ThromboembolismPhase 3GIFTNCT01006733
Genetics Informatics Trial (GIFT) of Warfarin to Prevent DVT
A Phase 3 study testing Pharmacogenetic and Target INR 1.8 in people with Thromboembolism, run by Washington University School of Medicine at 6 sites in United States.
Trial summary
Blood clots contribute to the death of at least 100,000 Americans each year. Because many of these deaths occur suddenly where treatment is impossible, the best treatment is prevention. Read more about this study
- Who is it for?
- Ages 65 years and olderHealthy volunteers can take part
- Conditions the study is for
- Thromboembolism
- What is being tested?
- Pharmacogenetic and Target INR 1.8
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,598 participants
- Where
- 6 sitesUnited States
- Study dates
- Mar 2011to Nov 2016
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 years and older
- All sexes
- Healthy volunteers accepted
- Older adult
Who may be able to join
- 65 years of age or older
- must anticipate taking warfarin for at least 4 weeks for VTE prophylaxis after hip or knee arthroplasty
- must be able to give written, informed consent
- must have venous access
- must not be institutionalized, incarcerated at the time of enrollment (nursing home okay)
- must have life expectancy > 6 months
- must have plans to have regular INR monitoring
- willing/able to follow-up in 3-7 weeks with a Doppler Ultrasound
Who cannot join
- Baseline INR > 1.35
- knowledge of CYP2C9, VKORC1, or CYP4F2 genotype
- knowledge of warfarin dose requirements from prior warfarin therapy
- absolute contraindication or allergy to warfarin therapy (e.g. pregnancy)
- receiving or planning to receive any anticoagulant besides warfarin (if low molecular weight heparin (LMWH) or subcutaneous heparin is deemed necessary by the clinician after enrollment, such patients will be allowed to remain in the study)
- unlikely to be compliant (e.g. due to history of non-compliance, or alcoholism)
- known thrombophilia, bleeding disorder, or history of serious bleed in the past 2 years (unless caused by trauma)
- personal history of venous thromboembolism
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
Rush University Medical Center
Chicago, Illinois, 60612
University of Texas Southwestern
Dallas, Texas, 75390-8870
Hospital for Special Surgery, Weill-Cornell
New York, New York, 10021
University of Utah
Salt Lake City, Utah, 84132
Intermountain Medical Center
Salt Lake City, Utah, 84157
Washington University in St. Louis, School of Medicine
St Louis, Missouri, 63110
About this study
Official title: Genetics Informatics Trial (GIFT) of Warfarin to Prevent Deep Venous Thrombosis (DVT)
Blood clots contribute to the death of at least 100,000 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 person's 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 1.8 is non-inferior to using a target INR of 2.5 in VTE prevention.
Read the 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 patient."(1) Recently, President Obama and Francis Collins (Director of the NIH) have made precision medicine a national priority.(2) Previously, the Acting Surgeon General issued a Call to Action to reduce the number of cases of VTE in the United States.(3) To facilitate precision dosing strategies for VTE prevention, we have made publically available a non-profit, web application, www.WarfarinDosing.org. A public version of www.WarfarinDosing.org 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 bleeding.(4, 5) Previously, the FDA approved the label change of warfarin/Coumadin™ to recommend considering lower initial doses in patients known to have certain polymorphisms in genes affecting warfarin metabolism and sensitivity.(6) 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 ≥ 4.0 in all patients, and/or in the subgroup of patients whose pharmacogenetic and clinical predicted therapeutic maintenance doses differ by > 1.0 mg/day. Based on our meta-analysis of prior trials(7), 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 15.7% in the clinical arm and 10.7% in the pharmacogenetic arm. We obtained these estimates because they average a rate of 13.2%, 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 0.05 for a test of proportions, a drop-out rate of 2%, and a partitioned (two-sided) alpha with 0.044 allocated to the whole population and 0.01 to the high-risk subgroup. Because of correlation between these two subgroups, using these alphas preserves an overall type 1 error rate of 0.05.
