COAG: Clarification of Optimal Anticoagulation Through Genetics

Sponsor

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00839657

Collaborator

Bristol-Myers Squibb (Industry)

1,015

Enrollment

Locations

Arms

Duration (Months)

56.4

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke Venous Thrombosis Atrial Fibrillation Atrial Flutter	Behavioral: Genotype-guided dosing algorithm for warfarin Behavioral: Clinical-guided dosing algorithm for warfarin	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

1015 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

A Randomized, Multi-Center, Double-Blind Clinical Trial to Evaluate the Use of Clinical Plus Genetic Information to Guide Warfarin Therapy Initiation and Improve Anticoagulation Control for Patients

Study Start Date :

Sep 1, 2009

Actual Primary Completion Date :

Apr 1, 2013

Actual Study Completion Date :

Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Genotype-guided dosing algorithm for warfarin	Behavioral: 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.
Active Comparator: 2 Clinical-guided dosing algorithm for warfarin	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.

Arm

Intervention/Treatment

Experimental: 1

Genotype-guided dosing algorithm for warfarin

Behavioral: 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.

Active Comparator: 2

Clinical-guided dosing algorithm for warfarin

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.

Outcome Measures

Primary Outcome Measures

Percentage of time participants spend within the therapeutic INR range (PTTR) [Measured during the first 4 weeks of therapy]

Secondary Outcome Measures

Occurrence of INR greater than 4 or serious clinical event [Measured during the first 4 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249
2	University of California San Francisco	San Francisco	California	United States	04143-0131
3	University of Florida	Gainesville	Florida	United States	32610-0486
4	Georgia Health Sciences University	Augusta	Georgia	United States	30912
5	Tulane University Health Science Center	New Orleans	Louisiana	United States	70112
6	University of Maryland School of Medicine	Baltimore	Maryland	United States	21201
7	Henry Ford Hospital	Detroit	Michigan	United States	48202
8	Mayo Clinic College of Medicine	Rochester	Minnesota	United States	55905
9	Washington University School of Medicine	St. Louis	Missouri	United States	63110
10	Montefiore Medical Center	Bronx	New York	United States	10467
11	Mount Sinai School of Medicine	New York	New York	United States	10029
12	Duke University	Durham	North Carolina	United States	27710
13	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
14	Vanderbilt University	Nashville	Tennessee	United States	37232
15	University of Texas Medical Branch	Galveston	Texas	United States	77555
16	Intermountain Medical Center	Murray	Utah	United States	84157-7000
17	University of Utah Health Care	Salt Lake City	Utah	United States	84132
18	Marshfield Clinical Research Foundation	Marshfield	Wisconsin	United States	54449