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PubMed2003

Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon.

Variability in the control of oral anticoagulant therapy has been associated with a heightened risk of complications. We compared control of anticoagulation between two commonly used coumarins, phenprocoumon and acenocoumarol, and among anticoagulation clinics. All qualifying patients were managed at six regional anticoagulation clinics in the Netherlands. This retrospective cohort study compiled data during a three-year period from a computerised dosing and management system. Anticoagulation control was expressed as the percent of time within the therapeutic range and stability expressed as the time-weighted variance in the international normalised ratio (INR). Data were available for 22,178 patients of whom 72% were treated with acenocoumarol. INRs of patients who received phenprocoumon were within the therapeutic range 50% of the time compared with 43% for acenocoumarol (OR 1.32, 95% CI 1.24-1.41). Moreover, patients on phenprocoumon required 15% fewer monitoring visits and had more stable INR values. These observations were consistent for all six clinics. There were also sizable differences between the clinics with respect to control and stability of anticoagulation that were stable from year-to-year and were unrelated to the drug used. With its longer half-life of three to five days, phenprocoumon produces more stable anticoagulation than acenocoumarol and should generally be the drug of choice when these are the available choices. The differences observed among clinics suggest that certain clinics employ policies and practices resulting in better control of anticoagulation.

Acenocoumarol↗
PubMedDate not supplied

A study on the safety, efficacy, and efficiency of sulodexide compared with acenocoumarol in secondary prophylaxis in patients with deep venous thrombosis.

This study was carried out to study the safety and efficacy of a fixed dosage of sulodexide compared to adjusted dosages (INR) of acenocoumarol as secondary prophylaxis in patients with deep vein thrombosis (DVT) in lower limbs. An economic evaluation based on the criteria of use in normal clinical practice was also performed. One hundred and fifty patients of both sexes were included, all over 18 years of age and diagnosed with proximal DVT of the lower limbs by color echo-Doppler, and with clinical evolution of less than 1 month. The patients were initially treated with low-molecular-weight heparin (LMWH) and urokinase in accordance with the established protocol. They were then randomized to continue treatment with acenocoumarol and INR adjustments every 30 days, or with sulodexide. Treatment was extended for 3 months with monthly follow-up visits and a final visit at 3 months posttreatment. No differences between the groups were detected concerning demographic or basal characteristics in clinical evolution or adverse reactions. In the group treated with sulodexide, no major/minor hemorrhagic complications were detected. On the other hand, in the acenocoumarol group, 1 major hemorrhage and 9 minor hemorrhages were produced (13.3%), reaching statistical difference in relation to the sulodexide group (p = 0.014; CI from 95% of 4.7% to 19.4%). Regarding the economic impact, treatment costs with sulodexide are much less than those with acenocoumarol, the data confirmed by the sensitivity analyses performed. The results prove the efficacy, safety, and efficiency of sulodexide as a secondary prophylaxis in thromboembolic disease, avoiding hemorrhagic risks and the monitoring of patients, and providing significant savings to the health system.

Acenocoumarol↗
PubMed2003

Pharmacokinetic study of the digoxin-acenocoumarol interaction in rabbits.

A study was carried out to evaluate the potential pharmacokinetic interaction between digoxin and acenocoumarol. The binding of digoxin to rabbit cardiac tissue homogenates was assessed in vitro, using the equilibrium dialysis technique. An increase in the first-order constant (p<0.05) and a reduction in the partition coefficient in the equilibrium situation (p<0.001) of digoxin were observed when the cardiac homogenates were previously treated with acenocoumarol. In the in vivo study, the kinetics of digoxin administered in single and multiple dosage regimens were compared in control rabbits and in rabbits treated simultaneously with acenocoumarol. Kinetic analysis of the results was performed using Non-linear Mixed Effects Modeling (NONMEM). In the presence of acenocoumarol, the population distribution volume (Vd) of digoxin was increased by 40-60%, no differences being found as regards the elimination clearance. Also, joint administration of both drugs led to a reduction in digoxin concentrations in the heart (p<0.01) at the end of the dosage regimen. Both sets of results point to the hypothesis of a hitherto unreported possible pharmacokinetic interaction between the two drugs affecting the distribution process. This interaction could lead to lower plasma digoxin levels, in view of the increased Vd, and a possible reduction in the therapeutic effect, owing to the decrease in affinity and in concentration in heart tissue.

