acenocoumarol and Hemorrhage

Vitamin K antagonist (VKA) is a commonly prescribed anticoagulant with a narrow therapeutic window. Genetic polymorphisms account for high VKA dosage variability. Hence, we performed an updated meta-analysis of all randomized clinical trials (RCTs) comparing genotype-guided VKA versus standard dosing algorithms. We conducted a systematic search of electronic databases from inception to October 2017 for all RCTs. The primary outcome was the percentage of time in therapeutic range (TTR). Secondary outcomes were international normalized ratio >4, major and all bleeding events, thromboembolism, adverse and serious adverse events, and all-cause mortality. We calculated the weighted mean difference for the primary outcome and risk ratio (RR) for secondary outcomes using a random-effect model. We included 20 RCTs and analyzed a total of 5,980 adult patients. Our pooled analysis showed greater improvement in TTR for the genotype-guided group in comparison with the standard group (mean difference 3.41%, 95% confidence interval [CI] 0.71 to 6.10, p = 0.01). In addition, there were significant reductions in major and all bleeding events ((RR 0.35, 95% CI 0.20 to 0.63, p = 0.0004) and (RR 0.79, 95% CI 0.66 to 0.95, p = 0.01), respectively). However, there were no significant differences between the groups for international normalized ratio >4 (RR 0.89, 95% CI 0.80 to 1.00, p = 0.06), thromboembolism (RR 0.81, 95% CI 0.56 to 1.17, p = 0.25), serious adverse events (RR 0.79, 95% CI 0.61 to 1.03, p = 0.08), any adverse events (RR 0.94, 95% CI 0.88 to 1.01, p = 0.07), or all-cause mortality (RR 0.73, 95% CI 0.32 to 1.66, p = 0.46). In conclusion, genotype-guided VKA dosing can improve the TTR and reduce the risk for bleeding episodes, in comparison with standard dosing algorithms.

Topics: Acenocoumarol; Anticoagulants; Cause of Death; Genotype; Hemorrhage; Humans; International Normalized Ratio; Mortality; Odds Ratio; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenprocoumon; Thromboembolism; Vitamin K; Warfarin

The periprocedural management of patients receiving chronic therapy with oral anticoagulants (OACs), including vitamin K antagonists (VKAs) such as warfarin and direct OACs (DOACs), is a common clinical problem. The optimal perioperative management of patients receiving chronic OAC therapy is anchored on four key principles: (i) risk stratification of patient-related and procedure-related risks of thrombosis and bleeding; (ii) the clinical consequences of a thrombotic or bleeding event; (iii) discontinuation and reinitiation of OAC therapy on the basis of the pharmacokinetic properties of each agent; and (iv) whether aggressive management such as the use of periprocedural heparin bridging has advantages for the prevention of postoperative thromboembolism at the cost of a possible increase in bleeding risk. Recent data from randomized trials in patients receiving VKAs undergoing pacemaker/defibrillator implantation or using heparin bridging therapy for elective procedures or surgeries can now inform best practice. There are also emerging data on periprocedural outcomes in the DOAC trials for patients with non-valvular atrial fibrillation. This review summarizes the evidence for the periprocedural management of patients receiving chronic OAC therapy, focusing on recent randomized trials and large outcome studies, to address three key clinical scenarios: (i) can OAC therapy be safely continued for minor procedures or surgeries; (ii) if therapy with VKAs (especially warfarin) needs to be temporarily interrupted for an elective procedure/surgery, is heparin bridging necessary; and (iii) what is the optimal periprocedural management of the DOACs? In answering these questions, we aim to provide updated clinical guidance for the periprocedural management of patients receiving VKA or DOAC therapy, including the use of heparin bridging.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Aortic Valve; Atrial Fibrillation; Elective Surgical Procedures; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Perioperative Care; Phenprocoumon; Prothrombin; Randomized Controlled Trials as Topic; Societies, Medical; Thromboembolism; Thrombosis; United States; Vitamin K; Warfarin

Numerous factors affect the response to vitamin K antagonists (VKA) including age, dietary vitamin K, other drugs, pharmacogenetics, and disease states. In antithrombotic guidelines, fever is mentioned as a factor that may increase response to VKA. The purpose of this article is to review the available evidence regarding the effect of fever on response to VKA, and to discuss possible mechanisms of this effect. We performed a search of the English literature from 1943 to June 2014, using the key words fever AND warfarin, acenocoumarol, phenprocoumon, coumarin anticoagulants and VKA; fever AND vitamin K dependent clotting factors II, VII, IX, and X. One animal investigation and 6 studies in humans suggest fever increases response to VKA, but one study did not find a significant effect. The magnitude of this effect is variable. Possible mechanisms for the increased effect of VKA associated with fever are increased catabolism of vitamin K dependent clotting factors, decreased vitamin K intake, and inhibition of VKA metabolism. More rigorous studies are needed to confirm that fever increases response to warfarin and other VKA.

Topics: Acenocoumarol; Animals; Anticoagulants; Clinical Trials as Topic; Coumarins; Fever; Hemorrhage; Humans; International Normalized Ratio; Phenprocoumon; Rats; Risk Factors; Treatment Outcome; Vitamin K; Warfarin

Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of the VKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 and VKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect of VKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anticoagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

Topics: Acenocoumarol; Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Biotransformation; Blood Coagulation; Cytochrome P-450 CYP2C9; Drug Interactions; Drug Monitoring; Hemorrhage; Humans; International Normalized Ratio; Mixed Function Oxygenases; Pharmacogenetics; Phenprocoumon; Polymorphism, Genetic; Risk Assessment; Vitamin K Epoxide Reductases; Warfarin

Coumarins are broadly employed in clinical practice and should therefore belong to the group of 'well known' drugs. The present review will deal with some concepts of anticoagulant therapy: the role of vitamin K in the synthesis of functional coagulation factors, some clinically relevant pharmacokinetic aspects of coumarins, the management of oral anticoagulant therapy with special emphasis on the laboratory monitoring, and the most frequent complication, bleeding.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Coumarins; Drug Interactions; Hemorrhage; Humans; Phenprocoumon; Vitamin K

Administration of vitamin K is the common mode of treatment in excessively anticoagulated patients. However, patient's response to vitamin K varies, depending on the vitamin K dose and the route of administration. Another potential source of variation is the pre-treatment INR which has not been accounted for in most previous studies. In the present study the effect of baseline INR on the response to a single dose of intravenous vitamin K (0.5 mg) was studied in 95 episodes of excessively anticoagulated patients (n = 76). In 67 episodes of moderately excessive baseline INR (6-10) mean INR declined from 8.0 +/- 1.2 to 2.6 +/- 0.9 at 24 hours, 59/67 (88%) responding within the first 12 hours and not requiring a second dose. In contrast, in 28 episodes with highly excessive baseline INR (> 10) response was slower; mean INR declining from 13.6 +/- 2.7 to 4.0 +/- 2.1 at 24 hours. In 14/28 of these episodes, patients failed to respond to vitamin K in the first 12 hours and required a second vitamin K dose. We conclude that INR at presentation affects the response to vitamin K and that this INR value should be considered in determining appropriate vitamin K doses.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Drug Overdose; Female; Follow-Up Studies; Hemorrhage; Humans; Infusions, Intravenous; International Normalized Ratio; Male; Middle Aged; Safety; Treatment Outcome; Vitamin K; Warfarin

Vitamin K antagonists (VKA) decrease the synthesis of the active forms of four coagulation factors (factors II, VII, IX, X) and three inhibitors (proteins C, S, Z). There are VKA having a short half life (Sintrom, Pindione) and VKA having a long half life (Apegmone, Previscan, Coumadine). The treatment is monitored by the INR which in the majority of the indications must range between two and three. The first INR is usually performed 36 to 72 h after starting the treatment. There are a number of drug interactions. The rate of major bleedings range from 1.1 to 4.9 for 100 patient-year according to the published studies. Since around 600,000 patients are treated by VKA in our country, the absolute number of serious bleeding is high (> or = 17,000 per year). Anticoagulant clinics are structures aimed to instruct the patient and to advise the general practitioner to monitor the treatment, using computer assisted methods. It has been reported that these structures reduce the incidence of bleeding and of thrombotic events by 3 to 4 times.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Drug Interactions; Family Practice; Food; Hemorrhage; Humans; Patient Education as Topic; Phenindione; Thrombosis; Time Factors; Vitamin K; Warfarin

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Half-Life; Hemorrhage; Humans; International Normalized Ratio; Patient Selection; Phenprocoumon; Risk; Vitamin K; Warfarin

Oral anticoagulants are frequently prescribed during lactation. Because these drugs could affect the hemostasis of the newborn, we did a literature search to find out whether precautions should be taken. It appeared that acenocoumarol and warfarin are not detectable in human milk. Besides the usual daily supplementation of 25 micrograms vitamin K for every breast-fed infant, precautions are not necessary. Phenprocoumon, ethylbiscoumacetate and phenindione are excreted in human milk and could affect neonatal hemostasis.

Topics: Acenocoumarol; Anticoagulants; Breast Feeding; Ethyl Biscoumacetate; Female; Hemorrhage; Humans; Infant; Infant, Newborn; Milk, Human; Phenprocoumon; Warfarin

The evaluation and management of patients who sustain recurrent thromboembolic events while taking therapeutic anticoagulation have not been well characterized; moreover, there has been no systematic review or randomized trial focused on treating patients with recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) during anticoagulant treatment. Therefore, we developed a pilot trial to compare rivaroxaban plus aspirin versus acenocoumarol in patients with recurrent venous thromboembolism despite ongoing anticoagulation with rivaroxaban.. The study was a multicenter, randomized clinical trial. We randomly assigned patients with objectively documented recurrent venous thromboembolism to receive rivaroxaban (20 mg once a day) plus aspirin (300 mg once a day) or an adjusted dose of acenocoumarol. The study was designed to evaluate the incidence of recurrent thromboembolic events (recurrent ipsilateral or contralateral DVT, PE, ischemic stroke, and myocardial infarction) and hemorrhagic events.. A total of 58 patients were randomized: 28 were allocated to the rivaroxaban plus aspirin group and 30 to the acenocoumarol group. After 90 days of follow-up, three recurrent thromboembolic events (primary outcome) occurred in the acenocoumarol group - two DVTs and one ischemic stroke - and zero events in the rivaroxaban plus aspirin group (risk ratio [RR] 0.15; 95 % confidence interval [CI] 0.008-2.83; P = 0.20). Minor bleeding occurred in five patients in the acenocoumarol group and zero in the rivaroxaban plus aspirin group (RR 0.09; 95 % CI 0.005-1.68; p = 0.10). There was one non-fatal gastrointestinal major bleed in the rivaroxaban plus aspirin group.. In this pilot study, there were no significant differences in any outcome assessed; however, recurrent thromboembolic events and minor bleeding events occurred numerically less frequently in the rivaroxaban plus aspirin group. These data suggest the need to carry out more extensive randomized studies with sufficient statistical power to clarify these results.

Topics: Acenocoumarol; Anticoagulants; Aspirin; Hemorrhage; Humans; Ischemic Stroke; Pilot Projects; Pulmonary Embolism; Rivaroxaban; Venous Thromboembolism; Venous Thrombosis

Non-vitamin K antagonist oral anticoagulants (NOACs) have been proposed as an alternative to vitamin K antagonists (VKA) for atrial fibrillation (AF) patients. Some studies have proposed that well-managed warfarin therapy is still a valid alternative as efficacious as NOACs but the potential impact and absolute effect of NOACs in "real world" optimally management of VKA AF patients is unknown.. To estimate the potential absolute benefit in clinical outcome rates if the optimally anticoagulated "real-world" AF patients with acenocoumarol had been treated with NOACs.. We included 1361 patients stable on acenocoumarol with a time in therapeutic range of 100% for the previous 6months and 6.5years of follow-up. The estimation of clinical events avoided was calculated applying absolute risk reductions, relative risk reductions and hazard ratios from the pivotal clinical trials, relative to acenocoumarol.. Compared to acenocoumarol, the highest estimated event reduction for stroke was seen with dabigatran 150mg, with an estimated reduction of 0.53%/year. For major bleeding, the highest estimated reduction was seen with apixaban (0.88%/year). For mortality, the largest estimated reduction was with dabigatran 150mg (0.75%/year). In net clinical outcome, apixaban had the estimated highest reduction (1.23%/year). All NOACs showed significantly lower rates for intracranial haemorrhage.. In optimally acenocoumarol anticoagulated AF patients, estimated reductions in stroke, bleeding and net clinical outcomes with various NOACs are evident. NOACs would potentially show an improvement even among optimally VKA AF patients.

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Mortality; Prospective Studies; Retrospective Studies; Treatment Outcome; Vitamin K

The first-line drugs for the treatment of non-valvular atrial fibrillation (AF) are non-vitamin K antagonist oral anticoagulants (NOACs), which are preferred over vitamin K antagonists (VKAs). There is some evidence that there are dis-crepancies between everyday clinical practice and the guidelines.. The study aimed to compare the characteristics of patients on VKAs, dabigatran, and rivaroxaban in everyday practice (i.e. baseline characteristics, drug doses, risk factors for bleeding and thromboembolic events). Additionally, we assessed the frequency of prescription of different oral anticoagulants (OACs) in recent years.. This study consisted of data from the multicentre CRAFT (MultiCentre expeRience in AFib patients Treated with OAC) study (NCT02987062). This was a retrospective analysis of hospital records of AF patients (hospitalised in the years 2011-2016) treated with VKAs (acenocoumarol, warfarin) and NOACs (dabigatran, rivaroxaban). A total of 3528 patients with non-valvular AF were enrolled in the CRAFT study.. The total cohort consisted of 1973 patients on VKA, 504 patients on dabigatran, and 1051 patients on rivaroxaban. Patients on rivaroxaban were older (70.5 ± 13.1 years) and more often female (47.9%), compared with those on VKAs (67.0 ± 12.8 years, p < 0.001; 35.5%, p < 0.001) and on dabigatran (66.0 ± 13.9 years, p < 0.001; 38.9%, p = 0.001). Among NOACs, patients with persistent and permanent AF were more likely to receive rivaroxaban (54.7% and 73.4%, re-spectively) than dabigatran (45.3%, p < 0.001 and 26.6%, p = 0.002, respectively). Patients on rivaroxaban had higher risk of thromboembolic events (CHA2DS2VASc 3.9 ± 2.0, CHADS2 2.2 ± 1.4) than those on VKAs (3.3 ± 2.0, 1.9 ± 1.3) and on dabigatran (3.1 ± 2.0, 1.8 ± 1.3). Patients on rivaroxaban had also a higher rate of prior major bleeding (11.2%) than those on VKAs (6.7%, p < 0.001) and on dabigatran (7.3%, p = 0.02). Patients on lower doses of dabigatran and rivaroxaban had a significantly higher risk of thromboembolic and bleeding events. Use of VKAs in the year 2011 was reported in over 96% of patients on OACs, but this proportion decreased to 34.6% in 2016. In the last analysed year (2016) AF patients were treated mainly with NOACs - dabigatran (24.2%) and rivaroxaban (41.3%).. The prescription of VKAs declined significantly after the introduction of NOACs. Patients treated with different OACs demonstrated a distinct baseline clinical profile. The highest risk of thromboembolic events and incidence of major bleedings was observed in patients on rivaroxaban, in comparison to patients on VKAs and dabigatran. Among NOACs, patients treated with lower doses of dabigatran and rivaroxaban were older and had a significantly higher risk of thromboembolic and bleeding events.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Retrospective Studies; Rivaroxaban; Thromboembolism; Warfarin

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

Topics: 4-Hydroxycoumarins; Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Fasting; Female; Hemorrhage; Humans; Indenes; Islam; Male; Middle Aged; Tunisia; Vitamin K

Vitamin K antagonists (VKA) are used to prevent recurrent disease in patients with venous thromboembolism (VTE). Their efficacy and safety depend on individual time in therapeutic range (iTTR) and variability of International Normalised Ratios (INR). We aimed to identify independent predictors of poor VKA control > 28 days. In a prospective cohort of 3825 VTE patients, separate logistic regression analyses were performed to identify predictors of low iTTR (first quartile) and instability (iTTR median). Subsequently, the association between these predictors and clinical outcomes was investigated. Weight < 50 kg (odds ratio [OR]=1.89; 95 % confidence interval [CI] 1.03-3.49), active cancer at baseline (OR=1.52; CI1.05-2.19), secondary VTE (OR=1.42; CI1.20-1.68), and INR < 2.0 at stop of double therapy (OR=1.35; CI1.09-1.67) were independent predictors of low iTTR. The first two were also predictive for instability (OR=1.96; CI1.06-3.63 and OR=1.95; CI1.36-2.80, respectively). ORs of early (≤ 28 days) low iTTR and instability depended on VKA type. In acenocoumarol users, early low iTTR was an independent predictor of subsequent low iTTR (OR=1.92; CI1.31-2.80) and instability (OR=1.55; CI1.07-2.23). In warfarin users, early low iTTR (OR=1.36; CI1.09-1.69) and instability (OR=1.25; CI1.01-1.55) were additionally predictive for low iTTR, but only the latter was predictive for instability (OR=1.91; CI1.57-2.32). Many predictors of VKA control also predicted premature discontinuation, but only region was prognostic for clinical outcome. In conclusion, we identified several independent predictors of low iTTR and instability > 28 days, which showed some similarities but did not fully overlap. Early VKA control was of additional value for prediction of both, but had to be interpreted in the context of VKA type.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Drug Therapy, Combination; Enoxaparin; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Prognosis; Recurrence; Risk Factors; Thrombophilia; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

The aim of the current analysis was to identify independent predictors of the overall clinical outcome of patients with atrial fibrillation (AF), including both stroke/thromboembolism and/or major bleeding. Given the overlap between stroke and bleeding risk factors, a composite risk-stratification score for stroke/thromboembolism or bleeding could potentially be developed.. We used data from the vitamin K antagonist (VKA) arm (n = 2,293; 65% men; mean age 70 ± 9 years) of the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial, which was a multicenter, randomized, open-label noninferiority study that compared fixed-dose idraparinux with VKA in patients with AF. We defined two composite end points: end point 1 was the combination of stroke/thromboembolism or major bleeding; end point 2 was defined as the combination of stroke, systemic or venous embolism, myocardial infarction, cardiovascular death, or major bleeding.. The independent predictors for composite end point 1 were age (P = .014), previous stroke/transient ischemic attack (P = .049), aspirin use (P = .002), and time in therapeutic range (P = .007). For composite end point 2, similar predictors were evident, plus left ventricular dysfunction (P = .011). Based on the regression models, two novel composite risk-prediction scores were developed and were validated externally in a "real-world" cohort of 441 outpatients with AF receiving anticoagulation treatment. Both composite scores 1 and 2 demonstrated numerically higher discriminatory performance (area under the curve [AUC], 0.728; 95% CI, 0.659-0.798 and AUC, 0.707; 95% CI, 0.655-0.758, for end points 1 and 2, respectively) and a positive net reclassification when compared with currently used risk models (CHADS2 [congestive heart failure, hypertension, age ≥ 75 years, diabetes, prior stroke or transient ischemic attack], CHA2DS2VASc [cardiac failure or dysfunction, hypertension, age ≥ 75 years [doubled], diabetes, stroke (doubled)-vascular disease, age 65 to 74 years, and sex category (female)], and HAS-BLED [hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly]), but the differences were not statistically significant.. We have developed and validated two novel composite scores for stroke/thromboembolism/bleeding that offer good discriminatory and predictive performance. However, these composite risk scores did not perform better than the easier and more practical "traditional" stroke and bleeding risk scores that are currently in use, which allow greater practicality and a more personalized balancing of risks.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Area Under Curve; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Middle Aged; Models, Statistical; Oligosaccharides; Regression Analysis; Reproducibility of Results; Risk Factors; Stroke; Warfarin

Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE).. This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment.. To date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety.. Eudra CT. Identifier: 2009-016643-18.

Topics: Acenocoumarol; Administration, Oral; Algorithms; Anticoagulants; Blood Coagulation; Clinical Protocols; Drug Dosage Calculations; Drug Monitoring; Hemorrhage; Humans; International Normalized Ratio; Pharmacogenetics; Research Design; Single-Blind Method; Spain; Time Factors; Treatment Outcome; Venous Thromboembolism

The safest duration of anticoagulation after idiopathic deep vein thrombosis (DVT) is unknown. We conducted a prospective study to assess the optimal duration of vitamin K antagonist (VKA) therapy considering the risk of recurrence of thrombosis according to residual vein thrombosis (RVT). Patients with a first unprovoked DVT were evaluated for the presence of RVT after 3 months of VKA administration; those without RVT suspended VKA, while those with RVT continued oral anticoagulation for up to 2 years. Recurrent thrombosis and/or bleeding events were recorded during treatment (RVT group) and 1 year after VKA withdrawal (both groups). Among 409 patients evaluated for unprovoked DVT, 33.2% (136 of 409 patients) did not have RVT and VKA was stopped. The remaining 273 (66.8%) patients with RVT received anticoagulants for an additional 21 months; during this period of treatment, recurrent venous thromboembolism and major bleeding occurred in 4.7% and 1.1% of patients, respectively. After VKA suspension, the rates of recurrent thrombotic events were 1.4% and 10.4% in the no-RVT and RVT groups, respectively (relative risk = 7.4; 95% confidence interval = 4.9-9.9). These results indicate that in patients without RVT, a short period of treatment with a VKA is sufficient; in those with persistent RVT, treatment extended to 2 years substantially reduces, but does not eliminate, the risk of recurrent thrombosis.

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; Drug Administration Schedule; Female; Hemorrhage; Humans; Lower Extremity; Male; Middle Aged; Prospective Studies; Recurrence; Risk Factors; Ultrasonography; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin

Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring.. We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study.. The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).. Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

Topics: Acenocoumarol; Acute Disease; Administration, Oral; Aged; Anticoagulants; Double-Blind Method; Enoxaparin; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Injections, Subcutaneous; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Middle Aged; Morpholines; Pulmonary Embolism; Rivaroxaban; Thiophenes; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin

Sitaxentan inhibits the metabolism of warfarin, resulting in a need for adjustment of warfarin dose when both drugs are coadministered. We report the long-term effects on bleeding of acenocoumarol co-administered as part of conventional therapy for pulmonary hypertension with sitaxentan in a subset of patients enrolled in the Sitaxentan To Relieve ImpaireD Exercise-3 (STRIDE-3) study.. STRIDE-3 is an ongoing, long-term, open-label trial, evaluating the safety and efficacy of sitaxentan, 100 mg once daily, in patients with pulmonary arterial hypertension. Information on bleeding events was collected prospectively, including the type of event, severity, anticoagulant use and investigator attribution of causality. Coagulation tests were performed on a monthly basis. A clinically significant interaction was defined as an international normalized ratio (INR) >/= 5.0, or any minor bleeding event plus an INR > 2.0 and < 5.0.. Of 55 patients enrolled in STRIDE-3, 50 received acenocoumarol. Average follow-up was 158.6 +/- 57.6 weeks. The average dose of anticoagulant therapy was 3.9 +/- 1.3 mg week(-1) (range, 1.5-7.0 mg week(-1)). Following treatment, an INR >/= 5 in at least one INR determination was observed in 13 patients, although none of these patients had a clinically significant bleeding event. Dose reductions in acenocoumarol were performed to adjust target INR to 1.5-2.0. Two patients died of massive haemoptysis, but these episodes were not attributed to a drug interaction. Four patients with an INR > 2.0 and < 5.0 experienced a minor bleeding event (nosebleeds/gingivitis).. No clinically significant bleeding events were recorded with coadministration of sitaxentan and acenocoumarol in this patient subgroup. These results suggest that coadministration of sitaxentan and acenocoumarol is clinically manageable and well tolerated.

Topics: Acenocoumarol; Adolescent; Adult; Anticoagulants; Antihypertensive Agents; Drug Administration Schedule; Drug Interactions; Endothelin Receptor Antagonists; Female; Hemorrhage; Humans; Hypertension, Pulmonary; International Normalized Ratio; Isoxazoles; Male; Prospective Studies; Survival Analysis; Thiophenes; Young Adult

Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with SSRI use in users of the coumarins acenocoumarol or phenprocoumon and compared this with the OR of bleeding as a result of use of nonsteroidal anti-inflammatory drugs.. We used data from a Dutch linkage system including pharmacy and linked hospitalization records for approximately 2 million subjects to conduct a case-control study in a cohort of new users of coumarins. Cases were patients who were hospitalized having a primary diagnosis of abnormal major bleeding while taking a coumarin and were matched with up to 4 control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CIs) for the risk of hospitalization because of abnormal bleeding associated with concurrent use of SSRIs or nonsteroidal anti-inflammatory drugs.. We identified 1848 case patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of nongastrointestinal tract bleeding (hereafter referred to as "nongastrointestinal bleeding") (adjusted OR, 1.7; 95% CI, 1.1-2.5) but not because of gastrointestinal tract bleeding (hereafter referred to as "gastrointestinal bleeding") (adjusted OR, 0.8; 95% CI, 0.4-1.5). Users of nonsteroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR, 1.7; 95% CI, 1.3-2.2), whereas the risk of gastrointestinal bleeding was higher (adjusted OR, 4.6; 95% CI, 3.3-6.5).. In users of coumarins, SSRI usage was associated with increased risk of hospitalization because of nongastrointestinal bleeding but not because of gastrointestinal bleeding.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Case-Control Studies; Coumarins; Drug Interactions; Female; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Risk Factors; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

To analyze the environmental factors associated to anticoagulation excess in adult patients who come to an emergency department of a tertiary hospital. To describe the characteristics of anticoagulant therapy, their diseases and associated drugs, clinical presentation and treatment received.. Prospective study of randomized patients conducted in the Emergency Department of Hospital Gregorio Marañón in Madrid during 6 months. Those patients whose INR was greater than or equal to 6 due to having taken acenocoumarol were included. Variables collected for all of them were: age, gender, INR when coming to the emergency department, anticoagulation indication, its beginning and duration, physician anticoagulation controlling, time since previous INR control, last INR assessment, treatment changes. Other variables were: comorbidity, associated medications, dietary changes, presence of bleeding, its location and treatment received. The statistical analysis was performed with the SPSS program (vs 13).. A total of 49 adult patients, 63.3% female, whose average age was 77.9 (48-94) were included. Mean INR value was 8.2 (6-12). Indication due to atrial fibrillation was found in 71.4%. The most common associated diseases were heart failure and chronic nephropathy (18.4% and 16.3%, respectively). Twelve patients (24.5%) had consumed paracetamol recently. Active hemorrhage occurred in 34.7% of cases.. Anticoagulation excess is a common problem in people over 70, where comorbidity and medications may determine the INR value. Bleeding risk is significant so that this group of patients should be closely monitored.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Emergency Medical Services; Female; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies

Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this randomised, open-label non-inferiority trial was to compare the efficacy and safety of idraparinux with vitamin K antagonists.. Patients with atrial fibrillation at risk for thromboembolism were randomly assigned to receive either subcutaneous idraparinux (2.5 mg weekly) or adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2-3). Assessment of outcome was done blinded to treatment. The primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism. The principal safety outcome was clinically relevant bleeding. Analyses were done by intention to treat; the non-inferiority hazard ratio was set at 1.5. This trial is registered with ClinicalTrials.gov, number NCT00070655.. The trial was stopped after randomisation of 4576 patients (2283 to receive idraparinux, 2293 to receive vitamin K antagonists) and a mean follow-up period of 10.7 (SD 5.4) months because of excess clinically relevant bleeding with idraparinux (346 cases vs 226 cases; 19.7 vs 11.3 per 100 patient-years; p<0.0001). There were 21 instances of intracranial bleeding with idraparinux and nine with vitamin K antagonists (1.1 vs 0.4 per 100 patient-years; p=0.014); elderly patients and those with renal impairment were at greater risk of such complications. There were 18 cases of thromboembolism with idraparinux and 27 cases with vitamin K antagonists (0.9 vs 1.3 per 100 patient-years; hazard ratio 0.71, 95% CI 0.39-1.30; p=0.007), satisfying the non-inferiority criterion. There were 62 deaths with idraparinux and 61 with vitamin K anatagonists (3.2 vs 2.9 per 100 patient-years; p=0.49).. In patients with atrial fibrillation at risk for thromboembolism, long-term treatment with idraparinux was no worse than vitamin K antagonists in terms of efficacy, but caused significantly more bleeding.

