phenprocoumon 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

Topics: Ambulatory Care; Anticoagulants; Atrial Fibrillation; Blood Coagulation Tests; Drug Monitoring; General Practice; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; International Normalized Ratio; Phenprocoumon; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

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

Antithrombotic medication can be performed by means of heparins (non-fractionated heparin, low molecular heparins) or the pentasaccharide Fondaparinux as well as with oral vitamin K antagonists. The use of a low molecular heparin is initially recommended for the sake of practicability and safety in case of patients suffering from deep venous thrombosis of the leg and pelvis with subsequent long-term oral medication using a vitamin K antagonist (Marcumar) for anticoagulation. The most frequent indications for long-term anticoagulation are deep leg and pelvis thromboses, pulmonary embolism with atrial fibrillation, artificial prosthetic valves and open oval foramen with ischaemic cerebral infarction. In case of patients with chronic atrial fibrillation it is expedient to initiate permanent anticoagulation according to a risk score. For the purpose of controlling oral anticoagulation it is recommended to employ the INR value in place of Quick's value because these data are better comparable. In case of atherothrombotic diseases secondary prevention will always indicate administration of a thrombocyte aggregation inhibitor. In such cases acetylsalicylic acid is recommended as the standard preparation.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atherosclerosis; Atrial Fibrillation; Blood Coagulation Tests; Cerebral Infarction; Drug Therapy, Combination; Female; Fibrinolytic Agents; Fondaparinux; Heart Valve Prosthesis; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Phenprocoumon; Platelet Aggregation Inhibitors; Polysaccharides; Preoperative Care; Prevalence; Primary Prevention; Pulmonary Embolism; Risk Factors; Sex Factors; Stroke; Time Factors; Venous Thrombosis

Despite 50 years of clinical experience with vitamin K antagonists such as phenprocoumon or warfarin, many clinicians are uncertain how to start treatment, deal with overdose or bleeding complications, and how to bridge anticoagulation when treatment with vitamin K antagonists is interrupted. Patients with overdose of vitamin K antagonists or bleeding complications are treated with vitamin K, prothrombin complex concentrates (PCC), or recombinant factor VIIa. Rapid reversal of anticoagulation is only achieved by using PCC or recombinant factor VIIa. Both should be combined with vitamin K for a sustained effect. For elective surgery, treatment with vitamin K antagonists is paused and vitamin K given either orally or intravenously. Unfractionated or low molecular weight heparin is given when INR levels are below therapeutic range. Patients with contraindications to heparin may be treated with alternative anticoagulants such as danaparoid, lepirudin or fondaparinux.

Topics: Anticoagulants; Critical Care; Emergency Medicine; Hemorrhage; Heparin; Humans; Medication Errors; Phenprocoumon; Vitamin K; 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

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

Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known.. From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA.. Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHA. In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis.. URL: https://www.. gov; Unique identifier: NCT02933697.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Myocardial Infarction; Phenprocoumon; Prospective Studies; Pyridones; Renal Dialysis; Stroke; Treatment Outcome

 The exact monitoring of the therapeutic-range international normalized ratio (INR) after left ventricular assist device (LVAD) implantation is an important aim to reduce the risk of thrombosis or bleeding complications. Service providers offer a telemedical anticoagulation service (CS)..  We compared LVAD patients using the CS (.  A total of 1,798 INR measurements were analyzed. The TTR.  We found that INR self-management is superior regarding the efficiency of post-LVAD anticoagulation therapy when compared with telemedical (CS)-based INR management in a small study cohort. Intensive training by experienced staff was able to replace CS.

Topics: Anticoagulants; Drug Monitoring; Germany; Heart Failure; Heart-Assist Devices; Hemorrhage; Humans; International Normalized Ratio; Patient Satisfaction; Phenprocoumon; Predictive Value of Tests; Prospective Studies; Prosthesis Implantation; Quality of Life; Self Care; Telemedicine; Thrombosis; Treatment Outcome; Ventricular Function, Left

Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis.. A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5 mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017.. The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598 f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals.. NCT02933697,Pre-results.

Topics: Adult; Anticoagulants; Atrial Fibrillation; Female; Germany; Hemorrhage; Humans; Male; Outcome Assessment, Health Care; Phenprocoumon; Pyrazoles; Pyridones; Renal Dialysis; Renal Insufficiency, Chronic; Thromboembolism

