Acenocoumarol Therapy Research Articles

Effect of Fasting in Patients Taking Acenocoumarol

Anticoagulation with acenocoumarol is influenced by dietary changes but the effect of fasting on acenocoumarol therapy is unknown. Objectives: To study changes in international normalized ratio (INR) and the percentage of time within therapeutic range (%TTR) before and during Ramadan. Methods/Patients: In this prospective study, weekly INR readings were taken from participating patients during two study periods: before and during Ramadan. Readings were blinded to patients and their primary physicians except for when pre-set study endpoints were reached. Results: Among 128 participating patients, mean INR increased by 0.25 (P = 0.006) during Ramadan from the pre-Ramadan month. There was no significant difference (P = 0,02) in mean INR between the non-Ramadan months. No bleeding or thrombotic events were recorded. Conclusion: Fasting significantly increases the mean INR of medically stable patients taking acenocoumarol and the likelihood of having an INR above therapeutic targets.

The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance

Introduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyze the influence of the most important genetic factors (VKORC1 and CYP2C9 genes) that affect coumarin therapy in patients from Serbia. Methods. A retrospective study involving 207 patients on acenocoumarol therapy was conducted. Genetic analyses were performed by direct sequencing. Influence on acenocoumarol dose of variants (VKORC1, CYP2C9*2, CYP2C9*3) causing hypersensitivity and VKORC1 variants causing resistance to acenocoumarol were analyzed. Multiple regression analysis was used to design a mathematical model for predicting individual drug dosage based on clinical-demographic and genetic data. Results. The study confirmed significant influence of the analyzed genetic factors on acenocoumarol maintenance dose. We designed mathematical model for predicting individual acenocoumarol dose and its unadjusted R2 was 61.8. In the testing cohort, our model gave R2 value of 42.6 and showed better prediction in comparison with model given by other authors. In the analyzed patients, nine different variants in the VKORC1 coding region were found. Among carriers of these variants 78% were completely resistant, and it was not possible to achieve therapeutic effect even with high doses of acenocoumarol. Conclusions. Population-specific model for prediction individual dose of acenocoumarol, may show advantages over protocols that are used in a generalized manner. Also, VKORC1 variants which cause coumarin resistance should be considered when planning therapy.

Successful outcome with outpatient acenocoumarol therapy for echocardiographically visible pulmonary thrombus

Visualisation of thrombus in the main pulmonary artery through two-dimensional transthoracic echocardiography (TTE) without cardiovascular instability is rare. We report a unique case of echocardiographically diagnosed acute pulmonary embolism (PE) in an ambulatory patient with concomitant cor pulmonale secondary to idiopathic interstitial lung disease. The mobile thrombus was first visualised at the junction of bifurcation of the pulmonary trunk with left pulmonary artery through routine two-dimensional TTE. Two days later, the contrast-enhanced computerised tomographic scan of the chest showed the thrombus to be in the distal portion of the right pulmonary artery. Complete resolution of pulmonary thrombus was achieved with a 3-month course of outpatient oral anticoagulation treatment with acenocoumarol without recurrence of PE during the 1-year follow-up.

VKORC1 and CYP2C9*3 Polymorphisms and Their Impacts to Acenocoumarol Dosage in Vietnamese Heart Valve Replacement Patients

Acenocoumarol therapy has been widely used for heart valve replacement (HVR) patients in Vietnam to improve dose management of this drug. The variety of responses among patients to this drug are driven by genetic background. Hence, aim of the study is to explore the relation between acenocoumarol dosages and genetic polymorphisms of CYP2C9*3, VKORC1-1173 C>T and VKORC1-1639 G>A genes. One hundred fifty HVR patients was enrolled in this study. Blood samples were collected and analyzed using PCR and Sanger’s sequencing. The result showed that there was no variant homozygous genotype (CC) of CYP2C9*3 observed, whereas wild-type (AA) and heterozygous (AC) were most abundant with 95.3, and 4.7 %, respectively. In contrast, variant homozygous genotypes of VKORC1-1173 C>T and -1639 G>A accounted for 70.7 and 87.3 % of Vietnamese HVR patient population while wildtype homozygous was not seen. Interestingly, there was significant difference in acenocoumarol doses between 2 genotypes of VKORC1-1173 C>T, but this result was not observed for CYP2C9*3. Patients with the variant homozygous genotype of VKORC1-1173 C>T have the lower dose of acenocoumarol in comparison with heterozygous genotype (p = 0.001). In conclusion, polymorphism of VKORC1-1173 C>T not CYP2C9*3 contributeseemed to relate to acenocoumarol dose responses of Vietnamese HVR patients.

