Clinical trial NCT00927862: Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin
Official title: The Clinical Impact of Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin in Patients Being Initiated on Oral Anticoagulation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Thromboembolism
Keywords: warfarin metabolism
CYP2C9
genotyping
VKORC1
anticoagulation
atrial fibrillation
deep vein thrombosis
pulmonary embolism
Patients initiating warfarin for thromboembolic conditions
Lead sponsor: Intermountain Health Care, Inc.
Sponsor class: OTHER
First posted: 2009-06-25
Enrollment: 2415
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Percent of Out of Range (OOR) International Normalized Prothrombin Time Ratio (INRs) in the Standard and Modified Pharmacogenetic Arms.
timeFrame: 1 month (from day 3 to day 30)
measure: The Percent of Out of Range (OOR) INRs in Pharmacogenetic-guided Patients and Parallel Controls
timeFrame: 1 month (from day 3 to day 30)
measure: The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms.
timeFrame: 1 month (from baseline to day 30)
measure: The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls
timeFrame: 1 month (from baseline to day 30)
Secondary outcomes:
measure: The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm
timeFrame: 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)
measure: The Percent of INRs ≥4 or ≤1.5 or SAEs Among the Modified IWPC Warfarin Algorithm and Standard IWPC Warfarin Algorithm.
timeFrame: 3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first)
measure: The Number of INRs Measured up to 3 Months in the Pharmacogenetic (PG) (Modified and Standard) Algorithms and Parallel Controls.
timeFrame: 1-3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first)
measure: Prediction of a Stable Maintenance Dose Among the Pharmacogenetic (PG)-Guided Dosing Algorithms and the Parallel Controls
timeFrame: 3 months (from baseline to 3 months or until stable dosing is achieved, whichever occurs first)
measure: The Percent of INRs ≥4 or ≤1.5 in the Pharmacogenetic (PG)-Guided Dosing Arms and the Parallel Control Arm
timeFrame: 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: Intermountain Healthcare Hospitals and Clinics
state: Utah
Study officials:
affiliation: Intermountain Health Care, Inc.
name: Jeffrey L Anderson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.