Non-vitamin K antagonist oral anticoagulants (NOACs) are at least as effective and safe as vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF). All pivotal trials have compared NOACs to warfarin. However, other VKAs are commonly used, for instance phenprocoumon.. A retrospective cohort study using a German claims database assessed the comparative risks of bleeding leading to hospitalization during therapy with NOACs and phenprocoumon in AF patients. Endpoints consisted of major bleeding, gastrointestinal bleeding, and any bleeding. Data were collected from January 1, 2013 to March 31, 2015. Patients newly initiated on dabigatran, apixaban, rivaroxaban, or phenprocoumon were included. Hazard Ratios for bleeding events were derived from Cox proportional hazard models, adjusting for differences in baseline characteristics. Propensity score matching was performed as a sensitivity analysis.. A total of 35,013 patients were identified, including 3138 on dabigatran, 3633 on apixaban, 12,063 on rivaroxaban, and 16,179 on phenprocoumon. Patients prescribed apixaban or phenprocoumon were older compared to those on dabigatran or rivaroxaban and had a higher CHA. Apixaban therapy is associated with a significantly reduced risk of bleeding compared to phenprocoumon. Bleeding risk with dabigatran was similar to that of phenprocoumon but bleeding risk with rivaroxaban was higher.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Female; Follow-Up Studies; Germany; Hemorrhage; Humans; Incidence; Male; Phenprocoumon; Product Surveillance, Postmarketing; Retrospective Studies; Stroke

Low-molecular-weight heparins (LMWH) are commonly used as peri-procedural bridging anticoagulants. The usefulness of measurement of anti-factor Xa activity (anti-Xa) to guide bridging therapy with LMWH is unknown. It was the objective of this study to determine levels of anti-Xa during standard bridging therapy with enoxaparin, and to examine predictors for residual anti-Xa. Consecutive patients receiving enoxaparin at a dosage of 1 mg/kg body weight/12 hours for temporary interruption of phenprocoumon were prospectively enrolled to the study. Blood-samples were obtained 14 hours after LMWH-application immediately pre- procedurally. Procedural details, clinical and demographic data were collected and subsequently analyzed. Seventy patients were included (age 75.2 +/- 10.8 years, Cr Cl 55.7 +/- 21.7ml/min, body mass index [BMI] 27.1 +/- 4.9). LMWH- therapy was for a mean of 4.2 +/- 1.6 days; overall anti-Xa was 0.58 +/- 0.32 U/ml. In 37 (52.8%) of patients anti-Xa was > or U/ml, including 10 (14.3%) patients with anti-Xa > 1U/ml. Linear regression analysis of single variables and logistic multivariable regression analysis failed to prove a correlation between anti-Xa and single or combined factors. No major bleeding, no thromboembolism and four (5.7%) minor haemorrhages were observed. When bridging OAC with therapeutic doses of enoxaparin a high percentage of patients undergo interventions with high residual anti-Xa. The levels of anti-Xa vary largely and are independent of single or combined clinical variables. Since the anti-Xa-related outcome of patients receiving bridging therapy with LMWH is not investigated, no firm recommendation on the usefulness of monitoring of anti-Xa can be given at this stage.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Drug Administration Schedule; Drug Monitoring; Enoxaparin; Factor Xa Inhibitors; Hemorrhage; Humans; International Normalized Ratio; Linear Models; Logistic Models; Middle Aged; Partial Thromboplastin Time; Phenprocoumon; Pilot Projects; Predictive Value of Tests; Prospective Studies; Risk Assessment; Surgical Procedures, Operative; Thromboembolism; Treatment Outcome

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

Heparin-free dialysis (HFD), i.e. only priming of the dialyser and no systemic heparinization, might reduce the risk of bleeding in dialysis patients receiving oral anticoagulation. The efficacy of HFD with two different membranes [polyacrylonitrile (AN69ST) vs. polysulphone (FX100)] was therefore investigated.. In a crossover design, 10 patients were treated with either membrane for 1 week (total 30 sessions). Weekly Kt/V and urea reduction rate (URR) were measured and thrombus formation evaluated by measurement of D-dimer and inspection of the air traps and dialyser.. Change of clotting markers was similar with both membranes. Complete thrombosis occurred in 3/30 patients with the AN69ST and in 1/30 patients with the FX100 membrane. Kt/V did not differ between the groups, but the URR was slightly higher with the FX100.. HFD prevents dialyser occlusion in the majority of patients treated with oral anticoagulants. Both polysulphone and polyacrylonitrile membranes seem to be equally effective.

Topics: Acrylic Resins; Administration, Oral; Adsorption; Aged; Aged, 80 and over; Anticoagulants; Biocompatible Materials; Cross-Over Studies; Equipment Design; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Heparin; Humans; International Normalized Ratio; Male; Membranes, Artificial; Middle Aged; Phenprocoumon; Polymers; Prospective Studies; Renal Dialysis; Sulfones; Thrombosis; Urea

Comparison of self-management of oral anticoagulant therapy versus conventional management has been hindered by use of different methods. We tested the hypothesis that there is no difference in the International Normalized Ratio (INR) variability, INR level, and coumarin dose among patients randomized to conventional management versus self-management.. The study design included uniform analysis of blinded control blood samples in both treatment arms. Ninety-two patients were randomly assigned to either self-management of oral anticoagulant therapy (including a teaching program for self-management followed by 6 months of independent self-management) or 6 months of conventional management. The endpoints were the variance (median square of the standard deviation) of the INR value, the median INR-value (using a blinded control sample analyzed monthly by a reference laboratory), and the coumarin dose.. Self-management was associated with a statistically significant smaller variance in INR values, a higher median INR value, and a higher dose of warfarin compared with conventional management. No difference was found in the group of patients using phenprocoumon.. Training and implementation of patient self-management leads to a smaller variance in INR values, a higher median INR value and a higher dose of coumarin compared with results obtained for conventionally managed patients.