Topics: Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Oligosaccharides; Risk Factors; Single-Blind Method; Stroke; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

This study aimed to determine whether a weight-adjusted dose of subcutaneous enoxaparin is as effective and safe as oral acenocoumarol for the secondary prophylaxis of pulmonary embolism. Three hundred and eighty consecutive noncancer outpatients hospitalized with an episode of symptomatic pulmonary embolism selected treatment with acenocoumarol or enoxaparin at a dose of 1 mg/kg once daily after being informed of the type of administration and expected frequency of laboratory monitoring for both medicinal products. Endpoints were symptomatic recurrent thromboembolic events evaluated by standard objective testing, and a composite endpoint of recurrent venous thromboembolism, major bleeding, and death from any cause. One hundred and ninety-nine patients (52%) chose acenocoumarol therapy and 181 chose enoxaparin monotherapy. Four patients in the enoxaparin group (2.2%) and six patients in the acenocoumarol group (3%) had an objective thromboembolic recurrence (hazard ratio, 1.35; 95% confidence interval, 0.38-4.79; P = 0.64). Nine patients in the enoxaparin group (5.0%) had a hemorrhagic complication compared with 11 in the acenocoumarol group (5.5%) (P = 0.81). The hospital length of stay was shorter with enoxaparin compared with acenocoumarol (11 versus 16 days, P = 0.0001). Enoxaparin is as effective and safe as acenocoumarol in the secondary prevention of recurrent thromboembolic disease and is associated with shorter hospitalization.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Enoxaparin; Female; Hemorrhage; Humans; In Vitro Techniques; Length of Stay; Middle Aged; Pulmonary Embolism; Secondary Prevention; Venous Thrombosis

Atherosclerotic peripheral arterial disease is associated with an increased risk of myocardial infarction, stroke, and death from cardiovascular causes. Antiplatelet drugs reduce this risk, but the role of oral anticoagulant agents in the prevention of cardiovascular complications in patients with peripheral arterial disease is unclear.. We assigned patients with peripheral arterial disease to combination therapy with an antiplatelet agent and an oral anticoagulant agent (target international normalized ratio [INR], 2.0 to 3.0) or to antiplatelet therapy alone. The first coprimary outcome was myocardial infarction, stroke, or death from cardiovascular causes; the second coprimary outcome was myocardial infarction, stroke, severe ischemia of the peripheral or coronary arteries leading to urgent intervention, or death from cardiovascular causes.. A total of 2161 patients were randomly assigned to therapy. The mean follow-up time was 35 months. Myocardial infarction, stroke, or death from cardiovascular causes occurred in 132 of 1080 patients receiving combination therapy (12.2%) and in 144 of 1081 patients receiving antiplatelet therapy alone (13.3%) (relative risk, 0.92; 95% confidence interval [CI], 0.73 to 1.16; P=0.48). Myocardial infarction, stroke, severe ischemia, or death from cardiovascular causes occurred in 172 patients receiving combination therapy (15.9%) as compared with 188 patients receiving antiplatelet therapy alone (17.4%) (relative risk, 0.91; 95% CI, 0.74 to 1.12; P=0.37). Life-threatening bleeding occurred in 43 patients receiving combination therapy (4.0%) as compared with 13 patients receiving antiplatelet therapy alone (1.2%) (relative risk, 3.41; 95% CI, 1.84 to 6.35; P<0.001).. In patients with peripheral arterial disease, the combination of an oral anticoagulant and antiplatelet therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with an increase in life-threatening bleeding. (ClinicalTrials.gov number, NCT00125671 [ClinicalTrials.gov].).

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Aspirin; Atherosclerosis; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Middle Aged; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Ticlopidine; Warfarin

Oral anticoagulants, in Hungary acenocoumarol being the one exclusively used, have a low therapeutic index and a high bleeding complication rate. The cytochrome P450 2C9 enzyme plays an important role in their metabolism.. To investigate the influence of CYP2C9 polymorphism on the occurrence of bleeding complications related to acenocoumarol therapy.. Genotyping of 421 patients (183 men and 238 women, mean age 66.2+/-11.8 years), who had been taking acenocoumarol for at least 6 months, was performed. Based on patient history and laboratory data, the correlations between genotype and acenocoumarol dose and bleeding complications were retrospectively analysed.. In 145 patients bearing alleles with reduced activity (CYP2C9*2 and/or *3), the optimal dose of acenocoumarol was significantly (p<0.001) lower than in patients with the wild type allele (2.12+/-0.96 mg/day and 2.90+/-1.46 mg/day, respectively). In comparison with wild type allele patients, the mean daily acenocoumarol dose was lower in the CYP2C9*2 group, and the lowest in *3 bearers. Although the occurrence of minor bleeding complications in patients with the variant allele was significantly (p <0.005) higher (OR=1.99 [CI: 1.20-3.33]) than in other patients, there was no difference in major bleeding complications.. Patients bearing CYP2C9 alleles with reduced enzymatic activity have a lower acenocoumarol requirement. In patients with CYP2C9*2 and *3 alleles the frequency of minor bleeding complications and the occurrence of high INR values were significantly higher, but there was no difference in the rate of major bleedings.

Topics: Acenocoumarol; Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Female; Gene Frequency; Genotype; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic

The optimal duration of oral anticoagulation in patients with idiopathic venous thromboembolism is uncertain. Testing of D-dimer levels may play a role in the assessment of the need for prolonged anticoagulation.. We performed D-dimer testing 1 month after the discontinuation of anticoagulation in patients with a first unprovoked proximal deep-vein thrombosis or pulmonary embolism who had received a vitamin K antagonist for at least 3 months. Patients with a normal D-dimer level did not resume anticoagulation, whereas those with an abnormal D-dimer level were randomly assigned either to resume or to discontinue treatment. The study outcome was the composite of recurrent venous thromboembolism and major bleeding during an average follow-up of 1.4 years.. The D-dimer assay was abnormal in 223 of 608 patients (36.7%). A total of 18 events occurred among the 120 patients who stopped anticoagulation (15.0%), as compared with 3 events among the 103 patients who resumed anticoagulation (2.9%), for an adjusted hazard ratio of 4.26 (95% confidence interval [CI], 1.23 to 14.6; P=0.02). Thromboembolism recurred in 24 of 385 patients with a normal D-dimer level (6.2%). Among patients who stopped anticoagulation, the adjusted hazard ratio for recurrent thromboembolism among those with an abnormal D-dimer level, as compared with those with a normal D-dimer level, was 2.27 (95% CI, 1.15 to 4.46; P=0.02).. Patients with an abnormal D-dimer level 1 month after the discontinuation of anticoagulation have a significant incidence of recurrent venous thromboembolism, which is reduced by the resumption of anticoagulation. The optimal course of anticoagulation in patients with a normal D-dimer level has not been clearly established. (ClinicalTrials.gov number, NCT00264277 [ClinicalTrials.gov].).

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Antiphospholipid Syndrome; Antithrombins; Drug Administration Schedule; Fibrin Fibrinogen Degradation Products; Follow-Up Studies; Hemorrhage; Humans; Middle Aged; Proportional Hazards Models; Prospective Studies; Pulmonary Embolism; Recurrence; Survival Analysis; Ultrasonography; Venous Thrombosis; Vitamin K; Warfarin

Control of oral anticoagulant treatment has been reported to be suboptimal, but previous studies suggest that patient self-management improves control.. To compare the quality of control and the clinical outcomes of oral anticoagulant treatment in self-managed patients versus patients following conventional management.. Randomized, controlled trial.. University-affiliated hospital in Spain.. 737 patients with indications for anticoagulant treatment.. The self-management group (n = 368) received simple instructions for using a portable coagulometer weekly and self-adjusting treatment dose. The conventional management group (n = 369) received usual care in an anticoagulation clinic (monthly measurement and control of international normalized ratio [INR], managed by hematologists).. Percentage of INR values within the target range and major related complications.. The median follow-up period was 11.8 months (range, 0.3 to 16.9 months). The unadjusted percentages of in-range INRs were 58.6% in the self-management group and 55.6% in the conventional management group (difference, 3.0 percentage points [95% CI, 0.4 to 5.4 percentage points]). Twenty-seven patients (7.3%) in the conventional management group and 8 (2.2%) in the self-management group had major complications related to anticoagulant treatment. The unadjusted risk difference for major complications between groups was 5.1 percentage points (exact 95% CI, 1.7 to 8.5 percentage points). Fewer patients had minor hemorrhages in the self-management group (14.9%) than in the conventional management group (36.4%). Fifteen patients (4.1%) in the conventional management group and 6 (1.6%) in the self-management group died (unadjusted risk difference, 2.5 percentage points [exact 95% CI, 0.0 to 5.1 percentage points]).. The trial was performed at only 1 center and was not blinded. The dropout rate in the intervention group was 21%.. Compared with conventional management by an anticoagulation clinic, self-management of oral anticoagulant treatment achieved a similar level of control. Of note, major complications and minor hemorrhages were less common in the self-management group.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Female; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Monitoring, Physiologic; Patient Compliance; Patient Dropouts; Patient Education as Topic; Risk Factors; Self Care; Thromboembolism; Treatment Outcome

This trial evaluated the efficacy and safety of the combination of antiplatelet and moderate-intensity anticoagulation therapy in patients with atrial fibrillation associated with recognized risk factors or mitral stenosis.. Warfarin was more effective than aspirin in preventing stroke in these patients; combined therapy with low anticoagulant intensity was ineffective. Mitral stenosis patients were not investigated.. We performed a multicenter randomized trial in 1,209 patients at risk. 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. The high-risk group included patients with prior embolism or mitral stenosis: 259 received anticoagulants and 236 received the combined therapy. Median follow-up was 2.76 years. Primary outcome was a composite of vascular death and nonfatal stroke or systemic embolism.. Primary outcome was lower in the combined therapy than in the anticoagulant arm in both the intermediate- (hazard ratio [HR] 0.33 [95% confidence interval (CI)0.12 to 0.91]; p = 0.02) and the high-risk group (HR 0.51 [95% CI 0.27 to 0.96]; p = 0.03). Primary outcome plus severe bleeding was lower with combined therapy in the intermediate-risk group. Nonvalvular and mitral stenosis patients had similar embolic event rates during anticoagulant therapy.. The combined antiplatelet plus moderate-intensity anticoagulation therapy significantly decreased the vascular events compared with anticoagulation alone and proved to be safe in atrial fibrillation patients.

Topics: Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Cause of Death; Dose-Response Relationship, Drug; Drug Therapy, Combination; Embolism; Female; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Intracranial Embolism; Male; Middle Aged; Mitral Valve Stenosis; Platelet Aggregation Inhibitors; Proportional Hazards Models; Salicylates; Survival Analysis; Treatment Outcome

The optimal duration of oral anticoagulant treatment after a first episode of pulmonary embolism remains uncertain.. To evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months (pulmonary embolism associated with temporary risk factors) or to 1 year (idiopathic pulmonary embolism) in patients with a first episode of pulmonary embolism.. Multicenter randomized study with independent, blinded assessment of the outcome events.. 19 Italian hospitals.. 326 patients who had had 3 months of oral anticoagulant therapy without experiencing recurrence or bleeding.. The primary study outcome was recurrence of symptomatic, objectively confirmed venous thromboembolism.. Among 165 patients assigned to extended anticoagulant therapy, 15 patients (9.1%) had a recurrence of venous thromboembolism (3.1% per patient-year; average follow-up, 34.9 months), as compared with 18 of 161 patients (11.2%) assigned to discontinue treatment (4.1% per patient-year; average follow-up, 32.7 months); the rate ratio was 0.81 (95% CI, 0.42 to 1.56). All but one of the recurrences occurred after anticoagulant treatment was discontinued. Nineteen recurrences (57.6%) were episodes of pulmonary embolism, two of which were fatal. Three major bleeding episodes were observed during extended anticoagulation (1.8%). Among patients with idiopathic venous thromboembolism, 11 of 90 patients assigned to extended anticoagulation and 11 of 91 patients assigned to discontinue treatment experienced a recurrence (relative risk, 0.99 [CI, 0.45 to 2.16]).. Patients with pulmonary embolism have a substantial risk for recurrence after discontinuation of oral anticoagulation, regardless of treatment duration. Physicians should try to identify patients who are at high risk for recurrent venous thromboembolism and are therefore potential candidates for indefinite oral anticoagulant therapy.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Drug Administration Schedule; Hemorrhage; Humans; Middle Aged; Pulmonary Embolism; Risk Factors; Secondary Prevention; Treatment Outcome; Warfarin; Withholding Treatment

Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer.. Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months).. During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oral-anticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group.. In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Dalteparin; Drug Therapy, Combination; Female; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Secondary Prevention; Survival Analysis; Thromboembolism; Venous Thrombosis; Warfarin

Oral anticoagulants and low-molecular-weight heparin are both recommended for venous thromboembolism prophylaxis after total hip replacement. To date, these regimens have not been compared by means of clinical end points in the extended prophylaxis setting.. 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. The primary end point was the failure rate, defined as the combined clinical events of a confirmed symptomatic thromboembolic event, a major hemorrhage, or death. All patients were followed up throughout the study interval. The primary objective was to compare the observed cumulative failure rate in the low-molecular-weight heparin vs oral anticoagulant group.. In the intent-to-treat population, objectively documented symptomatic thromboembolic events occurred in 15 (2.3%) of 643 patients vs 21 (3.3%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.30; 95% confidence interval for the difference, -0.8% to 2.8%). Major bleeding occurred in 9 (1.4%) of 643 patients vs 35 (5.5%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.001). The failure rate was 24 (3.7%) of 643 patients compared with 53 (8.3%) of 636 patients who received low-molecular-weight heparin or oral anticoagulants (P =.001).. A significantly higher benefit-risk ratio was observed for patients undergoing elective hip replacement who received extended out-of-hospital prophylaxis with low-molecular-weight heparin vs acenocoumarol. Low-molecular-weight heparin prophylaxis was at least as effective as oral anticoagulants, but with a marked improvement in safety.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Male; Thromboembolism; Venous Thrombosis

The purpose of this study was to evaluate whether low molecular weight heparin (LMWH) could be equal or more effective than conventional oral anticoagulants (OAs) in the long-term treatment of deep venous thrombosis (DVT).. 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. Quantitative and qualitative duplex scan scoring systems were used to study the evolution of thrombosis in both groups at 1, 3, 6, and 12 months.. During the 12-month surveillance period, two (2.5%) of the 81 patients who received LMWH and seven (9%) of the 77 patients who received OAs had recurrence of venous thrombosis (not significant). In the LMWH group no cases of major bleeding were found, and four cases (5.2%) occurred in the OA group (not significant). The mortality rate was nine (11.1%) in the LMWH group and 7.8% in the OA group (not significant). The quantitative mean duplex scan score decreased in both groups during the follow-up and had statistical significance after long-term LMWH treatment on iliofemoral DVT (1, 3, 6, and 12 months), femoropopliteal DVT (1-3 months), and infrapopliteal DVT (first month). Duplex scan evaluation showed that the rate of venous recanalization significantly increased in the common femoral vein at 6 and at 12 months and during each point of follow-up in the superficial and popliteal veins in the LMWH group. Reflux was significantly less frequent in communicating veins after LMWH treatment (17.9% vs 32.2% in the OA group). The reflux rates in the superficial (22.4% in the LMWH group, 30.6% in OA group) and deep (13.4% vs 17.7%) venous system showed no significant differences between groups.. The unmonitored subcutaneous administration of nadroparine in fixed daily doses was more effective than oral acenocoumarol with laboratory control adjustment in achieving recanalization of leg thrombi. With nadroparine, there was less late valvular communicating vein insufficiency, and it was at least as efficacious and safe as oral anticoagulants after long-term administration. These results suggest that LMWHs may therefore represent a real therapeutic advance in the long-term management of DVT.

Topics: Acenocoumarol; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Tests; Female; Hemorrhage; Humans; Injections, Subcutaneous; Long-Term Care; Male; Middle Aged; Nadroparin; Survival Rate; Thrombophlebitis; Treatment Outcome; Ultrasonography, Doppler, Duplex

The purpose of this study was to determine the optimal intensity of oral anticoagulation in patients who participated in a randomized trial of oral anticoagulants or aspirin after infrainguinal bypass graft surgery.. The distribution of patient-time spent in international normalized ratio (INR) classes of 0.5 INR unit was calculated assuming a linear change between successive measurements. INR-specific incidence rates of ischemic and hemorrhagic events were calculated as the ratio of the number of events at a certain INR category and the total patient-time spent in that class. The relationship between INR class and event rates was quantified by rate ratios calculated in a Poisson regression model.. In 1326 patients (mean age, 69 years) 41,928 INR measurements were recorded in 1698 patient-years. Patients spent 50% of the total time within the target range of 3.0 to 4.5 INR. Most of the patient-time (60%) was spent between 2.5 and 3.5 INR. For each increasing class of 0.5 INR, the incidence of ischemic events (n = 154, INR data on event available in 49%) decreased by a factor of 0.97 (95% CI, 0.87-1.08). The incidence of major bleeding (n = 123, INR data on event available in 65%) increased significantly by a factor of 1.27 (95% CI, 1.19-1.34) for each increasing 0.5 INR category. The optimal target range was 3.0 to 4.0 INR, with an incidence of 3.8 events (0.9 ischemic and 2.9 hemorrhagic) per 100 patient-years.. The target range of 3.0 to 4.0 INR is the optimal range of achieved anticoagulation intensity and is safe for the prevention of ischemic events in patients after infrainguinal bypass graft surgery.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Aspirin; Blood Vessel Prosthesis Implantation; Female; Graft Occlusion, Vascular; Hemorrhage; Humans; International Normalized Ratio; Ischemia; Leg; Male; Middle Aged; Netherlands; Phenprocoumon; Treatment Outcome

The risk of hemorrhage when coumarin anticoagulants are used sharply increases when the international normalized ratio (INR) is > or = 6.0. Such overanticoagulation may be caused by drug interactions. 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.. Three hundred case patients with INR values > or = 6.0 were compared with 302 randomly selected matched control subjects with INR values within the target zone. Information on changes in the use of 87 potentially interacting drugs in the 4 weeks before the index day was collected by interviewing patients and by reviewing the anticoagulant medical record.. Forty-five potentially interacting drugs were not used in the 4-week study period, and only 15 drugs were used by at least 10 patients. For a number of drugs, too few patients had a relevant change in use to judge their association with overanticoagulation. A course of a combination product of sulfamethoxazole and trimethoprim strongly increased the risk of overanticoagulation (adjusted odds ratio, 24.2; 95% confidence interval [CI], 2.8 to 209.1; population attributable risk percentage [PAR%], 5.7%), especially in patients receiving acenocoumarol. Penicillins were associated with a risk of overanticoagulation of 2.4 (95% CI, 1.00 to 5.5); the corresponding PAR% was 3.4%. The effect was confined to amoxicillin (INN, amoxicilline) plus clavulanic acid.. Drug interactions as a cause of overanticoagulation predominantly concerned antibacterial drugs. If possible, the use of sulfamethoxazole-trimethoprim and amoxicillin plus clavulanic acid should be avoided in patients receiving coumarins. If there is no therapeutic alternative available, increased monitoring of INR values is warranted to prevent overanticoagulation and potential bleeding complications.

Topics: Acenocoumarol; Aged; Anti-Infective Agents; Anticoagulants; Blood Coagulation Disorders; Case-Control Studies; Cohort Studies; Drug Interactions; Female; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Risk Factors

This study aims to establish the relative effectiveness and safety of low molecular weight heparin in elderly patients with venous thrombosis in order to find an alternative to oral anticoagulant therapy with less bleeding complications in the long-term treatment of deep venous thrombosis (DVT). One hundred consecutive elderly patients (>75 years old) with venographically demonstrated proximal DVT were included in a randomized trial. All patients were treated for ten days with adjusted doses of intravenous heparin. Informed consent was obtained and on the eight day, patients were randomly allocated to receive acenocoumarol (INR 2.0-3.0) or subcutaneous enoxaparin (4000 anti-Xa units once a day) for three months. All patients were followed-up clinically and venographically for a one year period. The results were analyzed with Fisher's exact test or chi-square test as appropriate. 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). Hemorrhagic complications occurred in six of the 50 patients (12%) who received acenocoumarol and in one (2%) of those on enoxaparin (p = 0.1; 95% CI for the difference: -1.8 to 21.8). Vertebral fractures developed in 2 patients (4%) in the enoxaparin group (p = 0.5; 95% CI for the difference: -11.4 to 3.4). These results show that fixed dose enoxaparin seems to be effective and safe in the long-term treatment of proximal DVT in the elderly. In comparison with oral anticoagulants, the findings are inconclusive due to the wide confidence intervals for differences between outcomes, however they suggest that the former may have less bleeding complications with similar efficacy.

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Enoxaparin; Female; Hemorrhage; Humans; Injections, Intravenous; Male; Thrombophlebitis; Treatment Outcome

Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism.. Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial.. One university and 2 regional teaching hospitals.. 188 patients treated with heparin or danaparoid for acute venous thromboembolism.. The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively.. Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders.. A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Topics: Acenocoumarol; Acute Disease; Adult; Aged; Body Surface Area; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Combinations; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Neoplasms; Odds Ratio; Prospective Studies; Risk Factors; Single-Blind Method; Thromboembolism; Thrombolytic Therapy

The authors examined the bleeding complications in 75 patients who received acenocoumarol and acetylsalicylic acid combined therapy. The studied population suffered from either acute myocardial infarction or unstable angina. Among the 75 patients in two cases (2.7%) appeared serious bleeding and in another 25 cases (33.3%) mild bleeding complications. There were no fatal cases. Comparing these data with literary data, the authors stated that in the study group the proportion of serious complications didn't increase in comparison with patients who received either acenocoumarol, warfarin or acetylsalicylic acid but mild bleeding appeared more frequently. This finding suggests that in high risk patients the combined acenocoumarol-acetylsalicylic acid therapy can be considered under strict control.

Topics: Acenocoumarol; Angina, Unstable; Aspirin; Drug Synergism; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Prothrombin; Warfarin

To compare two initial doses of oral anticoagulant (acenocoumarin) studying the haemorrhagic and thromboembolic episodes occurred during the first month of treatment, the mean time and necessary controls until achievement of the desired level of anticoagulation.. From january 1992 to december 1993; a comparative study of two groups of patients was performed: group 1, compiling 129 patients chosen at random and retrospectively, who begun oral anticoagulant treatment with 4 daily mg of acenocoumarin; and group 2, compiling 129 patients chosen prospectively, who begun with 2 mg daily. In both groups the mean time and the number of controls performed until achieving the desired level of anticoagulation were analyzed, as well as the haemorrhagic episodes occurred during the first month of treatment, their severity (classified into major and minor ones), the level of anticoagulation when they occurred and their possible causes. In the same way the thromboembolic processes occurred during that period in both groups were studied.. The mean time necessary to achieve the desired level of anticoagulation was 3.8 days in group 1 and 6.3 in group 2; the mean number of controls performed in group 1 was 1.2 and in group 2 it was 1.8. We have observed 19 haemorrhagic episodes, 15 in group 1 (4 minor and 11 major); and 4 in group 2 (2 minor and 2 major). We have found significant differences with respect to the mean time (p < 0.01), number of controls (p < 0.01) and incidence of hemorrhages (p = 0.017) between groups 1 and 2. One thromboembolic episode was registered in each group: in group 1 a deep venous thrombosis and in group 2 a stroke.. The initial daily doses of acenocoumarin of 2 mg is as effective as the 4 mg one in the prevention of thromboembolic episodes, with a significant reduction in the number of haemorrhages observed during the first month of treatment. However this produces a prolongation in the necessary mean time and more number of controls performed until the achievement of the desired level of anticoagulation.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Aged, 80 and over; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Thrombosis

Various methods have been described to evaluate efficacy of anticoagulant therapy using the international normalized ratio (INR). We compared the following approaches: (1) total INR's or the most recent measurement; (2) percent time within therapeutic range, with INR changing directly or halfway between visits; and (3) total observation time assuming INR changing linearly. The study population comprised 1700 post myocardial infarction patients. Treatment comprised 3725 patient-years. There were 61,471 INR assessments with target therapeutic level of 2.8-4.8. Acenocoumarol as well as phenprocoumon were employed. Therapeutic achievement in the first months of treatment was low: less than 60% of INR's were in range. Treatment stabilized after 6 months. Patients on acenocoumarol were within range 70% of the time compared to 80% for phenprocoumon. Method 3 is preferred because it incorporates time and is capable of calculating incidence rates at different INR levels. Our findings call for an urgent improvement of standard of anticoagulant control in the first months following commencement of treatment.

Topics: Acenocoumarol; Aged; Anticoagulants; Cardiovascular Diseases; Convalescence; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Phenprocoumon; Prothrombin Time; Quality Control; Reference Standards; Thromboplastin; Treatment Outcome

The use of long-term oral anticoagulant treatment after myocardial infarction remains controversial because of conflicting findings on mortality in previous trials and the increased risk of bleeding associated with anticoagulants. We have carried out a randomised, placebo-controlled, double-blind, multicentre trial in 3404 hospital survivors of myocardial infarction. Eligible patients were randomly assigned to anticoagulant (nicoumalone or phenprocoumon) or placebo treatment within 6 weeks of discharge. The target prothrombin time was 2.8-4.8 international normalised ratio. During mean follow-up of 37 (range 6-76) months there were 170 deaths among 1700 anticoagulant-treated patients and 189 in 1704 placebo-treated patients (hazard ratio 0.90 [95% CI 0.73-1.11]). Anticoagulant treatment led to significant reductions by comparison with placebo treatment in recurrent myocardial infarction (114 vs 242 patients; hazard ratio 0.47 [0.38-0.59]) and cerebrovascular events (37 vs 62; 0.60 [0.40-0.90]). Major bleeding complications were seen in 73 patients who received anticoagulants and 19 who received placebo. We conclude that long-term oral anticoagulant treatment after myocardial infarction in low-risk patients has a limited effect on mortality but achieves substantial benefit by reducing the risk of cerebrovascular events and recurrent myocardial infarction.

