PPARA gene and phenprocoumon: a new predictor of response variability.

Phenprocoumon is an anticoagulant used for thromboembolic disorder prophylaxis metabolized mainly by CYP3A4. However, polymorphisms in this gene did not explain the observed variability. PPARA (peroxisome proliferator-activated receptor-α) is a nuclear receptor that, among others, influences CYP3A4 gene expression. The aim of this study was to determine whether PPARA gene polymorphisms and the CYP3A4*22 allele are associated with phenprocoumon dose variability. A total of 198 patients on a stable dose of phenprocoumon were included in the study. Genotyping was performed by allele discrimination using standardized TaqMan assays. Differences between the average phenprocoumon dose and genotypes/haplotypes were assessed by analysis of variance and multiple linear regression analyses. Patients with the PPARA rs4253728A allele needed higher phenprocoumon doses. However, the effect size (3%) of this association was small. The CYP3A4*22 allele was not associated with the dose of phenprocoumon. As this is the first report of an association between PPARA gene polymorphisms and phenprocoumon dose, future studies are warranted to confirm these results.

A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population: role for CYP2C9, CYP3A4/5 and VKORC1 genes polymorphisms.

Phenprocoumon is widely used in prophylaxis and treatment of thromboembolic disorders. However, its pharmacokinetics and pharmacodynamics vary according to several genetic and non-genetic factors. Phenprocoumon metabolism is mediated by CYP2C9 and CYP3A enzymes. Moreover, VKORC1 is phenprocoumon target of action. Therefore, the aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in VKORC1, CYP2C9, CYP3A4 and CYP3A5 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors. A total of 198 patients with stable phenprocoumon dose, 81% of European ancestry, were investigated. Genotypes were determined by allelic discrimination with TaqMan assays. Polymorphisms -1639G>A and 1173C>T in VKORC1 and the presence of CYP2C9*2 and/or CYP2C9*3 are associated with lower doses. On the other hand, 3730G>A in VKORC1 gene is associated with higher doses. No association was found between CYP3A4*1B, CYP3A5*3 and CYP3A5*6 polymorphisms. Among non-genetic factors, gender, height, age and use of captopril, omeprazole, simvastatin and ß-blockers are associated with dose. Two algorithms were derived: one for the whole sample explained 42% of dose variation and one for patients of European ancestry only which explained 46% of phenprocoumon dose. The mean absolute difference between observed and predicted dose was low in both models (3.92 mg/week and 3.54 mg/week, for models 1 and 2, respectively). However, more studies with other genes and environmental factors are needed to test and to improve the algorithm.

Avaliação da estabilidade de anticoagulação entre a Varfarina e a Femprocumona / Oral anticoagulation stability assessment with Warfarin and Phenprocoumon

Fundamentos: A varfarina e a femprocumona são os anticoagulantes orais mais utilizados; no entanto, até então, não existem estudos randomizados comparando a estabilidade da anticoagulação entre estes dois fármacos. Objetivos: Comparar a varfarina e femprocumona quanto à estabilidade na manutenção de anticoagulação em nível terapêutico (razão normatizada internacional [RNI] entre 2,0 e 3,0) e avaliar a incidência de complicações hemorrágicas e tromboembólicas decorrentes de anticoagulação inadequada.Métodos: Ensaio clínico, randomizado, duplo-cego, incluindo pacientes em tratamento vigente com anticoagulante oral, porém com RNI abaixo do alvo terapêutico nas últimas três semanas, randomizados para uso de varfarina ou femprocumona. O ajuste da dose da medicação foi realizado conforme algoritmo pré-estabelecido. Resultados: Foram randomizados 62 pacientes, sendo 31 em cada grupo, durante as cinco primeiras semanas de estudo. Verificou-se que a femprocumona se mostrou mais instável comparada à varfarina. A partir da sexta aferição de RNI, o grupo femprocumona apresentou melhora na estabilidade do valor do RNI, porém não houve significância estatística. Também não houve diferença significativa em relação aos efeitos colaterais dos fármacos. Conclusão: A varfarina demonstrou maior eficácia na estabilidade do RNI em relação à femprocumona.

