Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin

Study Overview
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Brief Summary
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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.

Detailed Description
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Study Objectives: The specific objectives of CoumaGen-II to be tested are: 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. 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. 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.

Official Title
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The Clinical Impact of Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin in Patients Being Initiated on Oral Anticoagulation

Conditions
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Thromboembolism

Intervention / Treatment
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* Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin
* Genetic: Modified IWPC genetic-guided warfarin dosing algorithm
* Other: Standard of care treatment


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard IWPC warfarin dosing algorithm<br>Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm. | Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin<br>* 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.<br>* Other names: IWPC=international warfarin pharmacogenetic collaboration;|
| Experimental: Modified IWPC warfarin dosing algorithm<br>Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm | Genetic: Modified IWPC genetic-guided warfarin dosing algorithm<br>* 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.<br>* Other names: IWPC=international warfarin pharmacogenetic collaboration;|
| Other: Historical controls<br>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. | Other: Standard of care treatment<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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. | 1 month (from baseline to day 30) | 

Secondary Outcome Measures

| Outcome Measure | 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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warfarin metabolism, CYP2C9, genotyping, VKORC1, anticoagulation, atrial fibrillation, deep vein thrombosis, pulmonary embolism, Patients initiating warfarin for thromboembolic conditions