Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin

Condition(s) targeted: Thromboembolism

Intervention: IWPC adapted genotype-guided dosing algorithm for warfarin (Genetic); Modified IWPC genetic-guided warfarin dosing algorithm (Genetic)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Intermountain Health Care, Inc.

Official(s) and/or principal investigator(s):
Jeffrey L Anderson, MD, Principal Investigator, Affiliation: Intermountain Health Care, Inc.

Overall contact:
Jeffrey L Anderson, MD, Phone: 801.507.4704, Email: jeffrey.anderson@imail.org

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 US, 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.

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

Study design: Allocation: Randomized, Control: Active Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome:

A modified algorithm will be non-inferior overall and superior in specified subgroups to standard genotype-guided dosing

PG-guided dosing will decrease the %OOR INRs in wild type and multiple variant carriers vs historical controls

Secondary outcome:

PG-guided dosing will decrease the %OOR INRs in the overall study population versus controls over the first month of therapy (first secondary endpoint)

PG-guided dosing will decrease the number of dosing changes

PG-guided dosing will decrease the number of INRs measured

PG-guided dosing will decrease the number/% of INRs >=4 in multiple variant carriers versus their controls

PG-guided dosing will decrease the number/% of INRs >=4 in all patients versus their controls

PG-guided dosing will decrease the number/% of subtherapeutic INRs in wild type patients versus their controls

PG-guided dosing will decrease the number of serious adverse clinical events (death, MI, stroke, thromboembolic event, more than minor hemorrhage) or INR >=4

The PG-guided algorithm will better predict eventual stable maintenance dose than the initial empiric dose selection

Patients with one or more CYP2C9 variant will require a longer time to achieve steady state INR (i.e., stable maintenance INR).

A greater benefit trend will be seen for PG-guided dosing with outpatient initiation.

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 IHC facilities in the Urban Central Region (i. e., IMC, LDS, 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) 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 (mod-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 UCR (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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- New participants will be those >=18 years old who are appropriate candidates for and

being initiated on warfarin therapy with target 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 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.

Jeffrey L Anderson, MD, Phone: 801.507.4704, Email: jeffrey.anderson@imail.org

Intermountain Healthcare Hospitals and Clinics, Salt Lake City, Utah 84107, United States; Recruiting
Jeffrey L Anderson, MD, Phone: 801-507-4757, Email: jeffrey.anderson@imail.org
John F Carlquist, PhD, Phone: 801.408.1028, Email: john.carlquist@imail.org
Jeffrey L Anderson, MD, Principal Investigator
Joseph B Muhlestein, MD, Sub-Investigator
Kent Samuelsen, MD, Sub-Investigator
Marc Williams, MD, Sub-Investigator
Brent James, MD PhD, Sub-Investigator
John F Carlquist, PhD, Sub-Investigator
Scott Stevens, MD, Sub-Investigator
Benjamin D Horne, PhD, Sub-Investigator
Angela Schwab, MS, CGC, Sub-Investigator

Starting date: August 2008
Last updated: August 5, 2010