Atrial Fibrillation Clinical Trial
— EU-PACTOfficial title:
EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin
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.
Status | Completed |
Enrollment | 455 |
Est. completion date | October 2013 |
Est. primary completion date | October 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 |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject)
Country | Name | City | State |
---|---|---|---|
Sweden | Uppsala University | Uppsala | |
United Kingdom | University of Liverpool | Liverpool | |
United Kingdom | University of Newcastle | Newcastle |
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 |
Sweden, United Kingdom,
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
Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlström B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F, Wadelius M; EU-PACT Group. A — 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 16 references in all — Click here to view all references
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 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 | will be assessed after inclusion of all patients | No | |
Secondary | Number of patients with INR > or = 4.0, which indicates overanticoagulation | 12 weeks | No |
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