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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.
Study Objectives:
The specific objectives of CoumaGen-II to be tested are:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard IWPC warfarin dosing algorithm | Active Comparator | Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm. |
|
| Modified IWPC warfarin dosing algorithm | Experimental | Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm |
|
| Historical controls | Other | The parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records database of the 3 participating hospitals for the time interval spanning enrollment of the randomized pharmacogenetic (PG)-guided cohorts (July 2008 through December 2010). Patients ≥18 years old initiating warfarin therapy with a baseline and at least 1 follow-up international normalized prothrombin time ratio (INR) level between days 3-14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG based. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IWPC adapted genotype-guided dosing algorithm for warfarin | Genetic | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 1 month (from day 3 to day 30) |
| 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. | 1 month (from day 3 to day 30) |
| 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. | 1 month (from baseline to day 30) |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey L Anderson, MD | Intermountain Health Care, Inc. | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Intermountain Healthcare Hospitals and Clinics | Salt Lake City | Utah | 84107 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22431865 | Derived | Anderson JL, Horne BD, Stevens SM, Woller SC, Samuelson KM, Mansfield JW, Robinson M, Barton S, Brunisholz K, Mower CP, Huntinghouse JA, Rollo JS, Siler D, Bair TL, Knight S, Muhlestein JB, Carlquist JF. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation. 2012 Apr 24;125(16):1997-2005. doi: 10.1161/CIRCULATIONAHA.111.070920. Epub 2012 Mar 19. |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | PG Dosing Patients | Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms were randomized to receive either standard or modified International Warfarin Pharmacogenetics Consortium [IWPC] warfarin dosing. The IWPC derived and published a common algorithm to predict stable maintenance dose based on ~5000 patients across broad geographic and ethnic/racial groups (N Engl J Med 2009;360:753-764). Hence, we based our standard algorithm on the IWPC algorithm with minor modifications to accommodate different INR targets and smoking status, based on supplemental data from Gage et al (Clini Pharmacol Ther 2008;84:326 -331). The modified IWPC algorithm included 2 further modifications: (1) It ignored the CYP2C9 variant status for the first 2 days; and (2) It used a special dose-revision algorithm based on a day 4 (or day 5) INR after 3 (or 4) warfarin doses. |
| FG001 | Parellel/Historical Controls | A 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-guided cohorts (July 2008 through 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, with loading doses and clinical-factor modifications not specified. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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) |
| BG001 | Historical Controls |
| 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 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. | 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. | Posted | Mean | 95% Confidence Interval | percent | 1 month (from day 3 to day 30) |
|
Patients were included in the SAE safety analyses if they received an INR measurement on Day 4 or 5 and were taking warfarin. Patients were followed until 3 months after warfarin initiation.
Because only those who received an INR measurement on Day 4 or 5 and were taking warfarin were included in the calculation of the serious adverse events, the numbers in each arm are different from what is reported in the participant flow table.
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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 | 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) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| adjudicated death, MI, stroke, thromboembolic event, moderate or severe hemorrhage | Cardiac disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| INR >=4 or <=1.5 | Blood and lymphatic system disorders | Systematic Assessment | Number of patients who had an average INR >=4 or <=1.5 at the end of follow-up |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jeffrey L. Anderson, Director of CV Research and Professor of Medicine | Intermountain Healthcare | 801-507-4704 | jeffrey.anderson@imail.org |
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| ID | Term |
|---|---|
| D013923 | Thromboembolism |
| C564393 | Vitamin K-Dependent Clotting Factors, Combined Deficiency Of, Type 2 |
| D001281 | Atrial Fibrillation |
| D020246 | Venous Thrombosis |
| D011655 | Pulmonary Embolism |
| ID | Term |
|---|---|
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D001145 | Arrhythmias, Cardiac |
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| ID | Term |
|---|---|
| D014859 | Warfarin |
| ID | Term |
|---|---|
| D015110 | 4-Hydroxycoumarins |
| D003374 | Coumarins |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 |
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|
|
| Modified IWPC genetic-guided warfarin dosing algorithm | Genetic | 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. |
|
|
| Standard of care treatment | Other | 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. |
|
| 1 month (from baseline to day 30) |
| 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. | 3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first) |
| 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. | 1-3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first) |
| 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. | 3 months (from baseline to 3 months or until stable dosing is achieved, whichever occurs first) |
| 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. | 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first) |
A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing
| 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 |
|
Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification
| OG001 | Modified IWPC Warfarin Dosing Algorithm | Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications |
|
|
|
| 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. | All consented, randomized patients who were successfully genotyped and received at least 1 dose of warfarin with at least 1 postdose INR. | Posted | Mean | Standard Deviation | percent | 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first) |
|
|
|
| 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. | All patients receiving at least 1 dose of warfarin were included in safety analyses until 1 week after the last warfarin dose | Posted | Number | percent | 3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first) |
|
|
|
| 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. | 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 | Posted | Mean | Standard Deviation | INRs | 1-3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first) |
|
|
|
| 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. | 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 | Posted | Number | percent | 3 months (from baseline to 3 months or until stable dosing is achieved, whichever occurs first) |
|
|
|
| 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. | 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 | Posted | Mean | 95% Confidence Interval | percent | 1 month (from day 3 to day 30) |
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | percent | 1 month (from baseline to day 30) |
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | percent | 1 month (from baseline to day 30) |
|
|
|
| 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. | 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. | Posted | Mean | Standard Deviation | percent | 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first) |
|
|
|
| 22 |
| 487 |
| 75 |
| 488 |
| EG001 | Historical Controls | A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing | 162 | 1,726 | 511 | 1,866 |
|
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| D006331 |
| Heart Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D013927 | Thrombosis |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D004617 | Embolism |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |