Clinical trial NCT00839657: Clarification of Optimal Anticoagulation Through Genetics
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Stroke
Venous Thrombosis
Atrial Fibrillation
Atrial Flutter
Keywords: Embolism
Thrombosis
Lead sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Sponsor class: NIH
Collaborators: name: Bristol-Myers Squibb
First posted: 2009-02-09
Enrollment: 1015
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of time participants spend within the therapeutic INR range (PTTR)
timeFrame: Measured during the first 4 weeks of therapy
Secondary outcomes:
measure: Occurrence of INR greater than 4 or serious clinical event
timeFrame: Measured during the first 4 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Augusta
country: United States
facility: Georgia Health Sciences University
state: Georgia
city: New Orleans
country: United States
facility: Tulane University Health Science Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic College of Medicine
state: Minnesota
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Health Care
state: Utah
city: Marshfield
country: United States
facility: Marshfield Clinical Research Foundation
state: Wisconsin
Study officials:
affiliation: University of Pennsylvania
name: Stephen E Kimmel, MD, MSCE
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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, 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.
citation: 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.