Topics: Acenocoumarol; Administration, Oral; Aged; Cardiovascular Diseases; Cause of Death; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Phenprocoumon; Proportional Hazards Models; Recurrence; Risk Factors; Survival Rate

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; Aortic Valve; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Germany; Heart Valve Diseases; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Mitral Valve; Phenprocoumon; Postoperative Complications; Prospective Studies; Survival Rate; Thromboembolism; Warfarin

In most countries, heparin is used in the initial treatment of patients with deep-vein thrombosis. Well-designed studies establishing the efficacy of heparin therapy are lacking, however. Treatment with acenocoumarol alone, according to the hypothesis that high dosages of oral anticoagulants obviate the need for heparin, is considered an effective alternative in some countries.. 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. The principal study end point was a confirmed symptomatic extension or recurrence of venous thromboembolism during six months of follow-up. In addition, we assessed asymptomatic extension or pulmonary embolism by repeating venography and lung scanning after the first week of treatment. The incidence of major bleeding was determined during three months of follow-up.. The study was terminated early by the Data Safety and Monitoring Committee because of an excess of symptomatic events in the group that received acenocoumarol alone (in 12 of 60 patients [20 percent], as compared with 4 of 60 patients [6.7 percent] in the combined-therapy group by intention-to-treat analysis; P = 0.058). Asymptomatic extension of venous thrombosis was observed in 39.6 percent of the patients in the acenocoumarol group and in 8.2 percent of patients treated with heparin plus acenocoumarol (P < 0.001). Major bleeding complications were infrequent and comparable in the two groups.. Patients with proximal-vein thrombosis require initial treatment with full-dose heparin, which can safely be combined with acenocoumarol therapy.

Topics: Acenocoumarol; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Male; Middle Aged; Pulmonary Embolism; Recurrence; Thrombophlebitis

The antithromboembolic efficacy of once a day low molecular weight heparin in fixed combination with dihydroergotamine (LMWH-DHE) was compared with conventional heparin-DHE in combination with Acenocoumarol (heparin-DHE/A) in 191 patients undergoing gynaecological surgery. LMWH-DHE proved equally effective in preventing thromboembolic complications, with a similar incidence of postoperative bleeding and side effects. Deep vein thrombosis occurred once in each group and one non-fatal pulmonary embolism occurred in the LMWH-DHE group. The main advantage of LMWH-DHE was significantly better patient acceptance of the single daily subcutaneous injection as compared with the two injections of conventional heparin-DHE (P = 0.02). On the other hand, LMWH-DHE was associated with significantly increased incidence of intraoperative bleeding (P less than 0.02). The bleeding did not, however, cause any clinical problems. Discontinuation of therapy due to bleeding or pain at the site of injection occurred three times in each group. We consider the use of LMWH-DHE to be an attractive, economic and safe method of thromboembolic prophylaxis.

Topics: Acenocoumarol; Clinical Trials as Topic; Dihydroergotamine; Drug Combinations; Female; Genital Diseases, Female; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Hysterectomy; Postoperative Complications; Premedication; Prospective Studies; Pulmonary Embolism; Random Allocation; Thrombophlebitis

The British comparative thromboplastin (BCT) was used to monitor the effectiveness of oral anticoagulants in preventing deep vein thrombosis (DVT) in patients undergoing major gynaecological surgery. All patients were screened for DVT with the use of the (125)I-fibrinogen scan.One hundred and forty-five patients aged 40 years or more were randomised into three groups. Group 1 received oral anticoagulant (nicoumalone) treatment, stabilised over five days before surgery and continuing into the second postoperative week. The other patients served as two contrast groups and were managed on a double-blind basis. Group 2 received a subcutaneous low-dose regimen of heparin calcium. Group 3 received subcutaneous saline. Eleven of 48 patients in the saline group, three of 49 patients in the heparin group, and three of 48 patients in the oral anticoagulant group developed DVT as judged by (125)I-fibrinogen scanning. The incidences in groups 1 and 2 were significantly lower than in the saline group. The falls in haemoglobin concentration and incidence of haemorrhage were similar in all three groups.The study showed that oral anticoagulant prophylaxis stabilised preoperatively and low-dose heparin were equally effective in preventing deep vein thrombosis in a moderate-risk group. Immediate preoperative prothrombin ratios of 2.0-2.5 and postoperative ratios of 2.0-4.0 with the BCT gave adequate protection without increased haemorrhagic risk.

Topics: Acenocoumarol; Administration, Oral; Adult; Clinical Trials as Topic; Double-Blind Method; Female; Genitalia, Female; Hemoglobins; Hemorrhage; Heparin; Humans; Middle Aged; Thrombophlebitis; Thromboplastin

Topics: Acenocoumarol; Aged; Angina Pectoris; Blood Coagulation Tests; Coumarins; Evaluation Studies as Topic; Hemorrhage; Humans; Myocardial Infarction; Time Factors

In Spain, vitamin K antagonists (VKA) remain the standard treatment for the prevention of thromboembolic and hemorrhagic complications in patients with atrial fibrillation (AF), despite the high risks of suffering adverse effects. The objective of this study was to characterize the profile of VKA-treated patients suffering from stroke/systemic embolism (SE) or major hemorrhagic episodes, their evolution and the actions taken after those episodes.. EVENTHO was an observational multicenter study conducted in 22 Anticoagulation Spanish Units. The study included patients ≥18 years with AF who suffered major hemorrhagic episodes (67.8%) or stroke/SE (32.1%) during 2016 whileon VKA treatment [acenocoumarol (98.2%) or warfarin (1.8%)]. Time in therapeutic range (TTR) was calculated according to the Rosendaal method based on the international normalized ratio (INR) values of the previous 6 months.. The study included 585 patients (median age [range] 82.3 [43.6-96.2] years; 51.1% men; mean [95% confidence interval, CI] CHA. In the sample studied, half of the AF patients who suffered stroke/SE or major hemorrhagic episode had inadequate TTR and, despite this, after hospital discharge, they restarted treatment with VKA. These results highlight the need to evaluate safer and effective therapeutic alternatives in AF patients with poor TTR control after suffering a stroke/SE or major hemorrhagic episode.

Topics: Acenocoumarol; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Fibrinolytic Agents; Hemorrhage; Humans; International Normalized Ratio; Male; Stroke; Vitamin K; Warfarin

Several studies have shown that in patients treated with vitamin K antagonists (VKAs) time spent in therapeutic range (TTR) is lower in females than in males. This retrospective study has evaluated a possible association among over-anticoagulation and gender, type and indications to VKAs, TTR and bleeding. Moreover, the decrease of the INR level, after VKAs withdrawal, was considered.. From December 2020 to January 2004, 1230 patients with venous thromboembolism or atrial fibrillation were enrolled. Age, gender, type of VKAs, clinical indications, INR values and bleeding events were recorded. TTR was calculated considering the entire period of treatment.. A total of 1616 and 1759 over-anticoagulation episodes were found in males and females, respectively. The median INR value was 4.5 (4.0-19.04). Thirty-two percent of the patients did not have an overdose throughout the observation period. The median number of over-anticoagulation per year was significantly higher in females (0.39-year) than in males (0.28-year). After 24 h of VKAs withdrawal, INRs were similar in both genders. Logistic regression analysis showed that the episodes of over-anticoagulation per year were associated with females, atrial fibrillation, warfarin therapy, follow-up length longer than 4 years, and TTR <73%, but were not associated to bleeding episodes.. The higher number of over-anticoagulation can explain the lower TTR in females. An excess of anticoagulation is not associated with bleeding events. The recovery of INR performs better when acenocoumarol is used, therefore, in patients who present several episodes of over-anticoagulation, acenocumarolo could replace warfarin.

Topics: Acenocoumarol; Anticoagulants; Atrial Fibrillation; Female; Fibrinolytic Agents; Hemorrhage; Humans; International Normalized Ratio; Male; Retrospective Studies; Sex Factors; Vitamin K; Warfarin

Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA.. This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded.. Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6 years (range 2-8) during VKA and 1.9 years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09).. Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Topics: Acenocoumarol; Adult; Anticoagulants; Budd-Chiari Syndrome; Duration of Therapy; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Mesenteric Ischemia; Middle Aged; Portal Vein; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiazoles; Venous Thrombosis; Warfarin

An elderly, polytrauma patient receiving vitamin K antagonist (VKA) for atrial fibrillation required immediate surgery for open distal tibial fracture. As the initial reversal with vitamin K and fresh frozen plasma by the trauma team was ineffective, the "Bleeding Team" was convened and administrated the appropriate four-factor prothrombin complex regimen, reversing the VKA in a timely manner. Surgery was performed under peripheral nerve blockade subsequently. The postoperative course of the patient was uneventful.. The individualized approach and the multidisciplinary experts' team guidance is of outmost importance in patients who are treated with anticoagulants and present for nonelective surgery.

Topics: Acenocoumarol; Aged; Anticoagulants; Fractures, Open; Hemorrhage; Humans; Vitamin K

Vitamin K antagonists (VKA) based oral anticoagulation, is widely used for the prevention and treatment of thromboembolic disease. The major complication of this therapy is bleeding, and sometimes it can occur in unsuspected areas. Spontaneous pectoral hematoma is one of the rare complications due to over anticoagulation by VKA therapy, with only a few cases reported in the literature. Concomitant use of this therapy with commonly used antibiotic, especially in the elderly with multiple comorbidities, can increase the risk of bleeding. Herein, we report a case of a 72-year-old woman under VKA for the treatment of atrial fibrillation, who presented with a spontaneous massive pectoral hematoma, while using antibiotic to treat a respiratory tract infection, who was successfully managed.

Topics: Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Female; Hematoma; Hemorrhage; Humans; Thromboembolism; Vitamin K

The embolization of thrombi formed within the atria can occur in any form of atrial fibrillation (AF), i.e., paroxysmal, persistent, or permanent. Although ischemic stroke is the most frequent embolic event associated with AF, embolization to other sites in the pulmonary and systemic circulations may occasionally occur. To avert the risk of embolization, long-term oral anticoagulation therapy is recommended for all AF patients if the CHA2DS2-VASC score is at least 1 for men and at least 2 for women. Since anticoagulant therapy is associated with an increased risk of bleeding, the choice of oral anticoagulant agent should be made by careful consideration of the benefit-to-risk ratio. The use of a newer class of direct oral anticoagulants (DOACs) as an alternative to the anti-vitamin K (AVK) anticoagulants (warfarin, acenocumarol, etc.) can help mitigate the need for periodic monitoring of International Normalized Ratio (INR) and adverse bleeding events that are commonly associated with the use of AVK anticoagulants. Though the use of DOACs (dabigatran, rivaroxaban, edoxaban, apixaban, etc.) is gaining ground due to their relative safety profile and the low overall cost, quite a few clinicians remain skeptical about their use.. Our objective was to evaluate the risk of thromboembolism, stroke, neuropsychiatric illness, depression, and dementia, in patients with non-valvular atrial fibrillation who have been treated with either acenocumarol or apixaban, as well as to see the inflammatory status (ESR) and levels of fibrinogen. Our team at Municipal Emergency University Hospital, Timisoara, Romania, conducted a retrospective study using the medical records of AF patients who were treated with either apixaban or acenocumarol between 2016-2019. We divided the patients into two groups and compared the groups for the aforementioned outcomes.. AF patients who were prescribed apixaban had a lower rate of stroke and psychiatric illness compared to those on acenocumarol. No significant correlation was found in terms of risk of developing depression or dementia between the groups.. Non-valvular AF patients on apixaban had lower rates of thromboembolic events than the patients on acenocumarol. This article will serve as a reminder of the positive health and financial outcomes of apixaban use, especially to those healthcare systems that are still oblivious to the decrease in economic burden and gain in quality-adjusted life years (QALY) by the long-term use of NOACS/ DOACS instead of the AVK anticoagulants.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Clinical Decision-Making; Female; Hemorrhage; Humans; Incidence; International Normalized Ratio; Male; Middle Aged; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Retrospective Studies; Risk Assessment; Romania; Stroke

Intra-alveolar bleeding is a rare and severe medical emergency due to numerous causes. We report the clinical case of a patient who could contribute to extend the literature on this subject. The study included a 62-year old man, with a history of a trial fibrillation, under anti-vitamins K antagonist admitted with dyspnoea of sudden onset associated with haemoptysis and practising self-medication using non-steroidal anti-inflammatory drugs. X-rays and chest scan showed diffuse bilateral alveolar opacities. Haemostatic screening tests on admission showed non-coagulable INR. The diagnosis of intra-alveolar bleeding was clinically and radiologically suspected and then confirmed by bronchial endoscopy with broncho-alveolar lavage (BAL) which detected uniformly hemorrhagic liquid. Previous studies of similar complications occurring after anti-vitamins K antagonists assumption are rare. In conclusion, it seems very important to emphasize the interest of strict and optimal clinico-biological monitoring of patients treated in anti-vitamins K antagonists to avoid an overdose which could contribute to a life-threatening severe haemorrhagic event.

Topics: Acenocoumarol; Anticoagulants; Dyspnea; Hemoptysis; Hemorrhage; Humans; Male; Middle Aged; Pulmonary Alveoli; Vitamin K

Non-operative management (NOM) may be particularly challenging in patients receiving synchronous antithrombotic therapy (AT). The current study examined the feasibility of NOM in patients under AT who sustained blunt splenic or hepatic injuries.. We analyzed the results of a 5-year (2010-2014) pre-decided treatment protocol, including 15 patients under AT who were treated for splenic and/or hepatic injuries at our institution. The antithrombotic therapy consisted of acenocoumarol 4 mg, acetylsalicylic acid 100 mg and clopidogrel 75 mg. Vitamin K (Vit K), Fresh frozen plasma (FFP) and Prothrombin Complex Concentrate (PCC) were transfused to patients receiving anticoagulant therapy, while platelets (PLTs) were given to patients under antiplatelet therapy if their level was excessively low. The organ injury grading scale, injury severity score (ISS), the need for blood transfusion and intensive care unit (ICU)/ high dependency unit (HDU) admission, morbidity, mortality and duration of hospital stay were also recorded.. Ten patients fulfilled the criteria for NOM and were treated accordingly. No conversion to operative management (OM) was required (success rate 100%). Five patients were managed surgically due to hemodynamic instability and/or signs of peritonitis. Reversal of AT was attempted in all cases.. Hemodynamically stable patients under AT with blunt hepatic or splenic injuries (grade ≤ III) and no signs of peritonitis, may be good candidates for NOM, despite their bleeding tendency. The type of AT does not seem to influence the final outcome. Reversal of AT should be stratified individually.. Antithrombotic therapy, Hemodynamic stability, Non-operative management.. La gestione non operatoria (NOM) può essere particolarmente difficile nei pazienti sottoposti a contemporaneo trattamento antitrombotico (AT). Con questo studio è stata esaminata la fattibilità di NOM in pazienti con AT che hanno subito lesioni epatiche o spleniche. Per questo abbiamo analizzato i risultati a 5 anni (2010- 2014) di un protocollo prospettico su 15 pazienti sotto trattamento AT, trattati per lesioni spleniche e / o epatiche presso il nostro istituto. La terapia antitrombotica consisteva in 4 mg di acenocumarolo, 100 mg di acido acetilsalicilico e 75 mg di clopidogrel. La vitamina K (Vit K), il plasma fresco congelato (FFP) e il concentrato di complesso protrombinico (PCC) sono stati trasfusi nei pazienti sottoposti a terapia anticoagulante, mentre piastrine (PLT) sono state somministrate a pazienti sottoposti a terapia antiaggregante se il loro livello era eccessivamente basso. Sono state inoltre registrate il grado delle lesioni organiche, il punteggio di gravità (ISS), la necessità di trasfusione di sangue e di trattamento in terapia intensiva (HDU) di grado elevato, la morbilità, la mortalità e la durata della degenza ospedaliera. I pazienti con adeguati criteri per NOM e trattati di conseguenza sono stati dieci. Non è stata necessaria alcuna conversione alla gestione operativa (OM) con un tasso di successo del 100%. Cinque pazienti sono stati gestiti chirurgicamente a causa di instabilità emodinamica e / o segni di peritonite. In tutti i casi è stata tentata la In tutti i casi è stata tentata l’interruzione dell’AT. Si conclude che i pazienti emodinamicamente stabili sotto AT con lesioni epatiche o spleniche (grado ≤ III) e senza segni di peritonite, possono essere buoni candidati per il NOM, nonostante la loro tendenza al sanguinamento. Il tipo di AT non sembra influenzare il risultato finale. L’interruzione del trattamento AT dovrebbe essere deciso caso per caso.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Aspirin; Blood Coagulation Factors; Blood Transfusion; Combined Modality Therapy; Critical Care; Disease Management; Feasibility Studies; Female; Fibrinolytic Agents; Hemorrhage; Humans; Injury Severity Score; Length of Stay; Liver; Male; Middle Aged; Plasma; Prospective Studies; Spleen; Treatment Outcome; Vitamin K; Wounds, Nonpenetrating

Optimal antithrombotic therapy after lower limb infrainguinal revascularization remains a controversial topic. The use of anticoagulants, alone or in combination with antiplatelet drugs, can potentially improve patency rate and limb salvage, particularly in patients with risk factors for early thrombosis. Bleeding is the main complication of long-term anticoagulant use. New oral anticoagulants can represent an attractive alternative to the standard vitamin K antagonists. The objective of the study is to evaluate the effectiveness (bypass occlusion and major amputation) and safety (major bleeding and all-cause mortality) of rivaroxaban compared to acenocumarol after infrainguinal lower limb surgical revascularization.. Retrospective cohort study of patients with peripheral arterial disease submitted to lower limb infrainguinal bypass revascularization with vein or expanded polytetrafluoroethylene conduit, who were anticoagulated with acenocumarol or rivaroxaban after hospital discharge. Patients with proximal revascularization, revascularization due to any pathology other than peripheral arterial disease, coagulation disorder, stroke or acute myocardial infarction in less than 30 days, glomerular filtration rate <15 mL/min, or on hemodialysis were excluded.. One hundred nine patients were included (78.9% male), with a mean age of 64.8 years. After hospital discharge, 40 patients (36.7%) were medicated with rivaroxaban and 69 patients (63.3%) with acenocumarol. At 1 year of follow-up, patients under rivaroxaban and acenocumarol presented comparable major amputation rates (12.5 % vs. 10.1%, P = 0.756), bypass occlusion (22.5% vs. 24.6 %, P = 0.769), and mortality rate (10% vs. 8.7%, P = 0.756). Major bleeding occurred in 13.8% of patients. Patients with renal dysfunction had significantly higher bleeding risk with acenocumarol (45.5% vs. 0%, P = 0.028) compared to rivaroxaban, while patients with normal renal function presented similar bleeding rates with both anticoagulants (6.1% vs. 6.4%, P = 0.953).. Rivaroxaban has equivalent effectiveness to acenocumarol after infrainguinal bypass revascularization, with similar occlusion, major amputation, and mortality rates. Rivaroxaban has an improved safety profile in patients with moderate renal dysfunction due to a significantly lower incidence of major bleeding. In patients with normal renal function, rivaroxaban and acenocumarol present equivalent major bleeding rates.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Anticoagulants; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Comorbidity; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Limb Salvage; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Polytetrafluoroethylene; Prosthesis Design; Retrospective Studies; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; Veins

Bridging anticoagulation in atrial fibrillation (AF) patients who need to interrupt vitamin K antagonists for procedures is a clinical dilemma. Currently, guidelines recommend clinicians to take the stroke and bleeding risk into consideration, but no clear thresholds are advised. To aid clinical decision making, we aimed to develop a model in which periprocedural bridging therapy is compared with withholding anticoagulation in AF patients, for several bleeding and stroke risk groups.. A model was developed to simulate both a bridge and a non-bridge cohort, using simulated international normalized ratio (INR) values for patients on warfarin, acenocoumarol, and phenprocoumon. For both clinical strategies, stroke and bleeding risks were included and outcomes were stratified by CHA2DS2-VASc or CHADS2 and HAS-BLED groups. Quality-adjusted life expectancy was the main outcome considered. Our analyses show bridging to only be beneficial for patients with HAS-BLED scores equal or lower to 2 and with CHA2DS2-VASc scores of 6 or higher. For patients using acenocoumarol bridging may be beneficial starting at a CHA2DS2-VASc score of 7. Post-procedural time to therapeutic INR has a significant influence on the results: no significant benefit of bridging was found for patients reaching therapeutic INR values within 5 days.. When deciding whether to bridge anticoagulation, clinicians should consider the patient's individual stroke and bleeding risk, while also considering the patient's post-procedural INR management. In practice, only a small subset of patients is expected to benefit from bridging anticoagulation treatment.

Topics: Acenocoumarol; Anticoagulants; Atrial Fibrillation; Computer Simulation; Hemorrhage; Humans; International Normalized Ratio; Markov Chains; Phenprocoumon; Risk Assessment; Stroke; Time-to-Treatment; Warfarin; Withholding Treatment

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Antitussive Agents; Cough; Drug Interactions; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Netherlands; Nonprescription Drugs; Noscapine; Phenprocoumon; Thromboembolism

Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients.. Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.

Topics: Acenocoumarol; Administration, Oral; Adolescent; Age Factors; Anticoagulants; Blood Coagulation; Child; Child, Preschool; Drug Monitoring; Female; Guideline Adherence; Hemorrhage; Humans; Infant; International Normalized Ratio; Male; Netherlands; Phenprocoumon; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quality Indicators, Health Care; Retrospective Studies; Thromboembolism; Time Factors; Treatment Outcome

The efficacy and tolerability of vitamin K antagonists (VKAs) depends on the quality of anticoagulant control, reflected by the mean time in therapeutic range (TTR) of international normalized ratio 2.0 to 3.0. In the present study, we aimed to investigate the association between TTR and change in TTR (ΔTTR) with the risk of mortality and clinically significant events in a consecutive cohort of atrial fibrillation (AF) patients.. We included 1361 AF patients stable on VKAs (international normalized ratio 2.0-3.0) during at least the previous 6 months. After 6 months of follow-up we recalculated TTR, calculated ΔTTR (ie, the difference between baseline and 6-month TTRs) and investigated the association of both with the risk of mortality and "clinically significant events" (defined as the composite of stroke or systemic embolism, major bleeding, acute coronary syndrome, acute heart failure, and all-cause deaths).. The median ΔTTR at 6 months of entry was 20% (interquartile range 0-34%), 796 (58.5%) patients had a TTR reduction of at least 20%, while 330 (24.2%) had a TTR <65%. During follow-up, 34 (2.5% [4.16% per year]) patients died and 61 (4.5% [7.47% per year]) had a clinically significant event. Median ΔTTR was significantly higher in patients who died (35.5% vs 20%; P = 0.002) or sustained clinically significant events (28% vs 20%; P = 0.022). Based on Cox regression analyses, the overall risk of mortality at 6 months for each decrease point in TTR was 1.02 (95% CI, 1.01-1.04; P = 0.003), and the risk of clinically significant events was 1.01 (95% CI, 1.00-1.03; P = 0.028). Patients with TTR <65% at 6 months had higher risk of mortality (hazard ratio = 2.96; 95% CI, 1.51-5.81; P = 0.002) and clinically significant events (hazard ratio = 1.71; 95% CI, 1.01-2.88; P = 0.046).. Our findings suggest that in AF patients anticoagulated with VKAs, a change in TTR over 6 months (ie, ΔTTR) is an independent risk factor for mortality and clinically significant events. Even in a cohort with good anticoagulation control, the risk for mortality and clinically significant events increases with every point deterioration of TTR.

Topics: Acenocoumarol; Acute Coronary Syndrome; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Male; Regression Analysis; Risk Factors; Stroke; Vitamin K

Single nucleotide polymorphisms (SNP) in genes encoding proteins involved in metabolism and action of vitamin K antagonists (VKA) affect anticoagulation stability. We investigated how those polymorphisms influence bleeding rates in patients following venous thromboembolism (VTE).. In 324 patients following unprovoked VTE, 143 (44%) on warfarin and 181 (56%) on acenocoumarol, we recorded bleeds within the preceding 24 months. We assessed eight SNP, including those in cytochrome P450 isoform 2C9 (CYP2C9) and isoform 4F2 (CYP4F2), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), apolipoprotein E (APOE) and multidrug resistance gene 1 (MDR1).. Within 48 months before enrolment, bleeding events occurred in 80 (25%) patients, including 14 (4%) major bleeds. Patients with bleeds had 16.2% lower median time in therapeutic range (TTR) and were more often carriers of CYP2C9*3 variant (26 [33%] vs. 19 [8%], p < 0.001) compared with the remainder. Bleeding occurred more frequently in patients with ≥4 SNP compared with the remainder (27 [34%] vs. 47 [19%], p = 0.009) with no intergroup differences of TTR. Number of SNP was one of the predictors of any bleeding. The regression model for major bleeding including factors such as CYP2C9*3 c. 1075 C, VKORC1 c. -1639 A and APOE c. 388 C showed good predictive ability (area under the curve - 0.79).. In VTE patients on the maintenance treatment with VKA, bleeding episodes are associated with CYP2C9 gene variations and increased number of SNP of genes involved in the action and metabolism of VKA.

Topics: Acenocoumarol; Adult; Anticoagulants; Apolipoproteins E; Cytochrome P-450 CYP2C9; Female; Gene Frequency; Genetic Predisposition to Disease; Hemorrhage; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Venous Thromboembolism; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

Vascular disease is a frequent comorbidity in atrial fibrillation (AF) patients, resulting in concomitant use of antiplatelet therapy. In the present study, we investigated the incidence and risk of major bleeding, ischaemic stroke, and mortality in a cohort of AF patients taking acenocoumarol plus antiplatelet therapy, in comparison with AF patients taking only acenocoumarol monotherapy.. We consecutively included 1361 "real-world" AF patients stable for at least the previous 6 months on acenocoumarol (INR 2.0-3.0). The primary endpoint was major bleeding defined using the 2005 International Society on Thrombosis and Haemostasis (ISTH) criteria. As secondary endpoints, we analysed ischaemic strokes and all-cause mortality. During follow-up, all adverse events were recorded and compared within patients taking acenocoumarol plus antiplatelet therapy and patients taking only acenocoumarol.. During 6.5 years (IQR 4.3-7.9) of follow-up, there were 250 (2.83%/year) bleeds, 130 (1.47%/year) ischaemic strokes and 511 (6.23%/year) deaths. After multivariate Cox regression analyses, combined antithrombotic therapy was associated with major bleeding (HR 1.40, 95% CI 1.01-1.94; P = .048), but not lower mortality (HR 0.95, 95% CI 0.75-1.21; P = .674) or ischaemic stroke (HR 1.45, 95% CI 0.97-2.17; P = .072).. In AF patients, the risk of bleeding is higher when antiplatelet therapy is combined with acenocoumarol, but the risk of mortality and stroke was not significantly different from that of patients taking only acenocoumarol.

