genetically based warfarin initiating and maintaining dose algorthim

1. By Salman Ahmed

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. 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. 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. 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. 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

8. 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

9.  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

12. 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.