Trial Outcomes & Findings for Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin (NCT NCT00927862)

NCT ID: NCT00927862

Last Updated: 2012-09-25

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2/PHASE3
• Target enrollment: 2415 participants
• Primary outcome timeframe: 1 month (from day 3 to day 30)
• Results posted on: 2012-09-25

Participant Flow

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.

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.

Participant milestones

Measure	PG Dosing Patients 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.	Parellel/Historical Controls 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.
Overall Study STARTED	504	1911
Overall Study COMPLETED	477	1866
Overall Study NOT COMPLETED	27	45

Reasons for withdrawal

Measure	PG Dosing Patients 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.	Parellel/Historical Controls 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.
Overall Study Missing data needed for endpt analyses	27	45

Baseline Characteristics

Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin

Baseline characteristics by cohort

Measure	PG Dosing Patients n=504 Participants 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)	Historical Controls n=1911 Participants A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing	Total n=2415 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	288 Participants n=5 Participants	1214 Participants n=7 Participants	1502 Participants n=5 Participants
Age, Categorical >=65 years	216 Participants n=5 Participants	697 Participants n=7 Participants	913 Participants n=5 Participants
Age Continuous	61.3 years STANDARD_DEVIATION 14.6 • n=5 Participants	57.3 years STANDARD_DEVIATION 17.5 • n=7 Participants	58.0 years STANDARD_DEVIATION 16.8 • n=5 Participants
Sex: Female, Male Female	268 Participants n=5 Participants	984 Participants n=7 Participants	1252 Participants n=5 Participants
Sex: Female, Male Male	236 Participants n=5 Participants	927 Participants n=7 Participants	1163 Participants n=5 Participants
Region of Enrollment United States	504 participants n=5 Participants	1911 participants n=7 Participants	2415 participants n=5 Participants

PRIMARY outcome

Timeframe: 1 month (from day 3 to day 30)

Population: 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.

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.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=245 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=232 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
The Percent of Out of Range (OOR) International Normalized Prothrombin Time Ratio (INRs) in the Standard and Modified Pharmacogenetic Arms.	30.6 percent Interval 27.6 to 33.7	31.8 percent Interval 28.8 to 34.8

PRIMARY outcome

Timeframe: 1 month (from day 3 to day 30)

Population: 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

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.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=477 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=1866 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
The Percent of Out of Range (OOR) INRs in Pharmacogenetic-guided Patients and Parallel Controls	31.2 percent Interval 29.2 to 33.5	41.5 percent Interval 39.9 to 43.2

PRIMARY outcome

Timeframe: 1 month (from baseline to day 30)

Population: 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.

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.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=245 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=232 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms.	70.2 percent Interval 67.2 to 73.3	67.5 percent Interval 64.5 to 70.6

PRIMARY outcome

Timeframe: 1 month (from baseline to day 30)

Population: 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.

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.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=477 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=1866 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls	68.9 percent Interval 67.2 to 70.6	58.4 percent Interval 56.8 to 60.0

SECONDARY outcome

Timeframe: 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)

Population: All consented, randomized patients who were successfully genotyped and received at least 1 dose of warfarin with at least 1 postdose INR.

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.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=250 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=238 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm	15.2 percent Standard Deviation 20.5	15.4 percent Standard Deviation 18.2

SECONDARY outcome

Timeframe: 3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first)

Population: All patients receiving at least 1 dose of warfarin were included in safety analyses until 1 week after the last warfarin dose

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.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=250 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=238 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
The Percent of INRs ≥4 or ≤1.5 or SAEs Among the Modified IWPC Warfarin Algorithm and Standard IWPC Warfarin Algorithm.	53.6 percent	59.2 percent

SECONDARY outcome

Timeframe: 1-3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first)

Population: 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

What is reported is the mean number of INRs measured/drawn among the patients in each arm.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=488 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=1866 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
The Number of INRs Measured up to 3 Months in the Pharmacogenetic (PG) (Modified and Standard) Algorithms and Parallel Controls.	7.70 INRs Standard Deviation 3.99	7.47 INRs Standard Deviation 7.27

SECONDARY outcome

Timeframe: 3 months (from baseline to 3 months or until stable dosing is achieved, whichever occurs first)

Population: 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

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.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=444 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=1866 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
Prediction of a Stable Maintenance Dose Among the Pharmacogenetic (PG)-Guided Dosing Algorithms and the Parallel Controls	63.2 percent	37.6 percent

SECONDARY outcome

Timeframe: 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first)

Population: 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.

What is reported is the percent of patients with an INR ≥4 or ≤1.5 at the end of follow-up.

Outcome measures

Measure	Standard IWPC Warfarin Dosing Algorithm n=488 Participants Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with minor modification	Modified IWPC Warfarin Dosing Algorithm n=1866 Participants Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm with 3 modifications
The Percent of INRs ≥4 or ≤1.5 in the Pharmacogenetic (PG)-Guided Dosing Arms and the Parallel Control Arm	15.3 percent Standard Deviation 19.4	27.4 percent Standard Deviation 32.5

Adverse Events

PG Dosing Patients

Serious events: 22 serious events

Other events: 75 other events

Deaths: 0 deaths

Historical Controls

Serious events: 162 serious events

Other events: 511 other events

Deaths: 0 deaths

Serious adverse events

Measure	PG Dosing Patients n=488 participants at risk；n=487 participants at risk 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)	Historical Controls n=1866 participants at risk；n=1726 participants at risk A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing
Cardiac disorders adjudicated death, MI, stroke, thromboembolic event, moderate or severe hemorrhage	4.5% 22/487 • 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. 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.	9.4% 162/1726 • 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. 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.

Other adverse events

Measure	PG Dosing Patients n=488 participants at risk；n=487 participants at risk 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)	Historical Controls n=1866 participants at risk；n=1726 participants at risk A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing
Blood and lymphatic system disorders INR >=4 or <=1.5	15.4% 75/488 • 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. 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.	27.4% 511/1866 • 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. 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.

Additional Information

Dr. Jeffrey L. Anderson, Director of CV Research and Professor of Medicine

Intermountain Healthcare

Phone: 801-507-4704

Email: jeffrey.anderson@imail.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place