Topics: Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cohort Studies; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk

We aimed to study potential variables involved in interindividual variability to acenocoumarol (AC) response in order to establish a pharmacogenetic algorithm (PA) that includes clinical and genetic factors to predict adequate AC dose to stabilize anticoagulation in a cohort of Tunisian patients.. Genotyping of the CYP2C9, VKORC1, CYP4F2, and CALU polymorphisms was conducted on 246 patients using PCR-RFLP technique. AC normalized maintenance dose (NMD): ((mean maintenance dose/international normalized ratio (INR)) equilibrium) was calculated. The statistical study was carried out with SPSS V20.. A significant correlation was found between age, BMI, and daily AC dose (r = - 0.397; p < 0.001 and r = 0.215; p = 0.001, respectively). The carriers of mutated alleles CYP2C9*2 or CYP2C9*3 or VKORC1 haplotypes (H1 and H7) were associated with AC hyper-sensibility. After adjustment to potential covariates, these patients presented supra-therapeutic INR during treatment period and needed low AC dose (ORs* = 0.28 [0.06-0.60], p = 0.004; ORs* = 0.12 [0.04-0.05], p < 0.001; ORs* = 0.45 [0.24-0.84], p = 0.01; and ORs* = 0.28 [0.06-0.98], p = 0.049, respectively). However, carriers of VKORC1 haplotypes (H3 and H12) or mutated alleles CYP4F2 (rs2108622) or CALU (rs1043550) tend to resist to treatment, hence long period of therapy initiation, and must be treated with high AC dose (ORs* = 2.67 [81.12-5.91], p = 0.013; ORs* = 8.76 [1.07-76.26], p = 0.019; ORs* = 3.12 [1.01-9.63], p = 0.047; and ORs* = 3.96 [1.41-11.09], p = 0.009, respectively). A final multivariate regression model explained 48.1% of the global interindividual variability in AC dose requirement.. The PA demonstrated that VKORC1 and CYP2C9 polymorphisms contribution was more important than clinical factors. Applying the PA would allow dose adjustment to treat patients in a personalized manner.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Anticoagulants; Atrial Fibrillation; Black People; Calcium-Binding Proteins; Cytochrome P-450 CYP2C9; Cytochrome P450 Family 4; Female; Genotype; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Polymorphism, Single Nucleotide; Tunisia; Venous Thrombosis; Vitamin K Epoxide Reductases; Young Adult

Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS-BLED score.. We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS-BLED score if the patient was a simultaneous carrier of the VKORC1 and CYP2C9 polymorphisms related to bleeding, and we called this modified score "GEN|HAS-BLED." During a median follow-up of 7.6 years (IQR 5.6-8.0), all major bleeding events were recorded.. During follow-up, 106 (16.2%) patients experienced a major bleeding (2.81%/y; 42 intracranial haemorrhages and 44 gastrointestinal bleeding) and 24 (3.7%) died from major bleeding (0.48%/y). Cox regression analyses demonstrated a significant association between HAS-BLED or GEN|HAS-BLED and major bleeds, both as continuous or categorical scores. Comparison of receiver operating characteristic (ROC) curves shows that original HAS-BLED clinical score had better predictive ability than GEN|HAS-BLED (0.660, 95% CI 0.622-0.696 vs 0.645, 95% CI 0.607-0.682; P = .030). Discrimination and reclassification analyses showed that GEN|HAS-BLED did not improve sensitivity compared with the original score and even showed significant negative reclassification.. Adding pharmacogenetic factors (ie polymorphisms of the VKORC1 and CYP2C9 genes) to the HAS-BLED score does not improve the prediction or discrimination performance for major bleeding.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cytochrome P-450 CYP2C9; Female; Gastrointestinal Hemorrhage; Genetic Predisposition to Disease; Hemorrhage; Humans; Intracranial Hemorrhages; Male; Pharmacogenetics; Polymorphism, Genetic; Proportional Hazards Models; Risk Assessment; ROC Curve; Stroke; Vitamin K Epoxide Reductases

Vitamin K antagonists (VKA) are the most widely used anticoagulants in the world. An appropriate management of treated patients is crucial for their efficacy and safety. The prospective, observational, multicenter, inception-cohort FCSA-START Register, a branch of START Register (NCT02219984) included VKA-treated patients managed by centers of Italian Federation of anticoagulation clinics (AC). Baseline patient characteristics and data during treatment were analyzed and compared with those of ISCOAT study, performed by the Federation and published in 1996/7. 5707 naïve patients [53% males, mean age 73.0 years (28.1% >80 years)], 61.6% treated for atrial fibrillation (AF), and 28.0% for venous thromboembolism were included. During the 8906 patient-years (pt-yrs) of observation, 123 patients had major bleeding (MB) (1.38% pt-yrs; fatal: 0.11% pt-yrs), while non-major clinically relevant bleeds were 144 (1.62% pt-yrs). Bleeding was more frequent in elderly (≥70 years; p = 0.04), and during initial 3-month therapy (p = 0.02). Bleeding rate was 2.5% pt-yrs for temporally related INR results <3.0, increasing to 12.5% for INR ≥ 4.5. Thrombotic events were 47 (0.53% pt-yrs; 4 fatal 0.04% pt-yrs). Compared with ISCOAT-1996/7 results, patients older than 80 y are increased from 8 to 28% (p < 0.01), and those treated for AF are increased from 17 to 61%. The quality of anticoagulation control and incidence of MB are not different. However, thrombotic complications fell drastically from 3.5 to 0.53% pt-yrs (p < 0.01), with lower mortality (p = 0.01). VKA-treated patients monitored in Italian AC have good clinical results, with low bleeding and thrombotic complications rates. Important changes in the treated population and improvement in thrombotic complications are detected compared with the ISCOAT-1996/7 study.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Ambulatory Care Facilities; Anticoagulants; Atrial Fibrillation; Chi-Square Distribution; Female; Heart Valve Prosthesis; Hemorrhage; History, 20th Century; History, 21st Century; Humans; Incidence; Italy; Male; Middle Aged; Population Groups; Registries; Risk Factors; Thromboembolism; Vitamin K; Warfarin

Thromboembolic complications can be life-threatening during atrial fibrillation (AF) catheter ablation. The aim of our study was to evaluate the safety and efficacy of continuous treatment using direct oral anticoagulants (DOACs) as an alternative to uninterrupted acenocoumarol for periprocedural anticoagulation.. Continuous treatment with DOACs has similar safety and efficacy compared to acenocoumarol.. We enrolled 474 patients (mean age, 58 years; 68.4% male) undergoing AF catheter ablation between June 2013 and December 2016. All patients were equally assigned to take acenocoumarol (group 1, 136 patients) or DOACs (group 2, 338 patients) for ≥2 months before the procedure. We compared thromboembolic and bleeding complications between the 2 groups.. Our analysis showed no significant difference in major and minor complications between the 2 patient groups. Specifically, 3 of 136 patients (2.2%) using uninterrupted acenocoumarol had a major complication (1 patient [0.7%] had transient ischemic attack resolved 8 hours later, 1 [0.7%] had pericardial tamponade, and 1 [0.7%] had a subcapsular renal hematoma) and 2 patients (1.4%) had minor complications (1 [0.7%] pseudoaneurysm and 1 [0.7%] groin hematoma). In group 2, 1 of 338 patients (0.3%) had a major complication (transient ischemic attack). In the same group, 7 patients (2.1%) had a minor complication (1 patient [0.3%] presented with pseudoaneurysm, 4 [1.2%] with pericardial effusion <1 cm, 1 [0.3%] femoral arteriovenous fistula between the femoral artery and femoral vein, and 1 [0.7%] groin hematoma).. DOACs and acenocoumarol have similar safety and effectiveness regarding thromboembolic complications prevention without increasing bleeding complications.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Catheter Ablation; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Thromboembolism; Time Factors; Treatment Outcome

The prevalence of atrial fibrillation (AF) has increased over the past years due to aging of the population, and healthcare costs associated with AF reflect a significant financial burden. The aim of this study was to explore predictors for the real-world AF-related in-hospital costs in patients that recently initiated anticoagulation with acenocoumarol or dabigatran.. Predictors for claimed total hospital care costs and cardiology costs in AF patients were explored by using hospital financial claims data from propensity score matched patient groups in a large Dutch community hospital. This study analyzed the total dataset (n = 766) and carried out a secondary analysis for all matched pairs of anticoagulation naïve AF patients (n = 590) by ordinal regression.. Dabigatran was a predictor for significantly lower cardiology and total hospital care costs (Odds Ratio [OR] = 0.43, 95% confidence interval (CI) = 0.33-0.57; and OR = 0.60, 95% CI = 0.46-0.79, respectively). Female gender was a predictor for lower total hospital care costs. Predictors for an increase in total hospital care costs were the occurrence of stroke or systemic embolism, major bleeding, and minor bleeding. The costs predictors were comparable when limiting the analysis to patients that were anticoagulation naïve. Age and CHA. Dabigatran treatment was as a predictor for lower cardiology costs and lower total hospital care costs in AF patients that initiated oral anticoagulation.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cardiology; Dabigatran; Embolism; Female; Hemorrhage; Hospital Charges; Humans; Male; Middle Aged; Netherlands; Propensity Score; Retrospective Studies; Sex Factors; Stroke

Bleeding risk with vitamin K antagonists (VKAs) is closely related to the quality of anticoagulation in atrial fibrillation (AF) patients, reflected by time in therapeutic range (TTR). Here we compared the discrimination performance of different bleeding risk scores and investigated if adding TTR would improve their predictive value and clinical usefulness. We included 1361 AF patients stables on VKA for at least 6 months. Bleeding risk was assessed by the HAS-BLED, ATRIA, ORBIT and HEMORR

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Risk Assessment; ROC Curve; Time Factors

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Retrospective Studies; Risk Assessment; Stroke; Treatment Outcome

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.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Aortic Valve; Aspirin; Bioprosthesis; Electrocardiography; Female; Fibrinolytic Agents; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Postoperative Complications; Practice Guidelines as Topic; Retrospective Studies; Thromboembolism

Randomized trials showed non-inferior or superior results of the non-vitamin-K-antagonist oral anticoagulants (NOACs) compared with warfarin. The aim of this study was to assess the effectiveness and safety of dabigatran (direct thrombin inhibitor) vs. acenocoumarol (vitamin K antagonist) in patients with atrial fibrillation (AF) in daily clinical practice.. In this observational study, we evaluated all consecutive patients who started anticoagulation because of AF in our outpatient clinic from 2010 to 2013. Data were collected from electronic patient charts. Primary outcomes were stroke or systemic embolism and major bleeding. Propensity score matching was applied to address the non-randomized design. In total, 920 consecutive AF patients were enrolled (442 dabigatran, 478 acenocoumarol), of which 2 × 383 were available for analysis after propensity score matching. Mean follow-up duration was 1.5 ± 0.56 year. The mean calculated stroke risk according to the CHA2DS2-VASc score was 3.5%/year in dabigatran vs. 3.7%/year acenocoumarol-treated patients. The actual incidence rate of stroke or systemic embolism was 0.8%/year [95% confidence interval (CI): 0.2-2.1] vs. 1.0%/year (95% CI: 0.4-2.1), respectively. Multivariable analysis confirmed this lower but non-significant risk in dabigatran vs. acenocoumarol after adjustment for the CHA2DS2-VASc score [hazard ratio (HR)dabigatran = 0.72, 95% CI: 0.20-2.63, P = 0.61]. According to the HAS-BLED score, the mean calculated bleeding risk was 1.7%/year in both groups. Actual incidence rate of major bleeding was 2.1%/year (95% CI: 1.0-3.8) in the dabigatran vs. 4.3%/year (95% CI: 2.9-6.2) in acenocoumarol. This over 50% reduction remained significant after adjustment for the HAS-BLED score (HRdabigatran = 0.45, 95% CI: 0.22-0.93, P = 0.031).. In 'real-world' patients with AF, dabigatran appears to be as effective, but significantly safer than acenocoumarol.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Blood Coagulation; Chi-Square Distribution; Dabigatran; Disease-Free Survival; Drug Monitoring; Electronic Health Records; Female; Hemorrhage; Humans; Incidence; International Normalized Ratio; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Netherlands; Patient Safety; Propensity Score; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stroke; Time Factors; Treatment Outcome

Bridging with low molecular weight heparins (LMWH) is used in patients undergoing invasive procedures that require interruption of vitamin K antagonists (VKA). Little is known on the mechanisms underlying observed thrombotic and bleeding events. In this exploratory study we investigated the interactive effects of the co-administration of VKA, LMWH and surgery on coagulation.. Blood was sampled daily from day -3 to day +5 in 13 patients. In addition to measurement of INR, anti-Xa activity, thrombin generation (TG) testing and assessment of its protein determinants was performed.. At the time of intervention the mean INR was 1.0 (SD 0.1, range 0.9-1.2); the mean residual anti-Xa level was 0.19 units/ml (SD 0.20 units/ml, range<0.05-0.60). The intervention caused a 2-3 fold increase in TG at day 0. Factor (F) XI had the strongest correlation with TG (peak and endogenous thrombin potential (ETP)) (r=0.6; p=0.02). Thrombomodulin-induced reduction of ETP increased from 10.0% (SD 9.2) at day -3 to 18.2% (SD 9.5) at day 0, p=0.02. After surgery, FVIII (175.9%(SD 58.9% to 246.7% (SD 71.4%); p=0.002) and fibrinogen (4.3 g/L (SD 1.1 g/L) to 5.6 g/L (SD 1.7 g/L); p=0.003) were significantly increased.. Residual anti-Xa activity was present in 84.6% of patients at the day of the intervention. Three prothrombotic mechanisms were exposed: FXI dependent TG, reduced activity of the activated protein C pathway and postoperative rises in FVIII and fibrinogen. For the perioperative management the value of TG merits further study.

Topics: Acenocoumarol; Aged; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Factor VIII; Female; Fibrinogen; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Perioperative Care; Surgical Procedures, Operative; Thromboembolism; Vitamin K

Essentials Minor bleeding is associated with subsequent major bleeding in patients treated with vitamin K antagonists. This study confirms that patients with minor bleeds have a 2.5-fold increased risk of major bleeds. A case-crossover analysis revealed that the increased risk is due to fixed underlying risk factors. Future research may unveil these unknown fixed risk factors and improve major bleeding risk scores.. Background Patients who have a minor bleed during treatment with vitamin K antagonists (VKAs) have a 3-fold increased risk of subsequent major bleeding. The nature of the underlying risk factors is largely unknown. Objectives To indicate why patients with minor bleeds are at increased risk of subsequent major bleeds (e.g. are risk factors of a transient or a fixed nature). Methods Patients who started VKA treatment between 2003 and 2013 were included. Exposure was from the minor bleed until 3 months later. We used two analyses: a Cox model which we adjusted for several known risk factors, and a case-crossover (CCO) design, which corrects for all fixed risk factors (such as chronic diseases and genes) as patients are compared with themselves. The combination of both analyses gives insight into whether the association of minor with major bleeds is a result of fixed or transient risk factors. Results Out of 26 130 patients who were included and followed for '61 672 patient years', 7194 experienced a minor bleed and 913 a major bleed. The Cox model indicated that patients with minor bleeds had a 2.5-fold increased risk of experiencing subsequent major bleeding after adjustment for known risk factors, whereas the CCO gave risk estimates around unity (odds ratio, 0.9; 95% confidence interval, 0.5-1.5). Conclusions The combination of both analyses indicates that minor bleeds are markers for fixed and currently unknown risk factors for major bleeding events.

Topics: Acenocoumarol; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Cohort Studies; Female; Fibrinolytic Agents; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Odds Ratio; Phenprocoumon; Proportional Hazards Models; Risk Factors; Vitamin K

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Polycythemia Vera; Proportional Hazards Models; Risk Factors; Smoking; Thrombophilia; Thrombosis; Warfarin

Oral anticoagulants are commonly used to treat patients with thromboembolic pathology. Genetic variations could influence personal response to anticoagulant drugs. Acenocoumarol (AC) is a vitamin K antagonist used in anticoagulant therapy and as a prophylaxis measure in Europe. In this study, we assessed the effect of CYP4F2 rs2108622, ABCB1, and GGCX polymorphisms on the safety profile and regime dosing of AC in patients with nonvalvular atrial fibrillation.. Fifty patients aged 40-70 years were included. All patients received AC in the dose of 1-6 mg daily with a target international normalized ratio of 2.0-3.0. Genotyping for polymorphism markers C3435T for the ABCB1 gene, rs2108622 for the CYP4F2 gene, and rs11676382 for the GGCX gene were designed using polymerase chain reaction and restriction fragment length polymorphism. Statistical analysis was performed using the Fisher exact test and the Mann-Whitney U test.. We found that CYP4F2 rs2108622 CT carriers required a higher AC dose than CC (p=0.0366), and CT and TT carriers required a higher AC dose than CC (p=0.0314).. We found that ABCB1 CT and TT genotypes are associated with a higher risk of bleeding. No influence of ABCB1 and GGCX polymorphisms on the doses of AC was established. CYP4F2 could still be a genetic factor responsible for the personal variability of AC metabolism.

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Carbon-Carbon Ligases; Cytochrome P450 Family 4; Dose-Response Relationship, Drug; Female; Hemorrhage; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Russia

Vitamin K antagonists (VKA) are widely used for the prevention and curative treatment of thromboembolic events. This study aims to describe the epidemiological, clinical and evolutionary aspects of overdose in Vitamin K antagonists administration and determine its hemorrhagic factors. We conducted a monocentric cross-sectional descriptive study at the Principal Hospital in Dakar. All patients with an INR greater than 5 were included. We studied patients' gender and age, VKA used, drug use period, indications, INR value, associated drugs, presence of hemorrhage, immediate management and evolution. We enrolled 154 patients. Acenocoumarol was the most prescribed VKA. Sex ratio favoured women. The average age was 63 years. Overdose was asymptomatic in 43% of patients. Hemorrhagic symptoms were mainly represented by gingival bleeding, epistaxis. Major bleeding episodes were found in 8.6% of patients and they were represented by melena in 6 patients (3.9%), deep muscle hematoma in 2 patients (1.3%) and intracerebral parenchymal hematoma in 2 patients. Two patients had cardiovascular collapse associated with deglobulisation. Nonsteroidal anti-inflammatory drugs (NSAIDs) assumption was noted in 21% of patients. VKA assumption was suspended transiently in all patients. Mortality was 2%, due to intracranial hemorrhage. The reduction in VKA overdose requires caregivers to manage overdose factors and provide proper patient education.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Cross-Sectional Studies; Drug Overdose; Female; Hematoma; Hemorrhage; Humans; International Normalized Ratio; Intracranial Hemorrhages; Male; Middle Aged; Senegal; Vitamin K; Young Adult

Risk scores for patients who are at high risk for major bleeding complications during treatment with vitamin K antagonists (VKAs) do not perform that well. BLEEDS was initiated to search for new biomarkers that predict bleeding in these patients.. To describe the outline and objectives of BLEEDS and to examine whether the study population is generalizable to other VKA treated populations.. A cohort was created consisting of all patients starting VKA treatment at three Dutch anticoagulation clinics between January-2012 and July-2014. We stored leftover plasma and DNA following analysis of the INR.. Of 16,706 eligible patients, 16,570 (99%) were included in BLEEDS and plasma was stored from 13,779 patients (83%). Patients had a mean age of 70 years (SD 14), 8713 were male (53%). The most common VKA indications were atrial fibrillation (10,876 patients, 66%) and venous thrombosis (3920 patients, 24%). 326 Major bleeds occurred during 17,613 years of follow-up (incidence rate 1.85/100 person years, 95%CI 1.66-2.06). The risk for major bleeding was highest in the initial three months of VKA treatment and increased when the international normalized ratio increased. These results and characteristics are in concordance with results from other VKA treated populations.. BLEEDS is generalizable to other VKA treated populations and will permit innovative and unbiased research of biomarkers that may predict major bleeding during VKA treatment.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Longitudinal Studies; Male; Middle Aged; Phenprocoumon; Prognosis; Risk Factors; Venous Thrombosis; Vitamin K

Vitamin K antagonists, despite their tight therapeutic spectrum and the fear of bleeding complications, were long the most important drugs used in anticoagulant therapy. The aim of this study was to evaluate the quality of anticoagulant therapy and its relation with bleedings in everyday clinical practice.. We analyzed the data of 272 patients with non-valvular atrial fibrillation treated in our county hospital using retrospective data collection of the last 1008±384 days. The INR (International Normalized Ratio) values and the time in therapeutic range (TTR) were analyzed. We asked patients about bleeding complications and searched the medical records.. The TTR proved to be 64% and there was no statistically significant difference between that of 252 (92.7%) patients taking acenocoumarol and 20 (7.3%) on warfarin. Analyzing various factors leading to TTR under 70%, we found that none of them have a significant impact. Significantly more bleeding events occurred in the first 3 months after the initiation of anticoagulant therapy and in patients with TTR under 70%, but the latter was not significant after adjustment for factors influencing bleeding (OR 1.607, CI 0.571-4.522, p=0.392).. Although the present study's TTR values were similar to those found in the warfarin branch of various large-scale international trials and in real-life settings, further improvement of vitamin K antagonist therapy are necessary. As the possibilities for this are limited, we believe that the new type anticoagulant agents have a place in everyday clinical practice.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Hungary; Male; Retrospective Studies; Statistics, Nonparametric; Time Factors; Vitamin K; Warfarin

Time in therapeutic range (TTR) reflects the quality of anticoagulation and is inversely correlated with ischemic stroke in atrial fibrillation (AF) patients. Few data on the relationship between TTR and myocardial infarction (MI) are available. We investigated the association between TTR and Major Adverse Cardiovascular Events (MACE) in a cohort of anticoagulated AF patients.. We calculated TTR for 627 AF patients on vitamin K antagonists, who were followed for a median of 30.8 months (1755 patients/year). The primary outcome was a combined endpoint of MACE including fatal/nonfatal MI and cardiovascular death.. Mean age was 73.3 (±8.2) years, and 40.2% were women. During follow-up, we recorded 67 events: 19 stroke/TIA (1.1%/year) and 48 MACE (2.9%/year): 24 MI and 24 cardiovascular deaths. The cohort was categorized according to tertiles of TTR values: TTR 13-58%, 59-74%, and 75-100%. There was a significant increased rate of MACE across tertiles of TTR (Log-Rank test: p<0.001). On Cox proportion hazard analysis, the 2nd vs. 1st tertile of TTR (p=0.002, hazard ratio [HR] 0.347, confidence interval [CI] 95% 0.177-0.680), 3rd vs. 1st tertile of TTR (p<0.001, HR 0.164, CI 95% 0.067-0.402), age (p<0.001, HR 1.094, CI 95% 1.042-1.148), history of stroke/TIA (p=0.015, HR 2.294, CI 95% 1.172-4.490) and smoking (p=0.003, HR 3.450, CI 95% 1.532-7.769) predicted MACE.. TTR was an independent predictor of MACE in our cohort of AF patients. Our findings suggest that a good anticoagulation control is necessary to reduce not only the risk of stroke but also that of MACE.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Myocardial Infarction; Patient Outcome Assessment; Proportional Hazards Models; Prospective Studies; Regression Analysis; Stroke; Vitamin K; Warfarin

Topics: Acenocoumarol; Aged; Anticoagulants; Cross-Sectional Studies; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Randomized Controlled Trials as Topic; Residence Characteristics; Spain; Thromboembolism; Warfarin

Patients with non-valvular atrial fibrillation who are receiving or have been previously exposed to a vitamin K antagonist could be switched to a non-vitamin K-antagonist oral anticoagulant (NOAC) but little information is available about the risk of bleeding and arterial thromboembolism after such a switch. We aimed to compare the risk of bleeding between individuals who switched and those who remained on a vitamin K antagonist (non-switchers) in real-world conditions.. We did a matched-cohort study with information from French health-care databases. We extracted data for adults (aged ≥18 years) with non-valvular atrial fibrillation who received their first prescription for a vitamin K antagonist (fluindione, warfarin, or acenocoumarol) between Jan 1, 2011, and Nov 30, 2012, and who were either switched to a NOAC (dabigatran or rivaroxaban) or maintained on the vitamin K antagonist. Each switcher was matched with up to two non-switchers on the basis of eight variables, including sex, age, and international normalised ratio number. The primary endpoint was incidence of bleeding (intracranial haemorrhage, gastrointestinal haemorrhage, or other) in switchers versus non-switchers, and switchers stratified by type of NOAC versus non-switchers, noted from databases of hospital admissions. Each patient was followed up to 1 year; the study closed on Oct 1, 2013.. Of 17,410 participants, 6705 switched to a NOAC (switchers) and 10,705 remained on vitamin K-antagonist therapy (non-switchers). Median age of participants was 75 years (IQR 67-82), 8339 (48%) were women, and the median duration of vitamin K-antagonist exposure before a switch was 8.1 months (IQR 3.9-14.0). After a median follow-up of 10.0 months (IQR 9.8-10.0), we noted no difference between groups for bleeding events (99 [1%] in switchers vs 193 [2%] in non-switchers, p=0.54). In adjusted multivariate analyses, the risk of bleeding in switchers was not different from that in non-switchers (hazard ratio [HR] 0.87; 95% CI 0.67-1.13, p=0.30). Additionally, no differences were noted when the risk of bleeding was compared between switchers from a vitamin K antagonist to dabigatran (HR 0.78, 95% CI 0.54-1.09, p=0.15), switchers from a vitamin K antagonist to rivaroxaban (HR 1.04, 95% CI 0.68-1.58, p=0.86), and non-switchers.. In this matched-cohort study, our findings suggest that patients with non-valvular atrial fibrillation who switch their oral anticoagulant treatment from a vitamin K antagonist to a non-vitamin K antagonist are not at increased risk of bleeding. Future studies with longer follow-up might be needed.. None.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Phenindione; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Thromboembolism; Vitamin K; Warfarin

Topics: Acenocoumarol; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Stroke

To identify, in a case-control study, the risk factors associated with a thrombotic or bleeding event in patients treated with vitamin K antagonists.. We performed a single-centre observational study during a three-month period where we consecutively included patients admitted to the emergency department of a secondary-level hospital and treated with vitamin K antagonists, regardless the reason for admission. Patients admitted for a thrombotic or bleeding event were included as cases and the other patients served as controls. Main thrombotic or bleeding risk factors during vitamin K antagonist therapy were a priori identified in literature and tested in conditional logistic regression.. Two hundred and forty subjects were identified, 40 of which (17%) were admitted for a bleeding event, 19 (8%) for a thrombotic event and 181 (75%) for another reason. Over 85% of patients were treated with fluindione. No risk factor was significantly associated with bleeding or thrombotic event in patients treated with vitamin K antagonist. Patients presenting a thrombotic event were however more likely to have a chronic respiratory disease.. In this study, no risk factor significantly associated with a bleeding or thrombotic event in patients treated with vitamin K antagonist were identified. The occurrence of these events supposes other risk factors, including potential genetic polymorphisms that should be considered in future studies.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Drug Interactions; Emergency Service, Hospital; Female; Genetic Predisposition to Disease; Hemorrhage; Humans; International Normalized Ratio; Male; Phenindione; Respiration Disorders; Risk Factors; Secondary Care Centers; Thrombosis; Vitamin K; Warfarin

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.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Alleles; Anticoagulants; Apolipoproteins E; ATP Binding Cassette Transporter, Subfamily B; Atrial Fibrillation; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Female; Follow-Up Studies; Genetic Association Studies; Genotype; Hemorrhage; Humans; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Venous Thromboembolism; Vitamin K Epoxide Reductases

The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug-drug interactions (DDIs) in older adults.. All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate.. Amongst all the ADR reporting forms (n=1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n=122, 35.5%), allergic reactions (n=56, 16.3%), and elevated International Normalized Ratio (INR>6, n=54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n=5); warfarin and a statin (major, n=38); warfarin and a proton pump inhibitor (moderate, n=40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%).. DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly.

