Loading and Maintenance Dose Algorithms for Phenprocoumon and Acenocoumarol Using Patient Characteristics and Pharmacogenetic Data

Study Questions:

How can the patient’s individual dose of phenprocoumon (PHE) and acenocoumarol (ACE) be estimated using patient characteristics and pharmacogenetic data?


The Dutch investigators of this study assessed 624 patients taking PHE and 471 taking ACE in their anticoagulation clinics, and determined data on age, gender, height, weight, co-medication, coumarin derivative doses, and international normalized ratio (INR) values. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, they developed genotype-guided and nongenotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, they derived loading doses from the calculated maintenance doses. They also performed external validation in an independent data set with 229 PHE and 168 ACE users.


The investigators found that CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. They found that genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose; the nongenetic 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 23.5% (PHE) and 17.8% (ACE) for the nongenotype-guided algorithms, without height and weight as parameters.


The authors concluded that genotype-guided loading and maintenance dose algorithms for PHE and ACE could be useful, and recommended that the utility of these algorithms should be tested in randomized controlled trials.


This is an important study because it incorporates polymorphisms in CYP2C9 and VKORC1 to determine PHE and ACE dose requirements. Given that determining dose of these agents has been a ‘fishing’ expedition in day-to-day clinical medicine, the validation of this algorithm will be welcome by patients, payers, and physicians who are involved in the management of patients requiring anticoagulation with warfarin and related agents.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, EP Basic Science

Keywords: Coumarins, Polymorphism, Single Nucleotide, Phenprocoumon, Pharmacogenetics

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