Topics: Administration, Oral; Anticoagulants; Drug Monitoring; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Patient Education as Topic; Phenprocoumon; Self Administration; Thromboembolism; Treatment Outcome; Warfarin

The present prospective study was designed to evaluate the effectiveness and safety of prothrombin complex concentrate (PCC) for emergency reversal of oral anticoagulation with phenprocoumon, a long-acting coumarin. Patients were eligible for study entry if they required emergency reversal of phenprocoumon anticoagulation because they needed invasive surgical or diagnostic procedures or were actively bleeding. Patients received one or more infusions of pasteurized nanofiltered PCC (Beriplex P/N). Primary study endpoints were changes in International Normalized Ratio, Quick value, factors II, VII, IX and X, and protein C 10, 30 and 60 min following PCC infusion. Eight adult patients were enrolled, seven requiring urgent invasive procedures and one experiencing intracranial bleeding. In the first infusion, patients received a median 3600 IU PCC at median infusion rate 17.0 ml/min. Mean (SD) baseline International Normalized Ratio was 3.4 (1.2). The International Normalized Ratio 10 min after PCC infusion declined to 1.3 or less in seven of eight patients and to 1.4 in one patient. After PCC infusion, the Quick value increased by a mean of 57% [confidence interval (CI), 45-69%], circulating factor II concentration by 85% (CI, 68-103%), factor VII by 51% (CI, 40-62%), factor IX by 61% (CI, 47-76%), factor X by 115% (CI, 95-135%) and protein C by 100% (CI, 82-117%). Clinical effectiveness of PCC treatment was rated 'very good' in seven patients and 'satisfactory' in one. No thromboembolic or other adverse events occurred. PCC treatment rapidly, effectively and safely reversed phenprocoumon anticoagulation in patients undergoing urgent invasive procedures or actively bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Female; Hemorrhage; Hemostasis; Humans; International Normalized Ratio; Male; Phenprocoumon; Prospective Studies; Surgical Procedures, Operative

Anticoagulation in cardioversion of atrial fibrillation is currently performed with unfractionated heparin (UFH) and oral anticoagulants, with or without guidance by transesophageal echocardiography (TEE). Low-molecular-weight heparins may reduce the risk of bleeding, may obviate the need for intravenous access, and do not require frequent anticoagulation monitoring.. In a randomized, prospective multicenter trial, we compared the safety and efficacy of enoxaparin administered subcutaneously with intravenous UFH followed by the oral anticoagulant phenprocoumon in 496 patients scheduled for cardioversion of atrial fibrillation of >48 hours' and < or =1 year's duration. Patients were stratified to cardioversion with (n=431) and without (n=65) guidance by TEE. The study aimed to demonstrate noninferiority of enoxaparin compared with UFH+phenprocoumon with regard to the incidence of embolic events, all-cause death, and major bleeding complications. Secondary end points included successful cardioversion, maintenance of sinus rhythm until study end, and minor bleeding complications. Of 496 randomized patients, 428 were analyzed per protocol. Enoxaparin was noninferior to UFH+phenprocoumon with regard to the incidence of the composite primary end point in a per-protocol analysis (7 of 216 patients versus 12 of 212 patients, respectively; P=0.016) and in an intention-to-treat analysis (7 of 248 patients versus 12 of 248 patients, respectively; P=0.013). There was no significant difference between the 2 groups in the number of patients reverted to sinus rhythm.. Enoxaparin is noninferior to UFH+phenprocoumon for prevention of ischemic and embolic events, bleeding complications, and death in TEE-guided cardioversion of atrial fibrillation. Its easier application and more stable anticoagulation may make it the preferred drug for initiation of anticoagulation in this setting.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Drug Therapy, Combination; Electric Countershock; Enoxaparin; Female; Hemorrhage; Heparin; Humans; Incidence; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Phenprocoumon; Safety; Thromboembolism; Treatment Outcome

Topics: Administration, Oral; Adult; Aged; Aortic Valve; Aspirin; Clopidogrel; Drug Therapy, Combination; Female; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Pilot Projects; Thromboembolism; Ticlopidine; Treatment Outcome

