Involvement of genetics in poor outcomes in anticoagulation

therapy

Farhad KamaliFarhad KamaliThrombosis & Anticoagulation Research GroupThrombosis & Anticoagulation Research Group

Institute of Cellular MedicineInstitute of Cellular Medicine

IntroductionIntroduction

Warfarin a widely used oral anticoagulant for treatment Warfarin a widely used oral anticoagulant for treatment and prophylaxis of thromboembolism (e.g. DVT) and prophylaxis of thromboembolism (e.g. DVT)

Warfarin therapy decreases risk of stroke by 68% in Warfarin therapy decreases risk of stroke by 68% in patients with non-valvular atrial fibrillationpatients with non-valvular atrial fibrillation

In the West about 1% of the population are on warfarin In the West about 1% of the population are on warfarin (about 2 million people in the US start taking warfarin each year)(about 2 million people in the US start taking warfarin each year)

Stroke prevention in AFStroke prevention in AFWarfarin v placeboWarfarin v placebo

AFASAK-1 (671)

SPAF (421)

BAATAF (420)

CAFA (378)

SPINAF (571)

EAFT (439)

All trials (n=6)

0% -50% -100%100% 50%

Hart RG, et al. Ann Intern Med 2007; 146: 857-67

Dosing of warfarin is complexDosing of warfarin is complex

• Narrow therapeutic indexSmall separation between dose-response curves for

preventing emboli and excessive anticoagulation

• Nonlinear dose-responseSmall changes in dose may cause large changes

anticoagulation response with a time lag

• Between-patient variability in dose requirement Wide range (50x) in dose requirement (2-112 mg/week) to achieve target INR of 2-3 (difficulty with attaining a stable

control of anticoagulation during initiation of therapy)

Safety of warfarinSafety of warfarin

10-24 episodes of haemorrhage per 100 patients. Account for 3.6% of all drug-induced AEs; 3rd ranked drug in AEs

Major risk is bleeding: frequent and severe; 1.2 – 7 major bleeding episodes per 100 patients; Relative risk of fatal extracranial bleeds 0 - 4.8%

Responsible for 1 in 10 hospital admissions

Schulman, N Engl J Med 349:675-683, 2003Pirmohamed, British Med J 329:15-19, 2004 Kamali & Pirmohamed, Br J Clin Pharmacol 61: 746-751, 2006 Evans, Annals of Pharmaco 39:1161-1168, 2005Wadelius, The Pharmacogenomics J, 5:262-270, 2005

Anticoagulation Status Determined by INRAnticoagulation Status Determined by INR

Benefit: INR and Stroke PreventionBenefit: INR and Stroke Prevention

Risk: INR and intracranial hemorrhageRisk: INR and intracranial hemorrhage

Induction therapy-Induction therapy-Patients dosed on a trial and error Patients dosed on a trial and error

basisbasis

Day

s/w

eeks dose (INR<2.0) dose (INR<2.0)

or or dose (INR>3.0)dose (INR>3.0)

Fixed doseFixed dose

Maintenance doseMaintenance dose

Frequency of major bleeds following Frequency of major bleeds following initiation of warfarin dosinginitiation of warfarin dosing

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

Fre

qu

ency

(

% /

mo

nth

)

Up To 4 Weeks Up to 52 Weeks After 52 Weeks

Major Bleeding with Outpatient Warfarin

Landefeld, Am J Med 87:144-152, 1989Landefeld, Am J Med 87:144-152, 1989

OR

O

O

VII

VIIa

XXa

II

IIa

Thrombin(carboxylated)

Prothrombin

Vit K (epoxide)

RO

O

Vit K (quinone)

warfarin

Vit K reductase

_

warfarin _

Vit KH2

OH

OH

R

CarboxylaseVit K reductase

Factors Contributing to Factors Contributing to Inter-Individual variability in dose requirementInter-Individual variability in dose requirement

Disease Drug interactions Age

-ve correlation between age and liver volume

+ve correlation between liver volume and dose

Wynne, et al. Br J Clin Pharmacol (1995) 40: 203-207

Factors contributing to Factors contributing to inter-individual variability in dose requirementinter-individual variability in dose requirement

Dietary vitamin K

Changes in dietary vitamin K affect anticoagulation response Khan et al. BJH (2004) 124, 348-354

Sconce et al. Thromb Haemost (2005) 93, 872-875

-responsible for inter-individual variability in dose requirement?

Disease Drug interactions Age

Factors contributing to Factors contributing to inter-individual variabilityinter-individual variability

Disease Drug interactions Age Dietary Vitamin K Genetics

Warfarin chemical structureWarfarin chemical structure

O

O

CH3

R

Vitamin K(natural vitamin)

ONa

OO

CHCH2COH2

C6H5

Warfarin(vitamin K antagonist)

Warfarin is a coumarin derivative

CHCH2COH2

C6H5ONa

OO

Warfarin [(R)- & (S)-enantiomers)]

CYP2C9*1CYP2C9*2 (12% activity)CYP2C9*3 (5% activity)

Furuya, et al. Pharmacogenetics (1995) 5: 389-392Steward, et al. Pharmacogenetics (1997) 7: 361-367

Warfarin a 50:50 racemic mixture of R & S enantiomers

CYP2C9 PolymorphismsCYP2C9 Polymorphisms

CYP2C9 *1/*1 (wild-type)

CYP2C9 *1/*2

CYP2C9 *2/*2

CYP2C9 *2/*3

CYP2C9 *1/*3

CYP2C9 *3/*3

Decreasing Decreasing enzyme enzyme activityactivity

Genetic polymorphism for VKORC1Genetic polymorphism for VKORC1

• Several non-coding polymorphisms for VKOR influence coumarin dose requirements.