P4800Estimated effect of NOACs compared to Vitamin K Antagonists in real-world atrial fibrillation patients: Data from FANTASIA Registry

Abstract Background Despite of the effectiveness and safety profile of Non-vitamin K Antagonists Oral Anticoagulants (NOACs) even in real-world (RW) Atrial Fibrillation (AF) patients, Vitamin K Antagonists (VKAs) have remained widely used in clinical practice worldwide but the comparison with acenocoumarol therapy in RW is unknown. Purpose To estimate the potential absolute benefit in clinical adverse events if the AF patients anticoagulated with VKA therapy had been treated with NOACs. Methods We analyzed anticoagulated AF patients who were prospectively recruited into the multicentre FANTASIIA registry. Patients were treated with VKAs for at least 6 months prior to inclusion. The estimation of clinical adverse events avoided was calculated applying absolute risk reductions, relative risk reductions and hazard ratios from the meta-analysis of RW use of NOACs relative to VKAs. Results We analyzed 1,470 patients under VKA therapy (mean age 74.1±9.5 years; 56.4% male). Stroke rate with acenocoumarol treatment was 0.88%/year. The estimated rates for stroke using NOACs would be 0.80%/year for Dabigatran 150 mg; 0.76%/year for Rivaroxaban and 0.74%/year for Apixaban instead of VKA. No significant differences were observed between the different NOACs and VKA in stroke rate. Major bleeding with acenocoumarol was 3.40%/year. The estimated rates for major bleeding using NOACs would be 2.75%/year for Dabigatran 150 mg; 3.37%/year for Rivaroxaban and 2.18%/year for Apixaban instead of VKA. Apixaban was the only NOAC that showed a significant estimated reduction rates (p=0.046). Finally, the all-cause mortality rate with acenocoumarol was 4.69%/year. The estimated rates of all-cause mortality using NOACs would be 3.28%/year for Dabigatran 150mg; 4.88%/year for Rivaroxaban and 2.67%/year for Apixaban. Dabigatran and Apixaban showed significant estimated reduction rates with the highest reduction with Apixaban (Table). Annual Rate reduction of adverse events Conclusion The absolute estimated effect of NOACs in the AF patients anticoagulated with VKA showed a significant reduction in adverse clinical events. Apixaban performed the highest estimated reduction in major bleeding and all-cause mortality in comparison with acenocoumarol.

The Association Between Long-Term Acenocoumarol Treatment and Vitamin D Deficiency.

Both vitamin D and K2 are involved in a number of metabolic processes, including bone metabolism; however, associations between the vitamins are not fully understood. The aim of the study was to evaluate serum concentrations of 25-hydroxyvitamin D [25(OH)D] in adult patients receiving long-term acenocoumarol (AC) treatment. In this cross-sectional study, 58 Caucasian patients (31 women, 27 men) with a median age of 65 years receiving long-term AC therapy were evaluated and compared with 35 age- and gender-matched healthy controls. The AC treatment was used due to recurrent venous thromboembolism (34.5%), atrial fibrillation (31%), or mechanical heart valve prostheses (34.5%). Medical records and a questionnaire were used to obtain information about chronic diseases, smoking habits, and the duration of therapy and weekly dose of AC. Anthropometric measurements were performed, and serum concentration of 25(OH)D and total alkaline phosphatase (ALP) activity were measured. Among the 58 patients receiving long-term AC treatment, a high proportion (46.6%) demonstrated significant vitamin D deficiency with concentrations of 25(OH)D lower than 20 ng/mL. The median concentration of 25(OH)D in subjects receiving AC was significantly lower compared to the control group [20.4 (17.4; 26.1) vs. 28.2 (24; 32.7); p < 0.001]. No differences were found between women and men receiving AC therapy. In patients receiving AC, a negative correlation was found between the concentration of 25(OH)D and the weekly dose of AC (r = -0.337, p = 0.01). Patients with concentrations of 25(OH)D < 20 ng/mL were found to have a significantly higher median dose of AC, compared to those with concentrations of 25(OH)D ≥ 20 ng/mL [21 (17; 31) vs. 17 (12; 28); p = 0.045]. In conclusion, treatment with AC is associated with low 25-hydroxyvitamin D levels, although the path leading to this phenomenon is not entirely clear. Long-term administration of AC in adults may increase the risk of chronic vitamin D deficiency, thus, effective supplementation of vitamin D in these individuals needs careful consideration.