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

We sought to assess in outpatients with atrial fibrillation and oral anticoagulation (1) whether the complication rate is influenced by the presence of the risk factors age >65 years, arterial hypertension, diabetes, or previous stroke; (2) whether the complication rate is influenced by the number of additional drugs taken by patients; and (3) whether problems and interventions differ between patients with or without complications.. - Clinical characteristics, drugs, problems, interventions, and complications were registered during 2 years.. - Three hundred sixty patients (mean age, 68 years; 43% female) were observed for 383 patient-years. Patients aged >65 years had more serious, life-threatening, or fatal complications (11% versus 5.3%/100 patient-years; P=0.0428) than younger patients. Patients with diabetes had more life-threatening and fatal complications (2.8% versus 0.6%/100 patient-years; P=0.0354) than patients without. The complication rate did not differ regarding the presence of previous stroke or hypertension. Patients who took 3 drugs per day have an increased complication rate and thus need especially careful monitoring of oral anticoagulation, including adequate pain control.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Endpoint Determination; Female; Hemorrhage; Humans; Intracranial Embolism; Male; Middle Aged; Phenprocoumon; Risk Assessment; Risk Factors; Stroke

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

Topics: 4-Hydroxycoumarins; Aged; Aspirin; Clinical Trials as Topic; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Patient Compliance; Phenprocoumon; Random Allocation; Sex Factors; Sulfinpyrazone

Topics: Anticoagulants; Hemorrhage; Humans; Infant; Infant, Newborn; Phenprocoumon; Vitamin K Deficiency Bleeding; Vitamin K Epoxide Reductases

Bleeding after tooth extraction range from minor bleeding to life-threating haemorrhagic shock and are among the leading complications in patients under oral anticoagulation with direct oral anticoagulants (DOACs) or phenprocoumon. Little is known about how anticoagulation in patients under DOAC or phenprocoumon alters the characteristics, treatment or outcome of bleeding events, in comparison to non-anticoagulated patients.. Patients admitted to a tertiary ED in Bern, Switzerland, from June 1st 2012 to 31st May 2016 with bleeding related to tooth extraction under DOAC, phenprocoumon or without anticoagulation, were compared.. Out of 161,458 emergency consultations, 64 patients with bleeding from tooth extraction were included in our study. In anticoagulation groups, we found significantly more delayed bleeding events than in patients without anticoagulation (9 (81.3%) DOAC, 19 (86.4%) phenprocoumon, 8 (30.8%) no anticoagulation, p < 0.001). Anticoagulated patients had to stay longer in the ED than non-anticoagulated patients, with no significant difference between DOAC or phenprocoumon (hours: 4.8 (3.2-7.6 IQR) DOAC, 3.0 (2.0-5.5 IQR) phenprocoumon, p = 0.133; 2.7 (1.6-4.6) no anticoagulation; p = 0.039). More patients with anticoagulation therapy needed surgery than patients without anticoagulant therapy (11 (68.8%) DOAC, 12 (54.6%) VKA, p = 0.506; 7(26.9%) no anticoagulation; p = 0.020).. Delayed bleeding occur more often in anticoagulated patients with both DOAC and phenprocoumon compared to patients without anticoagulation. Bleeding events in anticoagulated patients with DOAC and phenprocoumon equally need longer ED treatment and more frequent surgical intervention.. Caution with delayed bleeding in anticoagulated patients with DOACs and phenprocoumon is necessary and treatment of bleeding is resource-demanding.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Emergency Service, Hospital; Female; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Retrospective Studies; Switzerland; Tooth Extraction; Treatment Outcome; Young Adult

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

Information on utilization of oral anticoagulants (OACs) in nursing homes is scarce. This study aimed to (i) describe OAC use in German nursing home residents, (ii) examine factors influencing whether treatment is initiated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) and (iii) assess which conditions predict switching to NOAC instead of continuing VKA.. Using claims data (2010-2014), we studied a cohort of new nursing home residents aged ≥65 years receiving OAC. Further, OAC use in patients with atrial fibrillation (AF) was examined over the years.. Overall, 16 804 patients (median age: 85 years, 75% female, 44% with renal disease) were included. The majority received phenprocoumon as first OAC (58.0%), followed by rivaroxaban (28.1%). Over the study period, NOAC use increased substantially. Initiating NOAC instead of VKA was predicted by a previous stroke (adjusted odds ratio: 1.76; 95% confidence interval: 1.49-2.08). In contrast, renal disease predicted VKA initiation (0.66; 0.59-0.75) as did the presence of a prosthetic heart valve. Switching from VKA to NOAC was predicted by a stroke (2.55; 2.00-3.24), bleeding events and a recent hospitalization. During 2010-2014, the proportion of AF patients with a CHADS2 score ≥2 receiving OAC increased from 27% to 46%.. NOACs are increasingly used in German nursing homes, both for initial anticoagulation but also in VKA pre-treated patients. Switching from VKA to NOAC was substantially influenced by aspects such as intended higher effectiveness and safety but probably also practicability due to less blood monitoring.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Drug Monitoring; Female; Germany; Hemorrhage; Humans; Kidney Diseases; Male; Nursing Homes; Phenprocoumon; Rivaroxaban; Stroke; Vitamin K

