Riesgo de sangrado en pacientes anticoagulados con antagonistas de la vitamina K que reciben antibióticos / Risk of bleeding in anticoagulated patients with vitamin K antagonists who receive antibiotics

Lograr un adecuado nivel de anticoagulación con antagonistas orales de la vitamina K suele ser un desafío frecuente en la práctica clínica, dado que su estrecho rango terapéutico suele verse afectado por diversas interacciones farmacológicas,alimentos y condiciones clínicas. A partir de un caso de un paciente anticoagulado que presenta una hemorragia gastro-intestinal posterior a realizar un tratamiento antibiótico, la autora de este artículo revisó la evidencia sobre el riesgo desangrado secundario a la interacción entre este tipo de anticoagulantes y antibióticos orales. Su conclusión tras realizar una búsqueda bibliográfica y seleccionar la mejor evidencia disponible, es que existe un aumento del riesgo relativo desangrado en pacientes anticoagulados que reciben antibióticos, por lo que deberían evitarse aquellos antibióticos con conocido potencial de interacción. Si ello no fuera posible, se recomienda monitorizar el estado de anticoagulación con dosaje de la razón internacional normatizada (RIN) posterior a la introducción del antibiótico. (AU)

Achieving an adequate level of anticoagulation with oral vitamin K antagonists is often a frequent challenge in clinical practice, given that their narrow therapeutic range is often affected by various drug interactions, food, and clinical conditions. Based on a case of an anticoagulated patient who presented gastrointestinal bleeding after antibiotic treatment, the authorof this article reviewed the evidence on the risk of secondary bleeding due to the interaction between this type of anticoagulants and oral antibiotics. Their conclusion, after performing a literature search and selecting the best available evidence, is that there is an increased relative risk of bleeding in anticoagulated patients receiving antibiotics, so antibiotics with known potential for interaction should be avoided. If it weren't possible, it is recommended to monitor the anticoagulation status with International Normalized Ratio (INR) dosing after the introduction of the antibiotic. (AU)

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study.

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. SUMMARY: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

Time to therapeutic range (TtTR), anticoagulation control, and cardiovascular events in vitamin K antagonists-naive patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists (VKAs) reduce cardiovascular events (CVEs) in atrial fibrillation (AF) when a time in therapeutic range (TiTR) >70% is achieved. Factors affecting the time to achieve the TR (TtTR) are unknown. METHODS: Prospective observational study including 1,406 nonvalvular AF patients starting VKAs followed for a mean of 31.3months (3,690 patient/year); TiTR, TtTR, and SAMe-TT2R2 score were calculated, and CVEs were recorded. RESULTS: Median TtTR was 8.0days (interquartile range 5.0-18.0). Patients with high TtTR (ie, >75th percentile) were more likely to be in AF than in sinus rhythm at entry (odds ratio [OR]: 1.423, P=.011). Median TiTR was 60.0%; low TiTR (below median) was associated with SAMe-TT2R2 score (OR: 1.175, P=.001), high TtTR (>75th percentile, OR: 1.357, P=.017), and number of international normalized ratio checks (OR: 0.998, P=.049). We recorded 113 CVEs (3.1%/y), with a higher rate seen in patients with TtTR >75th percentile compared to those below (log-rank test, P=.006). A multivariable Cox regression analysis showed that SAMe-TT2R2 score (hazard ratio [HR]: 1.331, P<.001), TtTR >75th percentile (HR: 1.505, P=.047), TiTR <70% (HR: 1.931, P=.004), number of international normalized ratio checks (HR: 0.988, P<.001), digoxin (HR: 1.855, P=.008), and proton-pump inhibitors (HR: 0.452, P<.001) were independently associated with CVEs. CONCLUSIONS: High TtTR is associated with poorer long-term quality of VKAs therapy. Patients with TtTR >18days or with high SAMe-TT2R2 score should be considered for treatment with non-vitamin K oral anticoagulants.

CYP2C9 and VKORC1 in therapeutic dosing and safety of acenocoumarol treatment: implication for clinical practice in Hungary.

