Clarification of OptimalAnticoagulation through Genetics

(COAG) trial,By Salman Ahmed

IntroductionObservational 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.

Pharmacogenetic dose-initiation algorithm2

Pharmacogenetic dose-initiation algorithm2The 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)]

Clinical dose-initiation algorithm2

Clinical dose-initiation algorithm2The 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)],

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)],

Study Design1013 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 therapySecondary outcomes included a composite outcome of any

INR of 4 or more, major bleeding, or thromboembolism in the first 4 weeks

ResultsAt 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

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

Conclusioninitiating 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.