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Comorbidity; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Patient Safety; Phenprocoumon; Proportional Hazards Models; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Treatment Outcome

Topics: Aged, 80 and over; Anesthesia, Spinal; Anticoagulants; Enoxaparin; Hemorrhage; Humans; Intraoperative Complications; Male; Phenprocoumon; Syndrome; Thrombosis; Transurethral Resection of Prostate; Urinary Bladder Diseases; Urologic Surgical Procedures

The pivotal trials for stroke prevention in non-valvular atrial fibrillation (NVAF) compared rivaroxaban, dabigatran, and apixaban with warfarin, as did most claims-based studies. Comparisons with phenprocoumon, the most frequently used vitamin K antagonist (VKA) in Germany, are scarce.. Risk of bleeding, ischemic stroke, and all-cause mortality in patients with NVAF were analyzed using data for 2010 to 2014 from a large German claims database. New users of oral anticoagulants from January 2012 to December 2013 were included and observed over 1 year. Baseline characteristics were adjusted using propensity score matching and logistic regression. Several sensitivity analyses were carried out.. Fifty-nine thousand four hundred forty-nine rivaroxaban, 23,654 dabigatran, 4894 apixaban, and 87,997 matched phenprocoumon users were included. Adjusted hazard ratios (95% confidence intervals) compared with phenprocoumon were as follows: hospitalized bleedings: rivaroxaban 1.04 (0.97; 1.11), dabigatran 0.87 (0.77; 0.98), and apixaban 0.65 (0.50; 0.86); ischemic stroke: rivaroxaban 1.05 (0.94; 1.17), dabigatran 1.14 (0.96; 1.35), and apixaban 1.84 (1.20; 2.84); all-cause mortality: rivaroxaban 1.17 (1.11; 1.22), dabigatran 1.04 (0.95; 1.13), and apixaban 1.14 (0.97; 1.34).. With rivaroxaban, no significant differences were observed compared to phenprocoumon with regard to hospitalized bleedings or ischemic strokes. Dabigatran was associated with fewer bleedings and a similar risk of ischemic strokes compared to phenprocoumon. Apixaban was also associated with fewer bleedings but was unexpectedly associated with more ischemic strokes, possibly reflecting selective prescribing. The association of rivaroxaban with higher all-cause mortality unrelated to bleedings or strokes has been described previously but remains to be explained.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Databases, Factual; Female; Follow-Up Studies; Germany; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Stroke; Vitamin K; Young Adult

We aimed to assess the efficacy and safety of vitamin K antagonist (VKA) monotherapy in atrial fibrillation (AF) patients undergoing transcatheter aortic valve implantation (TAVI).. In 735 TAVIs since 2008 we identified 167 patients suffering from concomitant AF who received either VKA monotherapy (n=77), VKA plus single antiplatelet therapy (SAPT, n=41) or a triple anticoagulation regimen (n=49). Thromboembolic as well as bleeding complications were analysed for six months after TAVI. Only one minor bleeding and no thromboembolic events occurred after VKA therapy had been initiated post TAVI. Compared to patients being treated with additional either single or dual antiplatelet therapy, the incidence of major/life-threatening bleeding complications was significantly lower in the VKA mono group (0/77 [VKA mono] vs. 3/41 [VKA+SAPT; p=0.04] vs. 4/49 [triple anticoagulation; p=0.02]). Analysis of a combined endpoint of post-procedural death, stroke, embolism and major bleeding revealed a significant superiority of VKA monotherapy compared to VKA plus SAPT or DAPT, respectively (5/77 vs. 9/41 [p=0.02] vs. 14/49 [p=0.002]).. VKA therapy without additional antiplatelet treatment is effective and safe in AF patients undergoing TAVI.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Feasibility Studies; Female; Germany; Hemorrhage; Humans; Male; Phenprocoumon; Postoperative Complications; Thromboembolism; Transcatheter Aortic Valve Replacement

Anticoagulation in patients with ventricular assist device (VAD) support is crucial and to date, no alternative to vitamin K antagonists (VKAs) can be safely used. Genetic variances of cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC) have been recently connected with variation of VKA maintenance as well as loading doses. In this retrospective study, we assessed the incidence of genetic variations and the influence of different genotypes of CYP2C9 and VKORC1 in VAD patients.. A total of 161 patients received a VAD implant in our institution between January 2006 and July 2014. Of these, 63 consented to genetic analysis and completed an interview with standardized questions on phenprocoumon (PC) dosage, international normalized ratio and anticoagulation-related complications. Determination of VKORC (-1639 G > A; -1173 C > T) and of CYP2C9 (*2, 430 C > T; *3, 1075 A > C) polymorphisms was performed by polymerase chain reaction and restriction analysis.. The most common VKORC-1639 allele combination was wild-type GG (41%) followed by GA (32%) and AA (27%). Patients with VKORC1 polymorphisms AA and GA needed less PC in the maintenance phase of anticoagulation (P < 0.001) compared with wild-type GG patients. In contrast, CYP2C9 polymorphisms showed no effect on PC doses. Similar findings were observed in the initiation phase of PC therapy. High complications rates under PC therapy were observed particularly at the beginning.. VKORC polymorphism affects PC dosage in the initiation as well as the maintenance phase. High rates of bleeding complications and thromboembolic events were found at the beginning of PC therapy in VAD patients. Therefore, a genotype-guided dosage algorithm might be useful in VAD patients.

