A severe case of warfarin–canrenoate interaction: a role for genetic predisposition?

Abstract

The interindividual variability in warfarin response is generally attributed to dietary vitamin K intake, drug interactions, demographic and genetic factors (D’Andrea et al, 2008). Many drugs are known to modify international normalized ratio (INR) values in warfarin-treated patients both for pharmacodynamic and pharmacokinetic interactions. We report an unusual case of interaction between potassium canrenoate (PC) and warfarin in a 77-year-old Caucasian female with atrial fibrillation, heart failure (New York Heart Association class II) and hypertension. During the previous 5 years, the patient had been effectively anticoagulated with warfarin 35·0 mg/week with a very stable INR (Fig 1); in the last 10 months drug therapy also included furosemide, bisoprolol and ramipril. Two weeks after PC addition (50 mg/d) to control a slight hypokalaemia, she suddenly developed an extensive facial and neck haematoma after a mild lesion of the internal jowl, followed by analogous limb lesions as consequences of mild traumas. Blood examinations revealed a marked INR increase (10·8), requiring warfarin discontinuation and vitamin K administration. Warfarin treatment was suspended until INR reached 1·0; subsequent titrations after warfarin reintroduction eventually resulted in a stable INR within the therapeutic range (2·0–3·0) with a final regimen of 22·5 mg/week (about 66% of the previous dose); PC was never withdrawn. Any other possible factor able to interfere with warfarin therapy was excluded, including: recent illness, changes in dietary vitamin K intake, over-the-counter products, fruit-juices, herbal products, alcohol, tobacco. The patient and her relatives confirmed adherence to drug therapy. Clinical manifestations of the patient. (A) Patient’s lesions. (B) Patient’s INR. Warfarin inhibits the synthesis of vitamin K-dependent clotting factors via inhibition of the vitamin K epoxide reductase complex 1 (vkorc1) and is primarily metabolized via cytochrome P450 2C9 (cyp2c9). The patient was genotypized for three warfarin-related SNPs, CYP2C9*2, CYP2C9*3 and VKORC1 -1639G>A (rs9923231, minor allele frequency 0·432 in Caucasian population) (D’Andrea et al, 2008). The Taqman Drug Metabolism Genotyping Assay (Applied Biosystems, Foster City, CA) was used. The patient was found to be homozygous wild-type for both CYP2C9 loci and homozygous -1639AA (low dose required) for VKORC1. Both PC and warfarin are highly bound to human serum albumin (HSA), and PC was previously shown to competitively displace warfarin from HSA to a significantly higher extent than spironolactone (the latter was, on the contrary, reported to decrease the anticoagulant effect of warfarin by means of clotting factors concentration) (O’Reilly, 1980; Takamura et al, 1997). This interaction may increase warfarin bioavailability, taking also into account that both R-Warfarin and PC undergo extensive hepatic metabolism via CYP3A (Cook et al, 1993; D’Andrea et al, 2008). To date, this is the first clinically relevant interaction between warfarin and PC. Its imputability was graded as ‘probable’ according to the objective causality assessment performed by our Pharmacovigilance Unit. As the combination of warfarin and PC might be quite common in cardiovascular therapy (e.g. 2042 out of 58 831 – 3·5%– warfarin users have at least a coexistent prescription of PC within a time window of 1–3 months according to recent prescription data of Tuscany), we hypothesize that the increase in warfarin serum concentration afforded by PC pharmacokinetic interactions may lead to a clinically relevant bleeding syndrome only in subjects with a warfarin-sensitive genotype (e.g. VKORC1 -1639AA as in the present case). We thank Dr Roberto Berni, Dr Emiliano Sessa and Dr Rosa Gini (Regional Authority for Healthcare Services of Tuscany) for their help in obtaining prescription data from Tuscan County. None. None.