Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 33 of 590 for:    WARFARIN

Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin (Coumagen-II)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00927862
Recruitment Status : Completed
First Posted : June 25, 2009
Results First Posted : September 25, 2012
Last Update Posted : September 25, 2012
Sponsor:
Information provided by (Responsible Party):
Intermountain Health Care, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Thromboembolism
Interventions Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin
Genetic: Modified IWPC genetic-guided warfarin dosing algorithm
Other: Standard of care treatment
Enrollment 2415
Recruitment Details Those >= 18 years and being initiated on warfarin therapy with a target international normalized prothrombin time ratio (INR) of 2-3 or 2.5 –3.5 among participating hospitals and outpatient clinics were invited to participate and sign informed consent.
Pre-assignment Details If after enrollment, pt was found to be not appropriate for warfarin or pharmacogenetic (PG)-guided dosing or physician preference not to have pt participate they were not randomized. Description below and baseline characteristics report combined PG arms because of similarities but outcome measures report combined and individual PG results.
Arm/Group Title PG Dosing Patients Parellel/Historical Controls
Hide Arm/Group Description Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms were randomized to receive either standard or modified International Warfarin Pharmacogenetics Consortium [IWPC] warfarin dosing. The IWPC derived and published a common algorithm to predict stable maintenance dose based on ~5000 patients across broad geographic and ethnic/racial groups (N Engl J Med 2009;360:753-764). Hence, we based our standard algorithm on the IWPC algorithm with minor modifications to accommodate different INR targets and smoking status, based on supplemental data from Gage et al (Clini Pharmacol Ther 2008;84:326 -331). The modified IWPC algorithm included 2 further modifications: (1) It ignored the CYP2C9 variant status for the first 2 days; and (2) It used a special dose-revision algorithm based on a day 4 (or day 5) INR after 3 (or 4) warfarin doses. A parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records databases of the 3 participating hospitals for the time interval spanning enrollment of the randomized pharmacogenetic-guided cohorts (July 2008 through December 2010). Patients >=18 years of age initiating warfarin therapy with a baseline and at least 1 follow-up INR level between days 3 and 14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG-based. A standard (fixed) initial maintenance dose of 5 mg/d is generally assumed, with loading doses and clinical-factor modifications not specified.
Period Title: Overall Study
Started 504 1911
Completed 477 [1] 1866
Not Completed 27 45
Reason Not Completed
Missing data needed for endpt analyses             27             45
[1]
477 patients evaluated in primary analyses and 488 evaluated in secondary analyses.
Arm/Group Title PG Dosing Patients Historical Controls Total
Hide Arm/Group Description Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the pharmacogenetic (PG)-dosing algorithms (standard or modified IWPC warfarin algorithms) A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing Total of all reporting groups
Overall Number of Baseline Participants 504 1911 2415
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 504 participants 1911 participants 2415 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
288
  57.1%
1214
  63.5%
1502
  62.2%
>=65 years
216
  42.9%
697
  36.5%
913
  37.8%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 504 participants 1911 participants 2415 participants
61.3  (14.6) 57.3  (17.5) 58.0  (16.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 504 participants 1911 participants 2415 participants
Female
268
  53.2%
984
  51.5%
1252
  51.8%
Male
236
  46.8%
927
  48.5%
1163
  48.2%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 504 participants 1911 participants 2415 participants
504 1911 2415
1.Primary Outcome
Title The Percent of Out of Range (OOR) International Normalized Prothrombin Time Ratio (INRs) in the Standard and Modified Pharmacogenetic Arms.
Hide Description The percent of out of range (OOR) international normalized prothrombin time ratio (INRs) in the standard and modified pharmacogentic algorithms at 1 month. To account for laboratory INR-measurement error, a 10% margin outside of the target range was allowed in determination of OOR values, ie, INRs <1.8, >3.3 for INR 2.5 target; <2.25, >3.85 for INR 3.0 target. What is reported is the percent of patients with an OOR INR at 1 month.
Time Frame 1 month (from day 3 to day 30)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients >= 18 years of age who have an indication for initiation of warfarin anticoagulation, gave written informed consent, and met other inclusion/exclusion criteria were studied.