Topics: Adolescent; Adult; Aged; Anticoagulants; Blood Coagulation; Cytochrome P-450 CYP2C9; DNA; Dose-Response Relationship, Drug; Female; Genetic Variation; Genotype; Germany; Heart Failure; Heart-Assist Devices; Hemorrhage; Humans; Incidence; Male; Middle Aged; Phenprocoumon; Polymorphism, Genetic; Retrospective Studies; Thromboembolism; Vitamin K Epoxide Reductases; Young Adult

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

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

The aim of the study was to evaluate potential differences between patients with spontaneous and non-spontaneous bleeding episodes during treatment with vitamin K antagonists which mainly resulted in compartment syndromes.. The population in this study comprised 116 patients who suffered at least one bleeding complication which required surgical treatment during therapy with an oral vitamin K antagonist. The patients were treated between September 2001 and July 2008.. Significant differences were observed between the two patient groups with regard to the presence of renal failure, arterial hypertension, and diabetes mellitus, which occurred more frequently in patients with spontaneous bleeding. Also, significantly more patients with spontaneous bleedings developed compartment syndrome that needed emergency operation. Overall mortality was 9.6 %, was associated with multiorgan failure in all patients, and was not different between the two patient groups.. The identification of high-risk patients before treatment with an oral vitamin K antagonist is of major importance. The existence of over-anticoagulation syndrome and compartment syndrome is associated with significant mortality and morbidity and should not be underestimated.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Algorithms; Anticoagulants; Compartment Syndromes; Female; Germany; Hemorrhage; Humans; International Normalized Ratio; Length of Stay; Male; Middle Aged; Phenprocoumon; Retrospective Studies; Risk; Tomography, X-Ray Computed; Vitamin K

There is major concern about coumarins interacting with various drug classes and increasing the risk of overanticoagulation. The aim of the study was to assess bleeding risk in patients with concurrent use of antibiotics and phenprocoumon, the most widely prescribed coumarin in many European countries. We conducted a nested-case-control study within a cohort of 513,338 incident and continuous phenprocoumon users ≥ 18 years of age using claims data of the statutory health insurance company AOK, covering 30% of the German population. Bleeding risk associated with current use of antibiotics for systemic use (antibacterials/antimycotics) was calculated using conditional logistic regression in 13,785 cases with a bleeding event and 55,140 risk-set sampling-matched controls. Bleeding risk associated with any antibacterial use in phenprocoumon users was significantly increased [odds ratio (OR) 2.37, 95% confidence interval (CI) 2.20-2.56]. The association was stronger for gastrointestinal than for cerebral bleeding (OR 2.09, 95% CI 1.84-2.38 and OR 1.34, 95% CI 1.03-1.74, respectively) and highest for other/unspecified bleeding (OR 2.92, 95% CI 2.62-3.26). Specific antibiotic classes were strongly associated with bleeding risk, e.g. cotrimoxazole (OR 3.86, 95% CI 3.08-4.84) and fluorquinolones (OR 3.13, 95% CI 2.74-3.59), among those highest for ofloxacin (OR 5.00, 95% CI 3.01-8.32). Combined use of phenprocoumon and antimycotics was not significantly associated with bleeding risk. Risk was not significantly modified by age (pint=0.25) or sex (pint=0.96). The association was stronger the closer the antibiotic exposure was to the bleeding event. Among continuous phenprocoumon users, antibiotics - particularly quinolones and cotrimoxazole - should be prescribed after careful consideration due to an increased bleeding risk. Close monitoring of international normalised ratio levels after prescription is recommended.

Topics: Aged; Anti-Bacterial Agents; Anticoagulants; Case-Control Studies; Drug Interactions; Drug Therapy, Combination; Female; Fluoroquinolones; Follow-Up Studies; Germany; Hemorrhage; Humans; Insurance, Health; Male; Middle Aged; Ofloxacin; Phenprocoumon; Population Groups; Risk; Trimethoprim, Sulfamethoxazole Drug Combination

