title: Pharmacogenetic testing for guiding de novo phenprocoumon therapy in stroke patients.
abstract: BACKGROUND
  For many conditions causing transient ischemic attack or minor stroke, secondary prevention with early initiation of oral anticoagulation is indicated. The individual response to coumarins is known to vary widely and is not well predicted by clinical variables. Patients' discharge from hospital care is often delayed only because the therapeutic target range has not been reached yet. A feasible tool to guide coumarin dosing and thereby safely shortening time in hospital is required.
  
  
  METHODS
  We established a polymerase chain reaction technique for rapid genotyping of the vitamin K epoxide reductase complex (VKORC1), which is the pharmaceutical target of the coumarins. C283 + 837C -> T (rs2359612) genotypes were determined in 49 patients who underwent de novo oral anticoagulation with phenprocoumon for cerebrovascular disease. Other variables potentially affecting phenprocoumon sensitivity were systematically evaluated.
  
  
  RESULTS
  Of 49 genotyped patients, 47 were treated in hospital until an international normalized ratio (INR) of 2-3 was reached. The time and the cumulative dose of phenprocoumon necessary to achieve the target INR both were strongly dependent on the individual C283 + 837C -> T genotype (Kruskal-Wallis test p = 0.0002, and p < 0.0001, respectively). Carriers of the TT genotype reached an INR of 2-3 after a mean time of 3.2 days (n = 5), CT carriers after 4.4 days (n = 27), and CC carriers after 6.5 days (n = 15). No other variable, including body weight, was significantly correlated with the treatment response.
  
  
  CONCLUSIONS
  In patients with cerebrovascular disease, genotyping for VKORC1 alone can strongly predict the individual response to de novo phenprocoumon treatment. The size of the pharmacogenetic test's potential effect on a more efficient use of hospital capacities remains to be shown by a controlled interventional study.
authors.affiliation: Department of Neurology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Arnold
authors.forename: Caspar
authors.initials: C
authors.lastname: Grond-Ginsbach
authors.forename: Manja
authors.initials: M
authors.lastname: Kloss
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Di Mascio
authors.forename: Roland
authors.initials: R
authors.lastname: Veltkamp
authors.forename: Peter
authors.initials: P
authors.lastname: Ringleb
authors.forename: Christoph
authors.initials: C
authors.lastname: Lichy
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics; D010644:Phenprocoumon / Q000627:therapeutic use*; D057285:Precision Medicine; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D010644:Phenprocoumon