EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol (EU-PACT)

Utrecht Institute for Pharmaceutical Sciences

Status and phase

Completed

Phase 4

Conditions

Venous Thromboembolism

Atrial Fibrillation

Treatments

Other: Non-genotype-guided dosing algorithm

Other: Genotype-guided dosing algorithm

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT01119261

COU-001A

2009-016992-31 (EudraCT Number)

223062 (Other Grant/Funding Number)

Details and patient eligibility

About

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. 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.

Enrollment

970 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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