The optimal long-term antithrombotic treatment of patients with coexisting atrial fibrillation and stable coronary artery disease is unresolved, and commonly, a single antiplatelet agent is added to oral anticoagulation. We investigated the effectiveness and safety of adding antiplatelet therapy to vitamin K antagonist (VKA) in atrial fibrillation patents with stable coronary artery disease.. Atrial fibrillation patients with stable coronary artery disease (defined as 12 months from an acute coronary event) between 2002 and 2011 were identified. The subsequent risk of cardiovascular events and serious bleeding events (those that required hospitalization) was examined with adjusted Cox regression models according to ongoing antithrombotic therapy. A total of 8700 patients were included (mean age, 74.2 years; 38% women). During a mean follow-up of 3.3 years, crude incidence rates were 7.2, 3.8, and 4.0 events per 100 person-years for myocardial infarction/coronary death, thromboembolism, and serious bleeding, respectively. Relative to VKA monotherapy, the risk of myocardial infarction/coronary death was similar for VKA plus aspirin (hazard ratio, 1.12 [95% confidence interval, 0.94-1.34]) and VKA plus clopidogrel (hazard ratio, 1.53 [95% confidence interval, 0.93-2.52]). The risk of thromboembolism was comparable in all regimens that included VKA, whereas the risk of bleeding increased when aspirin (hazard ratio, 1.50 [95% confidence interval, 1.23-1.82]) or clopidogrel (hazard ratio, 1.84 [95% confidence interval, 1.11-3.06]) was added to VKA.. In atrial fibrillation patients with stable coronary artery disease, the addition of antiplatelet therapy to VKA therapy is not associated with a reduction in risk of recurrent coronary events or thromboembolism, whereas risk of bleeding is increased significantly. The common practice of adding antiplatelet therapy to oral VKA anticoagulation in patients with atrial fibrillation and stable coronary artery disease warrants reassessment.

Topics: Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Clopidogrel; Cohort Studies; Comorbidity; Coronary Artery Disease; Drug Therapy, Combination; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Phenprocoumon; Platelet Aggregation Inhibitors; Risk Factors; Stroke; Ticlopidine; Vitamin K; Warfarin

Topics: Accidents, Occupational; Diagnosis, Differential; Female; Hematoma; Hemorrhage; Humans; Leg Injuries; Middle Aged; Muscle, Skeletal; Phenprocoumon; Pigmentation Disorders; Ultrasonography, Doppler, Duplex; Venous Thrombosis

This study aimed to evaluate the safety of continuous periprocedural rivaroxaban administration during left atrial radiofrequency ablation (RFA) in comparison with uninterrupted oral vitamin K antagonist administration. Data about the use of rivaroxaban in the setting of left atrial RFA procedures are lacking.. The study cohort included 544 patients (mean age, 63±10 years) who underwent left atrial RFA procedures between February 2012 and May 2013. All patients (n=272) receiving uninterrupted periprocedural rivaroxaban 15 or 20 mg/d before the procedure (rivaroxaban) were matched by age, sex, and type of rhythm disorder with an equal number of patients managed with uninterrupted vitamin K antagonist phenprocoumon (international normalized ratio, 2-3). During RFA, heparin was given intravenously to maintain an activated clotting time at 270 to 300 s. The safety end point was a composite of bleeding, thromboembolic events, and death. There were no thromboembolic complications and no deaths in either group. The prevalence of major bleeding complications was similar in both groups (1 tamponade in RivG and 1 groin hematoma requiring transfusion in phenprocoumon). Minor bleeding complications occurred equally in both groups (20 of 272; 7% in the rivaroxaban versus 33 of 272, 12% in the phenprocoumon; P=0.08). In multivariable analyses, female sex was associated with a greater risk of complications (odds ratio, 1.96; 95% confidence interval, 1.10-3.49).. In patients undergoing left atrial RFA, continuous periprocedural rivaroxaban use seems to be as safe as uninterrupted periprocedural phenprocoumon administration.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Chi-Square Distribution; Drug Administration Schedule; Female; Germany; Heart Atria; Hemorrhage; Humans; Logistic Models; Male; Middle Aged; Morpholines; Multivariate Analysis; Odds Ratio; Phenprocoumon; Registries; Retrospective Studies; Risk Factors; Rivaroxaban; Sex Factors; Thiophenes; Thromboembolism; Time Factors; Treatment Outcome