Arm/Group Title Standard IWPC Warfarin Dosing Algorithm Modified IWPC Warfarin Dosing Algorithm
Hide Arm/Group Description:
Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification
Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
Overall Number of Participants Analyzed 245 232
Mean (95% Confidence Interval)
Unit of Measure: percent
30.6
(27.6 to 33.7)
31.8
(28.8 to 34.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard IWPC Warfarin Dosing Algorithm, Modified IWPC Warfarin Dosing Algorithm
Comments Comparisons between groups for primary endpoints were made using the unpaired T-test. All consented, randomized patients who were successfully genotyped and received at least one dose of warfarin with at least one post-dose INR were included in efficacy analyses (modified intention to treat [mITT]).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Based on power calculations and feasibility, the minimum recruitment target for the randomized, PG-guided comparison was set at 500 patients. All qualifying parallel control patients were included, anticipated to number ≥1000. For hypothesis 1, the power to exclude inferiority of the modified PG arm vs standard PG arm at a margin (delta) of 5% with 250 patients per group at a 2-sided alpha <0.05 is 87%, assuming a common standard deviation of 0.20.
Statistical Test of Hypothesis P-Value <0.05
Comments Comparisons between groups for primary endpoints were made using the unpaired T-test.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.34
Parameter Dispersion
Type: Standard Deviation
Value: 0.2
Estimation Comments [Not Specified]
2.Primary Outcome
Title The Percent of Out of Range (OOR) INRs in Pharmacogenetic-guided Patients and Parallel Controls
Hide Description The percent of out of range (OOR) INRs in the pharmacogenetic (PG)-dosing (standard + modified IWPC warfarin algorithms) and parallel controls. A 10% margin outside of the target INR range was allowed in determination of OOR values, ie, INRs <1.8, >3.3 for INR 2.5 target; <2.25, >3.85 for INR 3.0 target. What is reported is the percent of patients with OOR INRs at 1 month.
Time Frame 1 month (from day 3 to day 30)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) were compared to parallel controls
Arm/Group Title PG Dosing Patients Parallel Controls
Hide Arm/Group Description:
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms)
The parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records databases of the 3 participating hospitals for the time interval spanning enrollment of the randomized PG-guided cohorts (July 2008 through December 2010). Patients >=18 years of age initiating warfarin therapy with a baseline and at least 1 follow-up INR level between days 3 and 14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG-based. A standard (fixed) initial maintenance dose of 5 mg/d is generally assumed, with loading doses and clinical-factor modifications not specified. However,the same standard INR-based dose-modification algorithm developed and promoted by Intermountain is generally recommended.
Overall Number of Participants Analyzed 477 1866
Mean (95% Confidence Interval)
Unit of Measure: percent
31.2
(29.2 to 33.5)
41.5
(39.9 to 43.2)
3.Primary Outcome
Title The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms.
Hide Description The percent of time in therapeutic INR range for the standard and modified pharmacogenetic algorithms at 1 month. To account for laboratory INR-measurement error, a 10% margin inside of the target range was allowed in determine TTR values, ie, INRs 1.8-3.3 for INR 2.5 target; 2.25-3.85 for INR 3.0 target. What is reported is the percent of TTR for each patient during 1 month.
Time Frame 1 month (from baseline to day 30)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients >= 18 years of age who have an indication for initiation of warfarin anticoagulation, gave written informed consent, and met other inclusion/exclusion criteria were studied.
Arm/Group Title Standard IWPC Warfarin Dosing Algorithm Modified IWPC Warfarin Dosing Algorithm
Hide Arm/Group Description:
Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification
Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
Overall Number of Participants Analyzed 245 232
Mean (95% Confidence Interval)
Unit of Measure: percent
70.2
(67.2 to 73.3)
67.5
(64.5 to 70.6)
4.Primary Outcome
Title The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls
Hide Description The percent of time in therapeutic INR range for the pharmacogenetic (PG)-dosing (standard + modified IWPC warfarin algorithms) guided patients and parallel controls. To account for laboratory INR-measurement error, a 10% margin inside of the target range was allowed in determine TTR values, ie, INRs 1.8-3.3 for INR 2.5 target; 2.25-3.85 for INR 3.0 target. What is reported is the percent of TTR for each patient during 1 month.