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.

IMPACT OF PHARMACIST LED ANTICOAGULATION MONITORING AND PATIENT EDUCATION ON ORAL ANTICOAGULATION THERAPY WITH ACENOCOUMAROL

Objective: Acenocoumarol is anoral anticoagulant with narrow therapeutic index, and the ideal dose of anticoagulation lies between International normalized ratio (INR) values of 2.0 and 3.5. Lack of monitoring and knowledge on acenocoumarol therapy may compromise patient’s safety resulting in under- or over-anticoagulation. A study was conducted to monitor for the safety of anticoagulation therapy, achievement of goal INR levels and to assess the impact of pharmacist led anticoagulation monitoring and patient education on the rational use of acenocoumarol in patients admitted in cardiology wards with thromboembolic disorders.Methods: The study was conducted in 70 patients; data collection was done, prescriptions were analyzed for drug-drug interactions and adverse drug reactions (ADRs). Patients’ knowledge on acenocoumarol therapy was assessed using a self-developed questionnaire at the baseline, then were subjected to a detailed patient education and on an average each patient received three sessions of education. They were again made to answer the same questionnaire on the day of discharge. The mean score of the responses before and after education was compared statistically using Wilcoxon signed rank test and McNemar test.Results: There were 60% patients under anticoagulated with the INR range of &gt;2.0. 123 drug interactions were observed in 58 patients, on an average of 2 interactions per prescription, but no ADRs were observed. 59 patients (84.3%) showed significant overall improvement in knowledge on anticoagulation therapy following education.Conclusion: This study implies the role of clinical pharmacists in achieving better clinical outcomes in patients receiving oral anticoagulation therapy with acenocoumarol.

Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

Influence of VKORC1 and CYP2C9 Polymorphisms on Daily Acenocoumarol Dose Requirement in South Indian Patients With Mechanical Heart Valves.

Chronic rheumatic heart disease (RHD) patients who undergo valve replacement with mechanical valves require lifelong anticoagulation. Acenocoumarol, a vitamin K antagonist has a narrow therapeutic range and wide inter-individual variability. Our aim was to investigate the influence of polymorphisms of VKORC1 and CYP2C9 genes on the mean daily dose requirement of acenocoumarol. 205 chronic RHD patients, with mechanical heart valves and on acenocoumarol therapy, were recruited. Genotyping for VKORC1 (-1639G>A and 1173C>T) and CYP2C9 (*2 & *3 alleles) polymorphisms was done by PCR-RFLP. There was complete linkage disequilibrium between VKORC1 polymorphisms (r2 = 0.98, D' = 1.0, LOD = 74.02). VKORC1 genotype distribution for GG/CC, GA/CT, and AA/TT were 57.6%, 36.1%, and 6.3%, respectively. CYP2C9 genotype distribution for *1/*1, *1/*3, *1/*2, *2/*2, and *2/*3 were 78.5%, 14.1%, 6.3%, 0.5%, and 0.5%, respectively. Patients with a wild type of both VKORC1 (-1639GG and 1173CC) and CYP2C9 gene variants required higher acenocoumarol dose compared to those with mutant genotype ( P = 0.023 and P = 0.008 respectively). On combined genotype analysis, patients having a combination of wild type of VKORC1 with wild type of CYP2C9 (44.4%) required higher daily dose compared to patients bearing heterozygous VKORC1 (-1639GA & 1173CT) with wild type of CYP2C9 (30.2%, P = 0.008). Presence of a mutant allele of VKORC1 (-1639A & 1173T) and CYP2C9 genes increased the odds of requiring a lower mean dosage of acenocoumarol. Studying the combination of genotypes in RHD patients could predict acenocoumarol dose requirement more accurately.

Cost-effectiveness Analysis of Rivaroxaban versus Acenocoumarol in the Prevention of Stroke in Patients with Non-valvular Atrial Fibrillation in Spain.

