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Open Access Study protocol

Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial

Antonio J Carcas1*, Alberto M Borobia1*, Marta Velasco2, Francisco Abad-Santos3, Manuel Quintana Díaz4, Carmen Fernández-Capitán5, Nuria Ruiz-Giménez6, Olga Madridano7, Pilar Llamas Sillero8 and And the PGX-ACE Spanish Investigators Group

Author Affiliations

1 Clinical Pharmacology Department, La Paz University Hospital, Pharmacology Department, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Paseo de la Castellana, 261, 28046, Madrid, Spain

2 Pharmacology Department, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain

3 Clinical Pharmacology Service, La Princesa University Hospital, Pharmacology Department, School of Medicine, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain

4 Emergency Department, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain

5 Internal Medicine Department, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain

6 Internal Medicine Department. La Princesa University Hospital, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain

7 Internal Medicine Department, Infanta Sofía Hospital, Madrid, Spain

8 Department of Hematology, Fundación Jiménez Díaz Hospital, Madrid, Spain

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Trials 2012, 13:239  doi:10.1186/1745-6215-13-239

Published: 13 December 2012

Abstract

Background

Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE).

Methods and design

This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment.

Discussion

To date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety.

Trial registration

Eudra CT. Identifier: 2009-016643-18.

Keywords:
Pharmacogenetic; Acenocoumarol; Hematology