Time Frame 1 month (from baseline to day 30)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) were compared to parallel controls.
Arm/Group Title PG Dosing Patients Parallel Controls
Hide Arm/Group Description:
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms)
The parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records databases of the 3 participating hospitals for the time interval spanning enrollment of the randomized PG-guided cohorts (July 2008 through December 2010). Patients >=18 years of age initiating warfarin therapy with a baseline and at least 1 follow-up INR level between days 3 and 14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG-based. A standard (fixed) initial maintenance dose of 5 mg/d is generally assumed, with loading doses and clinical-factor modifications not specified. However,the same standard INR-based dose-modification algorithm developed and promoted by Intermountain is generally recommended.
Overall Number of Participants Analyzed 477 1866
Mean (95% Confidence Interval)
Unit of Measure: percent
68.9
(67.2 to 70.6)
58.4
(56.8 to 60.0)
5.Secondary Outcome
Title The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm
Hide Description The percent of INRs ≥4 or ≤1.5 for the pharmacogenetic (modified IWPC warfarin algorithm and the standard IWPC warfarin) algorithms. What is reported is the percent of patients with INRs ≥4 or ≤1.5 at the end of follow-up.
Time Frame 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)
Hide Outcome Measure Data
Hide Analysis Population Description
All consented, randomized patients who were successfully genotyped and received at least 1 dose of warfarin with at least 1 postdose INR.
Arm/Group Title Standard IWPC Warfarin Dosing Algorithm Modified IWPC Warfarin Dosing Algorithm
Hide Arm/Group Description:
Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification
Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
Overall Number of Participants Analyzed 250 238
Mean (Standard Deviation)
Unit of Measure: percent
15.2  (20.5) 15.4  (18.2)
6.Secondary Outcome
Title The Percent of INRs ≥4 or ≤1.5 or SAEs Among the Modified IWPC Warfarin Algorithm and Standard IWPC Warfarin Algorithm.
Hide Description What is reported is the percent of patients with INRs ≥4 or ≤1.5 or having experienced a serious adverse event (SAE) at the end of follow-up.
Time Frame 3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first)
Hide Outcome Measure Data
Hide Analysis Population Description
All patients receiving at least 1 dose of warfarin were included in safety analyses until 1 week after the last warfarin dose
Arm/Group Title Standard IWPC Warfarin Dosing Algorithm Modified IWPC Warfarin Dosing Algorithm
Hide Arm/Group Description:
Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification
Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
Overall Number of Participants Analyzed 250 238
Measure Type: Number
Unit of Measure: percent
53.6 59.2
7.Secondary Outcome
Title The Number of INRs Measured up to 3 Months in the Pharmacogenetic (PG) (Modified and Standard) Algorithms and Parallel Controls.
Hide Description What is reported is the mean number of INRs measured/drawn among the patients in each arm.
Time Frame 1-3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) were compared to parallel controls
Arm/Group Title PG Dosing Patients Parallel Controls
Hide Arm/Group Description:
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms)
The parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records databases of the 3 participating hospitals for the time interval spanning enrollment of the randomized PG-guided cohorts (July 2008 through December 2010). Patients >=18 years of age initiating warfarin therapy with a baseline and at least 1 follow-up INR level between days 3 and 14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG-based. A standard (fixed) initial maintenance dose of 5 mg/d is generally assumed, with loading doses and clinical-factor modifications not specified. However,the same standard INR-based dose-modification algorithm developed and promoted by Intermountain is generally recommended.
Overall Number of Participants Analyzed 488 1866
Mean (Standard Deviation)
Unit of Measure: INRs
7.70  (3.99) 7.47  (7.27)
8.Secondary Outcome
Title Prediction of a Stable Maintenance Dose Among the Pharmacogenetic (PG)-Guided Dosing Algorithms and the Parallel Controls
Hide Description Prediction of a stable maintenance dose (within 1 mg/day) among the pharmacogenetic (PG)-guided dosing and the parallel control group. For the parallel control group, an empiric starting dose of 5 mg/day was assumed. What is reported is the percent of patients who had their maintenance dose predicted as described above.