Objective: The aim of this study was to evaluate, from the Spanish National Health System perspective, the cost-effectiveness of rivaroxaban (20 mg/day) versus use of acenocoumarol (5 mg/day) for the treatment of patients with non-valvular atrial fibrillation (NVAF) at moderate to high risk for stroke. Methods: A Markov model was designed and populated with local cost estimates, efficacy and safety of rivaroxaban in stroke prevention in NVAF compared with adjusted-dose warfarin clinical results from the pivotal phase III ROCKET AF trial and utility values obtained from the literature. Warfarin and acenocoumarol were assumed to have therapeutic equivalence. Results: Rivaroxaban treatment was associated with fewer ischemic strokes and systemic embolisms (0.289 vs.0.300 events), intracranial bleeds (0.051 vs.0.067), and myocardial infarctions (0.088 vs.0.102) per patient compared with acenocoumarol. Over a lifetime time horizon, rivaroxaban led to a reduction of 0.041 life-threatening events per patient, and increases of 0.103 life-years and 0.155 quality-adjusted lifeyears (QALYs) versus acenocoumarol treatment. This resulted in an incremental cost-effectiveness ratio of €7045 per QALY and €10 602 per life-year gained. Sensitivity analysis indicated that these results were robust and that rivaroxaban is cost-effective compared with acenocoumarol in 89.4% of cases should a willingness-to-pay threshold of €30 000/QALY gained be considered. Conclusions: The present analysis suggests that rivaroxaban is a cost-effective alternative to acenocoumarol therapy for the prevention of stroke and systemic embolisms in patients with NVAF in the Spanish healthcare setting.

Antithrombotic strategy after bioprosthetic aortic valve replacement in patients in sinus rhythm: evaluation of guideline implementation.

After elective aortic valve replacement, patients are at risk of developing valve thrombosis and systemic arterial thromboembolism. Current guidelines recommend antithrombotic therapy with aspirin or vitamin K antagonists (VKAs) during the first 3 months after the procedure, but have level 2 or 3 evidence. As a consequence, the most appropriate antithrombotic therapy is still a matter of debate. This retrospective study analysed all thromboembolic and bleeding complications in patients with either antiplatelet or anticoagulation therapy 1 year after bioprosthetic aortic valve replacement. A total of 402 patients undergoing bioprosthetic aortic valve implantation at the VU University Medical Centre and subsequently treated at three regional hospitals were included. The individual duration of either VKAs (acenocoumarol) or aspirin was determined and related to thrombotic and bleeding events. Patients were followed and censored at 1 year postoperatively for survival, cerebral ischaemia, myocardial infarction, peripheral arterial embolism, and minor and major haemorrhages. A total of 24 thromboembolic complications and 31 bleeding episodes occurred. Multivariable analyses revealed that acenocoumarol caused more bleeding episodes (risk ratio [RR]: 8.41, 95% CI: 3.58-19.79) and a similar amount of thromboembolic events (RR: 1.2, 95% CI: 0.47-3.02) compared with aspirin. Prior use of acenocoumarol was found to be a risk factor for thromboembolic events (RR: 3.1, 95% CI: 1.31-7.19). Gender, dyslipidaemia, prior percutaneous coronary intervention, prior use of acenocoumarol and concomitant coronary artery bypass grafting were found to be predictors for bleeding events. In patients 1 year following bioprosthetic aortic valve replacement, acenocoumarol therapy was associated with a significant increased risk of bleeding events and no reduction in thromboembolic events compared with antiplatelet therapy. These findings support the recommendations of aspirin over VKAs as postoperative thromboprophylaxis.

Poor Anticoagulation Control in Atrial Fibrillation: How Much Longer?

Revista Espanola de Cardiologia recently published the results of 3 retrospective studies of patients with atrial fibrillation in Spain. The 3 studies evaluate the quality of anticoagulation control over 1 year of primary care therapy with vitamin-K antagonists. In all studies, the majority of patients received acenocoumarol therapy and 40% of patients had inadequate anticoagulation control. In the ANFAGAL study (ANticoagulacion en pacientes con Fibrilacion Auricular en el ambito de atencion primaria de GALicia) study, conducted in Galicia, Cinza-Sanjurjo et al 1 studied 511 primary care patients with nonvalvular atrial fibrillation who received anticoagulant therapy with vitamin-K antagonists for more than 1 year. Overall, 41.5% of patients were in the therapeutic range on fewer than 60% of follow-up visits. This group of patients took more medication and had higher incidences of kidney disease and major bleeding. Furthermore, the study excluded patients who required temporary interruption of antic- oagulation therapy, as this increases the proportion of patients with poorly controlled anticoagulation. The other 2 studies are larger and national in scope. The CALIFA 2 study included 1542 patients who were followed-up by cardiol- ogists and who were receiving treatment for chronic atrial fibrillation, and adequate anticoagulation control was achieved in 60% of cases. The last study, PAULA, 3 evaluated 1524 patients, and anticoagulation was in the therapeutic range during 60% of the follow-up period.

