on screening protein C and S activity profile * Age ≥ 75 * Pre-menopausal women on oral contraception * Non-English speaking individuals
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | average of 2 - 13 days | 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. |
| Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) | 2-30 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status | average of 2 - 30 days | To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin. |
| Explained Variation in Combined Therapeutic Warfarin Dose Models | average of 2 - 30 days | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 3 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Warfarin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age Continuous | 32 years STANDARD_DEVIATION 8 |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 |
Outcome results
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.
Time frame: average of 2 - 13 days
Population: Of the 35 subjects enrolled, 30 were included in the study as listed above.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CYP2C9 | Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | Wild -Type | 52 milligrams |
| CYP2C9 | Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | Single Variant | 17 milligrams |
| CYP2C9 | Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | Double Variant | 27 milligrams |
| VKORC1 -1639 G>A | Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | Wild -Type | 52 milligrams |
| VKORC1 -1639 G>A | Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | Single Variant | 35 milligrams |
| VKORC1 -1639 G>A | Median Cumulative Therapeutic Warfarin Dose (Milligrams)Requirements by Genotype | Double Variant | 15 milligrams |
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.
Time frame: 2-30 days
Population: Of the 35 subjects enrolled, 30 were included in the study as above.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CYP2C9 | Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) | Group 1 | 52 milligrams |
| CYP2C9 | Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) | Group 2 | 42 milligrams |
| CYP2C9 | Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) | Group 3 | 35 milligrams |
| CYP2C9 | Median Cumulative Warfarin Dose Requirement by Genotype Category (CYP2C9 and VKORC1 -1639 G>A Combination) | Group 4 | 15 milligrams |
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.
Time frame: average of 2 - 30 days
Population: Of the 35 subjects enrolled, 30 completed the study as described above.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CYP2C9 | Explained Variation in Combined Therapeutic Warfarin Dose Models | 0.03 proportion of variance |
| VKORC1 -1639 G>A | Explained Variation in Combined Therapeutic Warfarin Dose Models | 0.57 proportion of variance |
| Demographic Plus CYP2C9 and VKORC1 | Explained Variation in Combined Therapeutic Warfarin Dose Models | 0.64 proportion of variance |
| Demographic Plus CYP2C9 and VKORC1 and CYP4F2 | Explained Variation in Combined Therapeutic Warfarin Dose Models | 0.65 proportion of variance |
Secondary
Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status
To assess the effect of CYP4F2 genotype variants on the anticoagulant response to warfarin.
Time frame: average of 2 - 30 days
Population: Of 35 subjects were enrolled, 30 were included as listed above.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CYP2C9 | Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status | Single-Variant | 52 milligrams |
| CYP2C9 | Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status | Double-Variant | 54 milligrams |
| CYP2C9 | Median Cumulative Warfarin Dose Requirements by CYP4F2 Genotype Status | Wild-Type | 31 milligrams |