Acenocoumarol↗
PubMed2005

Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol.

Vitamin K antagonists belong to the group of most frequently used drugs worldwide. They are used for long-term anticoagulation therapy, and exhibit their anticoagulant effect by inhibition of vitamin K epoxide reductase. Each drug exists in two different enantiomeric forms and is administered orally as a racemate. The use of vitamin K antagonists is complicated by a narrow therapeutic index and an unpredictable dose-response relationship, giving rise to frequent bleeding complications or insufficient anticoagulation. These large dose response variations are markedly influenced by pharmacokinetic aspects that are determined by genetic, environmental and possibly other yet unknown factors. Previous knowledge in this regard principally referred to warfarin. Cytochrome P450 (CYP) 2C9 has clearly been established as the predominant catalyst responsible for the metabolism of its more potent S-enantiomer. More recently, CYP2C9 has also been reported to catalyse the hydroxylation of phenprocoumon and acenocoumarol. However, the relative importance of CYP2C9 for the clearance of each anticoagulant substantially differs. Overall, the CYP2C9 isoenzyme appears to be most important for the clearance of warfarin, followed by acenocoumarol and, lastly, phenprocoumon. The less important role of CYP2C9 for the clearance of phenprocoumon is due to the involvement of CYP3A4 as an additional catalyst of phenprocoumon hydroxylation and significant excretion of unchanged drug in bile and urine, while the elimination of warfarin and acenocoumarol is almost completely by metabolism. Consequently, the effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are also least pronounced in the case of phenprocoumon; this drug seems preferable for therapeutic anticoagulation in poor metabolisers of CYP2C9. In addition to these vitamin K antagonists, oral thrombin inhibitors are currently under clinical development for the prevention and treatment of thromboembolism. Of these, ximelagatran has recently gained marketing authorisation in Europe. These novel drugs all feature some major advantages over traditional anticoagulants, including a wide therapeutic interval, the lack of anticoagulant effect monitoring and a low drug-drug interaction potential. However, they are also characterised by some pitfalls. Amendments of traditional anticoagulant therapy, including self-monitoring of international normalised ratio values or prospective genotyping for individual dose-tailoring may contribute to the continuous use of warfarin, phenprocoumon and acenocoumarol in the future.

Acenocoumarol↗
PubMed2002

Low dose oral vitamin K to reverse acenocoumarol-induced coagulopathy: a randomized controlled trial.

Low dose oral vitamin K rapidly reverses warfarin-associated coagulopathy. Its effect in patients receiving acenocoumarol is uncertain. We compared the effect of withholding acenocoumarol and administering 1 mg oral vitamin K with simply withholding acenocoumarol in asymptomatic patients presenting with INR values between 4.5 and 10.0. The primary end-point of the study was the INR value on the day following randomisation. We found that patients receiving oral vitamin K had more sub-therapeutic INR levels than controls (36.6% and 13.3%, respectively; RR 1.83, 95% confidence interval 1.16, 2.89) and a lower, but non-significant, proportion of INR values in range (50% and 66.6%, respectively) on the day following randomisation. After 5 +/- 1 days, there were more patients with an INR value in range in the vitamin K group than in controls (74.1% and 44.8%, respectively). There were no clinical events during 1 month follow-up. We conclude that the omission of a single dose of acenocoumarol is associated with an effective reduction of the INR in asymptomatic patients presenting with an INR value of 4.5 to 10.0. Furthermore, the use of a 1 mg dose of oral vitamin K results in an excessive risk of over-reversal of the INR.

Acenocoumarol↗
PubMed1975

Collaborative study of a semiautomated method for the analysis of acenocoumarol, phenprocoumon, and potassium warfarin tablets.

This collaborative study was undertaken to determine if the anticoagulants acenocoumarol, phenprocoumon, and potassium warfarin could be analyzed by the automated analysis system described in the collaborative study for the analysis of sodium warfarin and dicumarol. Collaborators were supplied with a composited tablet sample of each anticoagulant. Results agreed well with the National Formulary methods for phenprocoumon and potassium warfarin, and an unpublished method for acenocoumarol. For acenocoumarol, coefficients of variation on individual sets of data ranged from 0.30 to 1.94% For phenprocoumon, coefficients of variation ranged from 0.52 to 1.20%. For potassium warfarin, coefficients of variation ranged from 0.54 to 1.79%. The results of this study show that acenocoumarol, phenprocoumon, and potassium warfarin can be analyzed by the official AOAC method for the analysis of sodium warfarin and dicumarol tablets.