Reliability of thromboelastometry for detecting the safe coagulation threshold in patients taking acenocoumarol after elective heart valve replacement

BackgroundReversal of anticoagulation can be needed in patients undergoing heart valve surgery. ROTEM® has been correlated with international normalized ratio (INR) in patients on warfarin but not with patients on acenocoumarol. This study investigates the reliability of ROTEM® for detecting INR values below the 1.5 threshold in patients on acenocoumarol therapy. Material and methodsPatients on oral anticoagulation with acenocoumarol after elective heart valve replacement were prospectively included in the study. INR and the ROTEM® were measured simultaneously. ROTEM® parameters included coagulation time, clot formation time, alpha angle, and maximal clot firmness after tissue factor activation (EXTEM). Concordance between INR and ROTEM® was analyzed by Lin’s concordance coefficient (LCC) and the correlation with Spearman’s rho. ResultsFifty-four consecutive patients (40 female; median age 67years) were included. Clotting time (CT) was the parameter that best correlated with INR (r=0.81, p<0,001), and LCC was substantial (0.67). CT was able to predict INR values above or below 1.5: area under curve=0.998. CT≥84seconds, corresponding to a cut-off for likelihood ratio (LR+)=5, had a sensitivity and specificity of 100% and 80%, respectively, to detect an INR below 1.5. For the same INR threshold, CT≥84seconds had a predictive positive value of 92.9% and a predictive negative value of 100%. ConclusionOur preliminary results suggest that CT≥84seconds in the EXTEM ROTEM® test is a feasible method for predicting an insufficient reversion of oral anticoagulant therapy in patients taking acenocoumarol after elective heart valve surgery.

Low dose dabigatran versus uninterrupted acenocoumarol for peri-procedural anticoagulation in atrial fibrillation catheter ablation

BackgroundLeft atrial ablation for atrial fibrillation (AF) is associated with a transiently increased risk of thromboembolic and hemorrhagic events. We tested the hypothesis that the low dose dabigatran [110mg twice a day (bid)] can be safely used as an alternative to uninterrupted acenocoumarol for periprocedural anticoagulation in left atrial ablation procedures. Methods and ResultsA total of 149 consecutive patients undergoing pulmonary vein antral isolation for AF were included; 64 patients were on low dose dabigatran (110mg bid) and 85 patients were on acenocoumarol with therapeutic international normalized ratios. Two doses of dabigatran were withheld before the procedure and the drug was restarted 4hours after vascular hemostasis. Overall, the two groups were well-matched. Hemorrhagic and thromboembolic complications were similar in both groups within 90days from the procedure (4.7% for the dabigatran group versus 9.4% for the acenocoumarol group; P=0.275). Major hemorrhage occurred in 1.6% in the dabigatran group versus 3.5% in the acenocoumarol group (P=0.462). A single thromboembolic event occurred in the dabigatran group (1.6%) versus 2 (2.4%) in the acenocoumarol group (P=0.734). Despite higher doses of intraprocedural heparin (P<0.01), the mean activated clotting time was significantly lower in patients who were on dabigatran than those on acenocoumarol (P<0.01). ConclusionsThe low dose dabigatran regimen provides safe and effective peri-procedural anticoagulation in patients undergoing left atrial ablation for AF compared with uninterrupted acenocoumarol therapy.

Effect of VKORC1, CYP2C9 and CYP4F2 genetic variants in early outcomes during acenocoumarol treatment.

To analyze VKORC1, CYP2C9 and CYP4F2 polymorphisms in relation to the main outcomes in the first stages of acenocoumarol therapy. Nine hundred and forty one patients who had started therapy and in whom time to stable dosage, time to over-anticoagulation and adverse events occurred during 3 first months were retrospectively analyzed. VKORC1 AA patients needed fewer days to reach stable dosage (p = 0.017). International normalized ratio [INR] at 72 h, and VKORC1 and CYP2C9 genotypes conditioned INR values >2.5 (p < 0.001, p = 0.002 and p < 0.001, respectively), whereas CYP4F2 T carriers had a low risk of the same outcome (p = 0.009). In regards to combined genotypes, CYP4F2 had a significant effect on over-anticoagulation at the beginning of therapy except for the VKORC1 AA and CYP2C9*3 combination. In addition to VKORC1 and CYP2C9, CYP4F2 gene has a slight but significant role in reaching INR >2.5 during the first weeks of acenocoumarol therapy.

