Clinical trial NCT01119300: EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin
Official title: EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Venous Thromboembolism
Atrial Fibrillation
Keywords: Venous Thromboembolism (VTE)
Atrial Fibrillation (AF)
Lead sponsor: Utrecht Institute for Pharmaceutical Sciences
Sponsor class: OTHER
Collaborators: name: Utrecht University
name: Leiden University Medical Center
name: Erasmus Medical Center
name: University of Ulm
name: Newcastle University
name: University of Liverpool
name: LGC Limited
name: Uppsala University
name: Democritus University of Thrace
name: Elisabethinen Hospital
First posted: 2010-05-07
Enrollment: 455
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief summary: Rationale:

The narrow therapeutic range and wide inter-patient 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 cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) jointly account for about 40% of the inter-individual 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 randomised settings. Objective:

To determine whether a dosing algorithm containing genetic information increases the time within therapeutic INR range during anticoagulation therapy with each of warfarin, acenocoumarol and phenprocoumon compared to a dosing regimen that does not contain this information. Secondary outcomes of the study include cost effectiveness, number of thromboembolic and bleeding events, time to reach stable dose and number of supratherapeutic INR peaks.

Detailed description: Study design: This is a two-armed, single-blinded, randomised controlled trial. In one arm (intervention) patients commencing anticoagulation therapy with either warfarin, acenocoumarol or phenprocoumon will be dosed according to a drug-specific genotype-guided dosing algorithm, which is based on genetic information, clinical data and (in the monitoring phase) previous INR. For the other arm (control) patients will be dosed according to a non-genotype-guided dosing regimen which does not include genetic information. The follow-up period per patient is 3 months. Study population: Newly diagnosed patients of both genders and at least 18 years old who need anticoagulant treatment with either acenocoumarol, phenprocoumon or warfarin within the low intensity INR range will be included in the trial. Main study parameters/endpoints: The % time within therapeutic INR range in the first 3 months of anticoagulation therapy. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Six extra blood samples are taken from each participant at the start of the study. Patients also have to attend 8 scheduled visits within the 3 months study period and are asked to fill in questionnaires. The genotype-guided dosing algorithm is anticipated to improve the accuracy of coumarin dosing and thus improve the safety and efficacy of anticoagulation therapy.

Eligibility criteria: Inclusion Criteria:

* Patients with either venous thromboembolism (VTE) or atrial fibrillation (AF) requiring coumarin therapy for at least 12 weeks and a target INR in the low intensity range (INR range 2-3 in the United Kingdom, Sweden, Germany, Austria and Greece and INR 2.5-3.5 in the Netherlands)
* Age ≥ 18 years
* Ability to attend scheduled visits
* Signed informed consent

Exclusion Criteria:

* Presence of a mechanical heart valve
* Severe cognitive impairment
* Known genotype CYP2C9 or VKORC1 at start of the study
* Previous or current treatment with any coumarin
* Pregnancy or lactation
* Non-eligible subject

Primary outcomes:
measure: Percent time within therapeutic INR range 2-3 during 12 weeks following the initiation of coumarin therapy
timeFrame: 12 weeks
Secondary outcomes:
measure: Time INR > or = 4.0, which indicates overanticoagulation
timeFrame: 12 weeks
measure: Percent time spent > or = INR 4.0
timeFrame: 12 weeks
measure: Percent time spent < or = INR 2, which indicates under-anticoagulation
timeFrame: 12 weeks
measure: Time to reach therapeutic INR defined as the time to the first INR within target range, providing that a subsequent INR > or =1 week later is also within target range
timeFrame: 12 weeks
measure: Time to reach stable dose defined as INR within target range for a period of at least 3 weeks with <10% change in dose
timeFrame: 12 weeks
measure: Time to and number of minor and major bleeding events
timeFrame: 12 weeks
measure: Time to and number of thromboembolic events (therapeutic failure)
timeFrame: 12 weeks
measure: The incidence of coumarin sensitivity
timeFrame: 12 weeks
measure: The incidence of coumarin resistance
timeFrame: 12 weeks
measure: Number of coumarin dose adjustments
timeFrame: 12 weeks
measure: The clinical utility of the rapid genotyping test developed by LGC
timeFrame: 2 years
measure: Quality of life as reported by the patient tested by the EuroQol (EQ)-5D questionnaire
timeFrame: 12 weeks
measure: The cost-effectiveness of genotype-guided dosing for each coumarin compared with non-genotype-guided dosing
timeFrame: will be assessed after inclusion of all patients
measure: Number of patients with INR > or = 4.0, which indicates overanticoagulation
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Uppsala
country: Sweden
facility: Uppsala University
city: Liverpool
country: United Kingdom
facility: University of Liverpool
city: Newcastle
country: United Kingdom
facility: University of Newcastle
Study officials:
affiliation: University of Liverpool
name: Munir Pirmohamed, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Verhoef TI, Redekop WK, Darba J, Geitona M, Hughes DA, Siebert U, de Boer A, Maitland-van der Zee AH, Barallon R, Briz M, Daly A, Haschke-Becher E, Kamali F, Kirchheiner J, Manolopoulos VG, Pirmohamed M, Rosendaal FR, van Schie RM, Wadelius M; EU-PACT Group. A systematic review of cost-effectiveness analyses of pharmacogenetic-guided dosing in treatment with coumarin derivatives. Pharmacogenomics. 2010 Jul;11(7):989-1002. doi: 10.2217/pgs.10.74.
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