Impact of genetic and clinical factors on dose requirements and quality of anticoagulation therapy in Polish patients receiving acenocoumarol: dosing calculation algorithm.

Abstract

BACKGROUND:

Despite the recent emergence of new oral anticoagulants, vitamin K antagonists remain the primary therapy in patients with atrial fibrillation and the only therapy licensed for use in patients with artificial heart valves.

OBJECTIVE:

The aim of this study was (a) to assess the impact of clinical and genetic factors on acenocoumarol (AC) dose requirements and the percentage of time in therapeutic range (%TTR) and (b) to develop pharmacogenetic-guided AC dose calculation algorithm.

MATERIALS AND METHODS:

We included 235 outpatients of the Institute of Cardiology (Warsaw), mean age 69.3, 46.9% women, receiving AC for artificial heart valves and/or atrial fibrillation. A multiple linear-regression analysis was performed using log-transformed effective AC dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other clinical factors as independent predictors.

RESULTS:

We identified factors that influenced the AC dose: CYP2C9 polymorphisms (P=0.004), VKORC1 polymorphisms (P<0.0001), age (P<0.0001), creatinine clearance lower than 40 ml/min (P=0.035), body mass (P=0.02), and dietary vitamin K intake (P=0.026). Clinical and genetic factors explained 49.0% of AC dose variability. We developed a dosing calculation algorithm that is, to the best of our knowledge, the first one to assess the effect of such clinical factors as creatinine clearance and dietary vitamin K intake on the AC dose. The clinical usefulness of the algorithm was assessed on separate validation group (n=50) with 70% accuracy. Dietary vitamin K intake higher than 200 mcg/day improved international normalized ratio control (%TTR 73.3±17 vs. 67.7±18, respectively, P=0.04).

CONCLUSION:

Inclusion of a variety of genetic and clinical factors in the dosing calculation algorithm allows for precise AC dose estimation in most patients and thus improves the efficacy and safety of the therapy.

• Authors: Jolanta Wolkanin-Bartnik, Hanna Pogorzelska, Małgorzata Szperl, Aleksandra Bartnik, Jacek Koziarek, Zofia T Bilinska
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 23 Issue 11 Pg. 611-8 (Nov 2013) ISSN: 1744-6880 [Electronic] United States
• PMID: 24108193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticoagulants
• Genetic Markers
• Vitamin K
• Creatinine
• CYP2C9 protein, human
• Cytochrome P-450 CYP2C9
• Aryl Hydrocarbon Hydroxylases
• VKORC1 protein, human
• Vitamin K Epoxide Reductases
• Acenocoumarol

Topics

• Acenocoumarol (administration & dosage, therapeutic use)
• Adult
• Aged
• Aged, 80 and over
• Algorithms
• Anticoagulants (administration & dosage, therapeutic use)
• Aryl Hydrocarbon Hydroxylases (genetics)
• Atrial Fibrillation (drug therapy)
• Body Mass Index
• Creatinine (blood)
• Cytochrome P-450 CYP2C9
• Dose-Response Relationship, Drug
• Drug Dosage Calculations
• Female
• Genetic Markers
• Genetic Variation
• Genotype
• Heart Valve Prosthesis
• Humans
• Linear Models
• Male
• Middle Aged
• Poland
• Polymorphism, Single Nucleotide
• Venous Thrombosis (drug therapy)
• Vitamin K (metabolism)
• Vitamin K Epoxide Reductases (genetics)