Background: Although warfarin and phenprocoumon are the most widely used oral anticoagulants, there a r e n o r a n d o m i z e d s t u d i e s c o m p a r i n g t h e anticoagulation stability of these two drugs.Objectives: To compare warfarin and phenprocoumon in terms of therapeutic anticoagulation maintenance stability (international normalized ratio [INR] between 2.0 and 3.0) and evaluate the incidence of thromboembolic and hemorrhagic complications arising from inadequate anticoagulation.Methods: Randomized double-blind clinical trial with patients undergoing current oral anticoagulant treatment but with INR below the therapeutic target during the past 3 weeks, randomized for warfarin or phenprocoumon. Medication dosages were adjusted in compliance with a predetermined algorithm.Results: With 62 patients randomized into two groups of 31 each during the first five weeks of the study, phenprocoumon was found to be more unstable than warfarin. From the sixth INR measurement onwards, the stability of the INR value improved in the phenprocoumon group, but with no statistical significance. There were no significant differences in the side effects of the drugs.Conclusion: Warfarin demonstrated greater effectiveness for INR stability than phenprocoumon.

[Warfarin and phenprocoumon: experience of an outpatient anticoagulation clinic]. / Varfarina e femprocumona: experiência de um ambulatório de anticoagulação.

BACKGROUND: Oral anticoagulants are broadly used in cardiology. However, it is still necessary to evaluate their use in clinical practice. OBJECTIVES: To describe the differences in the maintenance of anticoagulation control, as well as the incidence of hemorrhagic and thromboembolic events among users of warfarin and phenprocoumon. METHODS: Non-concurrent cohort study of 127 patients using oral anticoagulation. RESULTS: Phenprocoumon was the most frequently used anticoagulant in 60% of the patients. The prevalence of RNI<2 at the last medical appointment was higher among warfarin users (46% vs. 19.5%; p<0.001). During the follow-up, Phenprocoumon users were within the therapeutic range during 60.7% of the period, in comparison with 45.6% of warfarin users (OR:1.84; 95%CI:1.59-2.13; P<0.001). The incidence of bleeding was 5.3/100 patients/year in the phenprocoumon group versus 18.8/100 patients/year in the warfarin group (RR: 3.5; 95%CI: 1.87-6.48; P<0.001). CONCLUSION: Patients that used Warfarin remained at subtherapeutic levels for a longer period; however, they also presented more hemorrhagic events. Phenprocoumon users were younger and had been using oral anticoagulation for longer periods, presenting fewer drug-related adverse events.

Varfarina e femprocumona: experiência de um ambulatório de anticoagulação / Warfarin and phenprocoumon: experience of an outpatient anticoagulation clinic / Warfarina y femprocumona: experiencia de una unidad de anticoagulación

Fundamento: Os anticoagulantes orais são amplamente utilizados na cardiologia. Contudo, uma avaliação sobre o seu uso na prática clínica ainda é necessária. Objetivos: Descrever as diferenças na manutenção do controle da anticoagulação, bem como a incidência de eventos hemorrágicos e tromboembólicos entre os usuários de varfarina e femprocumona. Métodos: Estudo de coorte não concorrente de 127 pacientes em uso de anticoagulação oral. Resultados: A femprocumona foi o anticoagulante mais utilizado em 60 por cento dos pacientes. A prevalência de INR<2 na última consulta era maior entre os usuários de varfarina (46 por cento vs. 19,5 por cento; p<0,001). Durante o seguimento, os usuários da femprocumona estiveram dentro dos níveis terapêuticos em 60,7 por cento do período em comparação com 45,6 por cento dos usuários da Varfarina (OR:1,84;CI95 por cento:1,59-2,13;p<0,001). A incidência de sangramentos foi de 5,3/100 pacientes/ano no grupo da femprocumona contra 18,8/100 pacientes/anos no grupo varfarina (RR:3,5;CI95 por cento:1,87-6,48;p<0,001). Conclusão: Pacientes que faziam uso da varfarina permaneceram em níveis subterapêuticos por um maior período, contudo também apresentaram mais eventos hemorrágicos. Usuários da femprocumona eram mais jovens e estavam utilizando a anticoagulação oral por um período maior, tendo apresentado menos efeitos adversos dessas medicações.

Background: Oral anticoagulants are broadly used in cardiology. However, it is still necessary to evaluate their use in clinical practice. Objectives: To describe the differences in the maintenance of anticoagulation control, as well as the incidence of hemorrhagic and thromboembolic events among users of warfarin and phenprocoumon. Methods: Non-concurrent cohort study of 127 patients using oral anticoagulation. Results: Phenprocoumon was the most frequently used anticoagulant in 60 percent of the patients. The prevalence of RNI<2 at the last medical appointment was higher among warfarin users (46 percent vs. 19.5 percent; p<0.001). During the follow-up, Phenprocoumon users were within the therapeutic range during 60.7 percent of the period, in comparison with 45.6 percent of warfarin users (OR:1.84; 95 percentCI:1.59-2.13; P<0.001). The incidence of bleeding was 5.3/100 patients/year in the phenprocoumon group versus 18.8/100 patients/year in the warfarin group (RR: 3.5; 95 percentCI: 1.87-6.48; P<0.001). Conclusion: Patients that used Warfarin remained at subtherapeutic levels for a longer period; however, they also presented more hemorrhagic events. Phenprocoumon users were younger and had been using oral anticoagulation for longer periods, presenting fewer drug-related adverse events.

