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

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ClinicalTrials.gov Identifier: NCT01119300
Recruitment Status : Completed
First Posted : May 7, 2010
Last Update Posted : December 3, 2014
Information provided by (Responsible Party):

Study Description
Brief Summary:


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.

Condition or disease Intervention/treatment Phase
Venous Thromboembolism Atrial Fibrillation Other: Genotype-guided dosing algorithm Other: Standard care Phase 4

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.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 455 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Official Title: EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin
Study Start Date : January 2011
Primary Completion Date : October 2013
Study Completion Date : October 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Active Comparator: Standard care
Standard care
Other: Standard care
Standard care
Experimental: Genotype-guided dosing algorithm
Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days.
Other: Genotype-guided dosing algorithm
Loading and monitoring dose according to genotype-guided dosing algorithm

Outcome Measures

Primary Outcome Measures :
  1. Percent time within therapeutic INR range 2-3 during 12 weeks following the initiation of coumarin therapy [ Time Frame: 12 weeks ]

Secondary Outcome Measures :
  1. Time INR > or = 4.0, which indicates overanticoagulation [ Time Frame: 12 weeks ]
  2. Percent time spent > or = INR 4.0 [ Time Frame: 12 weeks ]
  3. Percent time spent < or = INR 2, which indicates under-anticoagulation [ Time Frame: 12 weeks ]
  4. 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 [ Time Frame: 12 weeks ]
  5. Time to reach stable dose defined as INR within target range for a period of at least 3 weeks with <10% change in dose [ Time Frame: 12 weeks ]
  6. Time to and number of minor and major bleeding events [ Time Frame: 12 weeks ]
  7. Time to and number of thromboembolic events (therapeutic failure) [ Time Frame: 12 weeks ]
  8. The incidence of coumarin sensitivity [ Time Frame: 12 weeks ]
  9. The incidence of coumarin resistance [ Time Frame: 12 weeks ]
  10. Number of coumarin dose adjustments [ Time Frame: 12 weeks ]
  11. The clinical utility of the rapid genotyping test developed by LGC [ Time Frame: 2 years ]
  12. Quality of life as reported by the patient tested by the EuroQol (EQ)-5D questionnaire [ Time Frame: 12 weeks ]
  13. The cost-effectiveness of genotype-guided dosing for each coumarin compared with non-genotype-guided dosing [ Time Frame: will be assessed after inclusion of all patients ]
  14. Number of patients with INR > or = 4.0, which indicates overanticoagulation [ Time Frame: 12 weeks ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01119300

Uppsala University
Uppsala, Sweden
United Kingdom
University of Liverpool
Liverpool, United Kingdom
University of Newcastle
Newcastle, United Kingdom
Sponsors and Collaborators
Utrecht Institute for Pharmaceutical Sciences
Utrecht University
Leiden University Medical Center
Erasmus Medical Center
University of Ulm
Newcastle University
University of Liverpool
LGC Limited
Uppsala University
Democritus University of Thrace
Elisabethinen Hospital
Principal Investigator: Munir Pirmohamed, MD PhD University of Liverpool
More Information


Responsible Party: Anke-Hilse Maitland-van der Zee, PharmD, PhD, Utrecht Institute for Pharmaceutical Sciences
ClinicalTrials.gov Identifier: NCT01119300     History of Changes
Other Study ID Numbers: COU-001W
First Posted: May 7, 2010    Key Record Dates
Last Update Posted: December 3, 2014
Last Verified: December 2014

Keywords provided by Anke-Hilse Maitland-van der Zee, Utrecht Institute for Pharmaceutical Sciences:
Venous Thromboembolism (VTE)
Atrial Fibrillation (AF)

Additional relevant MeSH terms:
Atrial Fibrillation
Venous Thromboembolism
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases