Clarification of Optimal Anticoagulation Through Genetics (COAG)

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

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.

Study Overview

• Status: Completed
• Conditions: Stroke; Venous Thrombosis; Atrial Fibrillation; Atrial Flutter
• Intervention / Treatment: Behavioral: Genotype-guided dosing algorithm for warfarin; Behavioral: Clinical-guided dosing algorithm for warfarin

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 Type: Interventional
• Enrollment (Actual): 1015
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • California
    • San Francisco, California, United States, 04143-0131
      • University of California San Francisco
  • Florida
    • Gainesville, Florida, United States, 32610-0486
      • University of Florida
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Health Sciences University
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Science Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic College of Medicine
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Texas
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
  • Utah
    • Murray, Utah, United States, 84157-7000
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Care
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinical Research Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of time participants spend within the therapeutic INR range (PTTR)	Measured during the first 4 weeks of therapy

Secondary Outcome Measures

Outcome Measure	Time Frame
Occurrence of INR greater than 4 or serious clinical event	Measured during the first 4 weeks

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Stephen E Kimmel, MD, MSCE, University of Pennsylvania

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: February 6, 2009
• First Submitted That Met QC Criteria: February 6, 2009
• First Posted (Estimate): February 9, 2009

Study Record Updates

• Last Update Posted (Estimate): April 20, 2016
• Last Update Submitted That Met QC Criteria: April 19, 2016
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Embolism; Thrombosis
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Arrhythmias, Cardiac; Atrial Fibrillation; Thrombosis; Venous Thrombosis; Atrial Flutter; Anticoagulants; Warfarin
• Other Study ID Numbers: 623; N01 HV88210; HHSN268200800003C

Plan for Individual participant data (IPD)

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: COAG
   Information comments: 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.
2. Study Protocol
3. Study Forms
4. Manual of Procedures