Clinical and Economic Consequences of Pharmacogenetic-guided Dosing of Warfarin

Talitha I Verhoef; Tom Schalekamp; William K Redekop; Anthonius de Boer; Anke-Hilse Maitland-van der Zee


Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(4):375-378. 

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This study suggested that pharmacogenetic-guided dosing of warfarin could improve the health of patients initiating warfarin while also increasing healthcare costs compared with a standard dosing regimen. The probability that genotyping would cost less than US$50,000 per QALY gained was estimated to be almost 50%. However, owing to uncertainty regarding the values of several input parameters, Meckley et al. found that the possible impact of genotyping ranged from a possibility that genotype-guided dosing is the dominant strategy to a possibility that it is less effective and more costly than a standard dosing regimen.[1] This wide range of possible realities is mainly due to uncertainty regarding the effectiveness of pharmacogenetic-guided dosing on the risk of serious adverse events or therapeutic failure of warfarin therapy.

Patients with a variant genotype have a higher risk of bleedings due to warfarin therapy, because of a lower dose requirement. A genotype-guided dosing strategy might reduce this risk when patients with a variant genotype receive a lower dose. It is, therefore, remarkable that genotyping appeared to be less cost effective in patients with a variant genotype. This was explained by the increase in the number of thromboembolic events in this group, which might indicate that the dosages for these patients were overadjusted.

Since the clinical trials performed to date provide no direct evidence regarding the influence of genotyping on the incidence of adverse events or therapeutic failure, these authors used the time within, above and below therapeutic INR range as a surrogate for these clinical end points. This method has been used in two other studies investigating the cost–effectiveness of pharmacogenetic-guided dosing of warfarin.[5,9] In the study of Patrick et al., data from the COUMAGEN trial[6] together with data from Caraco et al.[8] were used to calculate the effect of genotyping on the time spent within therapeutic INR range.[9] In a probabilistic sensitivity analysis Patrick et al. found a chance of 42% that genotyping would be cost effective given a willingness to pay of $50,000 per QALY,[9] which is quite similar to the 46% in the study of Meckley et al.[1] In the study of You et al. this chance was 38%[5] and the base case results were also less optimistic than in the Meckley et al. study,[1] since they reported an ICER of $347,059 per QALY gained. In the study by You et al. lower baseline adverse event rates were used and the effect of genotyping was not stratified by genotype as in the current study. In the probabilistic sensitivity analysis by Meckley et al. the costs of the genetic test are also varied.[1] It would have been more useful to vary this parameter in a scenario analysis, because at the moment of decision-making the prices will be known already.

The development of this model using INR as a surrogate end point for bleedings and thromboembolic events seems very useful, as there is not enough evidence about the effect of genotyping on the adverse event rate. However, the uncertainty around the results of this study are still too large to allow any recommendations regarding the implementation of pharmacogenetics in treatment with warfarin. This uncertainty is mainly caused by the fact that there is not sufficient evidence regarding the effect of genotyping on INR ranges either, because this has only been investigated in a few small clinical trials. For some input parameters, such as the effect of genotyping on INR after the first month of therapy, the authors needed to make assumptions, because there is no evidence yet available on these parameters. Therefore, it is necessary to delay any recommendations regarding genotyping until more data from large clinical trials become available.


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