Aim 2: To determine whether warfarin therapy with a target INR of 1.8 is non-inferior to therapy with a target INR of 2.5 at preventing VTE or death in orthopedic patients. One randomized trial (PREVENT) found that a target INR value of 1.5-2.0 prevented 64% of VTE recurrence.(8) 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 ≤ 2.0, 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) guidelines,(10) which recommend, as one of their (Grade 1A) options (page 338 S), using an "…adjusted-dose vitamin K antagonist (INR target, 2.5; range 2.0 to 3.0)." Because lower target INR values may reduce the risk of hemorrhage and simplify warfarin management(8) we propose to test the following:
Hypothesis 2: For prevention of non-fatal VTE or death, a target INR of 1.8 will be non-inferior to a higher target INR (2.5). Using a non-inferiority margin of 3% absolute risk reduction in non-fatal VTE or death and an estimated composite rate of 5.56% (based on preliminary GIFT data), we will have 83% power to detect the non-inferiority of a target INR of 1.8 in 1600 patients.
- Conditions
- Thromboembolism
- Being tested
- Pharmacogenetic, Target INR 1.8
- Keywords
- pharmacogenetics, arthroplasty, VKORC1, thromboembolism, warfarin
- Medical subject headings
- Thromboembolism, Vitamin K-Dependent Clotting Factors, Combined Deficiency Of, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PharmacogeneticGenetic
The pharmacogenetic arm estimates therapeutic warfarin dose using cytochrome P 450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P 450 4F2 (CYP4F2) genotype and clinical information. The clinical arm estimates warfarin dose from clinical information alone.
Target INR 1.8Drug
We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.
| Study group | Role | What they receive |
|---|---|---|
| Target INR 1.8 and Pharmacogenetic | Experimental | The target International Normalized Ratio (INR) is 1.8. Warfarin initiation is via Pharmacogenetic dosing. Receives: Genetic: Pharmacogenetic; Drug: Target INR 1.8 |
| Target INR 2.5 and Pharmacogenetic | Experimental | The target INR is 2.5. Warfarin initiation is via Pharmacogenetic dosing. Receives: Genetic: Pharmacogenetic |
| Target INR 1.8 and Clinical | Experimental | The target INR is 1.8. Warfarin initiation is via clinical dosing. Receives: Drug: Target INR 1.8 |
| Target INR 2.5 and Clinical | No intervention | The target INR is 2.5. Warfarin initiation is via clinical dosing. |
What is being measured
The primary outcome is the main question the study is designed to answer.
For Aim 1: The composite outcome of: non-fatal venous thromboembolism (VTE), non-fatal major hemorrhage, INR>=4.0, and death.
Measured: 30-days, except that VTE may be detected up to day 60
For Aim 2: The composite outcome of: non-fatal venous thromboembolism (VTE) and death.
Measured: 30-days for death; 60 days for VTE
Secondary outcomes (4)
Percent Time in Therapeutic INR Range
We also we report INR Variability using the method of Lind et al. (2012 Thrombosis research).
Measured: 4-28 days
Composite Outcomes
We will compare the two arms in Aim 2 using the same composite outcome from Aim 1: VTE, major hemorrhage, death, or INR >= 4.0.
Measured: 30 days for death; 60 days for VTE, major bleed, INR >=4.0.
Ranked Outcomes
Outcomes will be ranked using the following tiers in hierarchical order, from worst to best: (1) death; (2) PE; (3) Major bleed; (4) symptomatic DVT; (5) INR >= 4 with minor bleed; (6) asymptomatic DVT; (7) INR >= 4 (w/out major/minor bleed); (8) PTTR.
Events that happen earliest receive the lowest (worst) score. For PTTR, lower time in the target INR range is worse. This approach, similar to that used in the RELAX trial (Redfield et al. 2013) weighs outcomes according to their clinical relevance. Ranks will be compared using a standard non-parametric test (Mann-Whitney 1947) to determine if one arm improves outcomes.
Measured: 4-28 days for PTTR (INR variability); 30 days for death; 60 days for VTE.
