Ignite Creation Date:
2024-05-05 @ 9:30 PM
Last Modification Date:
2024-10-26 @ 10:05 AM
Study NCT ID:
NCT00904293
Status:
COMPLETED
Last Update Posted:
2016-05-06
First Post:
2009-04-06
Brief Title:
Genotype-Guided Warfarin Therapy Trial
Sponsor:
University of North Carolina Chapel Hill
Organization:
University of North Carolina Chapel Hill
Study Overview
Official Title:
Randomized Controlled Trial of Genotype-Guided Dosing of Warfarin Therapy
Status:
COMPLETED
Status Verified Date:
2013-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
WARFPGX
Brief Summary:
The purpose of the investigators study is to determine the clinical utility of a warfarin-dosing algorithm that incorporates genetic information VKORC1 and CYP2C9 alleles for adult patients initiating warfarin therapy
Detailed Description:
Almost 20 million prescriptions are written for warfarin each year in the US and yet it is one of the most problematic drugs in the modern medical formulary Warfarin has a narrow therapeutic window and the hemorrhagic or thrombotic implications of modest over- or under-dosing can be devastating Warfarin is one of the leading causes of emergency department visits and hospitalizations due to adverse drug events worldwide Adverse events from warfarin are more common during the initial months of treatment before the optimal dose is determined Moreover there is substantial individual variation in response to warfarin necessitating frequent monitoring and dosage adjustments The monitoring and dosing of warfarin is so problematic that many primary care physicians have abdicated this role to specialized warfarin clinics which are devoted solely to following patients on this agent Unfortunately no good alternatives to warfarin exist for the common indications requiring chronic anticoagulation such as atrial fibrillation deep vein thrombosis pulmonary embolism and artificial heart valves
Pharmacogenomics offers substantial hope for improved care of patients taking warfarin One group estimated that formally integrating genetic testing into routine warfarin therapy in the US could result in the avoidance of 85000 serious bleeding events and 17000 strokes annually with a cost savings of over 1 billion annually Common single nucleotide polymorphisms SNPs in the gene encoding Vitamin K Epoxide Reductase VKOR substantially affect ones sensitivity to warfarin mediating a doubling or halving of the dose required for optimal anticoagulation Warfarin inhibits clotting by inhibiting the enzyme VKOR and thus inhibiting vitamin K dependent clotting factors A number of recent retrospective studies have shown that polymorphisms in the VKOR gene may account for 20-30 of the variance in warfarin dose seen in patients on stable long-term warfarin therapy
Another genetic determinant of variance in warfarin dose is the cytochrome p450 2C9 enzyme CYP2C9 It is almost wholly responsible for metabolism of the more active S-enantiomer of warfarin The 2C92 and 2C93 polymorphisms in the CYP2C9 gene are associated with reduced warfarin metabolism and a number of retrospective studies have shown that these polymorphisms may account for 10-15 of the variance in warfarin dosage in patients on stable long-term warfarin therapy In addition the variant CYP2C9 alleles have been associated with longer times to stabilization of INR and a higher risk for bleeding events These polymorphisms are seen in 20-30 of the Caucasian population but are rare in African Americans and Asians Together known VKOR and CYP2C9 variants may account for 40 of the variability in warfarin dosing
By combining clinical information such as weight height and concomitant medications with VKOR and CYP2C9 genotypic information several algorithms have been devised that calculate warfarin doses These algorithms have been shown to accurately predict warfarin doses in retrospective studies of patients already on long-term stable warfarin doses Some small pilot studies in orthopedic patients suggest that prospective genetic-based dosing is feasible and may result in achieving stable doses sooner in patients with certain genetic variants However the prospective studies are small pilot studies limited to orthopedic patients that did not include medical patients with common indications requiring chronic oral anticoagulation They are also limited by study designs that include only historical controls No RCTs have been reported in the literature and further evaluation is needed to determine the utility and cost-effectiveness of genetic-based algorithms The NHLBI is planning a double-blind randomized three-arm trial but the trial will not begin enrolling subjects until 2008 at the earliest and data analysis and dissemination is planned to begin beyond 2011
Pharmacogenomics offers substantial hope for improved care of patients taking warfarin One group estimated that formally integrating genetic testing into routine warfarin therapy in the US could result in the avoidance of 85000 serious bleeding events and 17000 strokes annually with a cost savings of over 1 billion annually Common single nucleotide polymorphisms SNPs in the gene encoding Vitamin K Epoxide Reductase VKOR substantially affect ones sensitivity to warfarin mediating a doubling or halving of the dose required for optimal anticoagulation Warfarin inhibits clotting by inhibiting the enzyme VKOR and thus inhibiting vitamin K dependent clotting factors A number of recent retrospective studies have shown that polymorphisms in the VKOR gene may account for 20-30 of the variance in warfarin dose seen in patients on stable long-term warfarin therapy
Another genetic determinant of variance in warfarin dose is the cytochrome p450 2C9 enzyme CYP2C9 It is almost wholly responsible for metabolism of the more active S-enantiomer of warfarin The 2C92 and 2C93 polymorphisms in the CYP2C9 gene are associated with reduced warfarin metabolism and a number of retrospective studies have shown that these polymorphisms may account for 10-15 of the variance in warfarin dosage in patients on stable long-term warfarin therapy In addition the variant CYP2C9 alleles have been associated with longer times to stabilization of INR and a higher risk for bleeding events These polymorphisms are seen in 20-30 of the Caucasian population but are rare in African Americans and Asians Together known VKOR and CYP2C9 variants may account for 40 of the variability in warfarin dosing
By combining clinical information such as weight height and concomitant medications with VKOR and CYP2C9 genotypic information several algorithms have been devised that calculate warfarin doses These algorithms have been shown to accurately predict warfarin doses in retrospective studies of patients already on long-term stable warfarin doses Some small pilot studies in orthopedic patients suggest that prospective genetic-based dosing is feasible and may result in achieving stable doses sooner in patients with certain genetic variants However the prospective studies are small pilot studies limited to orthopedic patients that did not include medical patients with common indications requiring chronic oral anticoagulation They are also limited by study designs that include only historical controls No RCTs have been reported in the literature and further evaluation is needed to determine the utility and cost-effectiveness of genetic-based algorithms The NHLBI is planning a double-blind randomized three-arm trial but the trial will not begin enrolling subjects until 2008 at the earliest and data analysis and dissemination is planned to begin beyond 2011
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None