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PubMed1985

Platelet inhibitors versus anticoagulants for prevention of aorto-coronary bypass graft occlusion.

The effects of the antiaggregant substance ticlopidine and of the anticoagulant acenocoumarol on patency rates of aorto-coronary bypass grafts were compared in a prospective randomized trial. Ticlopidine, 250 mg b.i.d. was administered orally from the first postoperative day till angiography, while anticoagulation with acenocoumarol was initiated on the second to third postoperative day. Side-effects of ticlopidine were rare and patient management with the standard dosage of this drug was easier than oral anticoagulation. From an initial group of 166 randomized patients 149 completed the trial by coronary angiography three months postoperatively. The 78 patients in the ticlopidine group showed a compliance of 85%. The average prothrombin time in the 71 patients receiving acenocoumarol was 26.9%. Detailed statistical analysis of the two study groups revealed no reason to doubt the correctness of randomization. Coronary angiography showed an average patency rate per patient of 84% with ticlopidine and of 82% with acenocoumarol. This and various other measures of graft occlusion did not reveal any substantial difference in graft patency of patients receiving ticlopidine or acenocoumarol. It is concluded that ticlopidine may well be used instead of anticoagulants for prevention of postoperative occlusion of aorto-coronary bypass grafts.

Acenocoumarol↗
PubMed2005

Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants.

OBJECTIVE: Vitamin K is an essential cofactor for the synthesis of several blood coagulation factors. It has been suggested that the apolipoprotein E (ApoE) genotype has profound effects on vitamin K status. Therefore, we investigated whether this common genetic polymorphism influenced dose requirements and effects of coumarin anticoagulants. METHODS: We did a cohort study in 1637 patients from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon. RESULTS: To attain the same level of anticoagulation, patients with genotype epsilon4/epsilon4 and genotype epsilon3/epsilon4 required respectively 3.4 mg (95%CI: -6.0 to -0.9) and 0.8 mg (95%CI: -1.6 to 0.1) acenocoumarol per week less than patients with genotype epsilon3/epsilon3. Patients homozygous for the epsilon2 allele required 3.5 mg (95%CI: 0.1 to 6.9) acenocoumarol per week more than patients with genotype epsilon3/epsilon3. The acenocoumarol maintenance dose showed a gene dose effect of the epsilon4 allele, but not of the epsilon2 allele. No significant dose difference was observed for phenprocoumon, possibly because of low numbers. CONCLUSION: The ApoE genotype affects the dose requirements of acenocoumarol.

Acenocoumarol↗
PubMed2000

Abrupt versus gradual withdrawal of vitamin K antagonist treatment in patients with venous thromboembolic disease: assessment of hypercoagulability and clinical outcome.

BACKGROUND: It is yet unclear whether vitamin K antagonist treatment should be stopped abruptly or gradually after an episode of venous thromboembolism. The mode of withdrawal might influence a potential development of a hypercoagulable state, which could influence the risk for recurrent disease. METHODS: We prospectively studied 37 consecutive patients in whom acenocoumarol was discontinued either abrupt (18) or gradually (19) (2/3 and 1/3 of the initial dose for one week). Blood sampling was performed at various time points up to 18 days after complete withdrawal and was analysed for INR, prothrombin fragment F1 + 2 and D-dimer. All patients were clinically followed-up for the assessment of the association between hypercoagulability and occurrence of disease such as recurrent venous thromboembolism or malignancy. RESULTS: An approximately fourfold increase was observed (median increase from 0.3 to 1.3 nmol/l) in the F1 + 2 levels after both abrupt and gradual withdrawal and in the D-dimer concentrations in the abrupt withdrawal group (0.10 to 0.44 mg/l), while those in whom acenocoumarol was discontinued gradually showed a less pronounced increase of the D-dimer levels (0.11 to 0.29 mg/L) (not significant). During follow-up one recurrent venous thromboembolic event occurred in each group, and a diagnosis of cancer was made four times. All these patients had the highest D-dimer concentrations measured in the entire study group. CONCLUSIONS: This study indicates the potential for a hypercoagulable state after acenocoumarol discontinuation, which was not prevented by tapering the acenocoumarol dose. D-dimer, measured 2 to 3 weeks after acenocoumarol withdrawal, might be an important tool to identify patients at risk for recurrent venous thromboembolism and/or for the presence of an underlying malignancy.

Acenocoumarol↗
PubMed2002

Initiation of oral anticoagulant therapy in orthopedic and surgical patients: an algorithm compared with routine dosing.