Topics: Acenocoumarol; Age Factors; Aged; Allopurinol; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hematologic Agents; Hemorrhage; Humans; International Normalized Ratio; Italy; Male; Prevalence; Proton Pump Inhibitors; Warfarin

Polymorphisms in CYP2C9 can vary the rate of metabolic clearance of oral anticoagulants, risking toxicity in patients. The present study focused on exploring the genetic etiology of idiopathic hyper sensitivity to coumarin anticoagulants in a patient who presented with multiple bleeding episodes and supra-elevated International Normalized Ratios.. Bidirectional gene sequencing of CYP2C9 and VKORC1 was carried out. Using allele-specific polymerase chain reaction, the identified novel variant was genotyped in 309 patients on anticoagulation therapy. The pharmacoproteomic significance of the novel genetic variant was elucidated by structural demonstration of binding of coumarin molecules within the mutant CYP2C9 204His protein model and in silico bioinformatic evolutionary analyses. Three-dimensional structure model of the mutant protein was constructed on the basis of the published X-ray crystal structure of human CYP2C9 protein (Protein Data Bank, 1R9O).. The patient was identified to have a novel heterozygous missense mutation in exon 4 of CYP2C9 gene (g.9172A > C; p.Asn204His; CYP2C9*57). The variant was absent in the 309 genotyped patients. In silico bioinformatic analyses indicated the variant to have a deleterious effect on the protein. Analysis of 3D structure model of the mutant protein revealed that the substituted His204 led to restricted binding of the coumarin drug within the binding site of CYP2C9 enzyme, thereby inhibiting its metabolic clearance and thus explaining the enhanced pharmacologic effect and bleeding in the patient.. The study elucidates the structurally deleterious role of the novel CYP2C9*57 missense mutation in coumarin toxicity.

Topics: Acenocoumarol; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Base Sequence; Binding Sites; Coumarins; Cytochrome P-450 CYP2C9; Female; Flurbiprofen; Genotype; Hemorrhage; Humans; International Normalized Ratio; Middle Aged; Molecular Docking Simulation; Mutation, Missense; Protein Binding; Warfarin

For patients who survive intracerebral haemorrhage (ICH) during treatment with oral anticoagulation (OAC), the balance between the benefits and risks of restarting OAC is unclear. The decision to restart OAC or to start antiplatelet therapy in these patients therefore poses a dilemma for all physicians involved. We assessed the long-term outcome of patients who did or did not restart antithrombotic therapy after OAC-associated ICH.. We conducted a retrospective follow-up study of all patients discharged from our institution after OAC-associated ICH over a 10-year period. Data on the use of OAC or platelet inhibitors and the occurrence of vascular events during follow-up were assessed through questionnaires and patient files. The primary outcome was recurrent fatal or non-fatal stroke. Secondary outcomes were the occurrence of other haemorrhagic, thrombotic or thromboembolic events. With patients without antithrombotic treatment as reference, we calculated incidence ratios with corresponding 95% confidence intervals (CI) for treatment with OAC and for treatment with antiplatelet therapy.. We included 38 patients, of whom 21 (55%) died during a mean follow-up of 3.5 years. The medication regime changed frequently during follow-up, illustrated by the fact that two thirds of the patients who had resumed OAC within 2 months of ICH terminated this at later points in time. Two recurrent strokes occurred during 35.4 patient-years without antithrombotic medication, 7 during 63.8 patient-years on antiplatelet medication (incidence ratio 1.9; 95% CI, 0.4-9.4), and 3 during 19.5 patient-years on OAC (incidence ratio 2.7; 95% CI, 0.5-16.3). There was only 1 recurrent ICH, which occurred during treatment with OAC.. In this observational study, no significant difference in the primary outcome measure was found between the treatment groups, but there was a tendency towards a higher long-term risk of any stroke in patients who resumed OAC or started antiplatelet therapy. However, based on these results it is difficult to draw any concrete conclusions or make any strong recommendations. A randomized trial to assess the optimal long-term strategy after OAC-related ICH is warranted. Based on the point estimates of our study, such a trial should involve at least 300 patient-years of follow-up.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Platelet Aggregation Inhibitors; Recurrence; Retrospective Studies; Risk Factors; Stroke; Surveys and Questionnaires; Survival Analysis; Thromboembolism; Treatment Outcome

The aim of this study was to test the hypothesis that a specific bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), was better at predicting major bleeding compared with CHADS2 (congestive heart failure, hypertension, 75 years of age or older, diabetes mellitus, and previous stroke or transient ischemic attack) and CHA2DS2-VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) in anticoagulated atrial fibrillation (AF) patients.. The CHADS2 and CHA2DS2-VASc scores are well-validated stroke risk prediction scores for AF, but are also associated with increased bleeding and mortality.. We recruited 1,370 consecutive AF patients (49% male; median age, 76 years) receiving oral anticoagulation therapy from our outpatient anticoagulation clinic, all of whom were receiving acenocoumarol and had an international normalized ratio between 2.0 and 3.0 during the preceding 6 months. During follow-up, major bleeding events were identified by the 2005 International Society on Thrombosis and Haemostasis criteria. Model performance was evaluated by calculating the C-statistic, and the improvement in predictive accuracy was evaluated by calculating the net reclassification improvement and integrated discrimination improvement.. After a median follow-up of 996 (range, 802 to 1,254) days, 114 patients (3.0%/year) presented with a major bleeding event; 31 of these events were intracranial hemorrhages (0.8%/year). Based on the C-statistic, HAS-BLED had a model performance superior to that of both CHADS2 and CHA2DS2-VASc (both p < 0.001). Both net reclassification improvement and integrated discrimination improvement analyses also show that HAS-BLED was more accurately associated with major bleeding compared with CHADS2 and CHA2DS2-VASc scores.. In anticoagulated AF patients, a validated specific bleeding risk score, HAS-BLED, should be used for assessing major bleeding. The practice of using CHADS2 and CHA2DS2-VASc as a measure of high bleeding risk should be discouraged, given its inferior predictive performance compared with the HAS-BLED score.

Topics: Acenocoumarol; Adult; Age Factors; Aged; Alcohol Drinking; Anticoagulants; Atrial Fibrillation; Diabetes Complications; Female; Follow-Up Studies; Heart Failure; Hemorrhage; Humans; Hypertension; International Normalized Ratio; Ischemic Attack, Transient; Kidney; Liver; Male; Middle Aged; Predictive Value of Tests; Risk Assessment; Risk Factors; Stroke; Substance-Related Disorders

There are well defined indications in which chronic anticoagulant treatment has been widely applied. However, complications of this therapy are less discussed, although these complications may lead to serious or even fatal consequences.. The aim of the authors was to analyze data of patients admitted to their multidisciplinary intensive care unit for complications of chronic anticoagulant therapy between January 1, 2006 and December 31, 2011.. Data of 73 patients admitted for serious hemorrhagic complications of chronic anticoagulant therapy were retrospectively analysed.. Of the 73 patients, 63 patients had intracranial bleeding, most of them with traumatic origin. A few patients with other hemorrhagic complications such as spinal hematoma, gastrointestinal bleeding, hemorrhagic cystitis, hemothorax and intraabdominal bleeding were also noted. The INR values were out of therapeutic range in 43 patients. The mortality of patients was very high in spite of complex intensive care; 49 of the 73 patients (75.5%) died due to hemorrhagic complications.. Due to the high proportion of traumatic origin, the large number of out-of-range INR, and the high mortality, the authors strongly believe that regular patient follow-up, transmission of detailed information, and time-to-time reevaluation of the indications and contraindications of chronic anticoagulant therapy could help to decrease the number of serious and fatal complications of chronic anticoagulant therapy.. Bevezetés: A krónikus antikoaguláns kezelést jól körülhatárolt indikációs körrel, széles körben alkalmazzák. Kevesebb szó esik azonban az általa okozott vérzéses szövődményekről, amelyek súlyosak vagy akár halálos kimenetelűek is lehetnek. Célkitűzés: A Szent János Kórház és Észak-budai Egyesített Kórházak Központi Aneszteziológiai és Intenzív Terápiás Osztályán 2006. január 1. és 2011. december 31. között krónikus antikoaguláns kezelés kapcsán kialakult vérzéses szövődményes esetek elemzése. Módszer: A szerzők multidiszciplináris intenzív osztályán a vizsgált hat év alatt összesen 73 betegnél fordult elő intenzív ellátást igénylő vérzéses szövődmény krónikus antikoagulálás kapcsán. Eredmények: Hatvanhárom esetben intracranialis vérzést észleltek, ezen belül leggyakrabban traumás eredetűt. Kisebb számban előfordult még spinalis haematoma, gastrointestinalis vérzés, haemorrhagiás cystitis, haemothorax és hasüregi vérzés. A betegek felvételi INR-értéke 43 esetben a terápiás tartományon kívül esett. A betegek mortalitása igen magas volt, a komplex intenzív kezelés ellenére 49 beteg halt meg a vérzéssel összefüggésben (75,5%). Következtetések: A gyakori traumás eredetre, a terápiás tartományon kívül eső INR-értékek nagy számára és a magas mortalitásra tekintettel a szerzők véleménye szerint rendszeres betegkövetéssel, részletes felvilágosítással, a társbetegségek alakulásával párhuzamosan revideált indikáció/kontraindikáció alapján folytatott krónikus antikoaguláns kezeléssel a vérzéses szövődmények száma csökkenthető lenne. Orv. Hetil., 2013, 154(46), 1829–1835.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Critical Care; Cystitis; Drug Administration Schedule; Female; Gastrointestinal Hemorrhage; Hemorrhage; Hemothorax; Humans; Hungary; Intensive Care Units; International Normalized Ratio; Intracranial Hemorrhages; Male; Middle Aged; Retrospective Studies; Warfarin

Topics: Acenocoumarol; Aged; Amiodarone; Anemia; Anti-Arrhythmia Agents; Anticoagulants; Dyspnea; Hemoptysis; Hemorrhage; Humans; Lung Diseases; Male

Topics: Acenocoumarol; Administration, Topical; Aged; Anticoagulants; Antifungal Agents; Blood Coagulation; Ciclopirox; Drug Interactions; Drug Monitoring; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Pyridones

The objective of this study was to identify the most clinically relevant drug-drug interactions (DDIs) at risk of affecting acenocoumarol safety in our tertiary care university hospital, a 2,000 bed institution.. We identified DDIs occurring with acenocoumarol by combining two different sources of information: a 1-year retrospective analysis of acenocoumarol prescriptions and comedications from our Computerized Physician Order Entry (CPOE) system (n = 2,439 hospitalizations) and a retrospective study of clinical pharmacology consultations involving acenocoumarol over the past 14 years (1994-2007) (n = 407). We classified these DDIs using an original risk-analysis method. A criticality index was calculated for each associated drug by multiplying three scores based on mechanism of interaction, involvement in a supratherapeutic international normalized ratio (INR) (≥ 6) and involvement in a severe bleeding.. One hundred and twenty-six DDIs were identified and weighted. Twenty-eight drugs had a criticality index ≥ 20 and were therefore considered at high risk for interacting with acenocoumarol by increasing its effect: 75% of these drugs involved a pharmacokinetic mechanism and 14 % a pharmacodynamic mechanism. An unknown mechanism of interaction was involved in 11 % of drugs.. Twenty-eight specific drugs were identified as being at high risk for interacting with acenocoumarol in our hospital using an original risk-analysis method. Most analyzed drugs interact with acenocoumarol via a pharmacokinetic mechanism. Actions such as the implementation of alerts in our CPOE system should be specifically developed for these drugs.

Topics: Acenocoumarol; Adverse Drug Reaction Reporting Systems; Anticoagulants; Blood Coagulation; Drug Interactions; Drug Prescriptions; Hemorrhage; Hospital Bed Capacity; Hospitals, University; Humans; International Normalized Ratio; Medical Order Entry Systems; Medication Errors; Odds Ratio; Retrospective Studies; Risk Assessment; Risk Factors; Switzerland; Tertiary Care Centers; Time Factors

Bleeding into the lung parenchyma is a rare phenomenon that usually occurs as a result of chest trauma, other causes are anticoagulant therapy, and infections. The following case presents a patient admitted to the hospital due to haemoptysis, which was a symptom of bleeding into the emphysematosus bulla caused by anticoagulation therapy. The decisive diagnostic examination was chest magnetic resonance. This imaging method allows the precise differentiation of tissues. Using modern imaging techniques can often dispense with invasive diagnostic methods.

Topics: Acenocoumarol; Anticoagulants; Blister; Diagnosis, Differential; Emphysema; Hemoptysis; Hemorrhage; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism; Tuberculosis, Pulmonary

Atrial fibrillation is a risk factor for ischemic stroke. To prevent stroke oral anticoagulants can be administered. Old and new types of anticoagulants are available. Nowadays, old type, acenocumarol based anticoagulants are used preferentially in Hungary.. The advantages and the disadvantages of anticoagulants are well known, but anticoagulants are underused in many cases.. The authors retrospectively examined how frequent atrial fibrillation was and whether the usage of anticoagulants in practice was in accordance with current guidelines among acute stroke cases admitted to the Department of Neurology, Medical and Health Science Centre of Debrecen University in 2009.. Of the 461 acute stroke cases, 96 patients had known and 22 patients had newly discovered atrial fibrillation. Half of the patients did not receive proper anticoagulation. Only 8.4% of them had their INR levels within the therapeutic range.. The findings are similar to those reported in other studies. Many factors may contribute to the high proportion of improper use of anticoagulants, and further investigations are needed to determine these factors. In any case, elimination of these factors leading to a failure of anticoagulation may decrease the incidence of stroke.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Drug Prescriptions; Female; Hemorrhage; Humans; Hungary; Incidence; International Normalized Ratio; Male; Middle Aged; Retrospective Studies; Risk Factors; Stroke; Treatment Outcome

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.

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; International Normalized Ratio; Lower Extremity; Male; Middle Aged; Treatment Outcome; Venous Thrombosis; Warfarin

Acenocoumarol is a vitamin K antagonist that is used for the treatment of acquired and congenital, both arterial and venous, thrombotic diseases. Its use is complicated by the narrow therapeutic range. Bleeding following oral anticoagulation, despite rare, remains the major complication. Most cases of hemorrhagic episodes usually require short hospitalization and transfusion, while surgical drainage of the hematoma is not recommended. However, in cases that conservative treatment isn't successful, surgical intervention remains an option. We present a case of severe spontaneous bleeding of the rectus abdominis muscle which was successfully managed surgically.

Topics: Abdominal Wall; Acenocoumarol; Aged; Anticoagulants; Female; Hemorrhage; Humans

Topics: Acenocoumarol; Adrenal Cortex Function Tests; Adrenal Gland Diseases; Adrenal Glands; Adrenal Insufficiency; Adrenocorticotropic Hormone; Anticoagulants; Antiphospholipid Syndrome; Female; Fluorodeoxyglucose F18; Hemorrhage; Hemothorax; Hormone Replacement Therapy; Humans; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thromboembolism

The study included 52 patients at a high risk of thromboembolic complications, with permanent atrial fibrillation. All patients were treated with acenocoumarol for 6 months and the incidence of hemorrhages was evaluated in all of them. All patients were genotyped by CYP2C9 and VKORC1. The presence of CYP2C9*2 and CYP2C9*3 alleles of CYP2C9 locus and AA genotype of VCORC1 gene polymorphic G-1639(3673)A marker was not associated with the development of hemorrhages under conditions of acenocoumarol treatment (p=0.144 for CYP2C9, p=0.809 and 0.918 for VCORC1 in the total group and subgroup of patients with CYP2C9*1/*1 genotype, respectively). The search for other genetic markers of acenocoumarol efficiency and safety is needed for predicting the risk of hemorrhages during this treatment.

Topics: Acenocoumarol; Alleles; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Atrial Fibrillation; Cytochrome P-450 CYP2C9; Genetic Loci; Genotype; Genotyping Techniques; Hemorrhage; Humans; International Normalized Ratio; Mixed Function Oxygenases; Polymorphism, Genetic; Retrospective Studies; Risk; Russia; Thromboembolism; Vitamin K Epoxide Reductases

Although prothrombin complex concentrate (PCC) is often used to counteract vitamin K antagonist (VKA) therapy, evidence regarding the optimal dose for this indication is lacking. In Dutch hospitals, either a variable dose, based on body weight, target INR (international normalised ratio) and initial INR, or a fixed dose is used.. In this observational, pilot study, the efficacy and feasibility of the fixed dose strategy compared to the variable dosing regimen, is investigated.. Consecutive patients receiving PCC (Cofact®, Sanquin, Amsterdam) for VKA reversal because of a major non-cranial bleed or an invasive procedure were enrolled in two cohorts. Data were collected prospectively in the fixed dose group, cohort 1, and retrospectively in the variable dose regimen, cohort 2. Study endpoints were proportion of patients reaching target INR and successful clinical outcome.. Cohort 1 consisted of 35 and cohort 2 of 32 patients. Target INR was reached in 70% of patients in cohort 1 versus 81% in cohort 2 (P = 0·37). Successful clinical outcome was seen in 91% of patients in cohort 1 versus 94% in cohort 2 (P = 1·00). Median INR decreased from 4·7 to 1·8 with a median dosage of 1040 IU factor IX (F IX) in cohort 1 and from 4·7 to 1·6 with a median dosage of 1580 IU F IX in cohort 2.. This study suggests that a fixed dose of 1040 IU of F IX may be an effective way to rapidly counteract VKA therapy in our patient population and provides a basis for future research.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Antidotes; Blood Coagulation Factors; Cohort Studies; Dose-Response Relationship, Drug; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Phenprocoumon; Prospective Studies; Retrospective Studies; Vitamin K; Warfarin

Vitamin K antagonists (VKA) are effective in primary and secondary prevention of thromboembolism, but the associated risk of bleeding is an important limitation. The majority of bleeds are clinically mild. In this study, we assessed whether these minor bleeds are associated with major bleeding, when controlling for other important risk indicators, including the achieved quality of anticoagulation. For this, 5898 patients attending a specialized anticoagulation clinic were retrospectively studied for 1 year after initiation of VKA therapy. The risk of major bleeding was estimated using a multivariate piecewise exponential model with time-varying exposure for occurring minor bleeds. In patients with a minor bleed (N=1015) subsequent major bleeding occurred more frequently than in patients without a minor bleed (N=4883), with an incidence rate of 2·3 [95% confidence interval (CI) 1·4-3·7] vs. 1·2 per 100 person-years (95% CI 0·9-1·7). The adjusted relative risk of subsequent major bleeding after a minor bleed was 2·9 (95% CI 1·1-7·2, P =0·024). The percentage of time that a patient had an International Normalized Ratio (INR) above 5 was also independently associated with major bleeding, with a 2·2-fold increased risk in patients with at least 9% of time above INR 5 (95% CI 1·3-4·0, P=0·006). Minor bleeds alert for subsequent major bleeding, independent of the quality of anticoagulation.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Epidemiologic Methods; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Prognosis; Recurrence; Thromboembolism; Vitamin K

The aim of this study was to investigate the effects of co-medication with selective serotonin re-uptake inhibitors (SSRIs) on overanticoagulation during acenocoumarol maintenance treatment.. All subjects from The Rotterdam Study who received acenocoumarol maintenance treatment between April 1 1991 and September 9 2009 were followed for the event of an international normalized ratio (INR) ≥6, until death, end of treatment or end of the study period. With the Andersen-Gill extension of the Cox proportional hazards model, risks for repeated events of overanticoagulation in relation to concomitant SSRI use were calculated.. The risk for overanticoagulation during acenocoumarol maintenance treatment was increased in combination with fluvoxamine (HR 2.63, 95% CI 1.49, 4.66) and venlafaxine (HR 2.19, 95% CI 1.21, 3.99). There was no increase in risk for the other SSRIs, but numbers of exposed cases were low for all SSRIs except paroxetine.. Fluvoxamine and venlafaxine were associated with a more than double risk of INR values ≥6 in acenocoumarol treated subjects.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Antidepressive Agents; Blood Coagulation; Cohort Studies; Cyclohexanols; Drug Interactions; Fluvoxamine; Hemorrhage; Humans; Middle Aged; Proportional Hazards Models; Risk Factors; Selective Serotonin Reuptake Inhibitors; Serotonin; Venlafaxine Hydrochloride

A case report of young woman diagnosed as having microscopic polyangiitis (MPO) presenting with diffuse alveolar hemorrhage (DAH). DAH is a rare, but life-threatening disorder. The patients presented with dyspnea, cough, hemoptysis (not constant). The radiographic features are very characteristic and reveal the signs of diffuse, bilateral alveolar filling in chest HRCT especially in middle and lower zones. Anaemia with iron deficiency and hypoxic respiratory failure. Elevation of diffuse capacity (above 30% of predicted) is often recognized as a result of presence of blood in the alveoli. Broncho-alveolar lavage reveal haemosiderin laden macrophages. It may occurs most frequently as a secondary condition due to microscopic polyangiitis (MPA), Wegener's granulomatosis (WG), Goodpasture syndrome. Among the many conditions it can accompany connective tissue disorders, antiphospholipid antibody syndrome, some medicines or toxic exposures.

Topics: Acenocoumarol; Anticoagulants; Diagnosis, Differential; Dyspnea; Female; Hemoptysis; Hemorrhage; Humans; Lung Diseases, Interstitial; Microscopic Polyangiitis; Venous Thrombosis

The variability in warfarin dose requirement is attributable to genetic and environmental factors. Acenocoumarol (AC) and phenprocoumon (PC) are coumarin derivates widely prescribed in European countries for the prevention and treatment of thromboembolic events. The aim of our study was to investigate the contribution of genes involved in the vitamin K cycle to AC and PC maintenance doses.. Common single nucleotide polymorphisms (SNPs) in the genes encoding cytochrome P450 family member 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU) and apolipoprotein E (APOE) were studied in 206 patients receiving AC or PC.. Compared to patients with the VKORC1 C1173C genotype, maintenance doses for AC or PC were reduced to 74.6 or 70.2% in heterozygous C1173T subjects and to 48.6 or 48.1% in homozygous T1173T subjects (P < 0.0001). Furthermore maintenance doses for AC and PC were significantly lower in heterozygous CYP2C9*1*3, CYP2C9*2*3, and in CYP2C9*3*3 homozygote individuals compared to homozygous CYP2C9*1*1 subjects (P = 0.0004 and P = 0.0017, respectively). A multiple regression model including age, sex, last INR, VKORC1, and CYP2C9 genotypes explained ~50% of the variability in AC/PC dose requirements. CALU genotype combinations showed minor effects on PC dose requirements. No associations with AC or PC dose requirements were observed for sequence substitutions in the GGCX or APOE genes.. These results reveal that interindividual variability in weekly AC and PC maintenance dose requirement is mainly dependent on the VKORC1 1173C>T and the CYP2C9*3 alleles. VKORC1 and CYP2C9 genotyping might provide helpful information to prevent serious bleeding events in subjects receiving AC or PC.

