The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon

Summary

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatmentyears, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.

Keywords

Clinical / epidemiological studies - gene mutations - coagulation inhibitors

• References

• 1 British Committee for Standards in Haematology. Guidelines on oral anticoagulation: third edition. Br J Haematol 1998; 101: 374-87.
• 2 Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865-75.
• 3 Rosendaal FR. The Scylla and Charybdis of oral anticoagulant treatment. N Engl J Med 1996; 335: 587-9.
• 4 Cannegieter SC, Rosendaal FR, Wintzen AR. et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-7.
• 5 Van der Meer FJ, Rosendaal FR, Vandenbroucke JP. et al. Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost 1996; 76: 12-6.
• 6 Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet 2000; 356: 1667-71.
• 7 Hermans JJ, Thijssen HH. Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics. Br J Pharmacol 1993; 110: 482-90.
• 8 He M, Korzekwa KR, Jones JP. et al. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9. Arch Biochem Biophys 1999; 372: 16-28.
• 9 Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000; 28: 1284-90.
• 10 Rettie AE, Wienkers LC, Gonzalez FJ. et al. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 04: 39-42.
• 11 Haining RL, Hunter AP, Veronese ME. et al. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996; 333: 447-58.
• 12 Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase. Pharmacogenetics 1997; 07: 203-10.
• 13 Higashi MK, Veenstra DL, Kondo LM. et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690-8.
• 14 Margaglione M, Colaizzo D, D’Andrea G. et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775-8.
• 15 Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816-9.
• 16 Aithal GP, Day CP, Kesteven PJ. et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-9.
• 17 Ogg M, Brennan P, Meade T. et al. CYP2C9*3 allelic variant and bleeding complications. Lancet 1999; 354: 1124.
• 18 Tassies D, Freire C, Pijoan J. et al. Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation. Haematologica 2002; 87: 1185-91.
• 19 Hummers-Pradier E, Hess S, Adham IM. et al. Determination of bleeding risk using genetic markers in patients taking phenprocoumon. Eur J Clin Pharmacol 2003; 59: 213-9.
• 20 Hofman A, Grobbee DE, de Jong PT. et al. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol 1991; 07: 403-22.
• 21 Aynacioglu AS, Brockmöller J, Bauer S. et al. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 1999; 48: 409-15.
• 22 Landefeld CS, Beyth RJ. Anticoagulant-related bleeding – clinical epidemiology, prediction, and prevention. Am J Med 1993; 95: 315-28.
• 23 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian study on complications of oral anticoagulant therapy. Lancet 1996; 348: 423-8.
• 24 Fihn SD, McDonell M, Martin D. et al. Risk factors for complications of chronic anticoagulation: a multicentre study. Ann Intern Med 1993; 118: 511-20.
• 25 Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989; 87: 144-52.
• 26 Petitti DB, Strom BL, Melmon KL. Duration of warfarin anticoagulant therapy and the probabilities of recurrent thromboembolism and haemorrhage. Am J Med 1986; 81: 255-9.
• 27 Lundstrom T, Ryden L. Hemorrhagic and thromboembolic complications in patients with atrial fibrillation on anticoagulant prophylaxis. J Intern Med 1989; 225: 137-42.
• 28 Forfar JC. A 7-year analysis of hemorrhage in patients on long-term anticoagulant treatment. Br Heart J 1979; 42: 128-32.
• 29 Visser LE, van Vliet M, van Schaik RHN. et al. The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics 2004; 14: 27-33.
• 30 Van der Meer FJM, Rosendaal FR, Vandenbroucke JP. et al. Bleeding complications in oral anticoagulant therapy – an analysis of risk factors. Arch Intern Med 1993; 153: 1557-62.
• 31 Xie HG, Prasad HC, Kim RB. et al. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 2002; 54: 1257-70.
• 32 Garcia-Martin E, Martinez C, Ladero JM. et al. High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur J Clin Pharmacol 2001; 57: 47-9.