involvement of genetics in poor outcomes in anticoagulation therapy farhad kamali thrombosis &...
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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