European pharmacogenomics approach to coumarin therapy
EU-PACT
Grant Agreement number:HEALTH-F2-2009-223062
EC contribution:€2.5 million
Duration in months: 48
Project type:Medium sized collaborative project
Starting date:1 October 2008
Project web-site:
Background:The narrow therapeutic range of coumarins and an unpredictable response due to large intra- and inter-patient variability makes careful patient monitoring necessary. The principal covariates (together accounting for 35-50% of the variability) are polymorphisms in genes encoding for CYP2C9 and VKORC1.It is not known whether genotype-guided dosing during induction and maintenance therapy of coumarins will increase the efficacy and safety of the treatment.
Objectives:The aim of the EU-PACT study is to determine whether a clinically applicable dosing algorithm including genetic information of the patient, clinical data and (when available) last INR increases the time in range (TIR) of the INR during anticoagulation with acenocoumarol, phenprocoumon and warfarin compared to a dosing algorithm without these genotypes.
Approach and methodology: Two dosing algorithms will be investigated in the EU-PACT trial. The trial will be performed at 13 centers in 7 European countries. The study will be a two-armed, single-blinded, randomized controlled trial in which genotype-guided dosing is compared to a standard clinical dosing algorithm with a maximum follow-up duration of 3 months. Patients receiving genotype-guided dosing will be genotyped with a point of care test before the first dose. In order to demonstrate that genotype-guided dosing improves TIR of the INR by 5% compared to the control regimen and assuming a 10% dropout after study entry, a minimum of 985 patients per drug should be recruited (80% power, 5% significance level and a mean %TIR of the INR of 47 to 63.4).
Expected results: It is expected that patients randomized to the genotype-guided dosing arm will spent a lager percentage of the time within the target range. Since TIR is closely related to bleeding and recurrent thrombosis risks, it is also expected that patients dosed according to the genotype-guided dosing algorithm will experience less bleedings and less recurrent thrombosis.
Potential impact:Bleedings and recurrent thrombosis are common in patients on coumarin therapy. If the genotype-guided dosing regimen shows an improvement inTIR, and therefore an improvement in the efficacy and safety of coumarin treatment, then it will help to reduce the frequency of one of Europe’s most common causes of drug-related hospital admissions and death.
Keywords: EU-PACT,pharmacogenomics, coumarin therapy, warfarin, CYP2C9, VKORC1
Co-ordinator (Name, Full address, Tel, Fax, e-mail (and web-site of organisation, if applicable)
A.H. Maitland-van der Zee
UtrechtUniversity, Faculty of Science
Utrecht Institute for Pharmaceutical Sciences
Division of Pharmacoepidemiology and Pharmacotherapy
Sorbonnelaan 16
3584CA Utrecht, The Netherlands
PO Box 80082
3508 TB Utrecht, The Netherlands
Tel +31-302534042
Fax +31-302539166
E-mail:
Website: and
Partners (Name, Full address)
A. de Boer
UtrechtUniversity, Faculty of Science
Utrecht Institute for Pharmaceutical Sciences
Division of Pharmacoepidemiology and Pharmacotherapy
PO Box 80082
3508 TB Utrecht, The Netherlands
F.R. Rosendaal
Leiden University Medical Center
Clinical Epidemiology
Albinusdreef 2
2333ZA Leiden, The Netherlands
W.K. Redekop
Erasmus Universitair Medisch Centrum Rotterdam Erasmus MC
Gravendijkwal 230
3015 CE Rotterdam, The Netherlands
J. Kirchheiner
Universitaet Ulm
Institute of Natural Medicine and Clinical Pharmacology
Helmholtzstrasse 16
89081 Ulm, Germany
A.K. Daly
University of Newcastle upon Tyne
6 Kensington Terrace
NE1 7RU Newcastle Upon Tyne, United Kingdom
F. Kamali
University of Newcastle upon Tyne
6 Kensington Terrace
NE1 7RU Newcastle Upon Tyne, United Kingdom
M. Pirmohamed
The University of Liverpool
Brownlow Hill, FoundationBuilding 765
L69 7ZX Liverpool, United Kingdom
R. Barallon
LGC Limited
Queens Road
TW11 OLY, TeddingtonMiddlesex, United Kingdom
L. Bequemont
Université Paris-Sud XI
Rue Georges Clemenceau 15
91405 Orsay, France
M. Wadelius
UppsalaUniversity
St Olofsgatan 10B
75105 Uppsala, Sweden
V.G. Manolopoulos
DemocritusUniversity of Thrace
Panepistimioupoli
69100 Komotini, Greece
E. Haschke-Becher
KH ElisabethinenLinz
Fadingerstrasse 1
4010 Linz, Austria
M. Briz