EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol

Atrial Fibrillation Clinical Trial

— EU-PACT  

Official title:

EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01119261
• Other study ID #: COU-001A
• Secondary ID: 2230622009-01699
• Status: Completed
• Phase: Phase 4
• First received: May 4, 2010
• Last updated: June 17, 2013
• Start date: November 2010
• Est. completion date: June 2013

Study information

• Verified date: June 2013
• Source: Utrecht Institute for Pharmaceutical Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: The Netherlands: Central Committee on Research inv. Human SubjectsGreece: National Drug Organisation
• Study type: Interventional

Clinical Trial 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. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 970
• Est. completion date: June 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject)

Related Conditions & MeSH terms

• Atrial Fibrillation
• Thromboembolism
• Venous Thromboembolism

Intervention

Other:
• Genotype-guided dosing algorithm
Loading and monitoring dose according to genotype-guided dosing algorithm
• Non-genotype-guided dosing algorithm
Loading and monitoring dose according to non-genotype-guided dosing algorithm

Locations

Country	Name	City	State
Greece	Democritus University of Thrace Medical School	Alexandropoulis
Netherlands	Utrecht University	Utrecht

Sponsors (11)

Lead Sponsor	Collaborator
Utrecht Institute for Pharmaceutical Sciences	Democritus University of Thrace, Elisabethinen Hospital, Erasmus Medical Center, Leiden University Medical Center, LGC Limited, Newcastle University, University of Liverpool, University of Ulm, Uppsala University, Utrecht University

Countries where clinical trial is conducted

Greece,  Netherlands, 

References & Publications (15)

Avery PJ, Jorgensen A, Hamberg AK, Wadelius M, Pirmohamed M, Kamali F; EU-PACT Study Group. A proposal for an individualized pharmacogenetics-based warfarin initiation dose regimen for patients commencing anticoagulation therapy. Clin Pharmacol Ther. 2011 Nov;90(5):701-6. doi: 10.1038/clpt.2011.186. Epub 2011 Sep 28. — View Citation

van Schie RM, Babajeff AM, Schalekamp T, Wessels JA, le Cessie S, de Boer A, van der Meer FJ, van Meegen E, Verhoef TI, Rosendaal FR, Maitland-van der Zee AH; EU-PACT study group. An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol. J Thromb Haemost. 2012 May;10(5):767-72. doi: 10.1111/j.1538-7836.2012.04694.x. — View Citation

van Schie RM, Cascorbi I, Maitland-van der Zee AH. Conference Scene: Pharmacogenomics at the second PharmSciFair 2009: adverse drug reactions and clinical implementation. Pharmacogenomics. 2009 Sep;10(9):1389-91. doi: 10.2217/pgs.09.95. — View Citation

van Schie RM, de Boer A, Maitland-van der Zee AH. Implementation of pharmacogenetics in clinical practice is challenging. Pharmacogenomics. 2011 Sep;12(9):1231-3. doi: 10.2217/pgs.11.81. — View Citation

van Schie RM, el Khedr N, Verhoef TI, Teichert M, Stricker BH, Hofman A, Buhre PN, Wessels JA, Schalekamp T, le Cessie S, van der Meer FJ, Rosendaal FR, de Boer A, Maitland-van der Zee AH, Visser LE. Validation of the acenocoumarol EU-PACT algorithms: similar performance in the Rotterdam Study cohort as in the original study. Pharmacogenomics. 2012 Aug;13(11):1239-45. doi: 10.2217/pgs.12.101. — View Citation

van Schie RM, Jorgensen AL, de Boer A, Maitland-van der Zee AH; EU-PACT study group. Systematic review of pharmacogenetic warfarin dosing. J Gen Intern Med. 2009 Oct;24(10):1171. doi: 10.1007/s11606-009-1083-9. — View Citation

van Schie RM, Verhoef TI, Boejharat SB, Schalekamp T, Wessels JA, le Cessie S, Rosendaal FR, van der Meer FJ, de Boer A, Maitland-van der Zee AH. Evaluation of the effect of statin use on the acenocoumarol and phenprocoumon maintenance dose. Drug Metabol Drug Interact. 2012;27(4):229-34. — View Citation

