An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol.

BACKGROUND: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. OBJECTIVES: We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol. PATIENTS/METHODS: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability. RESULTS: No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures. CONCLUSIONS: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.

VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement.

In a prospective follow-up study of the effects of VKORC1 and CYP2C9 genotypes on the anticoagulation status of patients, we assessed the CYP2C9 and the VKORC1 C1173T genotypes of patients during the initial 6 months of phenprocoumon treatment. We used linear regression models and Cox proportional hazard models to determine the effects of the VKORC1 and CYP2C9 genotypes on phenprocoumon dose requirements, overanticoagulation, and time to achieve stability. Allele frequencies of interest within the cohort (N=281) were 40.8% VKORC1 T-1173, 12.8% CYP2C9*2, and 6.9% CYP2C9*3. In patients with the VKORC1 CC genotype, carriers of a CYP2C9 polymorphism needed dosages that were nearly 30% lower than those for CYP2C9*1/*1 patients (P<0.001). In patients with a VKORC1 polymorphism, differences between carriers of a CYP2C9 polymorphism and CYP2C9*1/*1 were far smaller and largely not statistically significant. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (28.7% and 7.2%, respectively). Carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had a strongly increased risk of severe overanticoagulation (hazard ratio (HR) 7.20, P=0.002). Only carriers of a CYP2C9*2 allele had a decreased chance to achieve stability compared to CYP2C9*1/*1 patients (HR 0.61, P=0.004). In conclusion, the VKORC1 genotype modifies the effect of the CYP2C9 genotype on phenprocoumon dose requirements. A combination of polymorphisms of both genotypes is associated with a strongly increased risk of overanticoagulation, whereas delayed stabilization is mainly associated with the CYP2C9 genotype.

[Partial resistance to acenocoumarol and phenprocoumon caused by enzyme polymorphism]. / Partiële acenocoumarol- en fenprocoumonresistentie door enzympolymorfisme.

A 78-year-old man was treated with coumarin derivatives following myocardial infarction. The international normalised ratio was not increased by using standard loading doses and dose adjustments for acenocoumarol and phenprocoumon. The desired level of anticoagulation was achieved with a high dosage of phenprocoumon (18-21 mg daily). This dose was associated with a phenprocoumon serum concentration that was ten times higher than the normal therapeutic concentration. The serum concentration of vitamin K1 was low. After exclusion of alternative causes, we concluded that the exceptionally high dose of phenprocoumon needed was due to partial resistance to coumarin derivatives. Partial resistance is related to a polymorphism of the gene coding for the enzyme vitamin K epoxide reductase. The patient was successfully treated with chronic high-dose phenprocoumon. Resistance to coumarin derivatives caused by a congenital polymorphism in the vitamin K reductase gene is a rare phenomenon. Resistance is seldom absolute. The desired anticoagulation effect can be achieved with doses that are 10-20 times higher than standard doses. Phenprocoumon is advantageous in this situation because it requires fewer tablets than acenocoumarol. Determination of serum concentrations of acenocoumarol and phenprocoumon can be used to exclude other causes of treatment resistance.

Levels of vitamin K-dependent procoagulant and anticoagulant proteins in over-anticoagulated patients.

Coumarin anticoagulants impair the biological activity of the vitamin K-dependent procoagulant and anticoagulant proteins. There are no reports that focus on the levels of these proteins in over-anticoagulated patients. Therefore, we determined the levels of factor II, factor VII, factor IX and factor X, protein C and protein S in 25 randomly selected over-anticoagulated patients (International Normalized Ratio >/= 6.0) and in 25 matched, therapeutically anticoagulated patients with an International Normalized Ratio within the therapeutic zone. Furthermore, to study a possible effect of the cause of over-anticoagulation, coagulant levels were compared between 16 over-anticoagulated patients with fever in the preceding 2 weeks and 24 over-anticoagulated patients with stable congestive heart failure. The pattern of procoagulant level reductions in the three groups of over-anticoagulated patients was largely the same as in therapeutically anticoagulated patients: factor X was the lowest and factor IX the highest. The difference was that, in over-anticoagulated patients, factor VII was relatively low among the procoagulant factors compared with therapeutically anticoagulated patients. Protein C was lower than protein S in over-anticoagulated patients with congestive heart failure, but was similar to protein S in the other study groups. In over-anticoagulated patients with fever, the vitamin K-dependent coagulation proteins except factor X were significantly lower than in over-anticoagulated patients with congestive heart failure, especially factor VII and protein S.

Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation.

