Key result
Genotype-guided dosing explains ~3-fold more coumarin dose variance than clinical algorithms alone.
Why the study?
Polymorphisms in CYP2C9 and VKORC1 influence phenprocoumon and acenocoumarol dose requirements, necessitating tools to estimate individual dosing.
Do genotype-guided dosing algorithms better predict the maintenance dose of phenprocoumon and acenocoumarol compared to non-genotype-guided algorithms in patients requiring anticoagulation?
Observational (n=1,492)
Yes
Do genotype-guided dosing algorithms better predict the maintenance dose of phenprocoumon and acenocoumarol compared to non-genotype-guided algorithms in patients requiring anticoagulation?
Absolute Event Rate: 55.9% vs 17.3%
Genotype-guided algorithms incorporating CYP2C9 and VKORC1 polymorphisms significantly improve the prediction of phenprocoumon and acenocoumarol maintenance doses compared to clinical factors alone.
Genotype-guided algorithms enhance dose prediction for two VKAs; hypothesis-generating and requires prospective outcome trials before practice change.
AIMS: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE. METHODS AND RESULTS: In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters. CONCLUSION: To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.
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Schie et al. (2011) conducted an observational in Patients requiring anticoagulation with phenprocoumon or acenocoumarol (n=1,492). Genotype-guided dosing algorithms (CYP2C9 and VKORC1) vs. Non-genotype-guided algorithms was evaluated on Variance of the maintenance dose explained. Genotype-guided algorithms explained 55.9% and 52.6% of the variance in maintenance dose for phenprocoumon and acenocoumarol, respectively, outperforming non-genetic algorithms (17.3% and 23.7%).
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