The purpose of this work was to investigate the contribution of CYP2C9 and VKORC1 to acenocoumarol (AC) dose variability, bleeding events in Hungary. The study recruited 117 patients on long-term AC therapy (INR 2-3), and 510 healthy individuals to model the findings. Patients were genotyped for alleles proved to affect lower AC overdose CYP2C9*2, CYP2C9*3, VKORC1*2. Additionally, we tested VKORC1*3, VKORC1*4 to examine their effect in patients with higher AC requirements. Most impact on dose reduction is accountable for CYP2C9*2/*3 (59%) and for VKORC1*2/*2 (45.5%), and on dose increase for newly evaluated VKORC1*3/*4 (22.5%) diplotypes. VKORC1*3 and *4 alleles seem to balance the dose-reducing effect of VKORC1*2 allele. Being a carrier of combination of VKORC1*2 and CYP2C9*2,*3 polymorphisms, rather than of one of these SNPs, is associated with higher risk of over-anticoagulation (up to 34.3%) in long-term AC treatment. The pharmacogenetic dosing algorithm involving VKORC1, CYP2C9 diplotypes and age explains 30.4% of AC dosing variability (p<6.10×10-9). Correlation between the studied diplotypes and bleeding events could not be revealed.

Effect of ramadan fasting on acenocoumarol-induced antocoagulant effect.

Eating patterns, food intake and type of alimentation vary greatly during the month of ramadan. Furthermore, fasting, which practiced during the month of ramadan, can have an impact on drug's metabolism. These two factors, fasting and eating habits changes during the month of ramadan, may impact acenocoumarol anticoagulant effect, translated by variations of INR values. The aim of our study was to see ramadan fasting effects on INR variations in patients treated by acenocoumarol. A prospective monocentric study was conducted during the ramadan month on fasting outpatients that were treated by acenocoumarol. Baseline INR values (e.i. most recent available value before the month of ramadan) were compared to INR values obtained during the month of ramadan. All patients were monitored for signs of secondary haemorrhagic complications linked to treatment by anti-vitamin K (AVK). Thirty patients were included in the study with a sex ratio 1. Patients mean age was 65 years. Around two thirds of the patients were treated by AVK for atrial fibrillation. The majority of patients (94%) have been treated by AVK for more than a year. Mean INR was significantly higher during the month of ramadan than baseline (3.51 vs 2.52; p< 0.0001). There were also more overdoses during the month of ramadan than baseline (9 vs. 0; p=0.014). The increased INR values highlights the need of a close monitoring of INR values during the month of ramadan, particularly in patients with a high haemorrhagic risk.

Genotyping of CYP2C9 and VKORC1 polymorphisms predicts south Indian patients with deep vein thrombosis as fast metabolizers of warfarin/acenocoumarin.

Deep vein thrombosis (DVT) is a life-threatening disease. Warfarin and acenocoumarol are anticoagulants used to treat DVT and vary among individuals in terms of treatment response/toxicity. Single nucleotide polymorphisms (SNPs) in CYP2C9 and VKORC1 play a role in the pharmacokinetics and dynamics of warfarin and acenocoumarol and they determine the efficacy of treatment by controlling drug clearance in treated individuals. The aim of the current study was to genotype the critical SNPs of CYP2C9 and VKORC1 genes in a south Indian population in order to understand the metabolizer phenotype of patients with DVT. CYP2C9 (rs1799853, rs1057910, rs1057909, rs28371686) and VKORC1 (rs9923231) SNPs were genotyped in 124 cases of DVT. Genomic regions of these SNPs from genomic DNA were amplified with PCR and directly sequenced using Sanger sequencing except for the SNP rs1799853, which was detected using Sau96I restriction endonuclease-based digestion of variant alleles. Among south Indian patients with DVT, 6.5% (8/124) had the rs1799853 SNP of CYP2C9 and 11% (14/124) had the rs1057910 SNP while 16% (20/124) had the rs9923231 SNP of VKORC1 which were associated with the response to warfarin treatment. None of the patients tested positive for poor drug metabolizing genotypes of the CYP2C9 gene and only 1.6% of the south Indian population was sensitive to warfarin treatment. Genotyping results suggest that a relatively greater amount of the therapeutic drug is required to achieve/maintain the international normalized ratio (INR) in south Indian patients with DVT.

Acenocoumarol: A Review of Anticoagulant Efficacy and Safety.

