Trial Outcomes & Findings for Study to Develop a Reliable Nomogram That Incorporates Clinical and Genetic Information (NCT NCT00401414)
NCT ID: NCT00401414
Last Updated: 2013-08-30
Results Overview
Primary end point: mean percentage of time INR is within therapeutic range. Though target INR was 2.0-3.0, therapeutic INR is considered 1.8-3.2 (allows for INR measurement error and avoids problems inherent in overcorrection). The international normalized ratio (INR) is one way of presenting prothrombin time test results for people taking the blood-thinning medication warfarin. The INR formula adjusts for variation in laboratory testing methods so that test results can be comparable.
Recruitment status
COMPLETED
Study phase
NA
Target enrollment
344 participants
Primary outcome timeframe
90 Days
Results posted on
2013-08-30
Participant Flow
Warfarin naïve patients undergoing initiation of warfarin anticoagulation at participating Partners anticoagulation clinics, including Brigham and Women's Hospital, Massachusetts General Hospital, North Shore Medical Center, Faulkner Hospital, Spaulding Rehabilitation Hospital, and Newton Wellesley Hospital.
We enrolled patients over 9 months, following each patient for 3 months with twice weekly coagulation testing of the prothrombin time standardized to the International Normalized Ratio, and adjusted monthly the nomogram (if necessary) to improve the fit with emerging data from the cohort.
Participant milestones
| Measure |
Dosing Algorithm A
Algorithm A was a dosing decision-tree that included both clinical and genetic factors. It was based upon optimal clinical practice at the Brigham and Women's Hospital's Anticoagulation Management Service as well as published literature that has utilised warfarin pharmacogenetics.
Doses were subsequently adjusted based on serial INR measurements.
|
Dosing Algorithm B
Dosing Algorithm B was generated from an analysis of warfarin dose, INR, genetic factors, demographic factors and concomitant drug therapy from an initial prospective group of 74 patients treated using Algorithm A. Using these data, a mechanistic concentration-INR model was constructed to refine the estimates of the effect of CYP2C9 genotypes, VKORC1 haplotypes, age, and concomitant medications.
|
Dosing Algorithm C
Dosing Algorithm C was generated as an update of dosing Algorithm B and was based upon additional patient data, similar to what was described above for Algorithm B, from the prospective accrual of 203 patients in the CROWN trial. The major difference between Algorithm B and Algorithm C was an update of the half maximal inhibitory concentration (IC50) estimate for each VKORC1 haplotype in the model used to generate Algorithm B to reflect warfarin's PD effect as evident in the acquired patient data. Simulations using Algorithm C were repeated using the clinical endpoints described above to derive the optimal starting warfarin doses and titration scheme that was tested prospectively in subsequent patients enrolled in the CROWN study.
|
|---|---|---|---|
|
Overall Study
STARTED
|
118
|
147
|
79
|
|
Overall Study
COMPLETED
|
118
|
147
|
79
|
|
Overall Study
NOT COMPLETED
|
0
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Study to Develop a Reliable Nomogram That Incorporates Clinical and Genetic Information
Baseline characteristics by cohort
| Measure |
Dosing Algorithm A
n=118 Participants
Three dosing algorithms (A, B, and C, respectively) were used in this investigation. The algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximise the likelihood of achieving and maintaining the target INR. The algorithms were refined using adaptive methods that allow for continual reassessment of patient-level data to optimize the predictive power of the algorithms. Algorithm A was a dosing decision-tree that included both clinical and genetic factors. It was based upon optimal clinical practice at the Brigham and Women's Hospital's Anticoagulation Management Service as well as published literature that has utilised warfarin pharmacogenetics.
Doses were subsequently adjusted based on serial INR measurements.
|
Dosing Algorithm B
n=147 Participants
Three dosing algorithms (A, B, and C, respectively) were used in this investigation. The algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximise the likelihood of achieving and maintaining the target INR. The algorithms were refined using adaptive methods that allow for continual reassessment of patient-level data to optimize the predictive power of the algorithms. Dosing Algorithm B was generated from an analysis of warfarin dose, INR, genetic factors, demographic factors and concomitant drug therapy from an initial prospective group of 74 patients treated using Algorithm A. Using these data, a mechanistic concentration-INR model was constructed to refine the estimates of the effect of CYP2C9 genotypes, VKORC1 haplotypes, age, and concomitant medications.
