Clarification of Optimal Anticoagulation Through Genetics

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.

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