Genotype-Guided Dosing of Coumarin Derivatives: The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) Trial Design

Abstract

The narrow therapeutic range and wide interpatient 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 VKORC1 and CYP2C9 jointly account for about 40% of the interindividual 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 randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

“…Systematyczne wykorzystywanie informacji genetycznych w celu modyfikowania dawki VKA oceniono w kilku kontrolowanych badaniach klinicznych [498][499][500]. Badania genetyczne wywierają niewielki wpływ na TTR lub ryzyko krwawienia podczas stosowania warfaryny i obecnie nie zaleca się ich wykorzystywania w praktyce klinicznej [501].…”

Interpreting the clinical utility of a pharmacogenomic marker based on observational association studies

“…To date there have been very few examples of RCTs specifically designed to assess the clinical utility of a pharmacogenomic marker that are adequately powered to detect relevant clinical outcomes. Prominent examples are the RCTs of genotype-guided warfarin dosing (COAG 29 and EUPACT 30 ) and expression profiles to guide use of chemotherapy in early breast cancer (TAILORx 31 and MINDACT 32 ).…”

“…Consequently a prospective RCT will often be the only option if RCT evidence is required to confirm that genotype-guided dose adjustment improves treatment outcomes. 29,30 If RCT based data is unavailable additional observation studies may be of some value to better understand the likely clinical utility. Specifically, observational studies of the same pharmacogenomic marker in a similar patient cohort that are not on the treatment of interest may help provide support for whether the marker is likely to have 'prognostic' and/or 'predictive' effects.…”

Pharmacology

“…This is suggested to prevent overanticoagulation in carriers of a variant allele and to reach a stable dose earlier. RCTs are currently ongoing to provide evidence for the (cost) effectiveness of pre-treatment genotyping for coumarin derivatives (van Schie et al, 2009;French et al, 2010).…”

“…The problem with these analyses is that no robust data on the effectiveness of genotyping are available yet; the large RCTs that can provide this data are still ongoing (van Schie et al, 2009;French et al, 2010). This current lack of evidence results in a wide variability in cost-effectiveness ratios among the studies that have been done, ranging from dominance (where use of genotyping reduces costs and increases health) to a very high incremental cost of $347,000 per QALY gained (Verhoef et al, 2010).…”