Clarification of Optimal Anticoagulation Through Genetics

NCT ID: NCT00839657

Last Updated: 2016-04-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1015 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-09-30
• Study Completion Date: 2013-11-30

Brief Summary

Individuals taking warfarin often need frequent dose changes as the international normalized ratio (INR) gets too high or too low which could result in a higher risk of thromboembolism, bleeding and early discontinuation of a highly useful therapy. This study will compare two approaches to warfarin dosing to examine the utility of using genetic information for warfarin dosing.

Detailed Description

The objective of the Clarification of Optimal Anticoagulation through Genetics (COAG) trial is to conduct a 1,022 participant, multicenter, double-blind, randomized trial comparing two approaches to guiding warfarin therapy initiation: 1) initiation of warfarin therapy based on algorithms using clinical information and an individual's genotype using genes known to influence warfarin response ("genotype-guided dosing"), and 2) initiation of warfarin therapy based on algorithms using only clinical information ("clinical-guided dosing"). The study hypothesis is that the use of genetic and clinical information for selecting the dose of warfarin during the initial dosing period will lead to improvement in stability of anticoagulation(AC) relative to a strategy that incorporates only clinical information (without genetics) for initial dosing. Each study arm will include a baseline dose initiation algorithm and a dose revision algorithm applied over the first 4 to 5 doses of warfarin therapy. By comparing the two strategies in this trial, the study will be able to determine if genetic information provides added benefit above and beyond what can be gleaned simply with clinical information. This study is a proof-of-concept efficacy trial. Efficacy is defined as a measure of whether, under optimal application, dosing algorithms will lead to improvement in care. The trial will thus answer the question: "can the use of clinical plus genetic information lead to an improvement in anticoagulation control above and beyond the use of only clinical information during the initiation of warfarin, when applied in a uniform and optimal manner to all patients?" Because efficacy has not yet been established for genotype-guided dosing of warfarin, it is important to first test whether this approach can, indeed, improve anticoagulation outcomes under controlled conditions.

Conditions

Stroke; Venous Thrombosis; Atrial Fibrillation; Atrial Flutter

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

1

Genotype-guided dosing algorithm for warfarin

Group Type: EXPERIMENTAL

Genotype-guided dosing algorithm for warfarin

Intervention Type: BEHAVIORAL

Initial dosing of warfarin for the first 3-4 days of treatment will be determined by an algorithm that uses clinical and genetic information. Following this initiation dose of warfarin, a second dose adjustment will be made after 3 and/or 4 doses of warfarin using a dose revision algorithm that incorporates the clinical and genetic information.

2

Clinical-guided dosing algorithm for warfarin

Group Type: ACTIVE_COMPARATOR

Clinical-guided dosing algorithm for warfarin

Intervention Type: BEHAVIORAL

Initial dosing of warfarin for the first 3-4 days of treatment will be determined by an algorithm that uses clinical information. Following this initiation dose of warfarin, a second dose adjustment will be made after 3 and/or 4 doses of warfarin using a dose revision algorithm that incorporates the clinical information.

Interventions

Genotype-guided dosing algorithm for warfarin

Initial dosing of warfarin for the first 3-4 days of treatment will be determined by an algorithm that uses clinical and genetic information. Following this initiation dose of warfarin, a second dose adjustment will be made after 3 and/or 4 doses of warfarin using a dose revision algorithm that incorporates the clinical and genetic information.

Intervention Type: BEHAVIORAL

Clinical-guided dosing algorithm for warfarin

Initial dosing of warfarin for the first 3-4 days of treatment will be determined by an algorithm that uses clinical information. Following this initiation dose of warfarin, a second dose adjustment will be made after 3 and/or 4 doses of warfarin using a dose revision algorithm that incorporates the clinical information.

