Thromboembolism
Conditions
Keywords
warfarin metabolism, CYP2C9, genotyping, VKORC1, anticoagulation, atrial fibrillation, deep vein thrombosis, pulmonary embolism, Patients initiating warfarin for thromboembolic conditions
Brief summary
The purpose of this study is to determine whether DNA analysis improves the efficiency of dosing and safety in patients who are being started on warfarin therapy.Warfarin, a blood thinner (anticoagulant) prescribed to 1-2 million patients in the United States, is a leading cause of drug-related adverse events (e.g., severe bleeding), in large part due to dramatic (20-fold) differences between individuals in dose requirements. At least half of this variability now can be explained by 3 common genetic variants, age, body size, and sex; however, warfarin therapy continues to begin with the same dose in every patient with the correct individual dose determined by trial and error. This study proposes to determine genetic variations the same day from DNA simply obtained by swabbing the inside of the cheek and use this information to determine the proper dose regimen individually in each patient. The aim is to show that the investigators can achieve more rapid, efficient, and safe dosing in up to 500-1000 individuals who are initiating warfarin therapy for various clotting disorders across a large healthcare system in order to demonstrate improved dosing effectiveness, efficiency, and safety with genetic-based dosing, which could lead to a nationwide application resulting in as much as a $1 billion dollar annual benefit in healthcare outcomes.
Detailed description
Study Objectives: The specific objectives of CoumaGen-II to be tested are: 1. To apply routine pharmacogenetic (PG)-guided dosing of warfarin in clinical practice at Intermountain Healthcare facilities in the Urban Central Region (i.e., Intermountain Medical Center \[IMC\], LDS Hospital, Alta View Hospital \[AVH\]), and selected physician offices that are frequent initiators of warfarin) in a major new quality improvement and clinical research initiative. 2. To compare the percentage out-of-range (%OOR) international normalized prothrombin time ratios (INRs) during the first month (and secondarily, 3 months) of warfarin therapy using PG-guided dosing with parallel or historical standard (STD), empiric dosed controls. 3. To compare a modified PG-guided dosing algorithm (modified-International Warfarin Pharmacogenetics Consortium \[IWPC\]) with a previously generated and validated, multicenter PG-guided algorithm (IWPC). Study Design: Qualifying patients being initiated on warfarin therapy with a target INR of 1.5-2.5, 2-3, or 2.5-3.5 will be invited to participate and sign informed consent. Enrolled patients will receive DNA sampling by buccal swab, and samples will be processed and a PG-guided initial dose calculated with a goal of \<6 hours (maximum, 24 hours). Dosing and dose adjustments will be managed through the Urban Central Region (IMC/LDSH) anticoagulation management service (AMS). Dose adjustments through day 8 will use a PG-modified algorithm, after which modification will revert to the standard IHC algorithm. AMS pharmacists and study coordinators will ascertain warfarin doses, INRs, dose changes, and adverse events, and record information on case report forms. Study Duration: Each patient will participate for approximately 3 months (90 days ± 10 days). The anticipated enrollment period is 24 months or until 1000 patients are enrolled. The length of the enrollment period is subject to revision as it is dependent on the availability of a robust patient pool. Further study details on dosing algorithm and genotyping methodology may be provided by Intermountain Healthcare Inc.
Interventions
GENETICIWPC adapted genotype-guided dosing algorithm for warfarin
Within the first or second dose, apply an International Warfarin Pharmacogenetics Consortium (IWPC) adapted genotype-guided dosing algorithm to determine the daily maintenance dose of warfarin, based on clinical factors (age, sex, weight, height, etc.), and VKORC1 and CYP2C9 genotypes, to individualize the initial dosing of warfarin. (IWPC algorithm submitted for publication, 5-08) Note that a second comparison will be made between the combined genotype-guided dosing groups (standard and modified IWPC warfarin dosing algorithms) and a historical comparator group.
GENETICModified IWPC genetic-guided warfarin dosing algorithm
Within the first or second warfarin dose, apply a modified International Warfarin Pharmacogenetics Consortium (IWPC)-adapted genotype-guided dosing algorithm to determine the daily maintenance dose of warfarin. The active comparator algorithm (see above) will be further modified to account for the temporal pharmacodynamics of warfarin metabolism, e.g., by ignoring the CYP2C9 variants for the first 2 days. Note that a second comparison will be made between the combined genotype-guided dosing groups (standard and modified IWPC warfarin dosing algorithms) and a historical comparator group.
OTHERStandard of care treatment
The parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records databases of the 3 participating hospitals for the time interval spanning enrollment of the randomized pharmacogenetic cohorts (July 2008-December 2010). Patients \>=18 years of age initiating warfarin therapy with a baseline and at least 1 follow-up INR level between days 3 and 14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG-based. A standard (fixed) initial maintenance dose of 5 mg/d is generally assumed.
