Clarification of Optimal Anticoagulation Through Genetics "COAG"

Completed

Phase 3 Results N/A

Trial Description

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.

Conditions

Interventions

  • Warfarin vs Warfarin Other
    Intervention Desc: All patients in this study will receive warfarin (an anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors). Patients will be randomized to either having their initial warfarin doses determined according to a standard algorithm based on clinical factors alone or determined according to an algorithm based on their genotype and clinical factors.
  • Genotype-guided dosing algorithm for warfarin Behavioral
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: 1
    Description: Participants will receive warfarin genotype-guided dosing, which involves warfarin dosing using clinical and genotype data.
  • Clinical-guided dosing algorithm for warfarin Behavioral
    Intervention Desc: 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 1: Kind: Experimental
    Label: 2
    Description: Participants will receive warfarin clinical-guided dosing, which involves warfarin dosing using clinical data.

Trial Design

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

Patient Involvement

Prior to starting THEIR FIRST DOSE OF warfarin, patients will be approached about the trial. All consented patients will have blood drawn for rapid genotyping of CYP2C9 and VKORC1 variants, and all genotyping results will be entered into a computer system. Patients and clinicians will be blinded to genotype data. Patients will be randomized to either the genotype- or clinical-guided dosing arm, and assigned THEIR FIRST warfarin dose. Patients will continue to be followed for up to 6 months.

Outcomes

Type Measure Time Frame Safety Issue
Primary The percentage of time within the therapeutic INR range (PTTR) during the first 4 weeks of therapy.
Secondary PTTR during the first 2, 12, and 24 weeks of therapy; other endpoints at 2, 12, and 24 weeks, including time to stable warfarin dosing and INR above range (>4.0); number of dose changes required; and major bleeding and thromboembolic outcomes. A Genome Wide Association Study will be done as part of the trial to identify other variants related to warfarin dosing and blood will be stored for future analyses.
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

Sponsors