Time to first laboratory event (INR > 1.5 + Target INR)
Measured: Maximum of 90 days; median time to last INR is 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Nov 2009 (estimated)
- Study startMar 2011
- Primary completionOct 2016
- Study completionNov 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for ThromboembolismStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,598 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), Hospital for Special Surgery, New York, Intermountain Health Care, Inc., University of Utah, Rush University Medical Center, University of Texas Southwestern Medical Center
- Responsible party
- Sponsor
- Investigators
- Brian F Gage, MD, MSc, Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01006733
- Sponsor's protocol ID
- HL097036-01
- Other IDs
- R01HL097036
- Acronym
- GIFT
- Status last verified
- Dec 2016
- First submitted
- 30 Oct 2009
- Last updated
- 29 Dec 2016
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: GIFT plans to share anonymous IPD with other researchers via BioLINCC in March 2018.
Publications
Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, Caldwell MD, Limdi N, Burmester JK, Dowd MB, Angchaisuksiri P, Bass AR, Chen J, Eriksson N, Rane A, Lindh JD, Carlquist JF, Horne BD, Grice G, Milligan PE, Eby C, Shin J, Kim H, Kurnik D, Stein CM, McMillin G, Pendleton RC, Berg RL, Deloukas P, Gage BF. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther. 2010 May;87(5):572-8. doi: 10.1038/clpt.2010.13. Epub 2010 Apr 7.
PubMed 20375999Ferder NS, Eby CS, Deych E, Harris JK, Ridker PM, Milligan PE, Goldhaber SZ, King CR, Giri T, McLeod HL, Glynn RJ, Gage BF. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost. 2010 Jan;8(1):95-100. doi: 10.1111/j.1538-7836.2009.03677.x. Epub 2009 Oct 30.
PubMed 19874474King CR, Deych E, Milligan P, Eby C, Lenzini P, Grice G, Porche-Sorbet RM, Ridker PM, Gage BF. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost. 2010 Oct;104(4):750-4. doi: 10.1160/TH09-11-0763. Epub 2010 Aug 5.
PubMed 20694283Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol. 2011 Feb 1;57(5):612-8. doi: 10.1016/j.jacc.2010.08.643.
PubMed 21272753Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011 Oct;90(4):625-9. doi: 10.1038/clpt.2011.185. Epub 2011 Sep 7.
PubMed 21900891Horne BD, Lenzini PA, Wadelius M, Jorgensen AL, Kimmel SE, Ridker PM, Eriksson N, Anderson JL, Pirmohamed M, Limdi NA, Pendleton RC, McMillin GA, Burmester JK, Kurnik D, Stein CM, Caldwell MD, Eby CS, Rane A, Lindh JD, Shin JG, Kim HS, Angchaisuksiri P, Glynn RJ, Kronquist KE, Carlquist JF, Grice GR, Barrack RL, Li J, Gage BF. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost. 2012 Feb;107(2):232-40. doi: 10.1160/TH11-06-0388. Epub 2011 Dec 21.
PubMed 22186998Do EJ, Lenzini P, Eby CS, Bass AR, McMillin GA, Stevens SM, Woller SC, Pendleton RC, Anderson JL, Proctor P, Nunley RM, Davila-Roman V, Gage BF. Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. Pharmacogenomics J. 2012 Oct;12(5):417-24. doi: 10.1038/tpj.2011.18. Epub 2011 May 24.
PubMed 21606949Kawai VK, Cunningham A, Vear SI, Van Driest SL, Oginni A, Xu H, Jiang M, Li C, Denny JC, Shaffer C, Bowton E, Gage BF, Ray WA, Roden DM, Stein CM. Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics. 2014 Dec;15(16):1973-83. doi: 10.2217/pgs.14.153.
PubMed 25521356Bass AR, Rodriguez T, Hyun G, Santiago FG, Kim JI, Woller SC, Gage BF. Myocardial ischaemia after hip and knee arthroplasty: incidence and risk factors. Int Orthop. 2015 Oct;39(10):2011-6. doi: 10.1007/s00264-015-2853-0. Epub 2015 Jul 9.