Sponsors
Intermountain Health Care, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* New participants will be those \>=18 years old who are appropriate candidates for and being initiated on warfarin therapy with target international normalized prothrombin time ratio (INR) range of either 2-3 or 2.5-3.5 and with intent to be treated for at least 1 month and willing to sign informed consent. * Those with target INR 2.5-3.5 may be enrolled with dose adjustment for this higher target per Gage et-al. (i.e., 11% increase in dose). * Dose modification also will be made for amiodarone based on prior, published experience (i.e., 22% decrease in dose).
Exclusion criteria
* Those not appropriate for warfarin (e.g., pregnancy) or for pharmacogenetic (PG)-guided dosing for any reason, * Those having received rifampin within 3 weeks, * Those with severe co-morbidities (e.g., creatinine \> 2.5,hepatic insufficiency, active malignancy, advanced physiological age, noncompliance risk, expected survival \<6 months), and * Physician or patient preference.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percent of Out of Range (OOR) International Normalized Prothrombin Time Ratio (INRs) in the Standard and Modified Pharmacogenetic Arms. | 1 month (from day 3 to day 30) | The percent of out of range (OOR) international normalized prothrombin time ratio (INRs) in the standard and modified pharmacogentic algorithms at 1 month. To account for laboratory INR-measurement error, a 10% margin outside of the target range was allowed in determination of OOR values, ie, INRs \<1.8, \>3.3 for INR 2.5 target; \<2.25, \>3.85 for INR 3.0 target. What is reported is the percent of patients with an OOR INR at 1 month. |
| The Percent of Out of Range (OOR) INRs in Pharmacogenetic-guided Patients and Parallel Controls | 1 month (from day 3 to day 30) | The percent of out of range (OOR) INRs in the pharmacogenetic (PG)-dosing (standard + modified IWPC warfarin algorithms) and parallel controls. A 10% margin outside of the target INR range was allowed in determination of OOR values, ie, INRs \<1.8, \>3.3 for INR 2.5 target; \<2.25, \>3.85 for INR 3.0 target. What is reported is the percent of patients with OOR INRs at 1 month. |
| The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms. | 1 month (from baseline to day 30) | The percent of time in therapeutic INR range for the standard and modified pharmacogenetic algorithms at 1 month. To account for laboratory INR-measurement error, a 10% margin inside of the target range was allowed in determine TTR values, ie, INRs 1.8-3.3 for INR 2.5 target; 2.25-3.85 for INR 3.0 target. What is reported is the percent of TTR for each patient during 1 month. |
| The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls | 1 month (from baseline to day 30) | The percent of time in therapeutic INR range for the pharmacogenetic (PG)-dosing (standard + modified IWPC warfarin algorithms) guided patients and parallel controls. To account for laboratory INR-measurement error, a 10% margin inside of the target range was allowed in determine TTR values, ie, INRs 1.8-3.3 for INR 2.5 target; 2.25-3.85 for INR 3.0 target. What is reported is the percent of TTR for each patient during 1 month. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm | 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first) | The percent of INRs ≥4 or ≤1.5 for the pharmacogenetic (modified IWPC warfarin algorithm and the standard IWPC warfarin) algorithms. What is reported is the percent of patients with INRs ≥4 or ≤1.5 at the end of follow-up. |
| The Percent of INRs ≥4 or ≤1.5 in the Pharmacogenetic (PG)-Guided Dosing Arms and the Parallel Control Arm | 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first) | What is reported is the percent of patients with an INR ≥4 or ≤1.5 at the end of follow-up. |
| The Percent of INRs ≥4 or ≤1.5 or SAEs Among the Modified IWPC Warfarin Algorithm and Standard IWPC Warfarin Algorithm. | 3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first) | What is reported is the percent of patients with INRs ≥4 or ≤1.5 or having experienced a serious adverse event (SAE) at the end of follow-up. |
| The Number of INRs Measured up to 3 Months in the Pharmacogenetic (PG) (Modified and Standard) Algorithms and Parallel Controls. | 1-3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first) | What is reported is the mean number of INRs measured/drawn among the patients in each arm. |
| Prediction of a Stable Maintenance Dose Among the Pharmacogenetic (PG)-Guided Dosing Algorithms and the Parallel Controls | 3 months (from baseline to 3 months or until stable dosing is achieved, whichever occurs first) | Prediction of a stable maintenance dose (within 1 mg/day) among the pharmacogenetic (PG)-guided dosing and the parallel control group. For the parallel control group, an empiric starting dose of 5 mg/day was assumed. What is reported is the percent of patients who had their maintenance dose predicted as described above. |
Countries
United States
Participant flow
Recruitment details
Those \>= 18 years and being initiated on warfarin therapy with a target international normalized prothrombin time ratio (INR) of 2-3 or 2.5 -3.5 among participating hospitals and outpatient clinics were invited to participate and sign informed consent.
