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Prospective Genotyping For Total Hip or Knee Replacement Patients Receiving Warfarin (Coumadin)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gwen McMillin, University of Utah
ClinicalTrials.gov Identifier:
NCT00634907
First received: February 6, 2008
Last updated: April 25, 2017
Last verified: April 2017
Results First Received: April 23, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions: Venous Thromboembolism
Bleeding
Interventions: Genetic: Pharmacogenetic-based warfarin dosing
Other: Usual care warfarin dosing

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patients planning total hip or knee replacement surgery at the University of Utah Hospital, will be approached about participation in the study by Dr Chris Peters, MD or assigned orthopedic staff at the pre-operative office visit at the University of Utah Orthopaedic Center. Patients were enrolled from 9/27/06 - 10/2/08

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

Exclusion Criteria:

  1. Blood transfusion in previous two weeks
  2. Participant is already taking warfarin
  3. Pre-operative INR > 4.0
  4. Pre-operative bilirubin > 2.4 mg/dL
  5. Current active cancer diagnosis with ongoing treatment
  6. Concomitant medications known to exert a major interaction with warfarin

Reporting Groups
  Description
2 Genotype Arm

The initial dose of warfarin will be corrected by the AC services team to account for variant genotypes, according to the following:

Sqrt (Dose) = 0.628 - 0.0135(Age) - 0.240(CYP2C9*2) - 0.370 (CYP2C9*3) - 0.241(VKORC1) + 0.0162(Height) Age: input age in years CYP2C9: input 0, 1, or 2 based on the number of variant alleles VKORC1: input 1 for GG, 2 for GA, and 3 for AA Height: input height in centimeters Patients in this study group will be managed by designated AC services physicians, different from those in managing patients in the Control Arm of this study. Dosing adjustments will be made based on post-surgical INR values obtained initially on POD#2 daily during hospital stay, and 2 times weekly, or as needed, thereafter.

1 Control Arm This is a two-armed parallel study with randomized assignment designed to test the hypothesis that selection of the initial warfarin dose based on CYP2C9 and VKORC1 genotypes will improve warfarin pharmacotherapy outcomes. Initial dose of warfarin will be given as per standard protocol for the Control Arm. Briefly, 3 or 5 mg warfarin will be administered on the day of surgery (post-operative day zero, POD#0) and the subsequent day. Patients in this study group will be managed by designated AC services physicians. Dosing adjustments will be made based on post-surgical INR values obtained initially on POD#2, daily during hospital stay, and 2 times weekly, or as needed, thereafter.

Participant Flow:   Overall Study
    2 Genotype Arm   1 Control Arm
STARTED   131   132 
COMPLETED   114   115 
NOT COMPLETED   17   17 
Withdrawal by Subject                3                0 
Physician Decision                3                9 
Withdrawal by Subject                11                8 



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Genotype-Based Dosing Arm Initial warfarin dose calculated according to published Sconce algorithm
Control Arm Standard of care dosing
Total Total of all reporting groups

Baseline Measures
   Genotype-Based Dosing Arm   Control Arm   Total 
Overall Participants Analyzed 
[Units: Participants]
 114   115   229 
Age 
[Units: Participants]
Count of Participants
     
<=18 years      0   0.0%      0   0.0%      0   0.0% 
Between 18 and 65 years      78  68.4%      80  69.6%      158  69.0% 
>=65 years      36  31.6%      35  30.4%      71  31.0% 
Age 
[Units: Years]
Mean (Standard Deviation)
 58.18  (12.14)   59.25  (12.83)   58.75  (12.49) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      68  59.6%      72  62.6%      140  61.1% 
Male      46  40.4%      43  37.4%      89  38.9% 
Region of Enrollment 
[Units: Participants]
     
United States   114   115   229 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   The Number of Participants With Adverse Events Associated With Warfarin Anticoagulation Following Total Hip and Total Knee Replacement   [ Time Frame: 90 days post surgery ]

2.  Secondary:   Percentage of Determinations in Therapuetic Range (INR 1.8-2.9)   [ Time Frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) ]

3.  Secondary:   Percentage of Determinations Subtherapeutic (INR<1.8)   [ Time Frame: 2 weeks (knee arthroplasty) or 4 weeks (hop arthroplasty) ]

4.  Secondary:   Percentage of Determinations Supratherapeutic (INR>2.9)   [ Time Frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) ]

5.  Post-Hoc:   Mean Number of Doses Before First Dose Adjustment   [ Time Frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) ]

6.  Post-Hoc:   Mean Number of Dose Adjustments   [ Time Frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) ]

7.  Post-Hoc:   Percent of Patients With Dose Adjustments   [ Time Frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) ]

8.  Post-Hoc:   Mean Number of Doses Required for the First Therapeutic INR   [ Time Frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) ]

9.  Post-Hoc:   Mean Number of Doses Before the First Supratherapeutic INR   [ Time Frame: 2 weeks (knee arthroplasty) or 4 weeks (hip arthroplasty) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Limited by the fact that INR was used to adjust dose at the third dose, which may not have allowed enough time for steady-state concentrations of warfarin to be achieved, nor for the genotype-based dosing to be adequately studied.


  More Information
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Certain Agreements:  
All Principal Investigators ARE employed by the organization sponsoring the study.


Results Point of Contact:  
Name/Title: Dr. Gwen McMillin/Principal Investigator
Organization: University of Utah
phone: 801-583-2787 ext 2671
e-mail: gwen.mcmillin@aruplab.com


Publications of Results:

Responsible Party: Gwen McMillin, University of Utah
ClinicalTrials.gov Identifier: NCT00634907     History of Changes
Other Study ID Numbers: 00019469
Study First Received: February 6, 2008
Results First Received: April 23, 2013
Last Updated: April 25, 2017