PubMed 26156715Hyun G, Li J, Bass AR, Mohapatra A, Woller SC, Lin H, Eby C, McMillin GA, Gage BF. Use of signals and systems engineering to improve the safety of warfarin initiation. J Thromb Thrombolysis. 2016 Nov;42(4):529-33. doi: 10.1007/s11239-016-1402-z.
PubMed 27443162Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Anderson JL, Li J, Rodriguez T Jr, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple B, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Davila-Roman V, Eby CS. Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial. JAMA. 2019 Sep 3;322(9):834-842. doi: 10.1001/jama.2019.12085.
PubMed 31479138Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Li J, Rodriguez T Jr, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple BD, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Anderson JL, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Davila-Roman V, Eby CS. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial. JAMA. 2017 Sep 26;318(12):1115-1124. doi: 10.1001/jama.2017.11469.
PubMed 28973620
Study at a glance
From the registry record, last updated by the sponsor on 29 Dec 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genetics Informatics Trial (GIFT) of Warfarin to Prevent Deep Venous Thrombosis (DVT)
- ClinicalTrials.gov ID
- NCT01006733
- Acronym / sponsor ID
- GIFT / HL097036-01
- Conditions
- Thromboembolism
- Keywords
- pharmacogenetics, arthroplasty, VKORC1, thromboembolism, warfarin
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,598 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), Hospital for Special Surgery, New York, Intermountain Health Care, Inc., University of Utah, Rush University Medical Center, University of Texas Southwestern Medical Center
- Study start
- Mar 2011
- Primary completion
- Oct 2016 (actual)
- Study completion
- Nov 2016 (actual)
- First posted
- 3 Nov 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Blood clots contribute to the death of at least 100,000 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 person's 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 1.8 is non-inferior to using a target INR of 2.5 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 patient."(1) Recently, President Obama and Francis Collins (Director of the NIH) have made precision medicine a national priority.(2) Previously, the Acting Surgeon General issued a Call to Action to reduce the number of cases of VTE in the United States.(3) To facilitate precision dosing strategies for VTE prevention, we have made publically available a non-profit, web application, www.WarfarinDosing.org. A public version of www.WarfarinDosing.org 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 bleeding.(4, 5) Previously, the FDA approved the label change of warfarin/Coumadin™ to recommend considering lower initial doses in patients known to have certain polymorphisms in genes affecting warfarin metabolism and sensitivity.(6) 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 ≥ 4.0 in all patients, and/or in the subgroup of patients whose pharmacogenetic and clinical predicted therapeutic maintenance doses differ by > 1.0 mg/day. Based on our meta-analysis of prior trials(7), 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 15.7% in the clinical arm and 10.7% in the pharmacogenetic arm. We obtained these estimates because they average a rate of 13.2%, 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 0.05 for a test of proportions, a drop-out rate of 2%, and a partitioned (two-sided) alpha with 0.044 allocated to the whole population and 0.01 to the high-risk subgroup. Because of correlation between these two subgroups, using these alphas preserves an overall type 1 error rate of 0.05.