Pre-assignment details
If after enrollment, pt was found to be not appropriate for warfarin or pharmacogenetic (PG)-guided dosing or physician preference not to have pt participate they were not randomized. Description below and baseline characteristics report combined PG arms because of similarities but outcome measures report combined and individual PG results.
Participants by arm
| Arm | Count |
|---|---|
| PG Dosing Patients Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the pharmacogenetic (PG)-dosing algorithms (standard or modified IWPC warfarin algorithms) | 504 |
| Historical Controls A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing | 1,911 |
| Total | 2,415 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Missing data needed for endpt analyses | 27 | 45 |
Baseline characteristics
| Characteristic | Historical Controls | PG Dosing Patients | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 697 Participants | 216 Participants | 913 Participants |
| Age, Categorical Between 18 and 65 years | 1214 Participants | 288 Participants | 1502 Participants |
| Age Continuous | 57.3 years STANDARD_DEVIATION 17.5 | 61.3 years STANDARD_DEVIATION 14.6 | 58.0 years STANDARD_DEVIATION 16.8 |
| Region of Enrollment United States | 1911 participants | 504 participants | 2415 participants |
| Sex: Female, Male Female | 984 Participants | 268 Participants | 1252 Participants |
| Sex: Female, Male Male | 927 Participants | 236 Participants | 1163 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 75 / 488 | 511 / 1,866 |
| serious Total, serious adverse events | 22 / 487 | 162 / 1,726 |
Outcome results
Primary
The Percent of Out of Range (OOR) INRs in Pharmacogenetic-guided Patients and Parallel Controls
The percent of out of range (OOR) INRs in the pharmacogenetic (PG)-dosing (standard + modified IWPC warfarin algorithms) and parallel controls. A 10% margin outside of the target INR range was allowed in determination of OOR values, ie, INRs \<1.8, \>3.3 for INR 2.5 target; \<2.25, \>3.85 for INR 3.0 target. What is reported is the percent of patients with OOR INRs at 1 month.
Time frame: 1 month (from day 3 to day 30)
Population: Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) were compared to parallel controls
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | The Percent of Out of Range (OOR) INRs in Pharmacogenetic-guided Patients and Parallel Controls | 31.2 percent |
| Modified IWPC Warfarin Dosing Algorithm | The Percent of Out of Range (OOR) INRs in Pharmacogenetic-guided Patients and Parallel Controls | 41.5 percent |
Primary
The Percent of Out of Range (OOR) International Normalized Prothrombin Time Ratio (INRs) in the Standard and Modified Pharmacogenetic Arms.
The percent of out of range (OOR) international normalized prothrombin time ratio (INRs) in the standard and modified pharmacogentic algorithms at 1 month. To account for laboratory INR-measurement error, a 10% margin outside of the target range was allowed in determination of OOR values, ie, INRs \<1.8, \>3.3 for INR 2.5 target; \<2.25, \>3.85 for INR 3.0 target. What is reported is the percent of patients with an OOR INR at 1 month.
Time frame: 1 month (from day 3 to day 30)
Population: Patients \>= 18 years of age who have an indication for initiation of warfarin anticoagulation, gave written informed consent, and met other inclusion/exclusion criteria were studied.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | The Percent of Out of Range (OOR) International Normalized Prothrombin Time Ratio (INRs) in the Standard and Modified Pharmacogenetic Arms. | 30.6 percent |
| Modified IWPC Warfarin Dosing Algorithm | The Percent of Out of Range (OOR) International Normalized Prothrombin Time Ratio (INRs) in the Standard and Modified Pharmacogenetic Arms. | 31.8 percent |
Comparison: Comparisons between groups for primary endpoints were made using the unpaired T-test. All consented, randomized patients who were successfully genotyped and received at least one dose of warfarin with at least one post-dose INR were included in efficacy analyses (modified intention to treat \[mITT\]).p-value: <0.05t-test, 2 sided
Primary
The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms.
The percent of time in therapeutic INR range for the standard and modified pharmacogenetic algorithms at 1 month. To account for laboratory INR-measurement error, a 10% margin inside of the target range was allowed in determine TTR values, ie, INRs 1.8-3.3 for INR 2.5 target; 2.25-3.85 for INR 3.0 target. What is reported is the percent of TTR for each patient during 1 month.