Oral anticoagulant therapy is initiated in most hospitals in The Netherlands by clinicians who routinely dose oral anticoagulants (without using an algorithm). This may explain the low proportion of patients leaving the hospital stabilized. To test this hypothesis this study compared the dosing of acenocoumarol in orthopedic and surgical patients using an algorithm with routine dosing. Because of the routine administration of low molecular weight heparin for at least the first 5 days of acenocoumarol therapy, the study focused on supratherapeutic INR-values during this period. The study included 103 patients and was performed on orthopedic surgery and general surgery wards of a Dutch hospital over 5 months. The patients received acenocoumarol as an oral anticoagulant to prevent venous thromboembolism after general of orthopedic surgery. Patients were randomized into a group routinely dosed by physicians (n=54) and a group dosed using a dosing algorithm (n=49). A patient was defined as stable if he had two consecutive INR values within the range of 2-3 during hospitalization with the first (of the two consecutive INR values within range) having been measured on day 5 or later. The groups did not differ significantly in proportion of patients stabilized, time to stabilization, or length of hospitalization. In the first period (days 1-5) the routine dosing group had significantly more INR values above therapeutic range than the algorithm group, while the algorithm group had more INR values below the therapeutic range. There were two bleeding episodes in the routine dosing group and none in the algorithm group. Despite the lack of differences in stabilization between the two groups, this study suggests an advantage of dosing acenocoumarol using an algorithm in a study population consisting of prophylactically treated, mostly elderly orthopedic patients. The algorithm provides a safe dosing schedule for elderly postoperative patients who use low molecular weight heparin and NSAIDs concomitantly and are thus at high risk for bleeding complications.

Acenocoumarol↗
PubMed1996

Characterization of site I on human serum albumin: concept about the structure of a drug binding site.

Human serum albumin (HSA) possesses at least three sites or areas for high-affinity binding of drugs. Of these sites, site I was investigated by series of ultrafiltration and equilibrium dialysis experiments. Three ligands, acenocoumarol, dansyl-L-asparagine (DNSA) and n-butyl p-aminobenzoate (n-butyl p-ABE) were employed as marker ligands. Each ligand binds to a single high-affinity site on HSA, and binding studies with different pairs of the ligands revealed independent high-affinity binding. Preliminary displacement studies performed with the typical site I binding drugs warfarin, phenylbutazone and iodipamide showed different displacement patterns of the three marker ligands. These studies were followed by stringent competition experiments involving all possible combinations of the three test ligands themselves and of these and the three marker ligands. On the basis of the results obtained it seems that the acenocoumarol and DNSA binding regions correspond to the warfarin and azapropazone binding regions, respectively, of site I reported by others (Fehske, Schläfer, Wollert and Müller (1982) Mol. Pharmacol. 21, 387-393). The new binding region, represented by n-butyl p-ABE, is probably located adjacent to the acenocoumarol binding region but apart from that of DNSA. We have elaborated a model for binding site I in which we propose novel nomenclatures, region Ia, Ib, and Ic for the acenocoumarol, DNSA and n-butyl p-ABE binding regions, respectively. Furthermore, the relation between these regions and the high-affinity binding sites for other drugs have been discussed.

Acenocoumarol↗
PubMed2000

Prediction of pharmacokinetic drug/drug interactions from In vitro data: interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oral anticoagulants.

CYP2C9 is involved in the metabolism of the oral anticoagulants warfarin, phenprocoumon, and acenocoumarol. It is also responsible for the 5'-hydroxylation of the nonsteroidal anti-inflammatory drug lornoxicam. Therefore, lornoxicam and the oral anticoagulants are potential inhibitors of their metabolism. Their inhibitory potency was investigated in microsomes from six human livers. An approach to predict pharmacokinetic interactions of lornoxicam from in vitro inhibition data was developed. Where possible, the forecasts were verified by comparison with data from clinical interaction studies. The following increases in steady-state plasma concentrations or areas under the plasma concentration-time curve of the oral anticoagulants by concomitant lornoxicam medication were predicted (values in parentheses are for healthy volunteers): (S)-warfarin, 1. 58-fold (1.32-fold for racemate); racemic-acenocoumarol, 1.28-fold (1.09-fold); (R)-acenocoumarol, 1.10-fold (1.0-fold); racemic-phenprocoumon, 1.11-fold (1.18-fold); and (S)-phenprocoumon, 1.13-fold (1.24-fold). Lornoxicam 5'-hydroxylation was competitively inhibited in vitro by both phenprocoumon (K(i) = 1.2 +/- 0.4 microM) and acenocoumarol (K(i) = 5.5 +/- 3.5 microM). The present results indicate that relatively close predictions of the interactions of lornoxicam with oral anticoagulants from in vitro data are possible under the assumption that hepatic lornoxicam concentrations are similar to its total plasma concentrations. The degree of pharmacokinetic interactions exhibited by oral anticoagulants and lornoxicam is dependent on the respective contribution of CYP2C9 to their total clearance.