van Schie RM, Wadelius MI, Kamali F, Daly AK, Manolopoulos VG, de Boer A, Barallon R, Verhoef TI, Kirchheiner J, Haschke-Becher E, Briz M, Rosendaal FR, Redekop WK, Pirmohamed M, Maitland van der Zee AH. Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics. 2009 Oct;10(10):1687-95. doi: 10.2217/pgs.09.125. — View Citation

van Schie RM, Wessels JA, le Cessie S, de Boer A, Schalekamp T, van der Meer FJ, Verhoef TI, van Meegen E, Rosendaal FR, Maitland-van der Zee AH; EU-PACT Study Group. Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J. 2011 Aug;32(15):1909-17. doi: 10.1093/eurheartj/ehr116. Epub 2011 Jun 2. Erratum in: Eur Heart J. 2013 Jun;34(24):1854. — View Citation

van Schie RM, Wessels JA, Verhoef TI, Schalekamp T, le Cessie S, van der Meer FJ, Rosendaal FR, Visser LE, Teichert M, Hofman A, Buhre PN, de Boer A, Maitland-van der Zee AH. Evaluation of the effect of genetic variations in GATA-4 on the phenprocoumon and acenocoumarol maintenance dose. Pharmacogenomics. 2012 Dec;13(16):1917-23. doi: 10.2217/pgs.12.174. — View Citation

Verhoef TI, Redekop WK, Buikema MM, Schalekamp T, Van Der Meer FJ, Le Cessie S, Wessels JA, Van Schie RM, De Boer A, Teichert M, Visser LE, Maitland-Van Der Zee AH; EU-PACT Group. Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users. J Thromb Haemost. 2012 Apr;10(4):606-14. doi: 10.1111/j.1538-7836.2012.04633.x. — View 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. Review. — View Citation

Verhoef TI, Redekop WK, Hegazy H, de Boer A, Maitland-van der Zee AH; EU-PACT group. Long-term anticoagulant effects of CYP2C9 and VKORC1 genotypes in phenprocoumon users. J Thromb Haemost. 2012 Dec;10(12):2610-2. doi: 10.1111/jth.12007. — View Citation

Verhoef TI, Redekop WK, van Schie RM, Bayat S, Daly AK, Geitona M, Haschke-Becher E, Hughes DA, Kamali F, Levin LÅ, Manolopoulos VG, Pirmohamed M, Siebert U, Stingl JC, Wadelius M, de Boer A, Maitland-van der Zee AH; EU-PACT group. Cost-effectiveness of pharmacogenetics in anticoagulation: international differences in healthcare systems and costs. Pharmacogenomics. 2012 Sep;13(12):1405-17. Review. — View Citation

Verhoef TI, Zuurhout MJ, van Schie RM, Redekop WK, van der Meer FJ, le Cessie S, Schalekamp T, de Boer A, Maitland-van der Zee AH. The effect of omeprazole and esomeprazole on the maintenance dose of phenprocoumon. Br J Clin Pharmacol. 2012 Dec;74(6):1068-9. doi: 10.1111/j.1365-2125.2012.04295.x. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent time within therapeutic INR range 2-3 during 12 weeks following the initiation of coumarin therapy		12 weeks	No
Secondary	Time to INR > or = 4.0, which indicates overanticoagulation.		12 weeks	No
Secondary	Percent time spent > or = INR 4.0		12 weeks	No
Secondary	Percent time spent < or = INR 2, which indicates under-anticoagulation		12 weeks	No
Secondary	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		12 weeks	No
Secondary	Time to reach stable dose defined as INR within target range for a period of at least 3 weeks with <10% change in dose		12 weeks	No
Secondary	Time to and number of minor and major bleeding events		12 weeks	Yes
Secondary	Time to and number of thromboembolic events (therapeutic failure)		12 weeks	Yes
Secondary	The incidence of coumarin sensitivity		12 weeks	No
Secondary	The incidence of coumarin resistance		12 weeks	No
Secondary	Number of coumarin dose adjustments		12 weeks	No
Secondary	The clinical utility of the rapid genotyping test developed by LGC		2 years	No
Secondary	Quality of life as reported by the patient tested by the EuroQol (EQ)-5D questionnaire		12 weeks	No
Secondary	The cost-effectiveness of genotype-guided dosing for each coumarin compared with non-genotype-guided dosing		2 years	No
Secondary	Number of patients with INR > or = 4.0, which indicates overanticoagulation		12 weeks	No