Determination of bleeding risk using genetic markers in patients taking phenprocoumon.
BACKGROUND
In patients on oral anticoagulation with warfarin, genetic variations of the cytochrome P 450-CYP2C9 have recently been associated with very low warfarin requirements. Patients needing low doses had an increased risk for bleeding complications. In Germany, phenprocoumon (having a similar metabolic pathway) is the most commonly employed vitamin K antagonist. Treatment is usually monitored by general practitioners (GPs).


OBJECTIVE
To determine whether CYP2C9 variant alleles can serve as risk markers in general-practice patients anticoagulated with phenprocoumon.


METHODS
All adult anticoagulated patients in 12 teaching general practices and one university outpatient clinic were to be recruited. Blood samples were taken from 185 patients during routine anticoagulation controls and tested for CYP2C9 mutations. Subjects answered a questionnaire concerning bleeding complications, drug intolerance, and personal and family medical history. Phenprocoumon dosages required for stable anticoagulation were recorded. Odds ratios (OR) with 95% confidence intervals (CI) were calculated based on 2-way cross-tabulations and multivariate logistic regression models, t-tests used where appropriate.


RESULTS
Bleeding was reported by 19% of the patients, 2.2% of whom had suffered life-threatening bleeding. CYP2C9 variants were carried by 26.3% of 179 patients tested (17.9% *1/*2, 7.8% *1/*3, 0.6% *2/*3). While presence of a *2 allele was not associated with an increased risk (OR 0.35, CI 0.10-1.24), carriers of the rare *3 alleles had a higher risk of bleeding (OR 3.10, CI 1.02-9.40). With regard to bleeding, carrying CYP2C9*3 was highly specific (94%), though sensitivity was low at 17%; post-test probability of bleeding was 40%.


CONCLUSIONS
CYP2C9*3 variants are associated with an increased bleeding risk in patients anticoagulated with phenprocoumon. Screening can identify patients with a high risk of bleeding. Appropriate clinical consequences (restricted indication for anticoagulation, careful induction, adjustment of target INR, closer monitoring or self-testing of INR) as well as the cost-effectiveness of screening for variant CYP2C9 with regard to patient outcomes should be subject of further research.
Department of General Practice, University of Göttingen Medical School, Humboldtallee 38, 37073 Göttingen, Germany. ehummer@gwdg.de
Eva
E
Hummers-Pradier
Stephan
S
Hess
Ibrahim M
IM
Adham
Thomas
T
Papke
Burkert
B
Pieske
Michael M
MM
Kochen
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics*; D003430:Cross-Sectional Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006470:Hemorrhage / Q000175:diagnosis / Q000209:etiology*; D006801:Humans; D008875:Middle Aged; D010644:Phenprocoumon / Q000008:administration & dosage / Q000009:adverse effects*; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012680:Sensitivity and Specificity
D000925:Anticoagulants; D005819:Genetic Markers; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D010644:Phenprocoumon