|
Dosing Algorithm C
n=79 Participants
Three dosing algorithms (A, B, and C, respectively) were used in this investigation. The algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximise the likelihood of achieving and maintaining the target INR. The algorithms were refined using adaptive methods that allow for continual reassessment of patient-level data to optimize the predictive power of the algorithms. Dosing Algorithm C was generated as an update of dosing Algorithm B and was based upon additional patient data, similar to what was described above for Algorithm B, from the prospective accrual of 203 patients in the CROWN trial. The major difference between Algorithm B and Algorithm C was an update of the half maximal inhibitory concentration (IC50) estimate for each VKORC1 haplotype in the model used to generate Algorithm B to reflect warfarin's PD effect as evident in the acquired patient data.
|
Total
n=344 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
|
0 Participants
n=4 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
118 Participants
n=5 Participants
|
147 Participants
n=7 Participants
|
79 Participants
n=5 Participants
|
344 Participants
n=4 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Age Continuous
|
64.7 years
STANDARD_DEVIATION 16.6 • n=5 Participants
|
57.9 years
STANDARD_DEVIATION 16.5 • n=7 Participants
|
57.2 years
STANDARD_DEVIATION 15.6 • n=5 Participants
|
60.1 years
STANDARD_DEVIATION 16.7 • n=4 Participants
|
|
Sex: Female, Male
Female
|
60 Participants
n=5 Participants
|
64 Participants
n=7 Participants
|
38 Participants
n=5 Participants
|
162 Participants
n=4 Participants
|
|
Sex: Female, Male
Male
|
58 Participants
n=5 Participants
|
83 Participants
n=7 Participants
|
41 Participants
n=5 Participants
|
182 Participants
n=4 Participants
|
|
Region of Enrollment
United States
|
118 participants
n=5 Participants
|
147 participants
n=7 Participants
|
79 participants
n=5 Participants
|
344 participants
n=4 Participants
|
PRIMARY outcome
Timeframe: 90 DaysPrimary end point: mean percentage of time INR is within therapeutic range. Though target INR was 2.0-3.0, therapeutic INR is considered 1.8-3.2 (allows for INR measurement error and avoids problems inherent in overcorrection). The international normalized ratio (INR) is one way of presenting prothrombin time test results for people taking the blood-thinning medication warfarin. The INR formula adjusts for variation in laboratory testing methods so that test results can be comparable.
Outcome measures
| Measure |
Dosing Algorithm A
n=118 Participants
Three dosing algorithms (A, B, and C, respectively) were used in this investigation. The algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximise the likelihood of achieving and maintaining the target INR. The algorithms were refined using adaptive methods that allow for continual reassessment of patient-level data to optimize the predictive power of the algorithms. Algorithm A was a dosing decision-tree that included both clinical and genetic factors. It was based upon optimal clinical practice at the Brigham and Women's Hospital's Anticoagulation Management Service as well as published literature that has utilised warfarin pharmacogenetics.
Doses were subsequently adjusted based on serial INR measurements.
|
Dosing Algorithm B
n=147 Participants
|
Dosing Algorithm C
n=79 Participants
|
|---|---|---|---|
|
Mean Percentage of Time That INR Within Therapeutic Range Using Linear Interpolation (Rosendaal et al).
|
58.9 percentage of time
Standard Deviation 22
|
59.7 percentage of time
Standard Deviation 23
|
65.8 percentage of time
Standard Deviation 16.9
|
SECONDARY outcome
Timeframe: 90 DaysThe INR (international normalized ratio) is a derived measure of the prothrombin time. In this trial, a therapeutic INR was considered 1.8 to 3.2
Outcome measures
| Measure |
Dosing Algorithm A
n=118 Participants
Three dosing algorithms (A, B, and C, respectively) were used in this investigation. The algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximise the likelihood of achieving and maintaining the target INR. The algorithms were refined using adaptive methods that allow for continual reassessment of patient-level data to optimize the predictive power of the algorithms. Algorithm A was a dosing decision-tree that included both clinical and genetic factors. It was based upon optimal clinical practice at the Brigham and Women's Hospital's Anticoagulation Management Service as well as published literature that has utilised warfarin pharmacogenetics.
Doses were subsequently adjusted based on serial INR measurements.
|
Dosing Algorithm B
n=147 Participants
|
Dosing Algorithm C
n=79 Participants
|
|---|---|---|---|
|
Time to the First Therapeutic INR.
|
9.1 Days
Standard Deviation 4.5
|
10.4 Days
Standard Deviation 4.9
|
9.7 Days
Standard Deviation 4.4
|
SECONDARY outcome
Timeframe: 90 DaysThe INR (international normalized ratio) is a derived measure of the prothrombin time. In this trial, a therapeutic INR was considered 1.8 to 3.2
Outcome measures
| Measure |
Dosing Algorithm A
n=118 Participants
Three dosing algorithms (A, B, and C, respectively) were used in this investigation. The algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximise the likelihood of achieving and maintaining the target INR. The algorithms were refined using adaptive methods that allow for continual reassessment of patient-level data to optimize the predictive power of the algorithms. Algorithm A was a dosing decision-tree that included both clinical and genetic factors. It was based upon optimal clinical practice at the Brigham and Women's Hospital's Anticoagulation Management Service as well as published literature that has utilised warfarin pharmacogenetics.