D'Andrea et al. Blood. (2005) 105:645-649.Bodin et al. Blood. (2005) 106:135-40.

VKORC1VKORC1 Polymorphisms Polymorphisms

GGGGGAGAAAAA

Decreasing Decreasing dose requirementdose requirement

-1639G>A

Distribution of warfarin dose by Distribution of warfarin dose by CYP2C9 CYP2C9 and and VKORC1VKORC1 genotype genotype

Sconce et al. Blood. 2005; 106: 2329-2333.Sconce et al. Blood. 2005; 106: 2329-2333.

Warf

arin D

aily

Dose

(m

g)

CYP2C9VKORC1

*2*3/*3/*3(n=11)*2*2(n=8)*1*3(n=42)*1*2(n=66)*1*1(n=163)GGGAAAGGGAAAGGGAAAGGGAAAGGGAAA

12

10

8

6

4

2

0

1.00

1.92

1.06

2.50

2.02

2.933.03

1.64

4.28

3.50

2.68

5.20

4.36

2.41

Estimated warfarin daily dose requirements (mg) (95% confidence interval) based on patient age, genotype and height

Predicted dose will vary by varying height and VKOR genotype. Individuals with VKOR AA genotype will require lower doses of warfarin than those with AG or GG genotypes.

AA1700.75(0.50-1.05)

1.08(0.83-1.36)

1.47(1.23-1.74)

1.93(1.68-2.20)

2.45(2.15-2.76)

80

AA1701.29(0.97-1.66)

1.72(1.42-2.05)

2.21(1.94-2.51)

2.76(2.49-3.05)

3.38(3.06-3.71)

60

AA1701.99(1.55-2.49)

2.52(2.09-2.98)

3.10(2.69-3.54)

3.75(3.33-4.19)

4.45(3.97-4.96)

40

AA1702.84(2.20-3.56)

3.46(2.82-4.16)

4.14(3.49-4.84)

4.88(4.20-5.61)

5.68(4.93-6.49)

20

VKOR genotype

Height(cm)

*2*3(*3*3)

*2*2*1*3*1*2*1*1Age(years)

IWPC algorithmIWPC algorithmComparisons of Clinical and Pharmacogenetic algorithms based on Comparisons of Clinical and Pharmacogenetic algorithms based on

genotype and use of amiodaronegenotype and use of amiodarone

Genotype can markedly change the recommended dose from more than 45 mg per week to less than 10 mg per week when all other factors are the same. (NEJM, 2009; 19; 360(8):753-64.)

Genotype-guided dosing: Genotype-guided dosing: translation of research data to practicetranslation of research data to practice

Can pharmacogenetic-guided algorithms improve the accuracy of warfarin dosing during the initiation phase and reduce the

incidence of warfarin-related adverse events, i.e., unintentional bleeding (over-dosing) and embolisms (under-dosing)?

Prospective pharmacogenetic-guided Prospective pharmacogenetic-guided dosing studiesdosing studies

• COAG study across USA- funded by NIHLB involving patients starting warfarin-Primary end point: %TIR in the first 1 month of therapy-Primary end point: %TIR in the first 1 month of therapy

‘Genotype-guided warfarin doing was no better than a clinical algorithm’

• EU-PACT study across Europe- funded by EC-FP7 programme involving patients for each of warfarin, acenocoumarol and phenprocoumon -Primary end point : %TIR in the first 3 months of therapy-Primary end point : %TIR in the first 3 months of therapy

‘Genotype-guided warfarin dosing was superior to fixed-dose regimens’

Pirmohammed et al. NEJM, 2013, 12;369(24):2294-303

Kimmel SE et al. NEJM, 2013, 12;369(24):2283-93

Further analyses of the EU-PACT and COAG trial data

Analysis of the EU-PACT data- Analysis of the EU-PACT data- genotype-guided dosing caused greatest improvement in %TTR compared to the control arm in individuals with two or more CYP2C9 / VKORC1 variants (11.05% difference in TTR; P<0.009)

EU-PACT dosing- EU-PACT dosing- more accurate in predicting the maintenance dose to within 1mg/day than COAG for both the dose initiation (62% vs 53%) and the dose revision algorithms (80% vs 62%)

Unpublished data

PK/PD pharmacometric modellingPK/PD pharmacometric modelling

patients homozygous with CYP2C9 variants benefitted the most from genotype-guided dosing, consistent with the EU-PACT findings.

Unpublished data

ConclusionsConclusions

Current warfarin fixed dose regimens are inadequate

Genetic polymorphisms in CYP2C9 and VKORC1, age, body size influence warfarin dose requirement

Genotype-guided dosing regimens for initiation of warfarin therapy

-more ‘individualised’ warfarin therapy-more ‘individualised’ warfarin therapy

Improved safety, reduced monitoring/management and Improved safety, reduced monitoring/management and better patient satisfaction better patient satisfaction

AcknowledgementsAcknowledgements

Colleagues:

Hilary WynneJudith CoulsonMaggie FearbyJo WincupJill HendersonLiz SconceEllen HatchTayyaba KhanPeter AveryPatrick KestevenJohn HanleyPeter Wood

Sponsors:

Baxter Healthcare