The risk of hemorrhage when using coumarin anticoagulants sharply increases when the International Normalised Ratio (INR) is > or =6.0. We performed a prospective cohort study with a nested case-control design among 17,056 outpatients of an anticoagulation clinic to determine the incidence of overanticoagulation and to study the association between overanticoagulation and characteristics of anticoagulant therapy and comorbidity. The incidence rate of an INR > or =6.0 was 7.8 per 10,000 treatment days in prevalent users on the starting date and 22.5 per 10,000 treatment days in incident users during the study period. 300 cases with an INR > or =6.0 were compared with 302 randomly selected matched controls with an INR within the target zone. Patients on acenocoumarol had an increased risk of an INR > or =6.0 compared to patients on phenprocoumon. Regarding comorbidity, impaired liver function, congestive heart failure, diarrhea and fever were risk factors for overanticoagulation. Increased monitoring of INR values if risk factors are present or avoidance of risk factors could prevent excess anticoagulation and potential bleeding complications.

Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs.

BACKGROUND: The risk of hemorrhage when coumarin anticoagulants are used sharply increases when the international normalized ratio (INR) is > or = 6.0. Such overanticoagulation may be caused by drug interactions. We performed a case-control study among previously stable outpatients of an anticoagulation clinic using phenprocoumon or acenocoumarol to identify changes in the use of potentially interacting drugs related to overanticoagulation. METHODS: Three hundred case patients with INR values > or = 6.0 were compared with 302 randomly selected matched control subjects with INR values within the target zone. Information on changes in the use of 87 potentially interacting drugs in the 4 weeks before the index day was collected by interviewing patients and by reviewing the anticoagulant medical record. RESULTS: Forty-five potentially interacting drugs were not used in the 4-week study period, and only 15 drugs were used by at least 10 patients. For a number of drugs, too few patients had a relevant change in use to judge their association with overanticoagulation. A course of a combination product of sulfamethoxazole and trimethoprim strongly increased the risk of overanticoagulation (adjusted odds ratio, 24.2; 95% confidence interval [CI], 2.8 to 209.1; population attributable risk percentage [PAR%], 5.7%), especially in patients receiving acenocoumarol. Penicillins were associated with a risk of overanticoagulation of 2.4 (95% CI, 1.00 to 5.5); the corresponding PAR% was 3.4%. The effect was confined to amoxicillin (INN, amoxicilline) plus clavulanic acid. CONCLUSION: Drug interactions as a cause of overanticoagulation predominantly concerned antibacterial drugs. If possible, the use of sulfamethoxazole-trimethoprim and amoxicillin plus clavulanic acid should be avoided in patients receiving coumarins. If there is no therapeutic alternative available, increased monitoring of INR values is warranted to prevent overanticoagulation and potential bleeding complications.

Course of the international Normalized Ratio in response to oral vitamin K1 in patients overanticoagulated with phenprocoumon.

Oral vitamin K1 is used for the treatment of excessive anticoagulation. Detailed information on changes in the International Normalized Ratio (INR) in response to vitamin K1 is not available. We therefore measured the INR for the first 7 d following the oral intake of 1-5 mg of vitamin K1 in 24 patients routinely treated with phenprocoumon who had an INR > or =6.0 at presentation. On the first 2 d after administration of vitamin K1, the mean INR decreased by 40% and 23% respectively. After day 2, the day-to-day proportional change in the mean INR depended on the dose of vitamin K1 and varied from a decrease of 12% to an increase of 21%. On day 7 the mean INR was higher than on day 2 in three out of five treatment groups. Between day 2 and day 7, in general, 32% of the patients had an INR value within the target zone, 25% had an INR value > or =6.0 and 8% had an INR value <2.0. These findings suggest that our routine treatment of overanticoagulation in patients on phenprocoumon should be intensified to improve its efficacy.

Lack of interaction between tramadol and coumarins.

The objective of this study was to investigate whether the central analgesic tramadol influences the effects of the coumarin anticoagulant phenprocoumon during multiple-dose administration. Nineteen patients receiving long-term anticoagulant therapy who had been in a stable hypothrombinemic state for at least 3 months completed a double-blind, placebo-controlled, crossover study. Tramadol was administered in the usual therapeutic dose of 50 mg three times daily. The average daily phenprocoumon dose was identical for individual patients in both treatment periods. The equivalence ratio (tramadol/placebo) of the international normalized ratio (INR) values was 0.99 (90% confidence interval 0.89-1.10), thus fulfilling predetermined bioequivalence criteria (0.70-1.43). Therefore, tramadol does not affect INR in patients being treated with phenprocoumon. These data suggest a lack of interaction between tramadol and coumarin anticoagulants.