Topics: Acenocoumarol; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Apolipoproteins E; Aryl Hydrocarbon Hydroxylases; Calcium-Binding Proteins; Carbon-Carbon Ligases; Chi-Square Distribution; Cytochrome P-450 CYP2C9; Female; Gene Frequency; Genotype; Hemorrhage; Heterozygote; Homozygote; Humans; Male; Middle Aged; Mixed Function Oxygenases; Phenotype; Phenprocoumon; Polymorphism, Single Nucleotide; Regression Analysis; Vitamin K Epoxide Reductases; Young Adult

Patients with mechanical heart valve prostheses are obligated to receive lifelong oral anticoagulant therapy to prevent thromboembolic complications; however, this treatment is associated with an increased risk of bleeding. The aim of this study was to evaluate the frequency of major hemorrhagic and thromboembolic complications in patients with mechanical heart valves who received oral anticoagulant therapy.. The analysis involved 225 patients who underwent successful surgery in 2000; the mean (+/-SD) follow-up period was 43.3 +/- 9.2 months. Aortic, mitral, and double valve replacement was performed in 128 (56.7%), 70 (31.1%), and 27 (12.1%) of the patients, respectively. There were 128 men (57.3%), and the mean patient age was 57.9 +/- 18.8 years. The following data were assessed: rate of major hemorrhagic and thromboembolic complications, frequency of international normalized ratio (INR) rate measurements, and percentage of results within the therapeutic range.. Major hemorrhagic and thromboembolic complications occurred in 25 patients (11.1%). Seventeen patients (7.5%) survived, and 8 (3.6%) died of the complications. Major hemorrhagic and thromboembolic complications occurred in 17 patients (7.6%) and 8 patients (3.6%), respectively. The mean time between sequential measurements was 4.3 +/- 3.0 weeks, and of all the INR values collected, 42.4% were within, 31.3% were below, and 26.3% were above the target ranges.. Patients with a mechanical heart valve prosthesis receiving acenocoumarol are susceptible to major hemorrhagic and thromboembolic complications, some of which lead to death. Despite the danger related to these complications, patients receiving anticoagulant therapy still have difficulty achieving INR values within the therapeutic range.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Female; Follow-Up Studies; Heart Valve Diseases; Heart Valve Prosthesis; Hemorrhage; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Risk Factors; Survival Rate; Thromboembolism

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Drug Monitoring; Enoxaparin; Factor VII Deficiency; Hemorrhage; Humans; International Normalized Ratio; Male; Risk Assessment; Thrombosis; Time Factors; Treatment Outcome

To analyse incidence of hemorrhagic and thrombotic events in a series of ambulatory patients receiving acenocoumarol in a rural area of Spain (1997-2007).. Out of 1,544 patients, 1,086 are receiving acenocoumarol at present (2% of our region's population). The total follow-up was 5,462 patients-years. Median age was 74 years. INR therapeutic range was 2.0-3.0 in 82.5%. Atrial fibrillation (AF) was the most frequent indication (73%). Incidence of hemorrhagic and thrombotic events was 2.27 and 0.2/100 patients-year, respectively. Gastrointestinal tract was the most frequent site of bleeding. In multivariate analysis, patients with AF and prosthetic heart valves (PHV) had increased risk of bleeding (OR 2.1 and 4.8, respectively). Age and therapeutic ranges of INR were not associated with increased risk of bleeding.. 2% of our population is receiving acenocoumarol. Incidence of hemorrhagic and thrombotic events was low. Patients with AF and PHV had increased risk of bleeding.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care; Cohort Studies; Female; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Outpatient Clinics, Hospital; Prospective Studies; Risk Factors; Spain; Thrombosis; Treatment Outcome; Young Adult

Topics: Acenocoumarol; Anticoagulants; Hemorrhage; Humans; International Normalized Ratio; Phenprocoumon; Risk Factors; Thromboembolism; Time Factors

Subtherapeutic anticoagulation levels increase both the risk and severity of thromboembolism. The aim of this study was to determine the cumulative incidence of subtherapeutic international normalised ratios (INRs) and to identify risk factors associated with a low INR. We performed a cohort study in 7,419 patients from a Dutch anticoagulation clinic. Patients who started a first treatment with oral anticoagulants between January 2000 and December 2005 and who were stably anticoagulated (4 consecutive INRs in the therapeutic range) were included. Within the cohort a nested case control study was performed to identify risk factors of subtherapeutic INRs and to determine how often a subtherapeutic INR is the result of medical interference in case of invasive procedures, hospital admissions, haemorrhage or overanticoagulation. In patients with a stable anticoagulation, the median time to a first low INR was 40 weeks. A subtherapeutic INR occurred twice as often in patients using acenocoumarol as in those using phenprocoumon (hazard ratio [HR] 2.1, 95% confidence interval [95%CI]:2.0 - 2.3) and was more common in patients with a high therapeutic range compared to a low therapeutic range (HR 1.8, 95%CI:1.5 - 2.2). Occurrence of a low INR also depended on indication for anticoagulant therapy, with the highest risk in patients who used anticoagulants as prophylaxis and the lowest risk in patients with mechanical heart valves. In 30% of cases the subtherapeutic INR was preceded by an event necessitating vitamin K or discontinuation of the anticoagulant drug.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Phenprocoumon; Risk Factors; Thromboembolism; Time Factors

Unstable oral anticoagulation increases the risk of thrombotic events and bleedings. Acenocoumarol use has been reported to be associated with two-fold higher risk for instability of anticoagulation control compared to warfarin administration.. The aim of the study was to evaluate the effect of introducing warfarin on anticoagulation control in patients with a variable response to acenocoumarol.. Sixty-eight subjects treated with acenocoumarol for 5 months or more and displaying intraindividual variability of international normalized ratio (INR) results were switched to warfarin. Unstable anticoagulation was defined as a failure to achieve a target INR within the preceding 3 months, i.e. > or = 50% of 8 or more INR values below 2 or above 3.5. Patients with stable anticoagulation (<20% of out-of-range INRs), matched for age, gender, and anticoagulation indications, served as a reference group.. Patients with unstable anticoagulation on acenocoumarol had higher body mass index (p<0.01) and serum C-reactive protein levels (p<0.01) compared to stable counterparts. The transition factor between acenocoumarol and warfarin was 1.8 (95% CI 1.69-1.96). The percentage time within the target INR range in patients with unstable anticoagulation was 40.2% at baseline and increased to 60.4% following 6 months on warfarin therapy (p<0.05). The number of subjects with <20% of out-of-range INRs among individuals switched from acenocoumarol to warfarin was 22 (32.4%) vs. 63 (92.6%) in patients on stable anticoagulation after 6 months of follow-up (p<0.001).. Switching acenocoumarol to warfarin in patients with unstable anticoagulation can improve anticoagulation control.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Dose-Response Relationship, Drug; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Reproducibility of Results; Thromboembolism; Treatment Outcome; Warfarin

A single nucleotide polymorphism c.-1639G > A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral anticoagulants (OA). The aim of the study was to determine the incidence and the effect of c.-1639G > A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA.. Our study included 200 consecutive patients requiring low (n = 43), medium (n = 127) and high (n = 30) acenocoumarol dose.. Out of 43 low dose patients, 40 (93%) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p < 0.0001). In 33 patients (16.5%) the overdose occurred during the initiation of anticoagulant therapy and in 11 patients (5.5%) it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p < 0.000001).. VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5% of our patients--carriers of AA genotype, before anticoagulation therapy initiation.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Female; Genotype; Hemorrhage; Humans; Male; Middle Aged; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Single Nucleotide; Vitamin K Epoxide Reductases; Young Adult

Topics: Acenocoumarol; Administration, Topical; Aged; Drug Interactions; Hemorrhage; Humans; Male; Naphthalenes; Skin Diseases; Terbinafine

The use of the antivitamines K for more than 50 years, has largely been the proof of its interest: well shown effectiveness, weak cost. However, these drugs are the cause of complications of which most frequent and most serious are the hemorrhagic accidents.. To determine the characteristics of the patients hospitalized for grave bleeding under antivitamins K and identify the predictive factors of these accidents.. Retrospective study of pilot case type carried out in the service of cardiology of the hospital Habib Thameur of Tunis during the period going from January 2001 to December 2006. It related to a group of 50 patients admitted for "serious haemorrhage under antivitamines K". This group was compared with a reference group including/understanding 100 patients treated by antivitamines K and not having never presented a haemorrhage. The reserved criteria of gravity are the following ones: the location: intracérébrale, rétro péritonéale, articular, intra-ocular with blindness, muscular, subcutaneous if the nasty bruise is voluminous, hematurie, metrorragie, digestive bleeding (high or low), hemoptysie, hemothorax, hemopéricarde; the deglobulisation (fall of the haemoglobin of 2 g/dl or more) requiring or not a transfusion; the necessity of a surgical haemostatic gesture or endoscopique; the transfer in care unit or death.. The Middle Age of the patients was of 55 +/- 14 years, the sex ratio was of 0.85. The intermediate duration of the treatment was of 243 +/- 225 weeks. The most frequent indications were the disorder of the supra-ventricular rate/rhythm (72%) and the mechanical valves cardiac (40%). These indications appeared debatable to us at 16% of the patients. One or more supporting factors the hemorrhagic accident were found at half of the patients, the first cause being medicamentous association (20% of the cases). The hématurie was the most frequent complication (28%). The evolution was favorable in all the cases. An internal injury under unclaimed ignored was found at 24% of the patients. The hepatic dysfonction and medicamentous association were in our study of the risk factors of which has occurred of haemorrhage under antivitamines K. In multivariate analysis, medicamentous association was an independent risk factor (Odds ratio adjusted 4.9).. At least 50% of the hemorrhagic accidents under antivitamines K are avoidable with the help of a rigorous evaluation of the benefit ratio/risk and a vigilance with respect to medicamentous associations. The creation of centers of anticoagulation in our country is essential in order to improve quality of the clinical and biological monitoring.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Anticoagulants; Child; Female; Hemorrhage; Humans; Male; Middle Aged; Pilot Projects; Retrospective Studies; Vitamin K; Young Adult

Long half life oral anticoagulants have shown a higher anticoagulation stability and a lower hemorragic risk than those of a short half life. We have compared therapeutic stability and hemorragic risk of acenocoumarol versus warfarin in 2 groups of patients on preventive anticoagulation because of atrial fibrilation (international normalised ratio [INR]: 2-3).. Data on 120 patients treated with acenocoumarol and 120 on warfarin treatment who had started and continued treatment in our hospital for a minimum of a year was collected.. The percentage of visits within the intended range of INR (2 to 3) was 65.5% with warfarin and 63.4% with acenocoumarol. Thirty percent of patients on warfarin had 75% or more of their controls within range, while for those treated with acenocoumarol this percentage was 22.5%. In the acenocoumarol group, 0.3 visits/patient/year presented an INR > or = 6 versus 0.07 in the warfarin group (p = 0.003).. Patients treated with acenocoumarol show a higher risk of presenting with an INR > or = 6, but no statistically significant differences are observed in therapeutic stability.

Topics: Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Retrospective Studies; Risk Factors; Warfarin

Hospitalization attributable to gastrointestinal and other major bleeding is frequently associated with acenocoumarol treatment.. To assess the level of knowledge among patients in respect to harmful adverse effects, interactions with medication and nutrition regarding acenocoumarol treatment.. Questionnaires consisting of 66 questions were completed in offices of family doctors (77), and during consultations at the 3rd Department of Internal Medicine (80).. 157 patients (male:female=45:55; age=65.5 years) were involved. In the group informed by the whole team (doctors, nurses and dietitians) everyone heard about the possible adverse effects. In the group where family doctors or other specialists provided information, 14.5% or 31.1% did not hear about any side-effect. The importance of diet was unknown by 71.4% of the patients. The knowledge of interactions between acenocoumarol and other medications is low: aspirin was known by 24.4%, analgetics by 23.0% and vitamin K by 18.6% of the patient.. Regarding acenocoumarol treatment, patients' knowledge should be enlarged. However, it can be significantly improved by the contribution of other team members such as nurses and dietitians.

Topics: Acenocoumarol; Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Drug Interactions; Educational Status; Family Practice; Female; Food-Drug Interactions; Health Knowledge, Attitudes, Practice; Hemorrhage; Humans; Male; Medicine; Middle Aged; Patient Care Team; Residence Characteristics; Specialization; Surveys and Questionnaires; Young Adult

The aim of our study was to determine factors influencing occurrence of haemorrhagic events during acenocumarol therapy. A total of one hundred and forty patients were interviewed using a questionnaire. From one hundred forty (100%) of interviewed patients, forty one (29.3%) had haemorrhagic events and in eighteen (12.9%) cases the event followed the use of nonsteroid anti-inflammatory drugs (NSAID's) or paracetamol in combination with acenocumarol (AC). We found eleven cases of major bleeding in eight (5.7%) of patients Eight cases of bleeding were followed the use of NSAID's or paracetamol in combination with (AC). We found that there is a statistical relationship between the higher frequency of INR examination (at least as every four weeks) and decreased occurrence of haemorrhagic events (p<0.05). The frequency of INR examination should be done once every four weeks or more often, if there is evidence to suggest that testing more frequently. Monitoring of INR with frequency less than once in 4 weeks may increase the risk of bleeding in those patients. Concomitant use of NSAID's or paracetamol in combination with acenocumarol in patients without medical consultation can be associated with growing number of bleeding. Patients on AC therapy need to be inform about frequency of INR examination and acaenocumarol interactions with other medications, which are available without the prescription, to avoid haemorrhagic events.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged

Topics: Acenocoumarol; Aged; Anticoagulants; Hemorrhage; Humans; Kidney Diseases, Cystic; Male; Retroperitoneal Space; Rupture, Spontaneous; Syndrome

Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. In order to elucidate the bleeding risk of users of antiplatelet drugs among users of coumarins, we assessed the odds ratio of major bleeding associated with use of antiplatelet drugs in users of the coumarins acenocoumarol and phenprocoumon. We used data from a Dutch record linkage system, including pharmacy and linked hospitalization records for approximately two million subjects, to conduct a nested case control study in a cohort of new users of coumarins. Cases were patients who were hospitalized with a primary diagnosis of major bleeding while taking coumarin and were matched with up to four control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CI). We identified 1848 case patients who were matched to 5818 controls. Users of clopidogrel or aspirin showed a significantly increased risk of hospitalization because of major bleeding (OR 2.9, 95% CI 1.2-6.9 and OR 1.6, 95% CI 1.3-1.9, respectively), whereas users of dipyridamole and combinations of antiplatelet drugs showed a strong trend (OR 1.5, 95% CI 1.0-2.3 and OR 1.8, 95 % CI 1.0-3.3, respectively). In all cases, the risks were greater for upper gastrointestinal bleedings than for other bleedings. In conclusion, the use of any antiplatelet drug increases the risk of hospitalization for major bleeding among users of coumarins. Concurrent use of clopidogrel or dipyridamole and coumarins is probably not safer than concurrent use of aspirin and coumarins.

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Blood Coagulation; Case-Control Studies; Clopidogrel; Coumarins; Dipyridamole; Drug Therapy, Combination; Female; Gastrointestinal Hemorrhage; Hemorrhage; Hospitalization; Humans; Logistic Models; Male; Medical Records Systems, Computerized; Middle Aged; Netherlands; Odds Ratio; Phenprocoumon; Platelet Aggregation Inhibitors; Risk Assessment; Ticlopidine; Vitamin K

Coumarin anticoagulants are prone to drug-drug interactions. For example, antibiotic drugs may enhance the anticoagulant effect of coumarins. However, whether such interactions are associated with an increased risk of bleeding, and if so, how frequently this occurs remains unknown.. To assess the risk of major bleeding associated with the concomitant use of antibiotic drugs and coumarin anticoagulant therapy.. We analyzed a retrospective cohort study including all users of acenocoumarol or phenprocoumon in the PHARMO Record Linkage System (age range: 40-80 years). All patients were followed up until end of last coumarin treatment, hospitalization for bleeding, death, or end of study period. For each patient, the number of days on either coumarins alone, or on coumarins in combination with antibiotic drugs was determined. From these data, the relative risks of major bleeding were calculated.. A total of 52,102 users of acenocoumarol and 7885 users of phenprocoumon met the inclusion criteria of our study cohort and contributed 139,159 person-years of follow-up. During follow-up, 838 patients (1.4%) were hospitalized for a bleeding while taking coumarins. Of the 62 different antibiotics taken by study members, 19 were associated with a bleeding episode. Of these, 10 were associated with a statistically significant increased bleeding risk. The relative risk of bleeding was three to five for doxycycline, amoxicillin, amoxicillin/clavulanic acid, ciprofloxacin, cotrimoxazole, azithromycin and pheneticillin, nine for tetracycline and 43 for cefradine and neomycin.. Based on relative risks and incidence of use, amoxicillin (alone or with clavulanic acid) and doxycycline are the main antibiotic drugs associated with major bleeding when used in combination with coumarin.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Amoxicillin; Anti-Bacterial Agents; Anticoagulants; Doxycycline; Drug Synergism; Female; Follow-Up Studies; Hemorrhage; Hemorrhagic Disorders; Hospitalization; Humans; Male; Middle Aged; Netherlands; Phenprocoumon; Retrospective Studies; Risk

The available data on the utility of low-molecular-weight heparins (LMWH) in the secondary prophylaxis of deep vein thrombosis (DVT) are limited. We compared two cohorts of patients diagnosed of DVT. One group followed treatment with LMWH and the other group did with oral anticoagulants (acenocoumarol). Safety was evaluated by the rate of major hemorrhage and 2.5-years period fracture rate, and efficacy was evaluated as the rate of early recurrence and one-year recurrence rate.. Of 65 patients treated with LMWH, the hemorrhagic rate was 1.5% (95% CI 0.08-9.40), fracture rate was 7.7% (95% CI 2.87-17.75), early recurrence was 1.5% (95% CI 0.08-9.40) and one-year recurrence was 3% (95% CI 53-11.64). In 118 patients treated with oral anticoagulants the hemorrhagic rate was 3.4% (95% CI 1.09-8.97), odds ratio 0.33, the fracture rate was 11% (95% CI 16.23-18.44), odds ratio 0.66, the early recurrence rate was 5% (95% CI 2.08-11.20), odds ratio 0.60 and one-year recurrence was 3.4% (95%CI 1.09-8.97), odds ratio 0.33.. Secondary prophylaxis of DVT with LMWH is as safe and effective as classical treatment with oral anticoagulants. In this study the 2.5-year period fracture rate was similar in both groups of treatment.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Anticoagulants; Cohort Studies; Female; Fractures, Bone; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Recurrence; Registries; Thrombophlebitis

To study the characteristics of major bleeding episodes into a closed space (BCS) of patients under chronic anticoagulation with either unfractionated heparin (HS) or coumadin (CM), and to determine the relationship, if any, of anticoagulation parameters (INR, PT and PTT) values at the time of bleeding with the episode. Finally, to determine risk factors for BCS and mortality in this population.. Descriptive epidemiology of all cases of BCS seen in our hospital from 1995 to 2000 was obtained through the records and follow up visits of all patients under anticoagulation (HS or CM) during this period. A matched case-control study to determine risk factors for BCS was carried out. Cases and controls (1:2) were matched for age, gender, anticoagulant treatment and indication for anticoagulation. Cases were patients with a BCS while on anticoagulation (HS OR CM). Controls were patients under anticoagulation (HS or CM) without any bleeding episode during the study period that had anticoagulation parameter values (INR, PT or PTT) determined the very same day than the cases.. During the study period, 225 patients under anticoagulation were prospectively followed (75 cases and 150 controls) amid a total of 1650 patients under anticoagulation, for a 4.5% prevalence of BCS. Reasons for anticoagulation were: atrial fibrillation in 79 (35.3%), valvular heart disease in 59 (25.9%), pulmonary embolism or deep venous thrombosis in 48 (21.4%), dilated cardiomyopathy in 26 (11.6%) and vascular cerebral stroke in 13 (5.8%). Mean age of cases was 70.5 (SD 9.5) years and 41 (55%) were women, values similar to the controls. At the time of BCS 39 patients were on CM and 36 on HS. The mean INR value in the CM group at the time of the episode of BCS was 5.3 (SD + 7.5) while the PTT value was 2,25 (SD 0.95) in the HS group. There was previous antecedent bleeding in 24 (32%) cases. The most common sites of BCS were: muscular (40%), CNS (30.6%), retroperitoneal (18,6%) and articular (10.6%). Muscular (abdominal or thoracic wall) and retroperitoneal BCS were higher in the HS group (10 and 12 in the HS group versus 5 and 2 in the CM group, respectively; p < 0.0001). In contrast, CNS bleeding was commoner in the CM group (20 in CM versus 3 in HS; p < 0.001). BCS related mortality rate was 14.6% (11/75) and higher in the CM group (p = 0.04). Comparative analysis of the case-control study revealed that anticoagulation values in the CM group at the time of bleeding were within the recommended range in 38.5% of cases vs. 75% of the controls (p < 0.001). Also, there were significant differences in mean INR values between cases and controls (5.3 + 7.5 vs. 2.6 + 0.9, p < 0.029) In the HS group no differences were present in PTT values at the time of bleeding between cases and controls. In BCS cases, a previous bleeding episode was more frequent than in the control group (32% versus 1.3%, p < 0.001). Likewise, mortality was higher in cases (18,6%) than in controls (11.4%), p = 0.01.. In our study, the majority of patients under anticoagulation with CM had INR values above the recommended range at the time of BCS, in contrast with those on HS that had a PTT within the therapeutic range at the time of the BCS. A previous bleeding episode was an independent risk factor for a BCS episode. Bleeding was a late complication in the CM group and frequently in the CNS, while BCS was more frequently associated with muscular or retroperitoneal sites in the HS treated group. BCS related mortality was 15%. Close monitoring of INR is crucial to minimize bleeding complications.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Risk Factors

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Female; Follow-Up Studies; Hemorrhage; Hemothorax; Humans; Mediastinal Diseases; Prognosis; Time Factors

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Case-Control Studies; Fibrinogen; Genotype; Hemorrhage; Humans; Netherlands; Odds Ratio; Phenprocoumon; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors; Vitamin K

The number of patients receiving oral anticoagulant therapy has increased markedly in recent years, with the consequence that monitoring must be decentralized. The aim of this study was to provide reference values for the quality of care in patients receiving oral anticoagulants at large specialized Spanish centers for use in future comparative analyses.. The records of 20,347 outpatients who were receiving oral anticoagulants between January and December 2003 at four large Spanish centers were assessed. Databases at the four hospitals were searched for severe adverse events.. In total, 211,987 regular check-ups were carried out, 72.7% of which gave international normalized ratios (INRs) within the range 2-4. Overall, 2369 hemorrhagic events were observed, 190 (8%) of which were severe, with 20 deaths (0.1 per 100 patient-years). In addition, there were 299 thromboembolic events, with 11 deaths (0.05 per 100 patient-years). The frequency of these events was greater in patients with a cardiac prosthesis, who required more intense anticoagulation. The incidence of death with different diagnoses was also greater in anticoagulated patients with a cardiac prosthesis, and the highest probability of death (1 in 3) was associated with episodes of cerebral hemorrhage. The incidence of hemorrhage increased as the INR increased. In contrast, thrombotic events occurred principally when the INR was below 2, and were not observed with INRs over 6.. The incidence of adverse events in patients receiving oral anticoagulant therapy at large Spanish centers was similar to that observed in other European countries.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Chi-Square Distribution; Child; Female; Heart Valve Prosthesis; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Quality Indicators, Health Care; Regression Analysis; Spain

The analysis concerning the frequency of bleedings from the upper part of the gastrointestinal tract in group of patients suffering from ischaemic heart disease (IHD) treated and not treated with coronaroplasty. The other aim of the study was to analyse the incidence of using particular groups of drugs.. 150 patients were included in the study, aged from 17 to 86. They were divided into three groups: I group--patients treated with coronaroplasty (n=50), II group--patients who were not treated with coronaroplasty (n=50), III control group (n=50). The patients filled in a questionnaire (among other things the questions concerned methods and period of treating heart ischaemia and stomach complaints. The documentation of the keyhole examinations of the upper part of the digestive tract was analysed in flashback).. Bleeding from the upper part of the gastrointestinal tract (only single episode) was noticed in 5 patients (treated with IHD) (3.33%). All these patients belonged to the group II. Endoscopic examination of the upper part of gastrointestinal tract was carried out in 4 of these patients and haemorrhagic gastritis has been found. The following drugs were more frequently used in patients treated with coronaroplasty: acetylsalicylic acid, clopidogrel, ticlopidine. Acenocoumarol was more frequently used in patients not treated with coronaroplasty. The differences were not significant and concerned the usage frequency of the following drugs: beta-blockers, calcium canal blockers, ACE, systemic nitrates and statins.. Bleeding from the upper part of gastrointestinal tract occurred more frequently among patients not treated with coronaroplasty. The following drugs were used more frequently in the group of patients treated with coronaroplasty: acetylsalicylic acid, ticlopidine and clopidogrel, but acenocoumarol was used more frequently in the group of patients treated only pharmacologically.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Aspirin; Body Mass Index; Clopidogrel; Female; Gastrointestinal Tract; Hemorrhage; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Ticlopidine

Topics: Acenocoumarol; Anticoagulants; Genotype; Hemorrhage; Humans; Odds Ratio; Phenprocoumon; Polymorphism, Genetic; Reproducibility of Results

Topics: Acenocoumarol; Aged, 80 and over; Anti-Bacterial Agents; Anticoagulants; Drug Synergism; Hemorrhage; Humans; Ketolides; Male

Topics: Acenocoumarol; Aged; Anticoagulants; Aspirin; Clopidogrel; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Platelet Aggregation Inhibitors; Ticlopidine

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Female; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Monitoring, Physiologic; Patient Compliance; Patient Dropouts; Patient Education as Topic; Risk Factors; Self Care; Thromboembolism; Treatment Outcome

Topics: Acenocoumarol; Aged; Alleles; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Female; Genetic Variation; Genotype; Hemorrhage; Humans; Male; Middle Aged; Pharmacogenetics; Retrospective Studies

Thromboembolic complications (cerebral infarction and system embolism) are the most threatening ones in patients with ciliary arrhythmia without valvular lesions. Transoesofhageal echocardiography is the method of choice in detection of left atrial auricle thrombosis, which is the main source of thromboembolism in this category of patients. Primary and secondary prevention of thromboembolic complications in patients with ciliary arrhythmia is a topical problem, still remaining unsolved. Administration of indirect anticoagulants, which are the preparations of choice, demands strict doctor's supervision and continuous laboratory monitoring. The study presents authors' own data, based upon the observation of patients treated with either warfarin or acenocumarol. The paper demonstrates equal efficiency of both cumarine anticoagulants. The frequency of haemorrhagic complications after 12-month therapy with either warfarin or acenocumorol in patients with ciliary arrhythmia without valvular lesions was comparable. Warfarin provided more stable level of anticoagulation and thus long-term warfarin therapy was characterized by lower risk of complication.

Topics: Acenocoumarol; Adult; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Middle Aged; Primary Prevention; Prospective Studies; Risk Factors; Thromboembolism; Time Factors; Warfarin

Topics: Acenocoumarol; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Male; Retrospective Studies; Risk Factors; Rural Population; Spain

For the primary and secondary prevention of thromboembolic events are used the oral anticoagulants, the drugs having a low therapeutic index and frequent bleeding complication rate. Establishing the proper therapeutic dose of these drugs for different patients is complicated by a variety of conditions, such as the comorbidity, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme.. The influence of CYP2C9 polymorphism on the effectiveness of the--in Hungary for oral anticoagulation exclusively used--acenocoumarol therapy and on the occurrence of bleeding complications was investigated.. Genotyping of 421 patients including 183 men and 238 women, (mean age 66.2 +/- 11.8 years) who took acenocoumarol (Syncumar) for at least 6 months was performed. Based on anamnestic and laboratory data, the correlation between the genotype and the acenocoumarol dose and bleeding complications were retrospectively analysed.. The frequency-distribution for the CYP2C9*1, *2, and *3 alleles were found to be: 0.814, 0.110, and 0.076, respectively. In the 145 patients bearing the alleles with reduced activity (CYP2C9*2 and/or *3), the optimised dose of the acenocoumarol was significantly (p < 0.001) lower than in patients with the wild type allele (2.12 +/- 0.96 mg/day and 2.90 +/- 1.45 mg/day, respectively). Although the occurrence of minor bleeding complications in the former group was significantly (p < 0.005) higher [OR = 1.99 (CI: 1.20-3.33)], there was no difference in major bleeding complications. In patients taking an acenocoumarol dose lower than 2 mg/day, the occurrence of an INR value higher than 6 in the anamnesis was significantly (p < 0.05) more frequent. Evaluating separately the variant alleles we have concluded, that in the presence of allele *2 a lower acenocoumarol dose was required than in wild-type subjects, and even lower in the presence of allele *3.. The frequency-distribution of the CYP2C9 alleles was as reported by others. In patients bearing alleles with reduced enzymatic activity, the occurrence of minor bleeding complications and the INR values higher than 6 were significantly more frequent. In patients with a lower acenocoumarol demand at the introduction of this therapy, a caution is required. In order to test the hypothesis that before the initiation of acenocoumarol therapy the determination of CYP2C9 polymorphism is cost-effective and could improve the optimization of anticoagulation and reduce the risk of bleeding complications a large prospective randomised trial is required.

Topics: Acenocoumarol; Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Female; Gene Frequency; Genotype; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic

To study the main comedications associated with major bleeding during anticoagulant therapy with coumarins in a non-selected population under everyday circumstances.. 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.. 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.. 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.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Cohort Studies; Coumarins; Drug Interactions; Drug Monitoring; Female; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Retrospective Studies; Salicylates

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Catchment Area, Health; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Prospective Studies; Risk Factors; Rural Population; Spain; Time; Venous Thrombosis

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.. 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).. 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.