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

• Willingness and ability to sign informed consent
• Able to be followed in outpatient AC clinic
• Expected duration of warfarin therapy of at least 1 month
• AC management for the patient will be performed in-hospital and as an outpatient by clinicians that will adhere to the study dosing algorithms and dose titration plans
• Target INR 2-3

Exclusion Criteria

• Currently taking warfarin
• Prior warfarin therapy with known required stable dose
• Clinician opinion that warfarin dosing needs to be adjusted for reasons not accounted for by dosing algorithm
• Abnormal baseline INR (off warfarin) (e.g., due to liver disease, antiphospholipid antibody)
• Contraindication to warfarin treatment for at least 3 months
• Life expectancy of less than 1 year
• Pregnant women or child-bearing women not using medically approved method of birth control (requires negative pregnancy test to exclude pregnancy in child-bearing women)
• Inability to follow-up on a regular basis with anticoagulation practitioners participating in the trial
• Any factors likely to limit adherence to warfarin
• Cognitive or other causes of inability to provide informed consent or follow study procedures
• Participating in another trial that prohibits participation in the COAG trial or planned enrollment in such a trial within the first 6 months of warfarin therapy
• Estimated blood loss of more than 1,000 cc requiring blood transfusions within 48 hours prior to randomization
• Genotype (CYP2C9 or VKORC1) known to participant from prior testing

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephen E Kimmel, MD, MSCE

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of California San Francisco

San Francisco, California, United States

University of Florida

Gainesville, Florida, United States

Georgia Health Sciences University

Augusta, Georgia, United States

Tulane University Health Science Center

New Orleans, Louisiana, United States

University of Maryland School of Medicine

Baltimore, Maryland, United States

Henry Ford Hospital

Detroit, Michigan, United States

Mayo Clinic College of Medicine

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Mount Sinai School of Medicine

New York, New York, United States

Montefiore Medical Center

The Bronx, New York, United States

Duke University

Durham, North Carolina, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

University of Texas Medical Branch

Galveston, Texas, United States

Intermountain Medical Center

Murray, Utah, United States

University of Utah Health Care

Salt Lake City, Utah, United States

Marshfield Clinical Research Foundation

Marshfield, Wisconsin, United States

Countries

United States

References

Joo J, Geller NL, French B, Kimmel SE, Rosenberg Y, Ellenberg JH. Prospective alpha allocation in the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. Clin Trials. 2010 Oct;7(5):597-604. doi: 10.1177/1740774510381285. Epub 2010 Aug 6.

Reference Type: BACKGROUND

PMID: 20693186 (View on PubMed)

Kimmel SE, French B, Anderson JL, Gage BF, Johnson JA, Rosenberg YD, Geller NL, Kasner SE, Eby CS, Joo J, Caldwell MD, Goldhaber SZ, Hart RG, Cifelli D, Madigan R, Brensinger CM, Goldberg S, Califf RM, Ellenberg JH. Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial. Am Heart J. 2013 Sep;166(3):435-41. doi: 10.1016/j.ahj.2013.04.009. Epub 2013 Jul 12.

Reference Type: BACKGROUND

PMID: 24016491 (View on PubMed)

Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, Abdel-Rahman SZ, Stevens SM, Yale S, Mohler ER 3rd, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA 3rd, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH; COAG Investigators. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013 Dec 12;369(24):2283-93. doi: 10.1056/NEJMoa1310669. Epub 2013 Nov 19.

Reference Type: RESULT

PMID: 24251361 (View on PubMed)

French B, Joo J, Geller NL, Kimmel SE, Rosenberg Y, Anderson JL, Gage BF, Johnson JA, Ellenberg JH; COAG (Clarification of Optimal Anticoagulation through Genetics) Investigators. Statistical design of personalized medicine interventions: the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. Trials. 2010 Nov 17;11:108. doi: 10.1186/1745-6215-11-108.

Reference Type: DERIVED

PMID: 21083927 (View on PubMed)

Study Documents

Document Type: Individual Participant Data Set

NHLBI provides controlled access to IPD through BioLINCC. Access requires registration, evidence of local IRB approval or certification of exemption from IRB review, and completion of a data use agreement.

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Document Type: Study Protocol

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Document Type: Study Forms

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Document Type: Manual of Procedures

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Other Identifiers

N01 HV88210

Identifier Type: -

Identifier Source: secondary_id

HHSN268200800003C

Identifier Type: -

Identifier Source: secondary_id

623

Identifier Type: -

Identifier Source: org_study_id