Acenocoumarol↗
PubMed2003

[Use of oral anticoagulants in patients discharged with atrial fibrillation in 2000].

INTRODUCTION AND OBJECTIVES: Although there is consensus about the use of oral anticoagulants to prevent thrombi and embolisms in most patients with atrial fibrillation, this treatment is underused in actual practice. Our objective was to determine and analyze the use of acenocoumarol in patients diagnosed as having atrial fibrillation at discharge. PATIENTS AND METHOD: Between January and July 2000, we retrospectively studied 501 consecutive patients with a diagnosis of atrial fibrillation. We recorded whether they were discharged with or without oral anticoagulation treatment. RESULTS: We identified 482 patients with at least one associated thromboembolic risk factor, who comprised the study population. Mean age was 79.3 years, and 33.3% of the patients were men. Forty-six percent were discharged with acenocoumarol, and 36.3% with platelet antiaggregants. Twenty-three percent had a known contraindication for acenoroumarol. Nearly 62% of the patients without contraindications for anticoagulation received treatment with acenocoumarol. Multivariate analysis showed that rheumatic mitral valve disease, previous stroke or thromboembolism and dilated left atrium were associated with a higher probability of receiving anticoagulant treatment. Age over 75 years was associated with a lower likelihood of receiving acenocoumarol. CONCLUSIONS: Oral anticoagulation was given in an inadequate proportion of patients who were discharged from a secondary-level hospital with atrial fibrillation and no contraindications. Rheumatic mitral valve disease, previous stroke or thromboembolism, and dilated left atrium were associated with a higher probability of anticoagulant treatment. Age over 75 years was related with less frequent use of this therapy.

Administration, Oral↗
PubMed2004

Management of oral anticoagulant in clinical practice: a retrospective study of 187 patients.

Oral anticoagulant (OA) therapy is widely used in elderly patients because of the increase of indications with age (venous thromboembolism and atrial fibrillation). A particularity of France is to administer three different OAs (warfarin and more often fluindione or acenocoumarol). In an attempt to assess the particularities of managing all three OAs in elderly patients in clinical practice, we studied the modalities of anticoagulation of 187 consecutive OA therapy patients (mean age = 74.4 years) hospitalized in an Internal Medicine department (95 patients on OA at admission and 92 patients initiated on OA during hospitalization). Patients aged 75 years or older more often required a low dosage of OA than those aged younger than 75, irrespective of the OA (warfarin and more often fluindione or acenocoumarol). Ambulatory patients aged 75 years or older were more susceptible to receive acenocoumarol than were ambulatory patients younger than 75 years (respectively 30/67 vs 8/28, respectively), whereas fluindione was prescribed at the same frequency in ambulatory patients and hospitalized patients, regardless of age group (> or =75: 32/67; <75: 19/28). In hospitalized patients with OA induction, fluindione was prescribed as often in patients younger than 75 than in patients aged 75 years or older (40/47 vs 35/45, respectively). On admission, international normalized ratio was in the target range in 26 of the 95 patients (27.4%) and was >3 in 51 of the 95 patients (51.6%). OA therapy was stopped during hospitalization in 35 patients (36.8%). In conclusion, we have a picture of the practice of anticoagulation with three different OA therapies. Although it is usually recommended to prescribe long half-time OA therapy (2), it appears that short half-time therapy such as acenocoumarol still represents an important number of OA prescriptions in France, especially in ambulatory and elderly patients. International normalized ratio is not in the target range as often as expected in clinical practice, and elderly patients require specific modalities of OA therapy management, such as half dose initiation, use of long-half-life OA, and close monitoring.

Administration, Oral↗
PubMed2005

Main comedications associated with major bleeding during anticoagulant therapy with coumarins.