Pharmacogenetics role in the safety of acenocoumarol therapy.

Vitamin K antagonists (VKAs) remain as the most prescribed drug for treatment and prevention of thrombotic disorders in many countries, despite the recent approval of the new oral anticoagulants (NOACs). Although effectiveness and safety of VKAs are tightly associated to maintaining the patient within the international normalised ratio (INR) therapeutic range (TWR), they have been likened to NOACs when patients are in good INR control (≥66% of TWR). Therefore, assessing the safety of patients should be a priority in the selection of the anticoagulation therapy. The aim of this study was to evaluate the association between CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2*3, ABCB1 C3435T, APOE, CYP2C19*2 and CYP2C19*17 gene polymorphisms and treatment safety in 128 patients diagnosed with atrial fibrillation or venous thromboembolism during the initial first seven months of acenocoumarol therapy. After the first month, VKORC1-T-allele and APOE-E3/E3 genotype were independently associated to higher time above therapeutic range (TAR) and lower time below the therapeutic range (TBR). After seven months, VKORC1 T-allele predicted higher TAR, and was also associated to increased INR>4, particularly the TT-genotype (odds ratio [OR]: 32; 95% confidence interval [CI95%]: 6-175; p=810⁻⁵). C-alleles for CYP2C9*3 (OR: 5.5; CI95%: 1.8-17; p=0.003) and ABCB1 (OR: 8.9;CI95%: 1.1-70; p=0.039) independently influenced on INR>6 . Patients VKORC1-TT/ABCB1-C remained 26.8% [19.7-38.9] TAR, with associated relative risk (RR) for INR>4 1.8 higher (CI95%: 1.2-2.5; p=0.015). Patients VKORC1-TT also presented the highest risk of bleeding events (RR: 3.5;CI95%: 1.4-8.4; p=0,010). In conclusion, VKORC1, CYP2C9*3, APOE and ABCB1 genotypes should be considered in prevention of overanticoagulation and bleeding events in the initiation of acenocoumarol therapy.

DGI-068 The Effect of Main Gene Polymorphisms on Stable Doses of Acenocoumarol in Long-Term Anticoagulation Treatment

BackgroundSeveral variants in CYP2C9 (CYP2C9*2 and especially the CYP2C9*3 allele) and VKORC1 genes (especially the 1639G>A polymorphism) are associated with effective coumarin derivative dose. The rs2108622 polymorphism in the gene...

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

Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. 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. 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. No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures. 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.

The efficacy and safety of acenocoumarol and warfarin therapy in patients with lower limb deep vein thrombosis

Only few studies are available on the comparison of the efficacy and safety of the acenocoumarol and warfarin. The authors treated patients with deep vein thrombosis according to latest recommendations using D-dimer measurements and duplex ultrasound exams. To examine the efficacy and safety of the two anticoagulants in patients with lower limb deep vein thrombosis. The authors included 100 consecutive patients with lower limb dee deep vein thrombosis. The patients were treated with acenocoumarol or warfarin in doses to achieve INR values between 2 and 3.5 for six months. After 6 months the authors performed physical examination, D-dimer measurements and ultrasound exams, and determined the rate of unchanged thrombotic process, as well as the rate of complete and incomplete recanalisations. There was no significant difference in the number of INR determinations during treatment between the two groups (acenocoumarol group 442, warfarin group 416). The INR values were in the therapeutic range in 71.2% and 75.4% of patients in the acenocoumarol and warfarin groups, respectively. Dose adjustment was necessary in 129 and 84 times in the acenocoumarol and warfarin groups, respectively (p = 0.0025). The therapy was optimally effective (INR value was within the therapeutic range throughout the treatment period) in 46% and 52% of patients in the acenocoumarol and warfarin groups, respectively. The thrombotic vein was completely recanalised in 91.9% of patients treated optimally, and only 80.4% of patients treated not optimally. There were 3 minor bleedings in the acenocoumarol and 4 minor bleedings in the warfarin groups, while one major bleedings occurred in both groups. The INR values were more stable in the warfarin group than in the acenocumarole group. In both groups the rate of complete vein recanalization was related to the rate of optimally stable INR values within the therapeutic range.