Time Frame 3 months (from baseline to 3 months or until stable dosing is achieved, whichever occurs first)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) and had a stable maintenance dose that could be determined were compared to parallel controls
Arm/Group Title PG Dosing Patients Parallel Controls
Hide Arm/Group Description:
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms)
The parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records databases of the 3 participating hospitals for the time interval spanning enrollment of the randomized PG-guided cohorts (July 2008 through December 2010). Patients >=18 years of age initiating warfarin therapy with a baseline and at least 1 follow-up INR level between days 3 and 14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG-based. A standard (fixed) initial maintenance dose of 5 mg/d is generally assumed, with loading doses and clinical-factor modifications not specified. However,the same standard INR-based dose-modification algorithm developed and promoted by Intermountain is generally recommended.
Overall Number of Participants Analyzed 444 1866
Measure Type: Number
Unit of Measure: percent
63.2 37.6
9.Secondary Outcome
Title The Percent of INRs ≥4 or ≤1.5 in the Pharmacogenetic (PG)-Guided Dosing Arms and the Parallel Control Arm
Hide Description What is reported is the percent of patients with an INR ≥4 or ≤1.5 at the end of follow-up.
Time Frame 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms) were compared to parallel controls.
Arm/Group Title PG Dosing Patients Parallel Controls
Hide Arm/Group Description:
Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms (standard or modified IWPC warfarin algorithms)
The parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records databases of the 3 participating hospitals for the time interval spanning enrollment of the randomized PG-guided cohorts (July 2008 through December 2010). Patients >=18 years of age initiating warfarin therapy with a baseline and at least 1 follow-up INR level between days 3 and 14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG-based. A standard (fixed) initial maintenance dose of 5 mg/d is generally assumed, with loading doses and clinical-factor modifications not specified. However,the same standard INR-based dose-modification algorithm developed and promoted by Intermountain is generally recommended.
Overall Number of Participants Analyzed 488 1866
Mean (Standard Deviation)
Unit of Measure: percent
15.3  (19.4) 27.4  (32.5)
Time Frame Patients were included in the SAE safety analyses if they received an INR measurement on Day 4 or 5 and were taking warfarin. Patients were followed until 3 months after warfarin initiation.
Adverse Event Reporting Description Because only those who received an INR measurement on Day 4 or 5 and were taking warfarin were included in the calculation of the serious adverse events, the numbers in each arm are different from what is reported in the participant flow table.
 
Arm/Group Title PG Dosing Patients Historical Controls
Hide Arm/Group Description Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the pharmacogenetic (PG)-dosing algorithms (standard or modified IWPC warfarin algorithms) A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing
All-Cause Mortality
PG Dosing Patients Historical Controls
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
PG Dosing Patients Historical Controls
Affected / at Risk (%) Affected / at Risk (%)
Total   22/487 (4.52%)   162/1726 (9.39%) 
Cardiac disorders     
adjudicated death, MI, stroke, thromboembolic event, moderate or severe hemorrhage   22/487 (4.52%)  162/1726 (9.39%) 
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
PG Dosing Patients Historical Controls
Affected / at Risk (%) Affected / at Risk (%)
Total   75/488 (15.37%)   511/1866 (27.38%) 
Blood and lymphatic system disorders     
INR >=4 or <=1.5  [1]  75/488 (15.37%)  511/1866 (27.38%) 
Indicates events were collected by systematic assessment
[1]
Number of patients who had an average INR >=4 or <=1.5 at the end of follow-up
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Jeffrey L. Anderson, Director of CV Research and Professor of Medicine
Organization: Intermountain Healthcare
Phone: 801-507-4704
EMail: jeffrey.anderson@imail.org
Layout table for additonal information
Responsible Party: Intermountain Health Care, Inc.
ClinicalTrials.gov Identifier: NCT00927862     History of Changes
Other Study ID Numbers: 154-001
First Submitted: June 23, 2009
First Posted: June 25, 2009
Results First Submitted: April 9, 2012
Results First Posted: September 25, 2012
Last Update Posted: September 25, 2012