Time frame: 1 month (from baseline to day 30)
Population: Patients \>= 18 years of age who have an indication for initiation of warfarin anticoagulation, gave written informed consent, and met other inclusion/exclusion criteria were studied.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms. | 70.2 percent |
| Modified IWPC Warfarin Dosing Algorithm | The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms. | 67.5 percent |
Primary
The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls
The percent of time in therapeutic INR range for the pharmacogenetic (PG)-dosing (standard + modified IWPC warfarin algorithms) guided patients and parallel controls. To account for laboratory INR-measurement error, a 10% margin inside of the target range was allowed in determine TTR values, ie, INRs 1.8-3.3 for INR 2.5 target; 2.25-3.85 for INR 3.0 target. What is reported is the percent of TTR for each patient during 1 month.
Time frame: 1 month (from baseline to day 30)
Population: Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) were compared to parallel controls.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls | 68.9 percent |
| Modified IWPC Warfarin Dosing Algorithm | The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls | 58.4 percent |
Secondary
Prediction of a Stable Maintenance Dose Among the Pharmacogenetic (PG)-Guided Dosing Algorithms and the Parallel Controls
Prediction of a stable maintenance dose (within 1 mg/day) among the pharmacogenetic (PG)-guided dosing and the parallel control group. For the parallel control group, an empiric starting dose of 5 mg/day was assumed. What is reported is the percent of patients who had their maintenance dose predicted as described above.
Time frame: 3 months (from baseline to 3 months or until stable dosing is achieved, whichever occurs first)
Population: Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) and had a stable maintenance dose that could be determined were compared to parallel controls
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | Prediction of a Stable Maintenance Dose Among the Pharmacogenetic (PG)-Guided Dosing Algorithms and the Parallel Controls | 63.2 percent |
| Modified IWPC Warfarin Dosing Algorithm | Prediction of a Stable Maintenance Dose Among the Pharmacogenetic (PG)-Guided Dosing Algorithms and the Parallel Controls | 37.6 percent |
Secondary
The Number of INRs Measured up to 3 Months in the Pharmacogenetic (PG) (Modified and Standard) Algorithms and Parallel Controls.
What is reported is the mean number of INRs measured/drawn among the patients in each arm.
Time frame: 1-3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first)
Population: Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) were compared to parallel controls
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | The Number of INRs Measured up to 3 Months in the Pharmacogenetic (PG) (Modified and Standard) Algorithms and Parallel Controls. | 7.70 INRs | Standard Deviation 3.99 |
| Modified IWPC Warfarin Dosing Algorithm | The Number of INRs Measured up to 3 Months in the Pharmacogenetic (PG) (Modified and Standard) Algorithms and Parallel Controls. | 7.47 INRs | Standard Deviation 7.27 |
Secondary
The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm
The percent of INRs ≥4 or ≤1.5 for the pharmacogenetic (modified IWPC warfarin algorithm and the standard IWPC warfarin) algorithms. What is reported is the percent of patients with INRs ≥4 or ≤1.5 at the end of follow-up.
Time frame: 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)
Population: All consented, randomized patients who were successfully genotyped and received at least 1 dose of warfarin with at least 1 postdose INR.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm | 15.2 percent | Standard Deviation 20.5 |
| Modified IWPC Warfarin Dosing Algorithm | The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm | 15.4 percent | Standard Deviation 18.2 |
Secondary
The Percent of INRs ≥4 or ≤1.5 in the Pharmacogenetic (PG)-Guided Dosing Arms and the Parallel Control Arm
What is reported is the percent of patients with an INR ≥4 or ≤1.5 at the end of follow-up.
Time frame: 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)
Population: Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) were compared to parallel controls.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | The Percent of INRs ≥4 or ≤1.5 in the Pharmacogenetic (PG)-Guided Dosing Arms and the Parallel Control Arm | 15.3 percent | Standard Deviation 19.4 |
| Modified IWPC Warfarin Dosing Algorithm | The Percent of INRs ≥4 or ≤1.5 in the Pharmacogenetic (PG)-Guided Dosing Arms and the Parallel Control Arm | 27.4 percent | Standard Deviation 32.5 |
Secondary
The Percent of INRs ≥4 or ≤1.5 or SAEs Among the Modified IWPC Warfarin Algorithm and Standard IWPC Warfarin Algorithm.
What is reported is the percent of patients with INRs ≥4 or ≤1.5 or having experienced a serious adverse event (SAE) at the end of follow-up.
Time frame: 3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first)
Population: All patients receiving at least 1 dose of warfarin were included in safety analyses until 1 week after the last warfarin dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard IWPC Warfarin Dosing Algorithm | The Percent of INRs ≥4 or ≤1.5 or SAEs Among the Modified IWPC Warfarin Algorithm and Standard IWPC Warfarin Algorithm. | 53.6 percent |
| Modified IWPC Warfarin Dosing Algorithm | The Percent of INRs ≥4 or ≤1.5 or SAEs Among the Modified IWPC Warfarin Algorithm and Standard IWPC Warfarin Algorithm. | 59.2 percent |