Fundamento: Los anticoagulantes orales son ampliamente utilizados en la cardiología. Con todo, una evaluación acerca de su utilización en la práctica clínica es necesaria todavía. Objetivo: Describir las diferencias en el mantenimiento del control de la anticoagulación, así como la incidencia de eventos hemorrágicos y tromboembólicos entre sus usuarios de warfarina y femprocumona. Métodos: Estudio de cohorte no concurrente de 127 pacientes en tratamiento con anticoagulación oral. Resultados: La femprocumona fue el anticoagulante más utilizado en el 60 por ciento de los pacientes. La prevalencia de INR<2 en la última consulta era mayor entre los usuarios de warfarina (46 por ciento vs 19,5 por ciento; P<0,001). Durante el seguimiento, los usuarios de la femprocumona estuvieron dentro de los niveles terapéuticos en el 60,7 por ciento del período en comparación con el 45,6 por ciento de los usuarios de la warfarina (OR:1,84;CI95 por ciento:1,59-2,13;P<0,001). La incidencia de sangrados fue de 5,3/100 pacientes/año en el grupo de la femprocumona contra 18,8/100 pacientes/años en el grupo warfarina (RR:3,5;CI95 por ciento:1,87-6,48;P<0,001). Conclusión: Pacientes que hacían uso de la warfarina permanecieron en niveles subterapéuticos por un mayor período, sin embargo presentaron también más eventos hemorrágicos. Los usuarios de la femprocumona eran más jóvenes y estaban utilizando la anticoagulación oral por un período mayor, habiendo presentado menos efectos adversos de estas medicaciones.

Dietary vitamin K intake and anticoagulation in elderly patients.

PURPOSE OF REVIEW: Vitamin K is an essential co-factor for the synthesis of several coagulation factors. Oral anticoagulants competitively inhibit enzymes that participate in vitamin K metabolism. The purpose of this review is to evaluate the potential interaction of dietary vitamin K and coagulation stability, particularly in the elderly patient. RECENT FINDINGS: Recent prospective evidences suggest that dietary vitamin K plays an essential role in anticoagulation stability. Vitamin K intake of more than 250 microg/day was shown to decrease warfarin sensitivity in anticoagulated patients consuming regular diets. In a randomized crossover study, brief periods of changes on vitamin K intake also had significant effects on coagulation parameters. Patients that were allocated to an 80% decrease of intake increased International Normalized Ratio (INR) by almost 30% 7 days after the intervention. Similarly, it was estimated by dietary records that for each increase in 100 microg of vitamin K intake, the INR would be reduced by 0.2. A recent study also demonstrated that over-the-counter multivitamin supplements contain enough vitamin K1 to significantly alter coagulation parameters. SUMMARY: Contemporary data strengthen the concept that the interaction between dietary vitamin K and coumarin derivatives is clinically relevant and plays a major role in INR fluctuations in chronic anticoagulated patients.

Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols.

PURPOSE: The potential association between vitamin K intake and coagulation instability has been explored primarily in case reports and small, retrospective, uncontrolled studies. We prospectively evaluated the effects of dietary vitamin K intake on anticoagulation parameters. METHODS: In an observational protocol, clinical characteristics and vitamin K intake, assessed semiquantitatively, were evaluated in 39 outpatients who made 230 visits to our anticoagulation clinic. In a randomized crossover protocol, 12 patients with stable anticoagulation underwent 4-day in-hospital dietary interventions, 1 to 2 weeks apart, providing a 500% increase and an 80% decrease in vitamin K intake relative to the baseline level. RESULTS: Univariate analysis of the observational data demonstrated a progressive, statistically significant inverse association between the vitamin K intake score and different levels of anticoagulation. Multivariate logistic regression analysis showed that vitamin K intake was independently associated with both overcoagulation and undercoagulation. In the randomized protocol, the international normalized ratio increased from 2.6 +/- 0.5 at baseline to 3.3 +/- 0.9 at day 7 (P = 0.005) in subjects on the vitamin K-depleted diet and decreased from 3.1 +/- 0.8 at baseline to 2.8 +/- 0.6 at day 4 (P = 0.04) in those on the vitamin K-enriched diet. CONCLUSION: Our prospective data strengthen the concept that the interaction between vitamin K and coumarin is a clinically relevant, major independent factor that interferes with anticoagulation stability.