Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design.
The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.
van Schie
Rianne M F
RM
Utrecht University, Faculty of Science, Utrecht, The Netherlands.
Wadelius
M I A
MI
Kamali
Farhad
F
Daly
Ann K
AK
Manolopoulos
Vangelis G
VG
de Boer
Anthonius
A
Barallon
Rita
R
Verhoef
Talitha I
TI
Kirchheiner
Julia
J
Haschke-Becher
Elisabeth
E
Briz
Montserrat
M
Rosendaal
Frits R
FR
Redekop
William K
WK
Pirmohamed
Munir
M
Maitland van der Zee
Anke-Hilse
AH
D000074:Acenocoumarol / Q000627:therapeutic use; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015331:Cohort Studies; D003362:Cost-Benefit Analysis; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions / Q000235:genetics; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics; D010644:Phenprocoumon / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D019057:Quality-Adjusted Life Years; D012449:Safety; D013997:Time Factors; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol; D010644:Phenprocoumon