Anticoagulant treatment is required for the treatment and prevention of thromboembolic disorders. Vitamin K antagonists are commonly used oral anticoagulants worldwide. Acenocoumarol is mono-coumarin derivative with racemic mixture of R (+) and S (-) enantiomers. Efficacy and safety of acenocoumarol has been evaluated in atrial fibrillation, cardiac valve replacement, after myocardial infarction, treatment of deep vein thrombosis, after major surgeries and after critical illness requiring prolonged hospitalization. Acenocoumarol is effective and safe in all age groups. It offers an advantage over warfarin in terms of better stability of anti-coagulant effect. Due to its economic advantage acenocoumarol may be suitable oral anticoagulant for long term use in countries like India.

Grado de control y cumplimiento terapéutico de la anticoagulación con acenocumarol en Atención Primaria / Level of control and treatment adherence of anticoagulation with acenocoumarol in Primary Care

Objetivos. Determinar el grado de control y cumplimiento terapéutico en una muestra de pacientes tratados con acenocumarol asistidos en Atención Primaria. Material y métodos. Estudio descriptivo transversal realizado en pacientes diagnosticados de fibrilación auricular no valvular tratados con acenocumarol en Atención Primaria. Se recogieron los datos de los pacientes que disponían de los valores de la International Normalized Ratio (INR, «razón normalizada internacional») de los últimos 6 meses en la consulta del centro de salud. Se consideró control de INR inadecuado cuando el porcentaje de valores de INR dentro del rango terapéutico fue inferior al 60% en los últimos 6 meses. Se realizó valoración de cumplimiento por entrevista telefónica mediante el Test de Morisky-Green. Resultados. Se incluyeron 191 pacientes, 110 mujeres (57,6%), con una edad media de 76,5±9,4 años. Setenta y seis pacientes (39,8%) estaban en rango terapéutico (INR: 2-3) y 115 pacientes (60,2%) fuera de rango (por debajo de 2 el 20,9% y por encima de 3 el 39,3%). El 62,9% de los varones y el 58,2% delas mujeres estaban mal controlados (p<0,05). El mal control de INR aumentó hasta la edad de 85 años (<75 años: 57,8%; 75-85 años: 67,6%;>85 años: 61,5%). Respondieron al cuestionario de cumplimiento 90 pacientes (78,3%), siendo cumplidores 74 (82,2%) y no cumplidores 16 (17,8%). Conclusiones. Seis de cada 10 pacientes que están en tratamiento con acenocumarol están fuera de rango y casi 2 de cada 10 pacientes fuera de rango no cumple el tratamiento con acenocumarol. Llamamos la atención sobre la necesidad de evaluar sistemáticamente el cumplimiento terapéutico en los pacientes anticoagulados en Atención Primaria (AU)

Objectives. To determine the level of control in treatment compliance in a sample of patients who were treated with acenocoumarol attended in Primary Care settings. Material and methods. Cross-sectional study. Patients with non-valvular atrial fibrillation treated with acenocoumarol were included. The sample size was calculated based on previous studies. Data of patients who possessed International Normalized Ratio (INR) values in last 6 months in medical consult were collected. It was considered that the INR control was inadequate when the percentage of INR values within the therapeutic range was less than 60% in the last 6 months. Assessment of compliance by telephone interview was conducted by the Morisky-Green Test. Results. One hundred and ninety-one patients, 110 women (57.6%) with an average age of 76.5±9.4 years were included. Seventy-six patients (39.8%) were in therapeutic range (INR: 2-3) and 115 patients (60.2%) were out of range (below 2 the 20.9% and above 3 the 39.3%). Poor control of INR increased to the age of 85 years (<75 years: 57.8%; 75-85 years: 67.6%;>85 years: 61.5%). Ninety patients responded to the compliance questionnaire (78.3%), being compliant 74 (82.2%) and non-compliant 16 (17.8%). Conclusions. Six of 10 patients undergoing treatment with acenocoumarol are out of range and nearly 2 of each 10 patients out of range does not accomplish the treatment. We call attention to the need to make a systematically review of adherence in anticoagulated patients attended in Primary Care settings (AU)

A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment.

Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of ≥6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study-a phase III, randomized, open-label, controlled study (N = 676)-to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance <60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2-6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for ≥5 days until international normalized ratio was 2.0-3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced ≥1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03-0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal renal function; however, anti-Xa monitoring could be considered to further support safety in selected patients, particularly those with very severe renal impairment.

Genotype-guided therapy improves initial acenocoumarol dosing. Results from a prospective randomised study.