Acenocoumarol↗
PubMed1994

A comparative study on the quality of oral anticoagulant therapy (warfarin versus acenocoumarol).

In our Center for the Surveillance of Anticoagulant Treatment, most of the 1700 patients followed-up are traditionally treated with acenocoumarol, while warfarin is administered nowadays to an increasing proportion of patients. To assess if the difference in the pharmacokinetics of these two drugs may determine a different laboratory quality of treatment, a retrospective study was performed on the computerized files of all 142 patients on treatment with warfarin for more than 100 days and on a control group of 142 patients treated with acenocoumarol, matched for age, sex, disease state and duration of oral anticoagulant therapy (OAT). The study considered 7071 assays for a total of 432 patient-years of treatment. The overall quality of treatment was significantly better in patients treated with warfarin (72% of controls within the therapeutic range versus 67% on acenocoumarol, p < 0.001). Also the individual quality of therapy, which was assessed as the percentage of patients with 75% or more assays in range, was in favour of warfarin (50.7% vs 34.5%, p < 0.05). Warfarin therapy was more stable and fewer assays were required for treatment monitoring. Confounding factors possibly influencing the treatment stability, such as interfering drugs, diagnostic or therapeutical procedures requiring withdrawal of anticoagulation, were evaluated and no significant difference between the two groups was found. The difference in the laboratory quality of OAT was marked in patients treated for prevention of arterial thromboembolism, while it was negligible in patients with venous thromboembolic disease, whose mean duration of OAT was considerably shorter. Since there is no evidence that acenocoumarol is more efficacious or safer than warfarin, the latter seems to be preferable for patients who are candidate to very prolonged OAT.

Acenocoumarol↗
PubMed2002

No effect of acenocoumarol therapy on levels of endothelial activation markers in sickle cell disease.

Sickle cell patients are characterized by a chronic inflammatory and hypercoagulable state, depicted by elevated levels of pro-inflammatory cytokines, endothelial adhesion molecules, and elevated markers of thrombin generation. We set out to determine whether anticoagulation with a coumadin derivative reduces inflammation in sickle cell disease. Therefore, serum levels of NFkappaB-regulated endothelial adhesion molecule soluble vascular cell adhesion molecule-1 and serum levels of non-NFkappaB-dependent markers of endothelial activation (soluble cellular fibronectin and von Willebrand factor antigen) were compared during treatment with acenocoumarol (INR 1.6-2.0) and placebo. No effect on circulating levels of the measured parameters was observed during treatment with acenocoumarol as compared to placebo. In the targeted INR range, anticoagulation of sickle cell patients with acenocoumarol does not seem to reduce endothelial activation.

Acenocoumarol↗
PubMed1977

GLC determination of plasma acenocoumarol levels.

A method for the quantitative estimation of acenocoumarol in plasma is described. Plasma containing acenocoumarol, to which a known amount of gamma-oxo derivative of phenylbutazone is added as an internal standard, is acidified and extracted with ethylene dichloride. The drug and the internal standard are then back-extracted into alkali, which, in turn, is acidified and reextracted with ethylene dichloride. The organic extract is evaporated and treated with an ethereal solution of diazomethane (100 microliter). The reacted mixture is evaporated, and the residue is dissolved in 25 microliter of carbon disulfide. Aliquots (2-3 microliter) are injected into a gas chromatograph equipped with a flame-ionization detector. The methyl derivatives of acenocoumarol and the internal standard give sharp, well-separated, symmetrical peaks. The method is of sufficient sensitivity to determine 0.25 microgram/ml of the drug in plasma with a relative standard deviation of 4%.

Acenocoumarol↗
PubMed1986

Lack of effect of cimetidine on pharmacodynamics and kinetics of single oral doses of R- and S-acenocoumarol.

