Ignite Creation Date:
2024-05-05 @ 9:59 PM
Last Modification Date:
2024-10-26 @ 10:12 AM
Study NCT ID:
NCT01006733
Status:
COMPLETED
Last Update Posted:
2016-12-29
First Post:
2009-10-30
Brief Title:
Genetics Informatics Trial GIFT of Warfarin to Prevent DVT
Sponsor:
Washington University School of Medicine
Organization:
Washington University School of Medicine
Study Overview
Official Title:
Genetics Informatics Trial GIFT of Warfarin to Prevent Deep Venous Thrombosis DVT
Status:
COMPLETED
Status Verified Date:
2016-12
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:
GIFT
Brief Summary:
Blood clots contribute to the death of at least 100000 Americans each year Because many of these deaths occur suddenly where treatment is impossible the best treatment is prevention With this grant researchers in Missouri New York Utah Illinois and Texas are developing strategies to improve the safety and effectiveness of clot prevention by customizing a popular blood thinner warfarin to each persons genetic and clinical profile They hypothesize that the use of genetics to guide warfarin therapy will reduce the risk of venous thromboembolism VTE postoperatively They further hypothesize that using a target international normalized ratio INR of 18 is non-inferior to using a target INR of 25 in VTE prevention
Detailed Description:
The overall objective of the Genetics-InFormatics Trial GIFT of Warfarin to Prevent DVT is to elucidate novel strategies to improve the safety and effectiveness of warfarin therapy With this study we directly respond to Health and Human Services HHS priorities to advance the field of personalized medicine and to prevent venous thromboembolic VTE disease In 2007 the Honorable Mike Leavitt Secretary of HHS announced the Personalized Health Care Initiative and wrote that a key goal was to use our personal genetic information to tailor treatments more effectively to each patient1 Recently President Obama and Francis Collins Director of the NIH have made precision medicine a national priority2 Previously the Acting Surgeon General issued a Call to Action to reduce the number of cases of VTE in the United States3 To facilitate precision dosing strategies for VTE prevention we have made publically available a non-profit web application wwwWarfarinDosingorg A public version of wwwWarfarinDosingorg estimates warfarin doses for the initial 5 days of warfarin therapy The version being evaluated in GIFT provides doses for the initial 11 days of warfarin therapy
Aim 1 To determine how pharmacogenetic-based warfarin therapy affects the safety and effectiveness of warfarin therapy The intensity of anticoagulant therapy is measured by the International Normalized Ratio INR During initiation the INR often falls outside the therapeutic range INRs that are too low predispose patients to VTE while supratherapeutic INR values increase risk of bleeding4 5 Previously the FDA approved the label change of warfarinCoumadin to recommend considering lower initial doses in patients known to have certain polymorphisms in genes affecting warfarin metabolism and sensitivity6 However whether this strategy improves the safety and effectiveness of warfarin therapy in general is unknown In particular how this strategy affects subgroups with and without the genetic variants of interest is also unknown
Hypothesis 1 Pharmacogenetic therapy decreases the composite risk of a non-fatal VTE non-fatal major hemorrhage death or INR 40 in all patients andor in the subgroup of patients whose pharmacogenetic and clinical predicted therapeutic maintenance doses differ by 10 mgday Based on our meta-analysis of prior trials7 we anticipate 80 power to simultaneously detect a 32 relative risk reduction in the composite outcome for
Aim 1 as measured by a chi-square test In the clinical arm based on preliminary data we anticipate that the rate of the composite outcome will be 157 in the clinical arm and 107 in the pharmacogenetic arm We obtained these estimates because they average a rate of 132 which is the rate of the composite outcome for Aim 1 observed from the initial 775 GIFT participants The power was calculated using a two-sided alpha of 005 for a test of proportions a drop-out rate of 2 and a partitioned two-sided alpha with 0044 allocated to the whole population and 001 to the high-risk subgroup Because of correlation between these two subgroups using these alphas preserves an overall type 1 error rate of 005