OBJECTIVE: To study the main comedications associated with major bleeding during anticoagulant therapy with coumarins in a non-selected population under everyday circumstances. METHODS: The study population for this retrospective cohort study included all new users of phenprocoumon or acenocoumarol aged 40-80 years, during the period 1992-2000 in the PHARMO Record Linkage System. All patients were followed until the last dispensing of phenprocoumon or acenocoumarol, the first bleeding complication requiring hospitalization, death, or the end of the study period. The number of days on coumarins alone and the number of days on coumarins in combination with several potentially interactive drugs during follow-up were determined for each patient. RESULTS: The inclusion criteria of this study were met by 19,935 new users of phenprocoumon or acenocoumarol. During follow-up, 552 patients were hospitalized for bleeding. Of all potentially interactive drugs started during anticoagulant therapy by at least 50 patients and with at least five bleedings, antibacterial drugs were associated with a four to seven times increased risk of bleeding. Among non-steroidal anti-inflammatory drugs, naproxen had the highest relative risk. Antithrombotic salicylates and tramadol were associated with a three times increased risk of bleeding. CONCLUSION: Antibacterial drugs, non-steroidal anti-inflammatory drugs, antithrombotic salicylates and tramadol were the main potentially interactive drugs associated with major bleeding during anticoagulant therapy with coumarins under everyday circumstances.

Acenocoumarol↗
PubMed2005

Selective binding of coumarin enantiomers to human alpha1-acid glycoprotein genetic variants.

Coumarin-type anticoagulants, warfarin, phenprocoumon and acenocoumarol, were tested for their stereoselective binding to the human orosomucoid (ORM; AGP) genetic variants ORM 1 and ORM 2. Direct binding studies with racemic ligands were carried out by the ultrafiltration method; the concentrations of free enantiomers were determined by capillary electrophoresis. The binding of pure enantiomers was investigated with quinaldine red fluorescence displacement measurements. Our results demonstrated that all investigated compounds bind stronger to ORM 1 variant than to ORM 2. ORM 1 and human native AGP preferred the binding of (S)-enantiomers of warfarin and acenocoumarol, while no enantioselectivity was observed in phenprocoumon binding. Acenocoumarol possessed the highest enantioselectivity in AGP binding due to the weak binding of its (R)-enantiomer. Furthermore, a new homology model of AGP was built and the models of ORM 1 and ORM 2 suggested that difference in binding to AGP genetic variants is caused by steric factors.

Acenocoumarol↗
PubMed2005

Long-term treatment of deep venous thrombosis with a low molecular weight heparin (tinzaparin): a prospective randomized trial.

OBJECTIVES: Evaluation of the effectiveness and safety of the low molecular weight heparin (LMWH) tinzaparin versus unfractionated heparin (UFH) followed by acenocoumarol in proximal deep venous thrombosis (DVT). DESIGN: Prospective, randomized clinical trial. MATERIAL AND METHODS: Consecutive patients (n=108) with acute leg DVT, confirmed by duplex, were randomized to either tinzaparin alone or UFH and acenocoumarol for 6 months. Patients were evaluated ultrasonographically at entry, 1, 3, 6 and 12 months. Thrombus regression, reflux distribution and the incidence of complications were studied. A cost-analysis, comparing the two treatments, was performed. RESULTS: The overall incidence of major events (mortality, DVT recurrence, pulmonary embolism, major bleeding, heparin-induced thrombocytopenia) was significantly different (p=0.035) in favor of tinzaparin (7 versus 17 events). The ultrasonographic clot volume score (an index of recanalization) decreased significantly in both treatment groups. However, tinzaparin produced significantly more extended overall recanalization from 3 months onwards (p<0.02). Thrombus regression was equivalent or in favor of tinzaparin in the different DVT subgroups and venous segments, but the statistical significance varied. Reflux showed non-significant differences overall or in subgroups. A cost-analysis resulted in favor of LMWH. CONCLUSIONS: A fixed daily dose of tinzaparin for 6 months was at least as effective and safe as UFH and acenocoumarol. Regarding major events and recanalization, there was a significant benefit in favor of tinzaparin. Long-term DVT treatment with tinzaparin could represent an alternative to conventional treatment.

Acenocoumarol↗
PubMed2004

A thromboembolic predisposition and the effect of anticoagulants on migraine.

