Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin

NCT00927862 | Completed Phase 2 Results DMC

• 1 other identifier: 154-001
• Study Type: interventional
• Target: 2,415
• Locations: 1 country
• Sites: 1

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.

Conditions

Thromboembolism

Keywords

warfarin metabolism; CYP2C9; genotyping; VKORC1; anticoagulation; atrial fibrillation; deep vein thrombosis; pulmonary embolism; Patients initiating warfarin for thromboembolic conditions

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (5)

• The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm

  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.

  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.

  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

  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

  3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)

Study Arms (3)

Standard IWPC warfarin dosing algorithm

ACTIVE COMPARATOR

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

Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin

Modified IWPC warfarin dosing algorithm

EXPERIMENTAL

Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm

Genetic: Modified IWPC genetic-guided 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.

Other: Standard of care treatment

Interventions

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.

Also known as: IWPC=international warfarin pharmacogenetic collaboration

Standard IWPC warfarin dosing algorithm

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.

Also known as: IWPC=international warfarin pharmacogenetic collaboration

Modified IWPC warfarin dosing algorithm

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.

Historical controls

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Intermountain Health Care, Inc.: lead

Study Sites (1)

Intermountain Healthcare Hospitals and Clinics

Salt Lake City, Utah, 84107, United States

Location

Related Publications (1)

• 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.

  PMID: 22431865 DERIVED

MeSH Terms

Conditions

Thromboembolism; Vitamin K-Dependent Clotting Factors, Combined Deficiency Of, Type 2; Atrial Fibrillation; Venous Thrombosis; Pulmonary Embolism

Interventions

Warfarin

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Thrombosis; Lung Diseases; Respiratory Tract Diseases; Embolism

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Dr. Jeffrey L. Anderson, Director of CV Research and Professor of Medicine
• Organization: Intermountain Healthcare

jeffrey.anderson@imail.org

801-507-4704

Study Officials

• Jeffrey L Anderson, MD

  Intermountain Health Care, Inc.

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 23, 2009
• First Posted: June 25, 2009
• Study Start: August 1, 2008
• Primary Completion: December 1, 2010
• Study Completion: June 1, 2011
• Last Updated: September 25, 2012
• Results First Posted: September 25, 2012

Record last verified: 2012-08

Locations

US (1)