Aim 2 To determine whether warfarin therapy with a target INR of 18 is non-inferior to therapy with a target INR of 25 at preventing VTE or death in orthopedic patients One randomized trial PREVENT found that a target INR value of 15-20 prevented 64 of VTE recurrence8 Although that trial excluded orthopedic patients such an approach has been endorsed by the American Academy of Orthopedic Surgeons AAOS On page 15 of the 2007 AAOS guidelines 9 they offer the following recommendation for VTE prophylaxis around the time of joint replacement Warfarin with an INR goal of 20 starting either the night before or the night after surgery for 2-6 weeks However the AAOS grade the overall evidence for VTE prophylaxis in this population as low level III The AAOS guidelines conflict with the prior American College of Chest Physician ACCP guidelines10 which recommend as one of their Grade 1A options page 338 S using an adjusted-dose vitamin K antagonist INR target 25 range 20 to 30 Because lower target INR values may reduce the risk of hemorrhage and simplify warfarin management8 we propose to test the following
Hypothesis 2 For prevention of non-fatal VTE or death a target INR of 18 will be non-inferior to a higher target INR 25 Using a non-inferiority margin of 3 absolute risk reduction in non-fatal VTE or death and an estimated composite rate of 556 based on preliminary GIFT data we will have 83 power to detect the non-inferiority of a target INR of 18 in 1600 patients
Aim 1 To determine how pharmacogenetic-based warfarin therapy affects the safety and effectiveness of warfarin therapy The intensity of anticoagulant therapy is measured by the International Normalized Ratio INR During initiation the INR often falls outside the therapeutic range INRs that are too low predispose patients to VTE while supratherapeutic INR values increase risk of bleeding4 5 Previously the FDA approved the label change of warfarinCoumadin to recommend considering lower initial doses in patients known to have certain polymorphisms in genes affecting warfarin metabolism and sensitivity6 However whether this strategy improves the safety and effectiveness of warfarin therapy in general is unknown In particular how this strategy affects subgroups with and without the genetic variants of interest is also unknown
Hypothesis 1 Pharmacogenetic therapy decreases the composite risk of a non-fatal VTE non-fatal major hemorrhage death or INR 40 in all patients andor in the subgroup of patients whose pharmacogenetic and clinical predicted therapeutic maintenance doses differ by 10 mgday Based on our meta-analysis of prior trials7 we anticipate 80 power to simultaneously detect a 32 relative risk reduction in the composite outcome for
Aim 1 as measured by a chi-square test In the clinical arm based on preliminary data we anticipate that the rate of the composite outcome will be 157 in the clinical arm and 107 in the pharmacogenetic arm We obtained these estimates because they average a rate of 132 which is the rate of the composite outcome for Aim 1 observed from the initial 775 GIFT participants The power was calculated using a two-sided alpha of 005 for a test of proportions a drop-out rate of 2 and a partitioned two-sided alpha with 0044 allocated to the whole population and 001 to the high-risk subgroup Because of correlation between these two subgroups using these alphas preserves an overall type 1 error rate of 005
Aim 2 To determine whether warfarin therapy with a target INR of 18 is non-inferior to therapy with a target INR of 25 at preventing VTE or death in orthopedic patients One randomized trial PREVENT found that a target INR value of 15-20 prevented 64 of VTE recurrence8 Although that trial excluded orthopedic patients such an approach has been endorsed by the American Academy of Orthopedic Surgeons AAOS On page 15 of the 2007 AAOS guidelines 9 they offer the following recommendation for VTE prophylaxis around the time of joint replacement Warfarin with an INR goal of 20 starting either the night before or the night after surgery for 2-6 weeks However the AAOS grade the overall evidence for VTE prophylaxis in this population as low level III The AAOS guidelines conflict with the prior American College of Chest Physician ACCP guidelines10 which recommend as one of their Grade 1A options page 338 S using an adjusted-dose vitamin K antagonist INR target 25 range 20 to 30 Because lower target INR values may reduce the risk of hemorrhage and simplify warfarin management8 we propose to test the following
Hypothesis 2 For prevention of non-fatal VTE or death a target INR of 18 will be non-inferior to a higher target INR 25 Using a non-inferiority margin of 3 absolute risk reduction in non-fatal VTE or death and an estimated composite rate of 556 based on preliminary GIFT data we will have 83 power to detect the non-inferiority of a target INR of 18 in 1600 patients
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01HL097036 | NIH | None | httpsreporternihgovquickSearchR01HL097036 |