OBJECTIVE: To investigate the presence of thromboembolic risk factors and the effect of low-dose acenocoumarol therapy on migraine in patients who spontaneously reported a reduction of their migraine attacks during previous therapeutic use of anticoagulants. BACKGROUND: The positive effect of anticoagulants on migraine has been described in case reports and observational studies. It remains unclear whether this concerns only a select group of migraineurs with certain common characteristics. METHODS: In 4 migraineurs with a self-reported reduction of attack frequency during previous use of anticoagulants (international normalization ratio [INR], 2.5:4.0), the presence of thromboembolic risk factors and the effect of low-dose acenocoumarol therapy (INR, 1.5:2.0) on migraine attacks were prospectively investigated in an open study. RESULTS: All patients had one or more thromboembolic risk factors. Two patients, both with factor V Leiden heterozygosity, experienced a clear improvement of migraine during low-dose acenocoumarol therapy. CONCLUSIONS: Our findings support the hypothesis that migraine, as a phenotype, has different underlying mechanisms, amongst which a thromboembolic tendency. In this group of patients, oral anticoagulants may be a suitable form of migraine prophylaxis, but this needs further clinical investigation.

Acenocoumarol↗
PubMed1996

[Risk and prevention of thromboembolism complications in gynecologic malignancies].

Gynecologic malignancies are often associated with deep vein thrombosis and pulmonary embolism, even before treatment is begun. But such complications also happen during treatment, also if thromboembolism prophylaxis is performed. The incidence of pulmonary embolism before treatment was investigated using scintigraphy. In a retrospective and in a prospective randomized trial, various methods of thromboembolism prophylaxis were evaluated during primary or postoperative radiation therapy. Pulmonary embolism was present in 11.9% of the patients admitted with uterine malignancy. Retrospectively, there were deep vein thromboses in 6.8%, pulmonary embolisms in 3.8% and bleeding complications in 5.3% of the patients receiving thromboembolism prophylaxis with acenocoumarol during radiation therapy of cervical and endometrial cancer. In the prospective study, deep vein thromboses occurred in 1.5%, pulmonary embolisms in 5.9% and bleedings in 2.2%, with both the LMW heparin and the acenocoumarol groups presenting similar results. Thromboembolism is a frequent paraneoplasia of uterine malignancies. The prevention of thromboembolic complications during radiation therapy of uterine malignancies is efficacious and safe using either LMW heparin or acenocoumarol.

Acenocoumarol↗
PubMed2005

A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk.

BACKGROUND: A C1173T polymorphism in intron 1 of the VKORC1 gene has been claimed to determine the interindividual variability in the response to vitamin K antagonist therapy (VKA), but it is unknown whether it also influences bleeding risk. We aimed to confirm the relationship between C1173T status and phenprocoumon or acenocoumarol use, and to examine the risk of severe bleeding for the various genotypes. METHODS AND FINDINGS: We studied this in a case-control study of 110 patients who bled during VKA therapy and 220 control patients free of bleeding under the same therapy. To achieve the same target INR, CT genotype and TT genotype control patients required less phenprocoumon (CC genotype 2.9 mg/d [95% confidence interval (CI): 2.6-3.2], CT genotype 2.6 mg/d [95% CI: 2.1-3.1], TT genotype 1.4 mg/d [95 % CI: 1.1-1.7]) or acenocoumarol (CC genotype 3.2 mg/d [95% CI: 2.9-3.5], CT genotype 2.3 mg/d [95% CI: 2.1-2.5], TT genotype 1.7 mg/d [95% CI: 1.3-2.1]) than CC genotype control patients. Compared with CC genotype individuals, carriers of at least one T allele had an increased risk of bleeding in the phenprocoumon users (crude odds ratio = 2.6, 95% CI: 1.2-5.7), but not in acenocoumarol users (crude odds ratio = 1.2, 95% CI: 0.6-2.3). CONCLUSION: These findings encourage taking further steps towards the evaluation of the use of VKORC1 genetic testing for bleeding prevention in individuals who receive VKA therapy.

Acenocoumarol↗
PubMed2002

Determination of coumarin-type anticoagulants in human plasma by HPLC-electrospray ionization tandem mass spectrometry with an ion trap detector.