A few trials so far have evaluated the effectiveness of algorithms designed to calculate doses in oral anticoagulant therapy, with negative or contradictory results. We compared a genotype-guided algorithm vs physician management for the initiation of acenocoumarol. In a two-arm, prospective, randomised study with patients with atrial fibrillation who started therapy, the first dose was administered to all patients according to the physician's criteria. At 72 hours, the corresponding dose was calculated based on INR in the standard care group (SC, N=92), whereas genetic data (VKORC1, CYP2C9 and CYP4F2) were also considered for the genotype-guided dosing (pharmacogenetic) group (PGx, N=87) by using an algorithm previously validated in 2,683 patients. The primary outcomes were: patients with steady dose, the time needed to reach the same and the percentage of therapeutic INRs. After 90 days, 25% of the SC and 39% of the PGx patients reached the steady dose (p=0.038). Kaplan-Meier analysis showed that PGx group needed fewer days to reach therapeutic INR (p=0.033). Additionally, PGx had a higher percentage of therapeutic INRs than SC patients (50% and 45%, respectively) (p=0.046). After six months the proportion of steadily anticoagulated patients remained significantly higher in PGx (p=0.010). In conclusion, genotype-guided dosing was associated with a higher percentage of patients with steady dose than routine practice when starting oral anticoagulation with acenocoumarol.

Adequacy of preadmission oral anticoagulation with vitamin K antagonists and ischemic stroke severity and outcome in patients with atrial fibrillation.

It is unclear whether vitamin K antagonists affect stroke severity and outcome in patients with atrial fibrillation (AF). We aimed to evaluate this association. We prospectively studied 539 consecutive patients admitted with acute ischemic stroke (41.2 % males, age 78.9 ± 6.6 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed with dependency rates at discharge (modified Rankin scale 2-5) and with in-hospital mortality. 177 patients had a history of AF. The median NIHSS at admission did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment [4 (range 0-26), 13 (0-39), 8 (0-33), 3 (2-23) and 7 (0-33), respectively; p = 0.433]. Dependency rates were lower in patients on acenocoumarol with INR 2.0-3.0 or on dual antiplatelet treatment than in those on acenocoumarol with INR < 2.0, single antiplatelet treatment, or no treatment (20.0, 22.2, 61.5, 58.7 and 68.0 %, respectively; p = 0.024). Independent predictors of dependency were age, NIHSS at admission and history of ischemic stroke. In-hospital mortality did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment (7.7, 18.2, 16.1, 16.7 and 22.2 %, respectively; p = 0.822). In conclusion, optimally anticoagulated patients with AF have more favorable functional outcome after stroke and a trend for less severe stroke whereas patients with subtherapeutic anticoagulation have similar stroke severity and outcome with those on no treatment.

Control de la anticoagulación con warfarina o acenocumarol en España. ¿Hay diferencias? / Control of anticoagulation with warfarin or acenocoumarol in Spain. Do they Differ?

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Genotype-based dosage of acenocoumarol in highly-sensitive geriatric patients.

OBJECTIVE: Our aim was to determinate the acenocoumarol dose requirement in highly sensitive geriatric patients, based on a minimum of genotype (VKORC1 and CYP2C9) data. METHODS: We used a Gaussian kernel density estimation test to identify patients highly sensitive to the drug and PHARMACHIP®-Cuma test (Progenika Biopharma, SA, Grifols, Spain) to determine the CYP2C9 and VKORC1 genotype. RESULTS: All highly sensitive geriatric patients were taking ≤5.6 mg/week of acenocoumarol (AC), and 86% of these patients presented the following genotypes: CYP2C9*1/*3 or CYP2C9*1/*2 plus VKORC1 A/G, CYP2C9*3/*3, or VKORC1 A/A. CONCLUSION: VKORC1 A and CYP2C9*2 and/or *3 allelic variants extremely influence on AC dose requirement of highly sensitive geriatric patients. These patients display acenocoumarol dose requirement of ≤5.6 mg/week.