Topics: Acenocoumarol; Anticoagulants; Case-Control Studies; Genetic Predisposition to Disease; Genotype; Hemorrhage; Humans; Mixed Function Oxygenases; Phenprocoumon; Polymorphism, Genetic; Risk Factors; Vitamin K; Vitamin K Epoxide Reductases

Increased risk of bleeding during oral anticoagulant (OA) treatment may be related to mutations in the precursor of coagulation factor IX. Missense mutations at Ala-10 (Ala-10Thre and Ala-10Val) in the factor IX propeptide lead to impaired carboxylation of factor IX. When patients carrying these mutations are treated with coumarins, functional factor IX levels decrease significantly, leading to an excessively prolonged activated partial thromboplastin time (aPTT) and an increased bleeding risk. Mutations at Ala-10 have been described in northern-European patients, but it is not known whether geographical differences play a role in the prevalence of these mutations. We aimed to analyze the prevalence of mutations at Ala-10 in factor IX in southern-European patients on OA treatment. Patients attending the Oral Anticoagulant Unit of the Hospital Clinic were prospectively included. The aPTT was determined at their normal International Normalized Ratio (INR) control. When the aPTT was excessively prolonged for the INR value, determination of factor IX and genotyping for Ala-10 mutations was performed. A total of 2360 patients were included (1289 men, 1071 women; mean age, 70.5 +/- 12.1 years). Twenty-four patients (16 men, eight women; mean age, 61.0 +/- 16.2 years) had an aPTT over that expected for the INR. The mean aPTT was 69.6 +/- 16.2 s. Only one patient presented with a factor IX level lower than 10%. None of the 24 patients carried mutations at Ala-10. Mutations at Ala-10 in factor IX were non-existent in the southern-European population analyzed, and thus, do not represent a relevant cause of bleeding during OA treatment.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Anticoagulants; Factor IX; Female; Hemorrhage; Humans; Male; Middle Aged; Point Mutation; Predictive Value of Tests; Spain

We studied the prevalence of genetic thrombophilic mutations in patients on chronic oral anticoagulant treatment (OAT) who had bleeding complications. In a case-control study we found ten (12.8%) carriers of factor V Leiden and two (2.5%) carriers of the PT20210A mutation among 78 patients with a history of moderate-severe bleeding while on OAT, and seven (4.4%) and four (2.5%), respectively, among 156 matched patients with no bleeding while on OAT (odds ratio 3.1+/-1.6, p=0.026). In patients on chronic OAT, FV Leiden is a risk factor for moderate-severe bleeding.

Topics: 3' Untranslated Regions; Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Factor V; Female; Follow-Up Studies; Gene Frequency; Hemorrhage; Hospitalization; Humans; International Normalized Ratio; Male; Middle Aged; Prevalence; Prothrombin; Sample Size; Thrombophilia; Warfarin

Some medical textbooks on drug interactions take note of the potential interaction between laxatives and coumarin anticoagulants, but epidemiological evidence that this interaction is of practical importance is lacking. We conducted a follow-up study in a large population-based cohort to investigate which laxatives are associated with overanticoagulation during therapy with coumarins. Of the 1124 patients in the cohort, 351 developed an International Normalized Ratio > or = 6.0. The only laxative with a moderate but significantly increased relative risk of overanticoagulation was lactulose (relative risk 3.4, 95% confidence interval 2.2, 5.3). In view of the widespread use of lactulose, especially among the elderly, awareness of this potential drug interaction is required.

Topics: Acenocoumarol; Anticoagulants; Cathartics; Cohort Studies; Drug Interactions; Female; Hemorrhage; Humans; International Normalized Ratio; Lactulose; Male; Phenprocoumon; Risk Factors

To obtain an impression of the extent and quality of the anti-coagulation treatment with coumarin derivatives carried out by the Thrombosis Services in the Netherlands.. Descriptive.. Data were drawn from the medical annual reports of 62 of the 63 Thrombosis Services in the Netherlands over the period 1998-2002. In 2002 the Thrombosis Services treated 325,072 patients and performed 4,469,730 INR laboratory tests. The half-yearly figures produced by the Thrombosis Services were calculated as an average percentage per year per thrombosis service and then recalculated as a percentage per year.. Seventy-three per cent of the patients were treated for an arterial and 27% for a venous indication. Depending on the required intensity of anticoagulation a mean of 74-78% of the long-term treated patients fell within the therapeutic range and a mean of 6-10% below. The mean number of major bleedings per 100 treatment years was 1.0. A mean of 79% of the patients was treated with acenocoumarol and 21% with phenprocoumon. When acenocoumarol was used, a mean of 72-77% fell within the therapeutic range and in the case of phenprocoumon 79-82%. In the last few years the number of patients had increased due to a growing number of patients treated for atrial fibrillation. The percentages of INR within the therapeutic range were unchanged or showed a slight increase.. The quality of the anticoagulation therapy with coumarin derivatives was good or acceptable.

Topics: Acenocoumarol; Anticoagulants; Atrial Fibrillation; Coumarins; Hemorrhage; Humans; International Normalized Ratio; Netherlands; Phenprocoumon; Quality of Health Care; Thrombosis; Treatment Outcome

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before sta

Topics: Acenocoumarol; Aged; Alleles; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Base Sequence; Cohort Studies; Cytochrome P-450 CYP2C9; DNA; Female; Genotype; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Risk Factors

The key complication of treatment with vitamin K antagonists (VKAs) is bleeding. The major determinant of VKA-induced bleeding is the intensity of anticoagulation. Individual patient characteristics may also influence bleeding risk. In addition, soluble thrombomodulin (s-TM) levels and mutations in the propeptide of factor (F)IX are important candidate risk factors in this respect.. A matched case-control study was designed to search for risk factors that predict bleeding during VKA treatment. We selected cases that had experienced major bleeding during treatment with VKA and matched controls without bleeding complications from the databases of two Thrombosis Services. The controls were matched for indication of treatment, age, gender, type of anticoagulant used and whether or not treatment with VKA was stopped. DNA and plasma were stored of all cases and controls.. In total 110 patients and 220 controls consented to participate. The results indicate that s-TM levels, measured by ELISA, may be a risk indicator for bleeding [crude odds ratio 3.25 for the highest quartile vs. the lowest quartile (95% confidence interval 1.40, 7.51)]. Three novel mutations, determined by direct sequencing, in the gene portion encoding the propeptide of FIX were identified that do not seem to play an important role in bleeding risk during treatment with VKAs.

Topics: Acenocoumarol; Aged; Anticoagulants; Case-Control Studies; Data Collection; DNA Mutational Analysis; Factor IX; Female; Hemorrhage; Humans; Male; Middle Aged; Mutation; Phenprocoumon; Prevalence; Risk Factors; Thrombomodulin; Vitamin K

Recently there are several evidence based facts about the beneficial effect of oral anticoagulant therapy in patients with cardiovascular diseases. In the other hand the often serious bleeding complications as well as the ineffective antithrombotic therapy should be avoided.. Authors had examined with a questionnaire some characteristic parameters of oral anticoagulant therapy in Hungarian hospitals. Based on the results they carried out a retrospective survey (488 consecutive patients) on the accuracy and other peculiarity of long-term acenocoumarol therapy in the district of County Hospital Gyula.. Mean value of all coagulation test's results (INR: 2.72 +/- 1.07, prothrombin %: 36.11 +/- 10.52) suggest a relatively favourable therapeutic activity in the patients required acenocoumarol therapy. According to their data the proportion of newly introduced anticoagulant therapy secondary to atrial fibrillation was highly increased (42%). They stated that the accuracy of documentation in conducting of oral anticoagulant therapy should be improved and it would be the time to use obligatory the INR value in the clinical practice. They found the best therapeutic punctuality among the patients controlled in the Special Cardiological Outpatient Department. There were relatively few event of serious bleedings. The authors called attention to the patients (about 5%) who were treated without any special cause for a longer period of time than it was necessary. They emphasize the pivotal role of permanent education of patients and the importance of their therapeutic compliance in the appropriate oral anticoagulant control.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Female; Heart Valve Prosthesis; Hemorrhage; Humans; Hungary; International Normalized Ratio; Male; Middle Aged; Outpatients; Patient Compliance; Patient Education as Topic; Prothrombin; Quality of Health Care; Retrospective Studies; Surveys and Questionnaires; Thromboembolism; Venous Thrombosis

Few studies have attempted to investigate the clinical course or identify factors responsible for excessive anticoagulation in patients with heart disease.. To determine the incidence of excessive anticoagulation in outpatients with heart disease treated with acenocoumarol, analyze the factors related with over-anticoagulation, and identify bleeding complications.. This 7-month prospective observational study included consecutive outpatients anticoagulated with acenocoumarol. They were seen in an anticoagulation unit. The high INR group of 55 over-anticoagulated patients had at least one test with INR > 5. The control group of 49 patients had INR results strictly within therapeutic range.. A total of 3,683 INR determinations were made in 512 patients. Seventy-seven tests had an INR > 5 (a 2% overall incidence of high-INR). In the group of 55 INR < 5 patients, 31% had more than one INR determination > 5 during follow-up. Multivariate analysis identified four variables as independent predictors of over-anticoagulation: artificial heart valve, poor treatment compliance, addition of potentially interactive new drugs, and illness in the last month. The high-INR group patients had more bleeding episodes (21.8 vs 4.08%; p = 0.008), one of which was major.. The incidence of excessive oral anticoagulation in our outpatient population was similar to that reported in other studies. Patients with INR > 5 had more total bleeding complications, mostly minor. It is recommended to proceed carefully with oral anticoagulant therapy in patients with an artificial heart valve, suspected poor treatment compliance, addition of potentially interactive new drugs, and illness in the last month.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Drug Utilization; Heart Diseases; Hemorrhage; Humans; International Normalized Ratio; Middle Aged; Outpatients; Prospective Studies; Risk Factors

Over the last years, the use of oral anticoagulant treatment (OAT) has increased dramatically, principally for the prevention of embolic stroke in patients with atrial fibrillation. This study was aimed at evaluating the efficacy and safety of the management of OAT in a real-practice situation.. Nine hundred and three consecutive unselected patients, 250 of whom with atrial fibrillation, referred for the control of OAT to the Anticoagulation Clinic of the University of Florence were studied. The total follow-up period was 1679 patient-years.. The rate of major bleeding events was 0.8 per 100 patient-years in atrial fibrillation patients. In patients with a target INR > or = 3 a significantly higher rate of bleeding (p = 0.02) with respect to patients with a target INR < 3 was observed.. A low incidence of complications may be obtained even in elderly atrial fibrillation patients on OAT followed in an Anticoagulation Clinic specifically devoted to this management.

Topics: Acenocoumarol; Administration, Oral; Age Distribution; Aged; Aged, 80 and over; Ambulatory Care; Anticoagulants; Atrial Fibrillation; Case-Control Studies; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Italy; Male; Middle Aged; Probability; Prospective Studies; Reference Values; Risk Assessment; Sampling Studies; Severity of Illness Index; Sex Distribution; Treatment Outcome; Warfarin

To evaluate the incidence of thromboembolic and haemorrhagic events in a cohort of patients with mechanical heart valves who had to withhold acenocumarol and were treated with enoxaparin.. Observational prospective study.. In hospital; after discharge, and follow up by telephone call.. All consecutive patients with mechanical heart valves admitted to the authors' hospital between May 1999 and January 2002 who had to interrupt treatment with acenocumarol and were treated with enoxaparin as an alternative to other methods were enrolled. In each patient, the following characteristics were prospectively determined: the reason for interrupting acenocumarol, demographic data, estimated global risk for thromboembolic events, international normalised ratio before starting enoxaparin treatment, number of days taking enoxaparin, and mean level of anti-Xa activity during treatment. All patients were followed up through clinical history during the hospitalisation and by telephone after discharge to detect thromboembolic events.. Presence of thromboembolic or haemorrhagic events.. 82 patients were identified and followed up for a mean of 2.8 months (range 1.5-3.5 months) after discharge. 61 of them (74%) had one or more associated thromboembolic risk factors. Acenocumarol was interrupted (to perform an invasive procedure in 74 patients and because of haemorrhagic complication in 8) an average of 11.2 days (range 3-40 days). Most patients received the standard enoxaparin dose (1 mg/kg at 12 hour intervals). Mean (SD) anti-Xa activity was 0.58 (0.3) IU/ml (median 0.51). There were 8 minor and 1 major bleeding events during enoxaparin treatment. No thromboembolic complications were clinically detected during hospitalisation or during follow up (95% confidence interval 0% to 3.6%).. Enoxaparin may be an effective and relatively safe substitute anticoagulant for patients with mechanical heart valves who must withhold acenocumarol.

Topics: Acenocoumarol; Anticoagulants; Blood Loss, Surgical; Cohort Studies; Contraindications; Enoxaparin; Factor Xa; Female; Heart Valve Prosthesis; Hemorrhage; Hospitalization; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Risk Factors; Thromboembolism; Withholding Treatment

Over past years, there has been a world-wide increase in oral anticoagulant treatment (OAT). This study was aimed at evaluating the efficacy and safety of OAT managing in a real-practice situation. Nine hundred and three consecutive unselected patients referred for the control of OAT to the Anticoagulation Clinic of the University of Florence were studied. The total follow-up period was 1679 patient-years. The rate of total, major and fatal bleeding events was 5.0, 1.1 and 0.06 per 100 patient-years, respectively. In patients with a target International Normalized Ratio (INR) > or = 3, a significantly higher rate of bleeding (P = 0.02) with respect to patients with a target INR < 3 was observed. The rate of all thrombotic events was 3.8 per 100 patient-years. The rate of major and fatal thrombotic events were 2.4 and 0.4 per 100 patient-years, respectively. At INR >/= 4.5 the rate of bleeding was significantly higher (P = 0.005) than at lower INR. At INR < 2 the rate of all thrombotic events was significantly higher (P = 0.00001) with respect to more elevated intensities of anticoagulation. A low incidence of complications may be obtained even in elderly outpatients on OAT followed at an anticoagulation clinic.

Topics: Acenocoumarol; Age Factors; Aged; Anticoagulants; Data Interpretation, Statistical; Female; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Software; Thrombosis; Warfarin

Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarinic metabolism. Variant alleles, CYP2C9*2 and CYP2C9*3, have been related to decreased enzymatic activity, but their clinical relevance in acenocoumarol metabolism has not been established. We investigated CYP2C9 polymorphisms in relation to acenocoumarol dose requirement, stability of anticoagulation and bleeding.. CYP2C9 genotyping was performed in 325 acenocoumarol-treated patients (INR target between 2.0 and 3.0) and in an additional group of 84 patients with repeated bleeding.. Patients with the wild-type CYP2C9*1/*1 genotype (n=169) required a higher maintenance dose of acenocoumarol (17.1 8.7 mg/week) than did patients with the CYP2C9*2 (14.6 6.4 mg/week, p<0.05, N=97) or the CYP2C9*3 allele (11.2 6.2 mg/week, p<0.001, n=59). Out of 170 patients requiring a low-dose of acenocoumarol (70 years (OR=3.73, 95%CI=2.29-6.08, p<0.001), and the CYP2C9*3 allele (OR=4.75, 95%CI=2.36-9.55, p <0.001). Carriers of CYP2C9*3 spent less time within the therapeutic range (64.7 23.1%) than did patients with the CYP2C9*1/*1 genotype (75.1 22.0%, p<0.01), and more frequently had an INR >4.5 at the initiation of treatment (43.9% vs.11.6%, p<0.001), but did not show repeated bleeding more frequently (19.0% vs.15.5%, p=NS).. CYP2C9*3 is related to lower acenocoumarol dose requirements, a higher frequency of over-anticoagulation at the initiation of therapy and an unstable anticoagulant response.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Blood Coagulation; Cytochrome P-450 CYP2C9; Drug Stability; Female; Genotype; Hemorrhage; Humans; Male; Middle Aged; Odds Ratio; Pharmacogenetics; Polymorphism, Genetic; Retrospective Studies

Several case reports associated combined use of coumarins and antibacterial drugs with overanticoagulation. Despite the fact that these drugs are frequently prescribed concurrently, there is little quantitative information on the risks of such complications.. To study which antibacterial drugs are associated with overanticoagulation during therapy with coumarins.. Population-based cohort study in a sample of the Rotterdam Study.. All patients who were treated with acenocoumarol or phenprocoumon in the study period from April 1, 1991 through December 31, 1998 and for whom INR data were available.. Patients were followed until an INR >/= 6.0, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of an INR >/= 6.0 in relation to concomitant use of an oral anticoagulant and antibacterial drugs after adjustment for several potentially confounding factors such as age, gender, hepatic dysfunction, malignancies, and heart failure.. Of the 1,124 patients in the cohort, 351 developed an INR >/= 6.0. The incidence rate was 6.9 per 10,000 treatment days. Sulfamethoxazole combined with trimethoprim most strongly increased the risk of overanticoagulation with an adjusted relative risk of 20.1 (95% CI: 10.7-37.9). Stratification showed that the induction period of overanticoagulation varied between different antibacterial drugs.. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, several antibacterial drugs strongly increased the risk of overanticoagulation. Awareness of these drug interactions and more frequent monitoring of INR values during the initial stages of antibacterial drug therapy are warranted to minimize the risk of bleeding complications.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anti-Infective Agents; Anticoagulants; Cohort Studies; Drug Interactions; Drug Overdose; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Netherlands; Phenprocoumon; Proportional Hazards Models; Sulfamethoxazole; Trimethoprim

To investigate whether the different pharmacokinetics of acenocoumarol (t(1/2) = 11 h) and phenprocoumon (t(1/2) = 140 h) result in a different quality of anticoagulation, we studied patients from the Leiden anticoagulation clinic treated between 1998 and 1999 for more than 16 weeks. Two hundred and twenty-eight pairs were closely matched for indication for oral anticoagulant therapy (OAT), age, sex and date of start of treatment. Four hundred and fifty six patients with 7245 International Normalized Ratio (INR) checks yielded 230 patient-years. Quality of OAT calculated over the whole treatment period was higher with phenprocoumon as expressed by the number of INR checks in the therapeutic range (phenprocoumon: 42.7%, acenocoumarol: 36.5%, difference: 6.1%, CI(95) of the difference: 3.0-9.3%) and by time in range (phenprocoumon: 46.6%, acenocoumarol: 41.6%, difference: 5.0%, CI(95) of the difference: 1.3-8.6%). After the initial 6 weeks of OAT, the differences became more pronounced (difference: 6.1%, CI(95): 1.8-10.4%). The incidence of severe bleeding complications was similar (phenprocoumon: 0.04/patient/year vs acenocoumarol: 0.03/patient/year) with a slight excess of minor bleeds with phenprocoumon (0.19/patient/year vs 0.06/patient/year). We conclude that phenprocoumon leads to a better quality of OAT than acenocoumarol. As there is no difference in major bleeding complications and only a small difference in minor bleeding complications, phenprocoumon is preferable to acenocoumarol for prolonged OAT.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Confidence Intervals; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Middle Aged; Phenprocoumon

We studied major bleeding complications, death related to hemorrhage, and tried to identify predisposing factors for bleeding in outpatients treated with acenocoumarol. We evaluated 811 outpatients attending a specialized anticoagulant therapy unit. The intended INR range was 3.5-4.5 for mechanical heart valve replacement (N= 384) and 2.0-3.0 for other indications (N= 427). The variability of INR for the total follow-up and the 2 months before the hemorrhage was calculated. The total follow-up was 1,963.26 years with 27,321 control tests. We observed 47 major bleeding episodes, including 2 fatal (central nervous system hemorrhages), in 37 patients. 49.5% of the patients had underlying diseases. The rate of major and fatal hemorrhage was 2.39 and 0.10 episodes per 100 patients year, respectively. Hemorrhagic complications were more frequently observed in patients with a more intense intended range (8.2% in the INR 3.5-4.5 group vs. 1.5% in the 2.0-3.0 INR group). The risk of major bleeding increased in patients with an achieved INR higher than 6 and in those with higher INR variability during follow-up. The estimated probability of bleeding also increased with time: it was 0.102% at 78 months, and at the beginning of therapy it was 0.006% and 0.007% at 1 and 4 months, respectively. The intensity of anticoagulation and the deviation of the INR from the target are the most important risk factors for bleeding in patients taking acenocoumarol. Monitoring the variability of INR can help identifying patients predisposed to bleeding. However, the screening for underlying disease should always be performed.

Topics: Acenocoumarol; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Child; Child, Preschool; Female; Hemorrhage; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors

Self-testing and self-monitoring with portable prothrombin time (PT) monitors has been shown to be feasible and safe. However the ability of patients on chronic oral anticoagulant therapy (OAT) to self-adjust their dose without specific training has never been properly evaluated. The aims of this study were to evaluate: 1) the ability of patients on chronic OAT to self-adjust their dose without specific training; 2) the integration of a portable PT monitor (Coagucheck, Roche Diagnostics, Germany) for home use into routine patient care in anticoagulation clinics.. A nested case-control study was conducted in four centers of the Italian Federation of Anticoagulation Clinics (FCSA). Patients (n=78) on stable OAT for at least 6 months (cases: 47 men, 31 women, age range: 18-75 years) were enrolled on a volunteer basis after passing an Abbreviated Mental Test and providing informed consent. After three instruction sessions on the use of Coaguchek, subjects performed the PT test at home, communicated the INR results to the Center and suggested the dose adjustment and date for next control as they thought appropriate. However, they were requested to follow the prescription made by the Center. Controls (78 subjects) matched by age (+/- 5 years), sex and therapeutic range with the cases, were selected from among those who attended the anticoagulation clinics and managed by usual care.. When compared with the dose prescribed by the Clinic, the dose suggested by warfarin and acenocoumarol users was equal to or within +/- 6% of the mean weekly dose in 80% and 82% of suggestions, respectively. Time spent in the therapeutic range during the study was the same (80%) for cases and controls.. Selected patients on chronic anticoagulant therapy can acquire a satisfactory ability for self-adjustment of OAT dose without specific training.

Topics: Acenocoumarol; Administration, Oral; Adolescent; Adult; Aged; Anticoagulants; Case-Control Studies; Female; Hemorrhage; Humans; International Normalized Ratio; Italy; Male; Middle Aged; Outcome Assessment, Health Care; Patient Acceptance of Health Care; Patient Compliance; Prothrombin Time; Random Allocation; Self Administration; Self Care; Surveys and Questionnaires; Thromboembolism; Warfarin

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Child; Child, Preschool; Hemorrhage; Humans; International Normalized Ratio; Middle Aged; Retrospective Studies; Risk Factors; Thrombosis

Anticoagulation therapy in the elderly poses some doubts on the possible increase in hemorrhagic risk. The hemorrhagic complications in a population of patients over 70 years of age anticoagulated with acenocoumarol by heart disease were studied.. A study was made of seventy-two patients (43 females and 29 males; mean age: 73 years) anticoagulated for one year and controlled on an outpatient basis by means of INR (international normalized ratio) measurement with a maximal interval of four weeks. INR values above 4.5 or below 2.0 were considered out of range.. Nineteen patients had an INR above the recommended value on one occasion and eleven patients on two or more occasions. Sixteen patients had hemorrhagic complications, five were admitted on account of hemorrhages although none of them required transfusional therapy. No cases of brain hemorrhage or peripheral embolism occurred.. Most anticoagulated elderly patients were within their therapeutic range. The percentage of severe hemorrhagic complications was low. Advanced age had did not prove to be a factor against therapy with oral anticoagulants.

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Tests; Female; Heart Diseases; Hemorrhage; Humans; Male; Outpatients; Time Factors

The authors report four cases of spontaneous retroperitoneal haematomas, which occurred in their department during a half year period. The patients were admitted from different internal medicine departments. They had anaemia, and bleeding with unknown origin and localisation, and were in a bad condition. Three patients could be suitable for operation after general preparation. One of these patients died and another one died without operation. Two of them went home after recovering. The patients were transferred to surgical department on average three days after the symptoms developed. Hypoprothrombinaemia was the reason for bleeding in three cases. One patient got overdosed Syncumar, and two patients suffered from alcoholic cirrhosis who had other serious diseases as well. The authors found that the fourth patient, who had the gluteal arterial rupture with inexplicable origin, also had hypoprothrombinaemia. It is very difficult to diagnose these disease. Bleeding always has to be taken into consideration, if the patients have liver disease, or any type of coagulopathy, or take some anticoagulant medicine. The blood test examinations, ultrasound, CT, MR, angiography, laparoscopy can be helpful in the diagnosis of these cases.

Topics: Acenocoumarol; Drug Overdose; Female; Hemorrhage; Humans; Hypoprothrombinemias; Liver Cirrhosis, Alcoholic; Magnetic Resonance Angiography; Male; Retroperitoneal Space; Tomography, X-Ray Computed; Treatment Outcome

Although the indications for oral anticoagulation (AO) in the treatment of cerebral vascular disease (CVD) are well established, their potential side effects continue to give cause for worry.. To describe the complications and ischemic relapses in patients treated with AO for secondary prevention of CVD of cardiac embolic origin.. We included 169 patients with embologenic cardiopathy who, following an CVD, were treated with AO and followed-up at our medical centre for at least three months. We recorded their past clinical history and risk factors, occurrence of vascular relapses (VR), complications involving hemorrhage (CH), and data regarding course and follow-up.. During an average follow-up of 50.3 months of a total of 707.9 patient/years, 20 VR (2.8% per year) were recorded; 15 of these were cerebro-vascular and mainly mild. We recorded 59 CH in 41 patients (8.3% per year) of which 6 were considered to be major. There was a 30% drop-out rate from follow-up at our centre, mainly due to death from other causes or to change of referral centre.. There is a low incidence of relapse and of complications (usually mild) following AO for the secondary prevention of CVD of cardio-embolic origin. Efficacy and security are maintained in the long term.

Topics: Acenocoumarol; Administration, Oral; Alcoholism; Anticoagulants; Arteriosclerosis; Atrial Fibrillation; Cardiomyopathy, Dilated; Cohort Studies; Comorbidity; Diabetes Mellitus; Disease-Free Survival; Follow-Up Studies; Heart Valve Diseases; Hemorrhage; Humans; Hyperlipidemias; Hypertension; Intracranial Embolism and Thrombosis; Life Tables; Myocardial Infarction; Recurrence; Risk Factors; Smoking; Spain; Treatment Outcome

To retrospectively analyze the hemorrhagic complications and thrombotic events associated with aging and the degree of anticoagulation in a series of ambulatory patients treated with acenocumarol and controlled in a specialized anticoagulant therapy unit.. A total of 1,613 ambulatory patients were studied. Patients were divided into two groups (group 1, 645 patients > 65 years old, mean age 71.7 +/- 4.5 years; INR, 2.1-2.8; group 2, 968 patients < or = 65 years, mean age 53.7 +/- 10 years; INR, 2.8-4.2) for a time period of twelve months. The prevalence of hemorrhagic complications and severity according to a validated international index (Bleeding Severity Index), as well as the thrombotic events occurred despite anticoagulation therapy.. Fifty-two hemorrhagic events (8/100 patients-year) were recorded in the older group (group 1). Twenty-six cases were considered banal episodes, 24 minor hemorrhages and two major hemorrhages. Ten patients (1.5/100 patients-year) had thrombotic complications. In the younger group (group 2) 150 bleeding episodes were recorded (15 patients-year), of which 11 were banal, 39 minor hemorrhages and no major hemorrhages. Only eight patients 0.8/100 patients-year) had thrombosis. The presence of local factors predisposing to bleeding was more common in group 1 (p < 0.001). Older patients had in general more complications than younger patients (p < 0.001), but no significant differences were observed between the occurrence of hemorrhages or thrombosis independently analyzed between both groups. The rate in the therapeutic range was greater among the youngest individuals (p < 0.05).. Our results support the idea that patients with advanced age can benefit from a less aggressive anticoagulation. A statistical trend was observed, although not significant, towards the presence of major hemorrhages and thrombosis in this group of patients. The presence of local or predisposing factors to hemorrhage (underlying disease and NSAIDs use) is more relevant in patients with advanced age.