Aim 2: To determine whether warfarin therapy with a target INR of 1.8 is non-inferior to therapy with a target INR of 2.5 at preventing VTE or death in orthopedic patients. One randomized trial (PREVENT) found that a target INR value of 1.5-2.0 prevented 64% of VTE recurrence.(8) 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 ≤ 2.0, 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) guidelines,(10) which recommend, as one of their (Grade 1A) options (page 338 S), using an "…adjusted-dose vitamin K antagonist (INR target, 2.5; range 2.0 to 3.0)." Because lower target INR values may reduce the risk of hemorrhage and simplify warfarin management(8) we propose to test the following:
Hypothesis 2: For prevention of non-fatal VTE or death, a target INR of 1.8 will be non-inferior to a higher target INR (2.5). Using a non-inferiority margin of 3% absolute risk reduction in non-fatal VTE or death and an estimated composite rate of 5.56% (based on preliminary GIFT data), we will have 83% power to detect the non-inferiority of a target INR of 1.8 in 1600 patients.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Target INR 1.8 and Pharmacogenetic | Experimental | Genetic: Pharmacogenetic, Drug: Target INR 1.8The target International Normalized Ratio (INR) is 1.8. Warfarin initiation is via Pharmacogenetic dosing. |
| Target INR 2.5 and Pharmacogenetic | Experimental | Genetic: PharmacogeneticThe target INR is 2.5. Warfarin initiation is via Pharmacogenetic dosing. |
| Target INR 1.8 and Clinical | Experimental | Drug: Target INR 1.8The target INR is 1.8. Warfarin initiation is via clinical dosing. |
| Target INR 2.5 and Clinical | No intervention | –The target INR is 2.5. Warfarin initiation is via clinical dosing. |
Who may qualify
- Ages
- 65 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Older adult
Key inclusion criteria (8 listed)
- 65 years of age or older
- must anticipate taking warfarin for at least 4 weeks for VTE prophylaxis after hip or knee arthroplasty
- must be able to give written, informed consent
- must have venous access
- must not be institutionalized, incarcerated at the time of enrollment (nursing home okay)
Key exclusion criteria (8 listed)
- Baseline INR > 1.35
- knowledge of CYP2C9, VKORC1, or CYP4F2 genotype
- knowledge of warfarin dose requirements from prior warfarin therapy
- absolute contraindication or allergy to warfarin therapy (e.g. pregnancy)
- receiving or planning to receive any anticoagulant besides warfarin (if low molecular weight heparin (LMWH) or subcutaneous heparin is deemed necessary by the clinician after enrollment, such patients will be allowed to remain in the study)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PharmacogeneticThe pharmacogenetic arm estimates therapeutic warfarin dose using cytochrome P 450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P 450 4F2 (CYP4F2) genotype and clinical information. The clinical arm estimates warfarin dose from clinical information alone. | Genetic | Target INR 1.8 and Pharmacogenetic, Target INR 2.5 and Pharmacogenetic |
| Target INR 1.8We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8. | Drug | Target INR 1.8 and Clinical, Target INR 1.8 and Pharmacogenetic |
Primary outcome
For Aim 1: The composite outcome of: non-fatal venous thromboembolism (VTE), non-fatal major hemorrhage, INR>=4.0, and death.
Time frame: 30-days, except that VTE may be detected up to day 60
For Aim 2: The composite outcome of: non-fatal venous thromboembolism (VTE) and death.
Time frame: 30-days for death; 60 days for VTE
4 secondary outcomes
Percent Time in Therapeutic INR Range
Time frame: 4-28 days
Composite Outcomes
Time frame: 30 days for death; 60 days for VTE, major bleed, INR >=4.0.
Ranked Outcomes
Time frame: 4-28 days for PTTR (INR variability); 30 days for death; 60 days for VTE.
Time to first laboratory event (INR > 1.5 + Target INR)
Time frame: Maximum of 90 days; median time to last INR is 28 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Dec 2016.
- Background: PubMed 20375999Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, Caldwell MD, Limdi N, Burmester JK, Dowd MB, Angchaisuksiri P, Bass AR, Chen J, Eriksson N, Rane A, Lindh JD, Carlquist JF, Horne BD, Grice G, Milligan PE, Eby C, Shin J, Kim H, Kurnik D, Stein CM, McMillin G, Pendleton RC, Berg RL, Deloukas P, Gage BF. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther. 2010 May;87(5):572-8. doi: 10.1038/clpt.2010.13. Epub 2010 Apr 7.
- Background: PubMed 19874474Ferder NS, Eby CS, Deych E, Harris JK, Ridker PM, Milligan PE, Goldhaber SZ, King CR, Giri T, McLeod HL, Glynn RJ, Gage BF. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost. 2010 Jan;8(1):95-100. doi: 10.1111/j.1538-7836.2009.03677.x. Epub 2009 Oct 30.
