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By Salman Ahmed
Introduction
 Observational studies have identified two genes, CYP2C9 and
VKORC1, that are associated with variation in w...
Pharmacogenetic dose-initiation
algorithm2
 Pharmacogenetic dose-initiation algorithm2
 The estimated daily dose in mg/d...
Clinical dose-initiation algorithm2
 Clinical dose-initiation algorithm2
 The estimated daily dose in mg/day is:
 exp[0...
Dose Revision Algorthim(4-5)
 Pharmacogenetic dose-revision algorithm
 The estimated daily dose in mg/day is:
 1/7 × ex...
Study Design
1013 Paients
Pharmacogenetic Dose intiating
and maintaning Algorthim
Pharmacogenetic Dose intiating and
maint...
Results
 At 4 weeks, there was no significant between-group
difference in anticoagulation : the mean percentage of time
i...
 There were no significant between-group differences
in the mean percentage of time above the therapeutic
range (INR, >3)...
Conclusion
 initiating warfarin therapy at a genotype-guided
maintenance dose for the first 5 days, as compared
with init...
Clarification of optimal anticoagulation through genetics (coag) trial
Clarification of optimal anticoagulation through genetics (coag) trial
Clarification of optimal anticoagulation through genetics (coag) trial
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Clarification of optimal anticoagulation through genetics (coag) trial

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genetically based warfarin initiating and maintaining dose algorthim

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Clarification of optimal anticoagulation through genetics (coag) trial

  1. 1. By Salman Ahmed
  2. 2. Introduction  Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses and starting dose.  FDA has updated the label for warfarin twice, suggesting that variants in CYP2C9 and VKORC1 may be taken into consideration when choosing the initial warfarin dose  Hypothesis:wide spread adoption of genotype-guided drug dosing and selection will improve anticoagulation?  The COAG trial was a multicenter, double-blind, randomized, controlled trial that compared a genotype- guided warfarin-dosing strategy with a clinically based dosing strategy during the first 5 days of therapy among patients initiating warfarin treatment.
  3. 3. Pharmacogenetic dose-initiation algorithm2  Pharmacogenetic dose-initiation algorithm2  The estimated daily dose in mg/day is:  exp[0.9751  − (0.2066 × CYP2C9*2)  − (0.4008 × CYP2C9*3)  − (0.3238 × VKORC1)  − (0.00745 × age in years)  − (0.0901 × black race)  + (0.0922 × smokes)  + (0.4317 × body surface area in m2)  − (0.2538 × amiodarone use)  + (0.2029 × target INR)  + (0.0664 × DVT/PE as indication for warfarin therapy)]
  4. 4. Clinical dose-initiation algorithm2  Clinical dose-initiation algorithm2  The estimated daily dose in mg/day is:  exp[0.613  − (0.0075 × age in years)  + (0.156 × black race)  + (0.108 × smokes)  + (0.425 × body surface area in m2)  − (0.257 × amiodarone use)  + (0.216 × target INR)  + (0.0784 × DVT/PE as indication for warfarin therapy)],
  5. 5. Dose Revision Algorthim(4-5)  Pharmacogenetic dose-revision algorithm  The estimated daily dose in mg/day is:  1/7 × exp[(3.10894  – (0.14745 × CYP2C9*2)– (0.30770 × CYP2C9*3)  – (0.23032 × VKORC1)  – (0.00767 × age in years)  – (0.09644 × black race)  + (0.24597 × body surface area in m2)  – (0.11216 × diabetes)  – (0.20590 × stroke)  – (0.10350 × amiodarone use)  – (0.19275 × fluvastatin use)  + (0.26729 × target INR)  – (0.51611 × ln INR)  + (0.01690 × dose-2)  + (0.02018 × dose-3)  + (0.01065 × dose-4)]  Clinical dose-revision algorithm  The estimated daily dose in mg/day is:  1/7 × exp[(2.81602  – (0.00590 × age in years)  + (0.07123 × black race)  + (0.17675 × body surface area in m2)  – (0.16759 × diabetes)  – (0.22844 × stroke)  – (0.11137 × amiodarone use)  – (0.25487 × fluvastatin use)  + (0.27815 × target INR)  – (0.76679 × ln INR)  + (0.03471 × dose-2)  + (0.03047 × dose-3)  + (0.01929 × dose-4)],
  6. 6. Study Design 1013 Paients Pharmacogenetic Dose intiating and maintaning Algorthim Pharmacogenetic Dose intiating and maintaning Algorthim Improved anticoagulation:percentage of time in the therapeutic range (INR, 2 to 3) from the completion of the intervention period (day 4 or 5) through day 28 of therapy Secondary outcomes included a composite outcome of any INR of 4 or more, major bleeding, or thromboembolism in the first 4 weeks
  7. 7. Results  At 4 weeks, there was no significant between-group difference in anticoagulation : the mean percentage of time in the therapeutic range: 45.2% in the genotype-guided group and 45.4% in the clinically guided  black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group (35.2% vs. 43.5%; adjusted mean difference, −8.3%; P=0.01).  no significant between-group differences in the principal secondary outcome (the time to any INR of ≥4, major bleeding, or thromboembolism) or any other adverse
  8. 8.  There were no significant between-group differences in the mean percentage of time above the therapeutic range (INR, >3) or below the therapeutic range (INR, <2) during 28 days in both groups  However black pts shows less improved anticoagulation when they were assigned to gentic- guided group
  9. 9. Conclusion  initiating warfarin therapy at a genotype-guided maintenance dose for the first 5 days, as compared with initiating warfarin at a clinically predicted maintenance dose Does Not improves anticoagulation control during the first 4 weeks of therapy.

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