Clarification of Optimal Anticoagulation Through Genetics (COAG)

National Institutes of Health (NIH)

Status and phase

Completed

Phase 3

Conditions

Atrial Flutter

Atrial Fibrillation

Stroke

Venous Thrombosis

Treatments

Behavioral: Genotype-guided dosing algorithm for warfarin

Behavioral: Clinical-guided dosing algorithm for warfarin

Study type

Interventional

Funder types

Industry

NIH

Identifiers

NCT00839657

N01 HV88210

623

HHSN268200800003C

Details and patient eligibility

About

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.

Full 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.

Enrollment

1,015 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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