- Background: PubMed 20694283King CR, Deych E, Milligan P, Eby C, Lenzini P, Grice G, Porche-Sorbet RM, Ridker PM, Gage BF. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost. 2010 Oct;104(4):750-4. doi: 10.1160/TH09-11-0763. Epub 2010 Aug 5.
- Background: PubMed 21272753Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol. 2011 Feb 1;57(5):612-8. doi: 10.1016/j.jacc.2010.08.643.
- Background: PubMed 21900891Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011 Oct;90(4):625-9. doi: 10.1038/clpt.2011.185. Epub 2011 Sep 7.
- Background: PubMed 22186998Horne BD, Lenzini PA, Wadelius M, Jorgensen AL, Kimmel SE, Ridker PM, Eriksson N, Anderson JL, Pirmohamed M, Limdi NA, Pendleton RC, McMillin GA, Burmester JK, Kurnik D, Stein CM, Caldwell MD, Eby CS, Rane A, Lindh JD, Shin JG, Kim HS, Angchaisuksiri P, Glynn RJ, Kronquist KE, Carlquist JF, Grice GR, Barrack RL, Li J, Gage BF. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost. 2012 Feb;107(2):232-40. doi: 10.1160/TH11-06-0388. Epub 2011 Dec 21.
- Background: PubMed 21606949Do EJ, Lenzini P, Eby CS, Bass AR, McMillin GA, Stevens SM, Woller SC, Pendleton RC, Anderson JL, Proctor P, Nunley RM, Davila-Roman V, Gage BF. Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. Pharmacogenomics J. 2012 Oct;12(5):417-24. doi: 10.1038/tpj.2011.18. Epub 2011 May 24.
- Background: PubMed 25521356Kawai VK, Cunningham A, Vear SI, Van Driest SL, Oginni A, Xu H, Jiang M, Li C, Denny JC, Shaffer C, Bowton E, Gage BF, Ray WA, Roden DM, Stein CM. Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics. 2014 Dec;15(16):1973-83. doi: 10.2217/pgs.14.153.
- Background: PubMed 26156715Bass AR, Rodriguez T, Hyun G, Santiago FG, Kim JI, Woller SC, Gage BF. Myocardial ischaemia after hip and knee arthroplasty: incidence and risk factors. Int Orthop. 2015 Oct;39(10):2011-6. doi: 10.1007/s00264-015-2853-0. Epub 2015 Jul 9.
- Background: PubMed 27443162Hyun G, Li J, Bass AR, Mohapatra A, Woller SC, Lin H, Eby C, McMillin GA, Gage BF. Use of signals and systems engineering to improve the safety of warfarin initiation. J Thromb Thrombolysis. 2016 Nov;42(4):529-33. doi: 10.1007/s11239-016-1402-z.
- Derived from this study: PubMed 31479138Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Anderson JL, Li J, Rodriguez T Jr, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple B, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Davila-Roman V, Eby CS. Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial. JAMA. 2019 Sep 3;322(9):834-842. doi: 10.1001/jama.2019.12085.
- Derived from this study: PubMed 28973620Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Li J, Rodriguez T Jr, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple BD, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Anderson JL, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Davila-Roman V, Eby CS. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial. JAMA. 2017 Sep 26;318(12):1115-1124. doi: 10.1001/jama.2017.11469.
- pharmacogenetic and clinical warfarin dosing algorithms for trialLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. GIFT plans to share anonymous IPD with other researchers via BioLINCC in March 2018.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brian F Gage, MD, MSc principal investigator
Washington University School of Medicine
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Pharmacogenetic and Target INR 1.8 in people with Thromboembolism, run by Washington University School of Medicine at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Dec 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
For Aim 1: The composite outcome of: non-fatal venous thromboembolism (VTE), non-fatal major hemorrhage, INR>=4.0, and death. (time frame: 30-days, except that VTE may be detected up to day 60). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01006733, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Dec 2016.