The kinetics and dynamics of single doses (5 mg p.o.) of the optical isomers of acenocoumarol (R-AC and S-AC) were followed in healthy subjects and the effect on them of cimetidine 800 mg/day was also investigated. The AC enantiomers differed greatly in their pharmacokinetics. The mean residence time (MRT) of R-AC was about 10 times longer than that of S-AC, 15 h vs 1.2 h. There was no difference in the volume of distribution. Depression of blood clotting activity (Thrombotest) was observed only after administration of R-AC. The inactivity of S-AC as a vitamin K antagonist must be ascribed to its short MRT. Cimetidine did not affect the acute oral kinetics of R- and S-AC, nor did it affect the anticlotting activity of R-AC. The urinary excretion pattern of the 6- and 7-hydroxylated AC metabolites was not altered during cimetidine treatment. Although the present studies showed no effect of cimetidine on the pharmacokinetics and dynamics of acenocoumarol, the findings of Serlin et al. suggest that cimetidine should not be administered during acenocoumarol therapy.

Acenocoumarol↗
PubMed1981

May mothers taking acenocoumarol breast feed their infants?

In 20 women receiving Sintrom post partum, the acenocoumarol concentration in serum and breast milk at different times was measured. Even at the time of maximal serum concentration, or for the following 6 h, no acenocoumarol could be detected in the breast milk. In accordance with this finding, no effect of breast feeding on Thrombotest values of the infants could be demonstrated. These data suggest that mothers taking acenocoumarol for a short period may safely breast feed their infants.

Acenocoumarol↗
PubMedDate not supplied

Pharmacokinetic analysis of a new acenocoumarol tablet formulation during a bioequivalence study.

The pharmacokinetics of a new tablet formulation of acenocoumarol racemate, an oral anticoagulant agent, has been investigated in 8 normal healthy subjects. The drug was given as a single oral dose of 12 mg. 12 blood samples were collected after administration Plasma acenocoumarol concentrations were determined by a sensitive HPLC method. Areas under the plasma level-time curves for each subject were evaluated by means of the trapezoidal rule. The peak plasma concentration of 244.19-644.23 micrograms/l was reached 1-4 h after drug administration. The terminal phase half-life was 6.29-14.22 h and a systemic clearance was 1.86-5.62 l/h. The new table formulation of acenocoumarol seems to be bioequivalent when compared to the one used so far. For the prediction of systemic availability and estimation of the first-pass metabolism, from plasma level data, a hepatic blood flow rate limited model were used. The systemic availability was 94.22-98.01% and the elimination of the drug on its first-pass through the liver was 1.99-5.78%.

Acenocoumarol↗
PubMed1994

[Neutropenia caused by acenocoumarol associated with hairy cell leukemia].

We report the case of a woman splenectomized to treat her hairy cell leukemia (at the moment in remission) 11 years before the detection of neutropenia. The neutropenia began just after the treatment of pulmonary embolism by acenocoumarol. The neutropenia disappeared quickly after substitution of acenocoumarol by fluindione. We discuss the attribution of the neutropenia to acenocoumarol and the part played by hairy cell leukemia.

Acenocoumarol↗
PubMed2003

Age and first INR after initiation of oral anticoagulant therapy with acenocoumarol predict the maintenance dosage.

BACKGROUND: This retrospective study was performed to develop a model to predict the maintenance dosage of the vitamin K antagonist acenocoumarol, based upon the first INR after a standard initial dosage regimen. MATERIAL AND METHODS: Outpatients with atrial fibrillation ( n = 284) and initial regimens of 6-4 or 6-4-2 mg acenocoumarol on day 1, 2 and 3, respectively, were included. The maintenance dosage of the period 3-6 months after the installment was related to the first INR after those standard initial dosage regimens, because in that period the INR was 76% of the time within the therapeutic range and therefore considered suitable to perform the analysis. RESULTS: A clear relation was found between the first INR, the maintenance dosage and the age. A model that predicts the maintenance dosage immediately after the standard initial dosage and based on the first INR and adjusted for age, has been developed, according to the formula: required dosage = 5.03-1.65 * ln (first INR) - 0.01 * age. CONCLUSION: We have developed a formula to predict the maintenance dosage of acenocoumarol. With this formula it is possible to install this maintenance dosage and thus achieve oral anticoagulant therapy within the therapeutic range at an earlier stage. This will have to be shown in a prospective study.

