Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis

To the Editor: The recent position statement from the Warfarin Reversal Consensus Group provides a comprehensive, coherent and practical approach to warfarin reversal management. 1

In reviewing the position statement, and with particular reference to the paragraph about modifiers of warfarin response, we noted that the contribution of cytochrome P450 2C9 (CYP2C9) genotype to the response to warfarin was not addressed. There is debate in the current literature about the clinical utility of evaluating CYP 2C9 genotype in patients already taking or about to start warfarin therapy. Nonetheless, a significant body of evidence supports the contribution of CYP2C9 genetic variants as modifiers of response to warfarin therapy.

CYP2C9 is the enzyme principally involved in metabolising warfarin.2 Several studies have identified the presence of single nucleotide polymorphisms in the CYP2C9 gene resulting in the expression of two allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) that are associated with reduced enzymatic activity, impaired metabolism of and increased sensitivity to standard warfarin doses.2,3 The allelic frequency of the mutant genotypes is in excess of 21% in the white population2 (they occur at reduced frequencies in African American populations and are rare in Asian populations4). The presence of allelic variants (CYP2C9*2 and CYP2C9*3) with reduced enzymatic activity is closely correlated with increased bleeding complications.2,3 Thus, there is potential for a considerable clinical impact given the large number of patients taking warfarin.

We have identified an allelic frequency of CYP2C9*2 and CYP2C9*3 genotypes in an Australian population of patients attending an anticoagulant clinic comparable to that reported in the literature.2,3 We also identified international normalised ratios in excess of the target range in patients with the CYP2C9*2 or CYP2C9*3 genotype undergoing induction warfarin therapy with standard dosing regimens, relative to those who did not have these genotypes (personal, unpublished data, presented as: Cytochrome P450 CYP2C9 genotyping and warfarin induction therapy, presented at the 2004 Annual Scientific Meeting of the Haematology Society of Australia and New Zealand [Oct 17–20, Melbourne, Australia]).

Recent reports suggest that CYP2C9 genotyping before inducing warfarin therapy may avert bleeding complications.5 However, CYP2C9 genotyping is currently only available within research institutes and larger corporations with research and development facilities and does not attract a Medicare rebate. While simple and inexpensive, genetic CYP2C9 screening has yet to be proven cost effective. However, genotyping may be of benefit in averting over-anticoagulation in certain clinical scenarios. These include commencing warfarin therapy in “high risk” elderly patients; those in whom low-dose, long-term, low-testing-frequency warfarin regimens are being contemplated; and in other “high risk” patients, such as those with conditions affecting warfarin metabolism, including liver disease, and in those taking medications known to interact with the hepatic metabolism of warfarin.