Dosing anticoagulant therapy with coumarin drugs: is genotyping clinically useful? No

Oral anticoagulation with vitamin K antagonists (warfarin in the USA and Canada, warfarin or acenocoumarol in Europe) is widely used to prevent or treat thrombosis, particularly in patients with venous thromboembolism, artificial cardiac valves, myocardial infarction or non-rheumatic atrial fibrillation [1]. In the USA, warfarin is also used by orthopedic surgeons for primary prophylaxis of venous thromboembolism [2]. It is well known that, because of the high degree (up to twentyfold) of inter-individual variation in dose–response, coumarin derivatives require laboratory monitoring to both select and adjust dosages. Laboratory monitoring has become easier and more uniform since the introduction of the International Normalized Ratio (INR), a standardized method to express the prothrombin time prolongation. In this way, drug dosages can be adjusted to keep anticoagulation within the recommended limits to avoid either thrombosis or bleeding [2]. Despite this, the inter-individual variation in response to coumarin drugs still remains a concern for both physicians and patients. This may perhaps be one of the reasons for their suboptimal use, particularly in elderly patients with atrial fibrillation. Dose–response variability can, in part, be explained by factors such as age, sex, nutritional status, concomitant drug intake (particularly amiodarone and statins) and co-morbidities such as liver disease [3]. In 1999, Aithal et al. [4] were the first to demonstrate the important role played by a genetic component. In a retrospective study of 36 patients treated with warfarin, they showed that carriership of either polymorphic variant (CYP2C9*2 or CYP2C9*3) of the gene encoding cytochrome P-450 2C9 (the enzyme primarily responsible for warfarin metabolism) decreased dose requirements by approximately 6-fold in comparison with carriership of the wild-type allele (CP2C9*1) [4]. Other reports subsequently showed a similar effect on acenocoumarol dosing, although mainly for the CYP2C9*3 variant allele [5,6]. Six years later, D Andrea et al. [7] were the first to demonstrate that warfarin and acenocoumarol dosage variability was also affected by polymorphic variants in the gene encoding the vitamin K epoxide reductase complex subunit 1 (VKORC1), a rate-limiting enzyme in vitamin K dependent c-carboxylation that plays a key role in the pharmacodynamics of coumarin drugs. The VKORC1 effect is independent of the effects of CYP2C9 alleles. Although other genetic variants have been reported to affect dosages of coumarin drugs, their role and the magnitude of their impact are not firmly established [8]. Following these seminal findings, a number of retrospective studies confirmed that carriership of CYP2C9 and VKORC1 allele variants, alone or in combination, reduced the dosage of coumarin drugs required to keep the INR within the therapeutic range, accounting for approximately half of dose variability [9–13]. Several studies also indicated that carriers of these variants had a higher likelihood of an elevated INRwhen anticoagulant therapy was initiated, and that they spent longer time periods before reaching stable maintenance dosing within the INR therapeutic range [9,12,14]. These retrospective studies concluded that, owing to the association betweenCYP2C9 and VKORC1 variants and response to coumarins, knowledge of patient genotypes might help to select and adjust dosages. These studies did not evaluate directly the effect of genetic variations on the rates of clinical outcomes. The reason for this was because laboratory surrogates, including the time spent before the first INR reaches the therapeutic range, the percentage of time spent within or above the range, and the average daily dose of warfarin or acenocoumarol used during the initial or maintenance phases of therapy, were used as primary end-points. None of the studies had either appropriate design or sample size to be able to address the crucial issue for the clinician (i.e. whether or not knowledge of CYP2C9 or VKORC1 variants helps to decrease the rate of clinical events, such as bleeding as a result of excessive anticoagulation or thrombosis as a result of insufficient anticoagulation). Correspondence: Pier M. Mannucci, Via Pace 9, 20122 Milan, Italy. Tel. : +39 02 55035421; fax: +39 02 50320723. E-mail: piermannuccio.mannucci@unimi.it Journal of Thrombosis and Haemostasis, 6: 1450–1452 DOI: 10.1111/j.1538-7836.2008. 03073.x