Disease relevance of ACENOCOUMAROL

• METHODS: Patients with a first episode of idiopathic proximal deep venous thrombosis who had completed three months of oral anticoagulant therapy (with warfarin, in 97 percent of the cases and acenocoumarol in 3 percent) were randomly assigned to the discontinuation of oral anticoagulants or to their continuation for nine additional months [1].
• Patients with proximal-vein thrombosis require initial treatment with full-dose heparin, which can safely be combined with acenocoumarol therapy [2].
• Body weight explained 5% of acenocoumarol pharmacodynamic variability, whereas the NQO1*2 allele had no significant effect [3].
• To evaluate the applicability of a well-established model of tissue factor-dependent coagulation for defining anticoagulant potency, we investigated the effects of acenocoumarol in experimental human endotoxemia [4].
• During the treatment and surveillance period, 6 of the 50 patients (12%) who received acenocoumarol and 8 of the 50 patients (16%) who received enoxaparin had new episodes of venous thromboembolism confirmed by objective testing (p = 0.6; 95% CI for the difference: -19.5 to 11.5) [5].

High impact information on ACENOCOUMAROL

• In a randomized, double-blind study we compared the efficacy and safety of continuous intravenous heparin plus acenocoumarol with the efficacy and safety of acenocoumarol alone in the initial treatment of outpatients with proximal-vein thrombosis [2].
• Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis [2].
• Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity [6].
• The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose [6].
• The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 -1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy [6].

Chemical compound and disease context of ACENOCOUMAROL

• The incidence of venous thrombosis in patients with indobufen was 11% and in those treated with acenocoumarol 9% [7].
• METHODS: A double-blind, randomized, placebo-controlled study was conducted evaluating nabumetone (1-2 g daily for up to 4 weeks) in osteoarthritis patients with thromboembolic risk previously stabilized on acenocoumarol [8].
• Although the patient received acenocoumarol (Sintrom; Novartis Pharma, Vienna, Austria) and acetylsalicylic acid (Aspisol; Bayer AG, Leverkusen, Germany) as usual, ROTEG and the PFA-100 detected hypercoagulability while routine coagulation screening tests showed hypocoagulability [9].
• Despite anti-coagulation with acenocumarol, treatment with statins and angiotensin II receptor blocking agents and an excellent preservation of renal function, the patient presented with a second episode of myocardial infarction at 9 years post-transplant [10].
• Severe hemorrhage: nine episodes, six in the acenocoumarol group and three in the triflusal group [11].

Biological context of ACENOCOUMAROL

• In the second study, the oral pharmacokinetics of acenocoumarol was investigated in 6 subjects (*1/*1 [n = 3] and *1/*3 [n = 3]) [12].
• The effect of acenocoumarol on thrombotest activity was significantly weaker at 24 and 31 hours [13].
• Pharmacogenetics of acenocoumarol pharmacodynamics [3].
• OBJECTIVE: The aim of this study was to investigate the respective contribution of the different cytochrome P450 (CYP) 2C9 genetic polymorphisms to the interindividual variability of acenocoumarol pharmacodynamic response [3].
• BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 2C9 is one of the major CYP enzymes involved in the biotransformation of drugs, among others, the oral anticoagulant acenocoumarol [12].

Anatomical context of ACENOCOUMAROL

• From 1987 until 1991 a large prospective randomized multicentre study was performed in The Netherlands, Germany and Switzerland entitled CABADAS (Prevention of Coronary Artery Bypass graft occlusion by Aspirin, Dipyridamole, and Acenocoumarol/Phenprocoumon Study) [14].
• A female patient is described who developed skin and subcutaneous fat necrosis on two occasions after intake of acenocoumarol [15].
• METHODS: One hundred fifty-eight patients with symptomatic DVT of the lower limbs confirmed by means of duplex ultrasound scan were randomized to receive 3 to 6 months' treatment with nadroparine calcium or acenocoumarol [16].
• In addition, we incubated acenocoumarol enantiomers with pooled human microsomes with and without E7070 and measured the in vitro plasma protein binding of acenocoumarol after incubation with E7070 [17].
• After cardiac valve replacement patients were blindly randomized into two groups, both receiving aspirin (330 mg) and dipyridamole (75 mg) twice daily and the oral anticoagulant acenocoumarol (Sintrom) [18].

Associations of ACENOCOUMAROL with other chemical compounds

• In all study groups phenprocoumon outperformed acenocoumarol by 11.6% (95% confidence interval [CI], 6.6%-16.5%) [19].
• METHODS: We randomly assigned 1279 patients 3 days after total hip replacement surgery to fixed-dose subcutaneous low-molecular-weight heparin (reviparin sodium, 4200 anti-Xa IU) or adjusted-dose oral anticoagulant (international normalized ratio, 2-3; acenocoumarol) for a 6-week period [20].
• The intermediate-risk group included patients with risk factors or age >60 years: 242 received the cyclooxygenase inhibitor triflusal, 237 received acenocumarol, and 235 received a combination of both [21].
• CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences [22].
• Coronary angiography showed an average patency rate per patient of 84% with ticlopidine and of 82% with acenocoumarol [23].

Gene context of ACENOCOUMAROL

• The major enzyme involved in the metabolism of acenocoumarol in man is CYP2C9 [17].
• Also, drugs interfering with CYP1A2 and CYP2C19 may potentiate acenocoumarol anticoagulant therapy [24].
• 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 [25].
• 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 [26].
• There exists a genetic factor that determines a decreased level of two vitamin-K dependent glycoproteins, namely protein C and protein S. We present the case of an obese woman that developed an extensive cutaneous necrosis while receiving acenocoumarol for a deep venous thrombosis [27].

Analytical, diagnostic and therapeutic context of ACENOCOUMAROL

• We performed a case-control study among previously stable outpatients of an anticoagulation clinic using phenprocoumon or acenocoumarol to identify changes in the use of potentially interacting drugs related to overanticoagulation [28].
• In a multi-centre (n = 12), observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n = 280), acenocoumarol (n = 226), fluindione (n = 99), warfarin (n = 63) and phenindione (n = 2) to a non-exposed control group (n = 1,094) [29].
• The study was carried out at the Groningen Outpatient Thrombosis Service. A retrospective cohort study among patients who received both acenocoumarol and one of the NSAIDs under study was performed [30].
• As soon as the diagnosis of DVT was confirmed by phlebography, 101 were randomly assigned to receive LMWH (nadroparin) for secondary prophylaxis and 101 to receive OA (acenocoumarol) [31].
• Three patients receiving chronic therapy with the oral anticoagulant acenocoumarol experienced bleeding and/or a prolonged prothrombin time after treatment with E7070 at a dose of 700 mg/m2 given as a 1-h infusion [17].

References