Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin (Coumagen-II)

Intermountain Health Care, Inc.

Status and phase: Completed; Phase 3; Phase 2

Conditions: Thromboembolism

Treatments: Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin; Other: Standard of care treatment; Genetic: Modified IWPC genetic-guided warfarin dosing algorithm

Study type: Interventional

Funder types: Other

Identifiers

NCT00927862

154-001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 2,415 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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2,415 participants in 3 patient groups

Standard IWPC warfarin dosing algorithm

Active Comparator group

Description:

Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm.

Treatment:

Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin

Modified IWPC warfarin dosing algorithm

Experimental group

Description:

Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm

Treatment:

Genetic: Modified IWPC genetic-guided warfarin dosing algorithm

Historical controls

Other group

Description:

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.

Treatment:

Other: Standard of care treatment