Tratamiento a largo plazo con una heparina de bajo peso molecular subcutánea comparado con un antagonista de la vitamina K: subanálisis de pacientes con cáncer / Long-term treatment with a low-molecular-weight heparin administered subcutaneously compared with a vitamin K antagonist: subanalysis of patients with cancer

Realizamos un subanálisis de los pacientes con cáncer incluidos en un ensayo clínico en el que se comparaba el tratamiento a largo plazo (6 meses) con una heparina de bajo peso molecular (HBPM) subcutánea o con acenocumarol, para evaluar si las características del tumor tenían alguna influencia sobre la respuesta clínica. En un ensayo aleatorizado y abierto se incluyó a 69 pacientes con cáncer y trombosis venosa profunda proximal sintomática de miembros inferiores. Se registraron las características del tumor y el tipo de tratamiento. El criterio de valoración principal fue la incidencia a 12 meses de tromboembolia venosa (TEV) sintomática recurrente. Se analizó a 61 pacientes (88,4%). En el momento de la inclusión, las características y tratamiento del cáncer eran comparables entre ambos grupos. A lo largo del período de 12 meses, la TEV recurrente fue significativamente mayor en los pacientes ancianos (71,5 ± 6,4 frente a 62,0 ± 15,1; p = 0,006). En el análisis de regresión logística no se encontró ninguna asociación entre la recurrencia de TEV y la localización o la extensión del tumor. Sin embargo, el uso de quimioterapia trombogénica (p = 0,045) se asoció de forma independiente a la recurrencia de la TEV y el tratamiento a largo plazo con tinzaparina estuvo cerca de ser un factor de protección (p = 0,15). En esta pequeña muestra se observó una asociación entre la quimioterapia trombogénica y la TEV recurrente. La tendencia a una disminución de la recurrencia de la TEV a los 12 meses en pacientes con cáncer del grupo de la HBPM podría atribuirse al efecto de la dosis plena de HBPM (AU)

We performed a subanalysis of cancer patients enrolled in a clinical trial that compared long-term (6 months) treatment with a low-molecular-weight heparin (LMWH) administered subcutaneously or with acenocoumarol. The subanalysis assessed whether the characteristics of the tumor had an influence on the clinical response. A randomized open trial included 69 patients with cancer and symptomatic proximal deep vein thrombosis of the lower limbs. The tumor characteristics and treatment type were recorded. The main assessment criterion was the 12-month incidence of recurrent symptomatic venous thromboembolism (VTE). Sixty-one patients (88.4%) were analyzed. At the time of inclusion, the cancer characteristics and treatment were comparable between the 2 groups. Over the course of 12 months, the recurrent VTE was significantly greater in the elderly patients (71.5±6.4 vs. 62.0±15.1; p=.006). The logistic regression analysis showed no association between VTE recurrence and the location or extent of the tumor. However, the use of thrombogenic chemotherapy (p=.045) was independently associated with VTE recurrence, and longterm treatment with tinzaparin was almost a protective factor (p=.15). In this small sample, we observed an association between thrombogenic chemotherapy and recurrent VTE. The tendency towards a reduction in VTE recurrence at 12 months in patients with cancer in the LMWH group could be attributed to the effect of the full LMWH dosage (AU)

Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: a potential role of CYP4F2 and GGCX polymorphisms.

INTRODUCTION: VKORC1 and cytochrome CYP2C9 genetic variants contribute largely to inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Cytochrome P450 4F2 isoform (CYP4F2), gamma-glutamyl carboxylase (GGCX) and apolipoprotein E (APOE) polymorphisms have been suggested to be of minor significance. MATERIALS AND METHODS: We sought to assess the impact of those polymorphisms on dose requirements in Central-Eastern European cohort of 479 patients receiving acenocoumarol (n=260) or warfarin (n=219). RESULTS: There were no differences between the acenocoumarol and warfarin groups with regard to the gender, age, body mass index and international normalized ratio. The VKORC1 c.-1639A allele carriers required a lower dose of acenocoumarol and warfarin than the non-carriers (28.0 [21.0-35.0] vs. 42.0 [28.0-56.0] mg/week, p<0.0001; 35.0 [28.0-52.0] vs. 52.0 [35.0-70.0] mg/week, p=0.0001, respectively). Carriers of 2 and/or 3 variant alleles for CYP2C9 also required a lower dose of warfarin as compared with 1 1 carriers (35.0 [31.5-52.5] vs. 43.8 [35.0-60.2] mg/week, p=0.02; 35.0 [23.5-35.0] vs. 43.8 [35.0-60.2] mg/week, p<0.0001, respectively). Similarly, possession of G allele of GGCX c.2084+45 polymorphism was associated with lower warfarin dose (35.0 [26.3-39.2] vs. 45.5 [35.0-65.1] mg/week, p=0.03). No effect of CYP2C9*2,-*3 and GGCX c.2084+45G>C polymorphisms on acenocoumarol dosage was observed. Interestingly, carriers of CYP4F2 c.1297A variant required a higher dose of acenocoumarol and warfarin than non-carriers (43.8 [35.0-60.2] vs. 35.0 [35.0-52.5] mg/week, p=0.01; 35.0 [28.0-52.5] vs. 28.0 [28.0-42.0] mg/week, p=0.05). CONCLUSIONS: We have shown for the first time, that besides VKORC1 and CYP2C9 genetic variants, the CYP4F2 c.1297A and GGCX c.2084+45G have a moderate effect on VKAs dose requirements in Slavic population from Central-Eastern Europe.