Doses were subsequently adjusted based on serial INR measurements.
|
Dosing Algorithm B
n=147 Participants
|
Dosing Algorithm C
n=79 Participants
|
|---|---|---|---|
|
Per-patient Percentage of INRs Out of the Therapeutic Range
|
42.2 percentage of INRs out of range
Standard Deviation 21.6
|
37.7 percentage of INRs out of range
Standard Deviation 22.8
|
33.3 percentage of INRs out of range
Standard Deviation 16.8
|
SECONDARY outcome
Timeframe: 90 DaysDefined as two consecutive INRs within the therapeutic range \>7 days apart and with no dose change during this time.
Outcome measures
| Measure |
Dosing Algorithm A
n=118 Participants
Three dosing algorithms (A, B, and C, respectively) were used in this investigation. The algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximise the likelihood of achieving and maintaining the target INR. The algorithms were refined using adaptive methods that allow for continual reassessment of patient-level data to optimize the predictive power of the algorithms. Algorithm A was a dosing decision-tree that included both clinical and genetic factors. It was based upon optimal clinical practice at the Brigham and Women's Hospital's Anticoagulation Management Service as well as published literature that has utilised warfarin pharmacogenetics.
Doses were subsequently adjusted based on serial INR measurements.
|
Dosing Algorithm B
n=147 Participants
|
Dosing Algorithm C
n=79 Participants
|
|---|---|---|---|
|
Time to Stable Anticoagulation (in Days).
|
50.8 Days
Standard Deviation 20.1
|
34.6 Days
Standard Deviation 14.9
|
31.5 Days
Standard Deviation 13.1
|
SECONDARY outcome
Timeframe: 90 DaysDefined as an INR\>4.0, use of vitamin K, major bleeding events (as defined by the Thrombolysis in Myocardial Infarction \[TIMI\] criteria), thromboembolic events, stroke (all cause), myocardial infarction, and death (all cause).
Outcome measures
| Measure |
Dosing Algorithm A
n=118 Participants
Three dosing algorithms (A, B, and C, respectively) were used in this investigation. The algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximise the likelihood of achieving and maintaining the target INR. The algorithms were refined using adaptive methods that allow for continual reassessment of patient-level data to optimize the predictive power of the algorithms. Algorithm A was a dosing decision-tree that included both clinical and genetic factors. It was based upon optimal clinical practice at the Brigham and Women's Hospital's Anticoagulation Management Service as well as published literature that has utilised warfarin pharmacogenetics.
Doses were subsequently adjusted based on serial INR measurements.
|
Dosing Algorithm B
n=147 Participants
|
Dosing Algorithm C
n=79 Participants
|
|---|---|---|---|
|
Proportion of Patients With Serious Adverse Clinical Events.
|
43 participants
|
41 participants
|
24 participants
|
Adverse Events
Dosing Algorithm A
Serious events: 43 serious events
Other events: 0 other events
Deaths: 0 deaths
Dosing Algorithm B
Serious events: 41 serious events
Other events: 0 other events
Deaths: 0 deaths
Dosing Algorithm C
Serious events: 24 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Dosing Algorithm A
n=118 participants at risk
|
Dosing Algorithm B
n=147 participants at risk
|
Dosing Algorithm C
n=79 participants at risk
|
|---|---|---|---|
|
Vascular disorders
INR ≥ 4
|
33.1%
39/118 • Number of events 39 • 90 Days
|
24.5%
36/147 • Number of events 36 • 90 Days
|
27.8%
22/79 • Number of events 22 • 90 Days
|
|
Vascular disorders
Major bleeding events (TIMI definition)
|
1.7%
2/118 • Number of events 2 • 90 Days
|
2.0%
3/147 • Number of events 3 • 90 Days
|
2.5%
2/79 • Number of events 2 • 90 Days
|
|
Investigations
Vitamin K administration
|
1.7%
2/118 • Number of events 2 • 90 Days
|
0.00%
0/147 • 90 Days
|
0.00%
0/79 • 90 Days
|
|
Vascular disorders
Thrombotic events (MI, stroke, VTE)
|
0.00%
0/118 • 90 Days
|
1.4%
2/147 • Number of events 2 • 90 Days
|
0.00%
0/79 • 90 Days
|
Other adverse events
Adverse event data not reported
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place