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. Conclusion: 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.

Intracerebral Bleeding in Patients on Antithrombotic Agents

“…21 VKA can be difficult to manage because of a narrow therapeutic international normalized ratio (INR) range (2-3). [21][22][23][24] Another major concern with VKA are hemorrhagic complications. Remarkably, 60 to 90% of all hemorrhageassociated deaths in patients on OAC are caused by OAC-ICH.…”

Impact of pharmacokinetic (CYP2C9) and pharmacodynamic (VKORC1, F7, GGCX, CALU, EPHX1) gene variants on the initiation and maintenance phases of phenprocoumon therapy

“…While warfarin is the most frequently prescribed anticoagulant in Anglo-American countries and Scandinavia, phenprocoumon is preferentially used in many European countries (2). Compared to warfarin, data regarding the influence of VKORC1 and CYP2C9 gene variants on anticoagulant therapy with phenprocoumon are scarce (20)(21)(22)(23)(24)(25). Data concerning the impact of GGCX, EPHX1, calumenin (CALU), and F7 gene variants on phenprocoumon are very limited or lacking (25).…”

Gene-Drug Interaction in Stroke

“…Several groups have studied the role of VKORC1 in warfarin/acenocoumarol dose finding, dose maintenance, and bleeding risk associated with these drugs [33, 34, 59–61]. Only two studies have focused on patients receiving vitamin K antagonist following cardioembolic stroke.…”

“…One found that the time and cumulative dosage of phenprocoumon needed to achieve target 2-3 INR ratio were associated with the presence of the VKORC1 C283 + C837T ( rs2359612 ) polymorphism. Carriers of TT genotype needed shorter time to achieve target INR ratio (3.2 days) compared to CC carriers (6.5 days) [33]. The second paper evaluated the roles of VKORC1 , gamma-glutamyl carboxylase ( GGCX ), calumenin ( CALU ), and cytochrome P450 2C9 ( CYP2C9 ) in warfarin maintenance dose on Japanese stroke sufferers.…”