Acenocoumarol↗
PubMed2003

Acenocoumarol therapy in pediatric patients.

To determine guidelines for administering and monitoring acenocoumarol therapy in children, 93 patients (median 5.1 years, range: 0.2-18 years) were prospectively evaluated over a 33-month period. The loading doses used were: <1 year, 0.20 mg x kg-1; >1-5 years, 0.09 mg x kg-1; 6-10 years, 0.07 mg x kg-1; 11-18 years, 0.06 mg x kg-1. In this study, the loading dose and the dose to achieve and maintain target therapeutic range (TTR) for acenocoumarol are age-dependent, with infants having the highest and teenagers having the lowest requirements. The use of a different loading dose according to age has allowed most of the children (80%) in all the age groups to achieve TTR in less than 1 week. No patients had serious bleeding or thrombotic complications. We conclude that there is an age-dependent response to acenocoumarol in pediatric patients. The implementation of an age-adjusted loading dose regimen reduces the length of hospitalization required to achieve effective anticoagulant therapy.

Acenocoumarol↗
PubMed1981

Pharmacokinetics of the enantiomers of acenocoumarol in man.

1 The pharmacokinetics of R(+)-, S(-)- and R,S(+/-)-acenocoumarol were studied in healthy volunteers after administration of single oral and intravenous doses. 2 After both oral and i.v. administration of either enantiomer in a dose of 0.25 mg/kg, the concentrations of R(+) found in the plasma were much higher than those of S(-). This indicates that the observed differences are not related to stereoselective absorption. 3 After intravenous administration of 25 mg of each enantiomer and the racemate, the total plasma clearance of S(-) was about 10 times that of R(+). The clearance of the racemate was between that of the enantiomers. 4 The apparent elimination half-life of S(-) was much shorter than those of R(+) and the racemate, which were similar. 5 The apparent volume of distribution VdSS of S(-) acenocoumarol was 1.5 to 2 times that of R(+). 6 Measurements of the extent of binding to serum proteins, made in vitro at much higher concentrations than those observed in vivo, revealed no differences between the two enantiomers and the racemate. 7 The results indicate that the greater anticoagulant potency of R(+) compared with S(-) acenocoumarol can be explained mainly by stereoselective differences in their metabolic clearance.

Acenocoumarol↗
PubMed2003

Acenocoumarol is not a safe alternative for anticoagulation in phenprocoumon-induced hepatic failure. Report of two cases.

Acenocoumarol has been proposed repeatedly as a safe alternative drug regimen for oral anticoagulation in patients who have suffered phenprocoumon-induced fulminant hepatic failure. The current report describes 2 patients with phenprocoumon-induced hepatic failure, necessitating liver transplantation in 1 case, who showed recurrence of liver damage when oral anticoagulation with acenocoumarol was attempted. Thus, acenocoumarol may not be a safe therapeutic alternative for patients who survived severe phenprocoumon-induced hepatotoxicity.

Acenocoumarol↗
PubMed1993

Lack of effect of influenza vaccine on anticoagulation by acenocoumarol.

OBJECTIVE: To analyze the effects of influenza vaccine on patients receiving chronic anticoagulant therapy with acenocoumarol. DESIGN: A prospective trial. SETTING: Hospital de la Santa Creu i Sant Pau, Barcelona. PATIENTS: Forty-three patients who received acenocoumarol, had stable levels of International Normalized Ratio (INR), and did not need dosage modification for four months before entering the study. INTERVENTION: A study of anticoagulation levels measured by INR at 7, 15, and 30 days from administration of the trivalent vaccine from the 91-92 campaign was conducted. MAIN OUTCOME MEASURES: Comparison was made between basal values (day 0) and anticoagulation levels at 7, 15, and 30 days from vaccine administration by means of a repeated-measures ANOVA. RESULTS: Nine patients (21 percent) had INR levels out of the therapeutic range during the study period. INR increased in three of these patients and decreased in six. There were no significant intraindividual changes in INR values during the time period analyzed (p = 0.125). No hemorrhagic or thrombotic manifestations occurred and no significant changes in renal or hepatic biochemistry were observed. CONCLUSIONS: Influenza vaccine does not modify acenocoumarol activity in patients receiving long-term anticoagulant therapy.

Acenocoumarol↗