Elsevier

Vascular Pharmacology

Volume 74, November 2015, Pages 151-157
Vascular Pharmacology

Extrapolation of acenocoumarol pharmacogenetic algorithms

https://doi.org/10.1016/j.vph.2015.06.010Get rights and content

Abstract

Introduction

Acenocoumarol (ACN) has a narrow therapeutic range that is especially difficult to control at the start of its administration. Various dosing pharmacogenetic-guided dosing algorithms have been developed, but further work on their external validation is required. The aim of this study was to evaluate the extrapolation of pharmacogenetic algorithms for ACN as an alternative to the development of a specific algorithm for a given population.

Material and methods

The predictive performance, deviation, accuracy, and clinical significance of five pharmacogenetic algorithms (EU-PACT, Borobia, Rathore, Markatos, Krishna Kumar) were compared in 189 stable ACN patients representing all indications for anticoagulant treatment.

Results

The correlation between the dose predictions of the five pharmacogenetic models ranged from 7.7 to 70.6% and the percentage of patients with a correct prediction (deviation ≤ 20% from actual ACN dose) ranged from 5.9 to 40.7%. EU-PACT and Borobia pharmacogenetic dosing algorithms were the most accurate in our setting and evidenced the best clinical performance.

Conclusions

Among the five models studied, the EU-PACT and Borobia pharmacogenetic dosing algorithms demonstrated the best potential for extrapolation.

Graphical abstract

Spearman correlation between actual stable and predicted doses for each pharmacogenetic algorithm.

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Introduction

Warfarin and acenocoumarol (ACN) are first-line oral anticoagulants for the prevention and treatment of thromboembolic disorders in patients with atrial fibrillation (AF), venous thromboembolism (VTE), or heart valve replacement (HVR) [20], [28], [50].

ACN is a 4′nitro warfarin analog administered as a racemic mixture of two enantiomers (R- and S-). Its anticoagulant effect derives from the R-enantiomer, which has a plasma half-life of ≈ 8 h, while the S-ACN enantiomer is rapidly metabolized and has a plasma half-life of < 2 h [41]. Coumarin derivates exert their action by inhibiting the enzyme vitamin k epoxide reductase complex subunit 1 (VKORC1), which catalyzes vitamin K 2,3-epoxide conversion to vitamin K hydroquinone by means of gamma-glutamyl carboxylation [11]. ACN and warfarin differ in their pharmacokinetic properties. The half-life of ACN is four-fold shorter than that of warfarin (34 to 42 h), while CYP2C9 plays a more relevant role in warfarin clearance [42].

The initial response to vitamin K antagonists (VKAs) depends on the characteristics of the patient, including: age, sex, height, weight, concomitant drugs; dietary vitamin K intake, smoking status, alcohol intake, and genetic factors [36]. VKORC1 (1639G > A; rs9923231 and 1173C > T; rs9934438) and CYP2C9 (CYP2C9  2 430C > T; rs1799853 and CYP2C9  3 1075A > C; rs1057910) genes have been widely related to VKAs dose requirements. Clinical and genetic factors have been reported to account for 50% of ACN dosage variability [3], [6], [40].

Patients with AF or VTE should maintain the International Normalized Ratio (INR) range between 2 and 3 to reduce the risk of either thromboembolic or bleeding events [27], [32], which are more frequent during the first few months of treatment, when numerous dose adjustments must be made [38]. Considerable research has been published on pharmacogenetic dosing algorithms designed to predict the individualized stable dose according to clinical and genetic factors, especially for warfarin [9], [13], [14], [15], [16], [19], [21], [34], [47], [49]. Algorithms for ACN have been less well developed and have focused on Caucasian populations [4], [10], [26], [29], [44], [48], with the exception of two models for Indian patients [22], [29]. The main indications for the application of ACN algorithms have been AF, VTE, and HVR [4], [10], [22], [26], [29], [44], [48]. Clinical variables and VKORC1/CYP2C9 gene polymorphisms were included in all pharmacogenetic algorithms for ACN [4], [10], [26], [29], [44], [48], which were found to explain between 41 and 62% of the total variability in ACN stable dose requirement [4], [10], [26], [29], [44], [48]. Eight pharmacogenetic algorithms are currently available to potentially predict the ACN dose in clinical practice [4], [10], [17], [22], [26], [29], [44], [48]. Before algorithms are implemented in different populations to those for which they were developed, their validity and suitability must be demonstrated in the new setting. External validation of the performance, predictive, and accuracy of various pharmacogenetic algorithms for warfarin has been conducted in a real clinical setting, and they were found to explain between 36 and 65% of the variation in warfarin dose requirement [2], [23], [25], [31], [37], [49], [51]. Out of recently published pharmacogenetic algorithms for ACN, only the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) guided dosing algorithm has been externally validated in an independent dataset, obtaining similar results to those found in the original study [43]. These promising results suggest that other models might be successfully adapted for prediction of the ACN dose in different clinical settings.

The objective of this study was to evaluate the potential extrapolation of ACN dose pharmacogenetic algorithms in an external cohort of patients representing all oral anticoagulant indications.

Section snippets

Material and methods

An observational retrospective study was conducted.

Clinical characteristics of study population

Table 2 exhibits the distribution of clinical and genetic variables in the 189 patients in the present cohort and in the derivation cohort of the pharmacogenetic models under study. The median stable dose was 15 [10–19] mg/week in the present cohort, and the doses did not differ as a function of the indication or INR target (14 [10–19] mg/week for VTE/AF/others vs. 16 [12–19] mg/week for HVR; p = 0.192).

The median age was lowest (p < 0.05) in the derivation cohort for the Rathore algorithm (37.5 ± 

Discussion

Oral anticoagulants are widely prescribed to treat and prevent thromboembolic events in patients with chronic AF, VTE and HVR. Various pharmacogenetic algorithms have been developed in an attempt to predict ACN stable dose requirement and improve dose adjustments at the start of the treatment [4], [10], [26], [29], [44], [48]. External validation of these algorithms is required as the next step before their clinical implementation.

This study evaluated the extrapolation of five different ACN

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported and there is no any competing financial interest in relation to the work described in this article.

Funding

This work was partly supported by a contract for Marisa Cañadas-Garre (Técnicos de Apoyo Subprogram) from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (CA12/00097).

Acknowledgments

The authors would like to acknowledge all the professionals from the Complejo Hospitalario Universitario de Granada that contributed to the management of the samples, especially the nursing team from the Haematology Department.

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