Topics: Acenocoumarol; Administration, Oral; Age Factors; Aged; Anticoagulants; Female; Hemorrhage; Humans; Male; Middle Aged; Retrospective Studies; Thrombolytic Therapy

To compare systemic anticoagulation with antiaggregation in patients with coronary stent, with regard to subacute occlusion, mean hospital staying and haemorrhagic complications.. Seventy-five patients with coronary stent were treated with one of two different antithrombotic protocols. A group comprised of 34 patients (group A) received sodium heparin and acenocoumarin, plus acetylsalicylic acid (325 mg) and dipyridamole (225 mg). The remaining 41 patients (group B) were given antiplatelet agents, namely ticlopidine (125-250 mg) and aspirin (125 mg).. One case of group A (2.9%) showed thrombosis due to stent occlusion. No thrombotic complications were seen in the patients with antiplatelet drugs. Haemorrhagic complications were present in 11 group A patients (32.3%), and blood transfusion was necessary in 3 of them. Hemorrhage was present in 9 cases of group B (21.8%), and none of them needed blood transfusion. The mean number of days to achieve INR > 2 was 3.06 (1-11) in group and 2.02 (1-5) in group B.. Antiplatelet regimes appear as a good choice in coronary stent, in spite of the fact that the primary indication seems that of group A.

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; Aspirin; Coronary Disease; Dipyridamole; Drug Evaluation; Drug Therapy, Combination; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Complications; Retrospective Studies; Stents; Thrombosis; Ticlopidine

Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications. We studied the frequency of bleeding complications in outpatients treated routinely in anticoagulation clinics.. In a prospective cohort from thirty-four Italian anticoagulation clinics, 2745 consecutive patients were studied from the start of their oral anticoagulation (warfarin in 64%, acenocourmarol in the rest). The target anticoagulation-intensity was low (international normalised ratio [INR] < or = 2.8) in 71% of the patients and high (> 2.8) in the remainder. We recorded demographic details and the main indication for treatment and, every 3-4 months, INR and outcome events. Such events included all complications (bleeding, thrombosis, other), although only bleeding events are reported here, and deaths. We divided bleeding into major and minor categories.. 43% of the patients were women. Nearly three-fifths of the patients were aged 60-79; 8% were over 80. The main indication for treatment was venous thrombolism (33%), followed by non-ischaemic heart disease (17%). Mean follow-up was 267 days. Over 2011 patient-years of follow-up, 153 bleeding complications occurred (7.6 per 100 patient-years). 5 were fatal (all cerebral haemorrhages, 0.25 per 100 patient-years), 23 were major (1.1), and 125 were minor (6.2). The rate of events was similar between sexes, coumarin type, size of enrolling centre, and target INR. The rate was higher in older patients: 10.5 per 100 patient-years in those aged 70 or over, 6.0 in those aged under 70 (relative risk 1.75, 95% Cl 1.29-2.39, p < 0.001). The rate was also higher when the indication was peripheral and/or cerebrovascular disease than venous thromboembolism plus other indications (12.5 vs 6.0 per 100 patient-years) (1.80, 1.2-2.7, p < 0.01), and during the first 90 days of treatment compared with later (11.0 vs 6.3, 1.75, 1.27-2.44, p < 0.001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR < 2, rate 7.7 per 100 patient-years of follow-up). The rates were 4.8, 9.5, 40.5, and 200 at INRs 2.0-2.9, 3-4.4, 4.5-6.9, and over 7, respectively (relative risks for INR > 4.5, 7.91, 5.44-11.5, p < 0.0001).. We saw fewer bleeding events than those recorded in other observational and experimental studies. Oral anticoagulation has become safer in recent years, especially if monitored in anticoagulation clinics. Caution is required in elderly patients and anticoagulation intensity should be closely monitored to reduce periods of overdosing.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cardiovascular Diseases; Cohort Studies; Female; Hemorrhage; Humans; Italy; Male; Middle Aged; Prospective Studies; Risk Factors; Warfarin

To analyze hemorrhagic complications in a series of outpatients treated with acenocoumarol in an anticoagulant specialized unit by a prospective observational clinical study.. 1,200 outpatients (682 women/518 men, mean age 54.6 +/- 15.8 yrs.) treated with acenocoumarol for at least 6 weeks, with a total follow-up of 2,795 patients-yr. Prevalence and incidence of bleeding was analyzed. The episodes that were potentially life-threatening, or forced to blood transfusion or hospital patient admittance were considered as major bleedings, and the remainder episodes were minor.. There were 379 minor bleedings in 258 patients (incidence 13.56/100 patients-yr.), 45 major bleedings (1.61/100 patients-yr.) and 2 lethal bleedings (0.07/100 patients-yr.). Minor bleedings correlated with more advanced age (57.3 +/- 11.8 vs. 53.9 +/- 16.7 yrs., p = 0.002), with the first two months in treatment in the 511 patients who start the treatment during the study (31.09 vs. 13.04/100 patients-yr., p < 0.001), and with a worse achievement of the desired anticoagulation (72.4% vs. 81.6%; p = 0.002). Major bleeding was associated with local causes in 48.9%, and with an excessive anticoagulation in 35.6%.. Bleeding is relatively frequent during acenocoumarol therapy, mainly in patients with worse control, but only in a few of these episodes is severe, and is usually associated with local lesions.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Outpatients; Prospective Studies; Time Factors

The optimal intensity of oral anticoagulant therapy for patients with mechanical heart valves (i.e., the level at which thromboembolic complications are effectively prevented without excessive bleeding) is not known. We attempted to determine the optimal intensity by calculating the incidence of both complications at different levels of anticoagulation.. Data were collected on all patients with mechanical heart valves who have been seen at four regional Dutch anticoagulation clinics since 1985. The primary outcome events were episodes of thromboembolism or major bleeding. The intensity-specific incidence of each type of event was calculated as the number of events that occurred at a certain intensity of anticoagulation (expressed in terms of the international normalized ratio [INR]) divided by the number of patient-years during which the INR was at this level in the total patient population.. A total of 1608 patients were followed during 6475 patient-years. Cerebral embolism occurred in 43 patients (0.68 per 100 patient-years) and peripheral embolism in 2 (0.03 per 100 patient-years). Intracranial and spinal bleeding occurred in 36 patients (0.57 per 100 patient-years) and major extracranial bleeding in 128 (2.1 per 100 patient-years). The optimal intensity of anticoagulation, at which the incidence of both complications was lowest, was achieved when the INR was between 2.5 and 4.9.. The intensity of anticoagulant therapy for patients with prosthetic heart valves is optimal when the INR is between 2.5 and 4.9. To achieve this level of anticoagulation, a target INR of 3.0 to 4.0 is recommended.

Topics: Acenocoumarol; Aged; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heart Valve Prosthesis; Hemorrhage; Humans; Incidence; Male; Middle Aged; Phenprocoumon; Prothrombin Time; Thromboembolism

The authors describe the possibilities of tooth extraction in patients who receive anticoagulant therapy. They propose the hospitalization of these patients. The authors also account of good results wits utilizing Lyostipt and Dicynone.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Cardiovascular Diseases; Ethamsylate; Female; Hemorrhage; Hemostatics; Humans; Male; Middle Aged; Thrombolytic Therapy; Tooth Extraction

The effectiveness of a commercial drug containing fibrinogen, thrombin and factor XIL (Tissucol, Immuno) was assessed in 127 patients receiving oral anticoagulant treatment with acenocoumarin who were subjected to 183 minor surgical procedures: 107 exodontia, 53 periodontal procedures, 17 combinations of the former, 4 liver biopsies and 2 skin biopsies. All but the liver biopsies were performed in the outpatient clinic. Mild haemorrhage appeared in 21 instances. None of the patients required systemic administration of coagulation factors, and the maneuvers did not take any longer than in patients with integrity of the coagulation mechanisms. The outstanding benefits of this technique are: less discomfort for patients, who can be subjected to a single procedure while otherwise requiring several sessions; anticoagulation needs not be discontinued, subcutaneous heparin being otherwise necessary; low risk of complications and avoidance of substitutive therapy; lesser economic burden, as no hospital admission is needed.

Topics: Acenocoumarol; Adult; Aged; Ambulatory Surgical Procedures; Biopsy; Drug Evaluation; Female; Fibrin Tissue Adhesive; Hemorrhage; Hemorrhagic Disorders; Hemostasis, Surgical; Humans; Liver; Male; Middle Aged; Periodontics; Safety; Skin; Tooth Extraction

A 77-year-old patient developed haemorrhagic bullae on her fingers 30 months after initiation of anti-coagulation treatment with warfarin sodium for chronic atrial fibrillation and mitral insufficiency. The bullae resolved 10 days after discontinuation of the medication. Two weeks after initiation of sintrom, (3-alpha-(4-nitrophenyl)-beta-acetylethyl-4-hydroxy coumarin), the lesions recurred and resolved again upon cessation of the drug. This adverse skin reaction has not been hitherto reported.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Female; Hemorrhage; Humans; Skin Diseases, Vesiculobullous; Warfarin

A selected group of patients who underwent valve replacement were analyzed to evaluate the feasibility, effectiveness and safety of combined treatment with moderate intensity anticoagulation plus aspirin. One hundred ninety-six patients who received a total of 204 mechanical valve prostheses between 1985 and 1991 were selected according to rigid criteria. The prostheses included 124 valves of caged ball design, 62 St. Jude valves and 18 others. The follow up of the whole population was 581.8 patient years, with an average of 2.97 patient years, and was complete by the definition criteria. All patients received moderate intensity anticoagulation with acenocoumarol (target International Normalized Ratio 2.5 to 3.5) and daily aspirin (100 mg or 325 mg). The incidence of thromboembolic events for the whole group was 3.26% per patient year, but only 1.6% in patients "compliant" with treatment. Preoperative embolism and non-compliance with treatment had a strong correlation with postoperative thromboembolism. The INR values had a strong correlation with both thromboembolic and hemorrhagic events. The incidence of serious hemorrhagic events was 4.12% patient years although only two cases (0.34%/pty) were fatal (cerebral hemorrhages). There was no difference in hemorrhagic incidence between patients receiving either 325 mg or 100 mg daily. A low incidence of thromboembolic complications was attained with the use of combined antithrombotic and antiplatelet therapy, even in the first generation caged ball type prostheses. However, the combination of moderate intensity anticoagulation with either 325 mg or 100 mg aspirin was associated with a risk of bleeding similar to high intensity anticoagulation alone. The risk of bleeding appeared to be greater in the presence of gastric pathology, and the combination of anticoagulants and aspirin should be avoided in patients with these conditions.

Topics: Acenocoumarol; Adult; Aged; Aspirin; Blood Coagulation Tests; Dose-Response Relationship, Drug; Drug Therapy, Combination; Feasibility Studies; Female; Follow-Up Studies; Heart Valve Diseases; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Postoperative Complications; Prosthesis Design; Retrospective Studies; Survival Rate; Thromboembolism; Treatment Outcome

To assess age-related risks of long term anticoagulation, the records of 348 patients followed up at our university hospital outpatient anticoagulation clinic during a seven year period were reviewed. There were 129 patients, under 56 years of age, 144 from 56 to 69 and 75 over 70 years old. The total observation period was 1089 patient-years (3.3 yrs per pt). 64% of the patients had adequate anticoagulation level (prothrombin time < 35%, INR 2.2-4.5) 70 to 100% of the observation period. Prothrombin time was slightly, but significantly higher in the elderly group. During this period 21 patients developed major bleeding complications (1.84/100 pt yrs), 8 of them with fatal intracranial hemorrhages, and 20 embolic complications (1.93/100 pt yrs), 3 of them fatal. No significant differences in the incidence of both bleeding and embolic complications were observed in the three groups. The results of this retrospective follow-up study suggest that long term anticoagulation can be carried out in elderly pts with risk of hemorrhagic and embolic complications similar to those observed in the general population.

Topics: Acenocoumarol; Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Cerebral Hemorrhage; Embolism; Female; Hemorrhage; Humans; Incidence; Intracranial Embolism and Thrombosis; Male; Middle Aged; Prothrombin Time; Retrospective Studies; Time Factors

To report two cases of enhanced oral anticoagulant effect induced by doxycycline coadministration.. Case report.. University teaching hospital.. Two patients on chronic oral anticoagulation therapy who presented with severe bleeding and marked impairment in blood coagulation tests shortly after the initiation of doxycycline therapy.. The literature concerning the possible effects of tetracyclines on hemostasis with or without antecedent anticoagulation therapy is reviewed and the speculated mechanisms for such an interaction are discussed.. The administration of tetracyclines such as doxycycline to patients on chronic oral anticoagulation therapy may be associated with a marked enhancement in anticoagulant effect. In such patients the prothrombin ratio should be closely monitored and the anticoagulant dosage adjusted accordingly.

Topics: Acenocoumarol; Aged; Blood Coagulation; Doxycycline; Female; Hemorrhage; Hospitals, University; Humans; Male; Middle Aged; Thrombolytic Therapy; Thrombophlebitis

Topics: Acenocoumarol; Aged; Biopsy; Drug Eruptions; Erythema; Hemorrhage; Humans; Male; Necrosis; Skin

Rats received a single subcutaneous dose of the inflammatory agent carrageenin on the top of the skull, followed by oral acenocoumarol for 3 days; in every case, an extensive haematoma was observed on the skull on day 4. The capillary resistance on the depilated dorsal skin was significantly reduced by this combined inflammatory + anticoagulant treatment. Haematoma development was not inhibited by cortisone, non-steroidal anti-phlogistics (piroxicam, proquazone) or benzopyrone derivatives (hesperidin methylchalcone, oligomeric procyanidin). On pretreatment with vitamin K1 for 1 day, followed by daily treatment for 3 days, no haematoma was observed.

Topics: Acenocoumarol; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Capillaries; Carrageenan; Chromones; Coumarins; Disease Models, Animal; Female; Hematoma; Hemorrhage; Male; Rats; Rats, Inbred Strains; Steroids; Vascular Resistance; Vitamin K 1

Topics: Acenocoumarol; Drug Therapy, Combination; Hemorrhage; Humans; Male; Middle Aged; Nephrectomy; Polycystic Kidney Diseases; Salicylates

Acenocoumarol sensitivity index (ASI) was calculated in 36 patients receiving amiodarone and acenocoumarol concomitantly, by dividing the acenocoumarol daily dose (micrograms kg-1 day-1) by the prothrombin ratio expressed as International Normalised Ratio (INR). It was found to be significantly lower (4.2 +/- 0.3 micrograms kg-1 day-1) than the ASI (11 +/- 0.6 micrograms kg-1 day-1) determined in 35 patients in the control group, who received acenocoumarol and not amiodarone. In 15 patients, ASI was 13.2 +/- 1.4 and 4.2 +/- 0.6 micrograms kg-1 day-1 before and after initiation of amiodarone therapy, respectively. In 5 patients, ASI was 6.2 +/- 0.6 micrograms kg-1 day-1, while patients were receiving both medications, and 28.1 +/- 6.1 micrograms kg-1 day-1 following discontinuation of amiodarone therapy. ASI determined while patients were on both medications was not affected by the presence of mild impaired renal or liver function. In 7 patients treated with both drugs concomitantly, severe bleeding diathesis developed. It is concluded that amiodarone augmented the anticoagulant effect of acenocoumarol in all patients receiving both drugs. An initial reduction of acenocoumarol daily dose by 50% and further adjustment of acenocoumarol dose according to daily prothrombin ratio is recommended. It is also suggested that acenocoumarol dose should be adjusted after cessation of amiodarone therapy.

Topics: Acenocoumarol; Aged; Amiodarone; Drug Interactions; Female; Hemorrhage; Humans; Male; Middle Aged

Topics: Acenocoumarol; Administration, Oral; Amiodarone; Drug Synergism; Hemorrhage; Humans; Injections, Intravenous; Prothrombin Time; Retrospective Studies

Topics: Acenocoumarol; Hemorrhage; Humans; Risk

Topics: Acenocoumarol; Aged; Amiodarone; Blood Coagulation Disorders; Drug Combinations; Drug Synergism; Female; Hemorrhage; Humans; Male; Middle Aged

From 1978-1986, 63 patients (48-79 years) under coumarin derivatives had to be hospitalized neurosurgically because of intracranial or intraspinal bleedings. This corresponds to a twelvefold increased risk compared to the untreated people. The male/female ratio was 1.5. At the time of the bleeding there was no true indication for anticoagulation in at least 60% of the patients. 80% with coma on admission died. Only for 2/7 with an intraspinal hemorrhage the outcome was better than paraplegic. Women proved to have a better chance of survival. There is a need for more concise indications for chronic anticoagulation.

Topics: Acenocoumarol; Aged; Cerebral Hemorrhage; Coma; Coumarins; Female; Follow-Up Studies; Hematoma, Subdural; Hemorrhage; Humans; Male; Middle Aged; Paraplegia; Phenprocoumon; Risk Factors; Spinal Cord Diseases

Topics: Acenocoumarol; Diclofenac; Drug Interactions; Hemorrhage; Humans; Lung Diseases; Male; Middle Aged

This report documents our experience with long term antithrombotic therapy (acenocoumarol plus aspirin) in 31 children and adolescents, from 5 months to 16 years of age. The valves replaced were mitral in 20 patients, aortic in 4, mitral-aortic in 4 and tricuspid in 3; the overall follow-up time was of 1336 months. Anticoagulant requirement in each children was not in correlation with age, but a significant increase (p less than 0.01) was found in association with sexual development. Our total incidence of embolic episodes was 1.49/1000 patient-months. The embolic incidence on adequate anticoagulated patients was 0.74/1000 patient-months and 93.7% of all patients were free of thrombo-embolic accidents up to 96 months of follow-up. Minor haemorrhage in relation to an excess of anticoagulant was 1.49/1000 patient-months. There has been only one major bleeding episode associated with severe sepsis, with an incidence of 0.74/1000 patient-months. No major difficulties were found in the management of anticoagulant treatment and its association with antiplatelet drugs in children.

Topics: Acenocoumarol; Adolescent; Age Factors; Aspirin; Child; Child, Preschool; Drug Therapy, Combination; Fibrinolytic Agents; Heart Valve Prosthesis; Hemorrhage; Humans; Postoperative Complications; Sex Factors; Sexual Maturation; Thromboembolism

Topics: Acenocoumarol; Aged; Back Pain; Diagnosis, Differential; Hemorrhage; Humans; Male; Middle Aged; Retroperitoneal Space

A hundred and fifty-two patients who were to undergo major orthopaedic surgery were divided into two groups in order to study the value of dextrans administered as adjuvants to oral anticoagulants in the prevention of deep venous thrombosis. The control group had oral anticoagulants only from the evening before the day of operation, aimed at the 15 per cent thrombotest level. The dextran group had peroperative and postoperative dextran infusions as well. Radionuclide venography was used for thrombosis detection. The dextran group had a lower incidence of thrombosis, but more haemorrhagic problems. The incidence of thrombosis was high in both groups.

Topics: Acenocoumarol; Anticoagulants; Dextrans; Female; Hemorrhage; Humans; Intraoperative Care; Male; Orthopedics; Postoperative Care; Postoperative Complications; Premedication; Thrombophlebitis

It is reported on the occurrence of haemorrhagic complications at old age in patients treated with coumarin. Altogether 352 patients were examined, 96 of them were older than 70 years. A small part of the patients, above all men with obliterating vascular occlusions of the lower extremity were additionally given also thrombocyte aggregation inhibitors. The effective prothrombin level was nearly the same in the two, groups, i.e. in the patients younger and older than 70 years. There was no difference in frequency and severity of the haemorrhages with the exception of macrohaematuria which, however, appeared above all in the younger age group and in women older than 70 years. Under observation of the indications and with a regular control a long-term treatment with coumarin preparations can performed without any particular risk also at old age.

Topics: Acenocoumarol; Aged; Arteriosclerosis Obliterans; Cerebral Hemorrhage; Female; Hemorrhage; Humans; Long-Term Care; Male; Prothrombin; Pulmonary Embolism; Thromboembolism; Thrombophlebitis

A group of 690 patients (337 males and 353 females) on long-term acenocoumarol therapy was studied. 62.8% of the values of the prothrombin ratio were within the chosen therapeutic range (1.8 to 2.7), 21.9% were below 1.8 and 15.3% were above 2.7. The daily maintenance dose, expressed on a weight basis, was found to significantly decrease with increasing age. The daily maintenance dose taken by females was significantly higher than the dose taken by males (P less than 0.05); the differences between males and females were maximal among patients aged between 21 and 50 years, and disappeared at older ages. Two hundred and twenty-eight haemorrhagic episodes in 160 patients were recorded during a total of 7797 months of follow-up. No lethal haemorrhages were observed. The overall incidence of bleeding episodes among females (3.6%) was higher than among males (2.2%) (P less than 0.001), even if menorrhagia was excluded (P less than 0.01).

Topics: Acenocoumarol; Adolescent; Adult; Age Factors; Aged; Estrogens; Female; Hemorrhage; Humans; Male; Menopause; Middle Aged; Regression Analysis; Sex Factors

Topics: Acenocoumarol; Aged; Anticoagulants; Hemorrhage; Heparin; Humans; Male; Middle Aged; Retroperitoneal Space; Vitamin K

Topics: 4-Hydroxycoumarins; Acenocoumarol; Anticoagulants; Female; Gallbladder Diseases; Hemorrhage; Humans; Indenes; Middle Aged; Vitamin K

Topics: Acenocoumarol; Aged; Coronary Disease; Dose-Response Relationship, Drug; Hemorrhage; Humans; Male; Patient Education as Topic

Topics: Acenocoumarol; Aspirin; Drug Therapy, Combination; Hemorrhage; Humans; Platelet Aggregation; Prothrombin Time; Thrombosis

Topics: Acenocoumarol; Adolescent; Adult; Child; Female; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Prothrombin Time; Retrospective Studies

Topics: Acenocoumarol; Aged; Drug Synergism; Gastrointestinal Hemorrhage; Glycolates; Hemorrhage; Humans; Male; Phenoxyacetates; Thiophenes

Topics: Acenocoumarol; Aged; Anticoagulants; Aspirin; Blood Coagulation Disorders; Dextrans; Drug Therapy, Combination; Female; Germany, West; Hemorrhage; Heparin; Humans; Middle Aged; Postoperative Care; Postoperative Complications; Preoperative Care; Pulmonary Embolism; Thromboembolism; Time Factors

Topics: Acenocoumarol; Adrenal Gland Diseases; Adrenal Glands; Aged; Blood Coagulation Tests; Hemorrhage; Humans; Male

Topics: Acenocoumarol; Acute Disease; Blood Coagulation Disorders; Chemical and Drug Induced Liver Injury; Child, Preschool; Factor VII; Factor VIII; Factor X; Hemorrhage; Humans; Kidney Diseases; Kidney Function Tests; Liver Function Tests; Male; Medication Errors; Prothrombin; Prothrombin Time; Vitamin K

Topics: Acenocoumarol; Adult; Aged; Alopecia; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Coumarins; Dosage Forms; Drug Synergism; Female; Hemorrhage; Heparin; Heparinoids; Humans; Liver; Male; Middle Aged; Myocardial Infarction; Protamines; Thrombophlebitis; Thrombosis; Time Factors

Topics: Acenocoumarol; Hemorrhage; Humans; Male; Middle Aged; Shock, Hemorrhagic

Topics: Acenocoumarol; Adult; Aged; Ambulatory Care; Embolism; Female; Hemorrhage; Humans; Hungary; Male; Middle Aged; Myocardial Infarction; Physician-Patient Relations; Socioeconomic Factors; Thrombosis

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; Breast Diseases; Coumarins; Diabetes Complications; Female; Foot Diseases; Hemorrhage; Humans; Intracranial Embolism and Thrombosis; Middle Aged; Necrosis; Obesity; Pulmonary Embolism; Thromboembolism; Thrombophlebitis; Thrombosis

Topics: Acenocoumarol; Animals; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Blood Proteins; Cholesterol; Dietary Fats; Endotoxins; Hemorrhage; Hemorrhagic Disorders; Rats; Salmonella typhi; Shock, Septic; Shock, Surgical; Thrombosis; Triamcinolone

Topics: Acenocoumarol; Aged; Ethyl Biscoumacetate; Hematoma; Hemorrhage; Humans; Lung Diseases; Middle Aged; Neck

Topics: Acenocoumarol; Adult; Aged; Angina Pectoris; Anticoagulants; Coronary Disease; Coumarins; Female; Heart Diseases; Heart Valve Diseases; Heart Valve Prosthesis; Hemorrhage; Humans; Long-Term Care; Male; Middle Aged; Myocardial Infarction; Phenindione; Prothrombin Time; Thromboembolism

Topics: Acenocoumarol; Anticoagulants; Coumarins; Eye Diseases; Factor V; Factor VII; Factor X; Hemorrhage; Hemostasis; Heparin; Humans; Phlebitis; Prothrombin Time; Retinal Hemorrhage; Vitamin K; Vitreous Body

Topics: Acenocoumarol; Aged; Anticoagulants; Ethyl Biscoumacetate; Female; Hemorrhage; Humans; Hypoprothrombinemias; Male; Postoperative Complications

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; Blood Coagulation Tests; Cardiovascular Diseases; Dicumarol; Female; Hemorrhage; Heparin; Humans; Hypertension; Male; Middle Aged; Phenindione

Topics: Acenocoumarol; Adult; Female; Hemorrhage; Humans; Skin Diseases

Topics: Acenocoumarol; Anticoagulants; Hematoma; Hematoma, Subdural; Hemorrhage; Humans; Pathology; Rheumatic Heart Disease; Spinal Cord; Spinal Diseases; Subdural Space; Toxicology

Topics: Acenocoumarol; Anticoagulants; Hemorrhage; Myocardial Infarction; Pericardial Effusion; Pericarditis; Surgical Procedures, Operative; Toxicology

Topics: Acenocoumarol; Angina Pectoris; Anticoagulants; Hemorrhage; Humans

Topics: Acenocoumarol; Anticoagulants; Breast Diseases; Carcinoma, Ductal; Hemorrhage; Humans; Nipples