Patients benefit from genetics-guided coumarin anticoagulant therapy.

Observational studies have overwhelmingly shown that variants in the genes CYP2C9 and VKORC1 are significant determinants of individual dose of coumarin anticoagulants needed to maintain a therapeutic international normalized ratio (INR).(1) Until recently, however, few randomized clinical trials had been performed relating to the use of genetic data to predict dosing. Three sucsh clinical trials have now reported their findings.

Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon.

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials.

Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.

Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 µM) and the more potent and specific P-gp inhibitor valspodar (5 µM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 µM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.

Impact of CYP2C9 polymorphisms on the vulnerability to pharmacokinetic drug-drug interactions during acenocoumarol treatment.

AIM: The objective of this study was to investigate the impact of CYP2C9 polymorphisms and drug-drug interactions on the risk of overanticoagulation in patients treated with acenocoumarol, a vitamin K antagonist. MATERIALS & METHODS: A prospective observational study was performed on patients starting acenocoumarol (n = 115). CYP2C9 genotypes were assessed. Data on International Normalized Ratio, comedications and doses of acenocoumarol were collected during the first 35 days of therapy. Overanticoagulation was defined as the occurrence of at least one International Normalized Ratio ≥4. RESULTS: The presence of a CYP2C9 inhibitor or a CYP2C9 polymorphisms statistically increased the risk of overanticoagulation (hazard ratio [HR]: 2.8, p < 0.001 and HR: 1.7, p = 0.04, respectively). The presence of CYP2C9 polymorphisms almost tripled the risk of overanticoagulation (HR: 2.91, p = 0.01) in the presence of a clinically significant drug-drug interaction. CONCLUSION: These findings support the fact that CYP2C9 genotyping could be useful to identify patients requiring closer monitoring, especially when a drug-drug interaction is expected.

Effect of CYP2C9 and VKORC1 genetic polymorphisms on mean daily maintenance dose of acenocoumarol in South Indian patients.

AIM: To determine the effect of CYP2C9 and VKORC1 genetic polymorphisms on mean daily maintenance dose of acenocoumarol in South Indian patients with heart valve replacement. MATERIALS AND METHODS: The study was conducted in 170 patients on therapy with acenocoumarol following heart valve replacement surgery. Single nucleotide polymorphisms (SNP) namely CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), and VKORC1 (rs9923231) were identified by quantitative Real-Time Polymerase Chain Reaction (RT-PCR) method. RESULTS: Patients with at least one variant allele of CYP2C9 (*1*2 or *1*3) required 44% and 28.2% lower daily maintenance dose of acenocoumarol (2.0mg and 2.5mg, respectively) than the normal CYP2C9*1*1 genotype group (3.4mg) (p<0.05). Patients with VKORC1 GG genotype required higher dose (3.3mg) as compared to those with genotype VKORC1 GA (2.3mg) and VKORC1 AA (1.0mg) (p<0.001). Patients with both CYP2C9*1*2/*1*3 and VKORC1 GA genotype required 38% lower dose (2.46mg) than patients with CYP2C9*1*1 and VKORC1 GG genotype (3.52mg) (p<0.0001). The clinical (age, body mass index) and genetic variables (VKORC1-1639 G>A, CYP2C9*2, CYP2C9*3) contribute together to predict 30.4% of the required maintenance dose of acenocoumarol. CONCLUSION: The genetic polymorphisms of CYP2C9 and VKORC1 results in decreased requirement of daily maintenance dose of acenocoumarol. The polymorphism VKORC1 (-1639 G>A) was found to be the major predictor of acenocoumarol dose requirement in South Indian population.