Clarification of Optimal Anticoagulation Through Genetics

Stroke Clinical Trial

— COAG  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00839657
• Other study ID #: 623
• Secondary ID: N01 HV88210HHSN2
• Status: Completed
• Phase: Phase 3
• First received: February 6, 2009
• Last updated: April 19, 2016
• Start date: September 2009
• Est. completion date: November 2013

Study information

• Verified date: May 2013
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1015
• Est. completion date: November 2013
• Est. primary completion date: April 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Atrial Fibrillation
• Atrial Flutter
• Stroke
• Thrombosis
• Venous Thrombosis

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Georgia Health Sciences University	Augusta	Georgia
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Montefiore Medical Center	Bronx	New York
United States	Henry Ford Hospital	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	University of Florida	Gainesville	Florida
United States	University of Texas Medical Branch	Galveston	Texas
United States	Marshfield Clinical Research Foundation	Marshfield	Wisconsin
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University	Nashville	Tennessee
United States	Tulane University Health Science Center	New Orleans	Louisiana
United States	Mount Sinai School of Medicine	New York	New York
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic College of Medicine	Rochester	Minnesota
United States	University of Utah Health Care	Salt Lake City	Utah
United States	University of California San Francisco	San Francisco	California
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. Erratum in: Am Heart J. 2014 Feb;167(2):281. Dosage error in article text. — View Citation

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, Desnic — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of time participants spend within the therapeutic INR range (PTTR)		Measured during the first 4 weeks of therapy	Yes
Secondary	Occurrence of INR greater than 4 or serious clinical event		Measured during the first 4 weeks	Yes