BACKGROUND: Coumarin-type anticoagulants are used for the long-term treatment and prevention of thromboembolic disorders. The identification of these drugs is crucial in patients with an increased prothrombin time of unknown origin. The aim of this study was to develop a sensitive and specific method for the simultaneous determination of phenprocoumon, acenocoumarol, and warfarin in human plasma by HPLC-electrospray ionization tandem mass spectrometry. METHODS: After addition of the internal standard, p-chlorowarfarin, plasma samples were extracted using Oasis MCX solid-phase extraction cartridges. The compounds were separated on a Symmetry C18 column (Waters) with a mobile phase of acetonitrile-1 g/L formic acid (75:25 by volume) at a flow rate of 0.5 mL/min. RESULTS: Extraction and separation of the three drugs and the internal standard were accomplished in 9 min. The overall extraction efficiency was >89% for all three compounds. The limits of detection were 1 microg/L for phenprocoumon and warfarin and 10 microg/L for acenocoumarol. Regression analysis of the calibration data revealed good correlation (r(2) >or=0.995) for all compounds. Within-run accuracies for quality-control samples were +/- 1% to 7% of the target concentration, with CVs <9%. CONCLUSIONS: The proposed method enables the unambiguous identification and quantification of phenprocoumon, warfarin, and acenocoumarol in both clinical and forensic specimens. This method combines a new, rapid solid-phase extraction procedure with an extremely fast chromatographic analysis, which is especially advantageous for clinical laboratories.

4-Hydroxycoumarins↗
PubMed1988

4-Hydroxycoumarin oral anticoagulants: pharmacokinetics-response relationship.

The blood coagulating factors II and VII and prothrombin times (Thrombotest) were followed during a dosage interval (= 24 h) in patients on acenocoumarol (n = 6) and on phenprocoumon (n = 6) therapy. The patients were on stable anticoagulation (%TT: 7-13%) for at least 6 months. The study was performed to investigate the concentration-response relationship of the 4-hydroxycoumarin-type oral anticoagulants. The three parameters were stable during the 24-h interval for patients on phenprocoumon therapy. Patients on acenoumarol showed fluctuations in their factor VII levels; peak activities were observed at about 2 h, trough activities at about 16 h after acenocoumarol intake. Factor II and Thrombotest activities were stable. Plasma levels of phenprocoumon were stable during daytime whereas acenocoumarol levels declined exponentially (t1/2 about 12 h). The results indicate the oral anticoagulants to exhibit a concentration-response relationship common to drug-receptor interactions. The results also suggest that for stable and long-lasting anticoagulant therapy oral anticoagulants with half-lives beyond the dosage interval (t1/2 greater than 24 h) should be preferred.

4-Hydroxycoumarins↗
PubMed2002

The potential interaction between oral anticoagulants and acetaminophen in everyday practice.

OBJECTIVE: The drug-drug interaction between oral anticoagulants (especially warfarin) and acetaminophen has been described, but evidence is conflicting and evidence for a similar interaction between acenocoumarol or phenprocoumon and acetaminophen is limited. Therefore, a study was performed to determine the influence of acetaminophen on oral anticoagulation with acenocoumarol or phenprocoumon in everyday practice. METHOD: Included were patients from two Dutch anticoagulant clinics who had used oral anticoagulants for at least three months and who started with acetaminophen (case group) or benzodiazepines (control group). RESULTS: Fifty-four patients were included who had a first prescription of acetaminophen in their pharmacy record (during oral anticoagulant use) and twenty patients with a first prescription of a benzodiazepine (during oral anticoagulant use). The INR (International Normalized Ratio) difference before and after acetaminophen use was not statistically significant between the two groups and showed no dose dependency. CONCLUSION: These data do not demonstrate that acetaminophen, in the dosages used in everyday practice, has a clinically relevant influence on the INR in patients using acenocoumarol or phenprocoumon.

Acetaminophen↗
PubMed2003

Pharmacogenetics of oral anticoagulants.

There is wide interindividual variation in oral anticoagulant dose requirement, which is partly genetically determined. Several cytochrome P450s contribute to oxidative metabolism of oral anticoagulants. The most important of these is CYP2C9, which hydroxylates the S-enantiomers of warfarin, acenocoumarol and phenprocoumon with high catalytic activity. In at least eight separate clinical studies, possession of the CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, has been associated with a significant decrease in a mean warfarin dose requirement. Several studies also suggest that possession of a CYP2C9 variant allele is associated with an increased risk of adverse events, such as bleeding. Possession of the CYP2C9*3 variant also appears to be associated with a low acenocoumarol dose requirement. Other genetic factors, such as polymorphisms in the cytochromes P450 that metabolize the R-enantiomers of warfarin and acenocoumarol, may also be relevant to anticoagulant dose. The molecular basis of anticoagulant resistance where a higher than normal dose of anticoagulant is required remains unclear, but could be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to an abnormality in the target enzyme vitamin K epoxide reductase (pharmacodynamic resistance).

Administration, Oral↗