Oral anticoagulation in mechanical heart valve recipients remains crucial, and vitamin K antagonists (VKA) are still the gold standard. Polymorphisms of vitamin K epoxide oxidase reductase (VKORC) and cytochrome p450 (CYP2C9) were recently found to influence VKA metabolism. We retrospectively investigated the prevalence of these genotypes and associated anticoagulation-related complications in our patients.. Between August 1998 and August 2008, 563 patients received mechanical heart valve replacement in our institution. Of these, 179 completed a questionnaire on anticoagulation-related complications and consented to genetic analysis. We analysed polymorphisms of VKORC (-1639 G>A; 1173 C>T) and of CYP2C9 (*2, 144 C>T; *3, 359 A>C) by PCR and restriction analysis.. For VKORC-1639/1173 alleles, there were 62 (35%) patients with the combination GG/CC, 91 (51%) with GA/CT, 25 (14%) with AA/TT and 1 (1%) with AA/CT. Phenprocoumon (PC) dosage was related to VKORC polymorphism (P < 0.001) with lower doses required for AA/TT patients. Overall, there were 27 severe bleedings and 11 thromboembolic events. For GG/CC, the incidence of major bleeding events and thromboembolic events was 13 and 6%, respectively, and for AA/TT, it was 27 and 12%, respectively. Variation in international normalized ratio (INR) >1.5 was associated with severe bleeding complications (P = 0.025) and GA/CT patients were predisposed to INR variations >1.5 (P = 0.028). No influence of CYP2C9 polymorphism on PC dosage and anticoagulation-related complications was found.. VKORC polymorphism affects PC dosage and anticoagulation-related complication rates in mechanical heart valve recipients. Genotyping may help to identify patients at particular risk of anticoagulation-related complications.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Female; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; Male; Middle Aged; Odds Ratio; Phenprocoumon; Polymorphism, Single Nucleotide; Postoperative Complications; Retrospective Studies; Thromboembolism; Vitamin K Epoxide Reductases

Even after the recent approval of newer oral anticoagulants for clinical use, the vitamin K antagonist phenprocoumon remains an important treatment option for many patients. In order to quantify the hitherto "accepted" risks of phenprocoumon treatment, we analyzed adverse drug reactions (ADRs) that led to hospitalization on the internal medicine wards of four German pharmacovigilance centers.. We prospectively analyzed ADRs leading to hospitalization on the internal medicine wards of the hospitals belonging to the German Network of Regional Pharmacovigilance Centers (Rostock, Greifswald, Jena, and the Sophien- und Hufeland-Klinikum in Weimar) in the years 2000 to 2008.. The 851 patients hospitalized for a phenprocoumon-associated ADR accounted for 12.4% of the 6887 ADR-related hospitalizations in the period of the study. 723 (85%) were admitted for a hemorrhage, usually in the gastrointestinal tract (482 patients); 8 patients died as a consequence of hemorrhage associated with phenprocoumon exposure. Using drug utilization data for the catchment areas of the participating hospitals, we calculate a rate of 5 to 7 hemorrhages leading to hospitalization in an internal medicine ward per 1000 patient-years under phenprocoumon treatment. One-third of the patients who had a hemorrhage were taking other interacting drugs, mainly inhibitors of platelet aggregation and non-steroidal anti-inflammatory drugs. Among the patients who were taking phenprocoumon because of a history of thromboembolic events or for atrial fibrillation, 60% to 70% of those who had hemorrhages had an international normalized ratio (INR) that was above the upper limit of the therapeutic range. Phenprocoumon-associated impairment of liver function arose in 23 patients (2.7%).. In this study, about one-eighth of all ADR-related admissions to hospital internal medicine wards were associated with phenprocoumon. There is a need for a comparative risk-benefit assessment of phenprocoumon and the newer oral anticoagulants under real-life conditions.

Topics: Aged; Anticoagulants; Chemical and Drug Induced Liver Injury; Comorbidity; Female; Germany; Hemorrhage; Hospitalization; Humans; Internal Medicine; Male; Pharmacovigilance; Phenprocoumon; Prevalence; Prospective Studies; Risk Assessment; Thromboembolism

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

Implanon is a widely used contraceptive. It is a progestagen-containing implant which is inserted subcutaneously on the inside of the upper arm. This procedure is relatively simple.. A 26-year-old woman had her contraceptive implant replaced in the outpatient clinic. Because of a mechanical heart valve, she used phenprocoumon, which she did not discontinue prior to the procedure. Three days after the Implanon replacement, the patient presented with persistent blood loss from the insertion site and a large hematoma around the new implant. The placement of a new pressure bandage was not sufficient. The concentration of Hb fell from 8.1 to 5.0 mmol/l with an INR of 3.5; therefore, the patient received a blood transfusion. The use of phenprocoumon was temporarily discontinued and the INR was corrected with prothrombin complex. Good hemostasis was ultimately achieved.. Although the replacement of a subcutaneous hormone implant is a relatively simple procedure, a severe complication such as hemorrhaging may occur, particularly when there are risk factors.

Topics: Administration, Cutaneous; Adult; Anticoagulants; Blood Transfusion; Contraceptive Agents, Female; Desogestrel; Female; Hemorrhage; Hemostasis; Humans; International Normalized Ratio; Phenprocoumon

Topics: Chemical and Drug Induced Liver Injury; Female; Hemorrhage; Hospitalization; Humans; Internal Medicine; Male; Phenprocoumon; Thromboembolism

Topics: Chemical and Drug Induced Liver Injury; Female; Hemorrhage; Hospitalization; Humans; Internal Medicine; Male; Phenprocoumon; Thromboembolism

Topics: Chemical and Drug Induced Liver Injury; Female; Hemorrhage; Hospitalization; Humans; Internal Medicine; Male; Phenprocoumon; Thromboembolism

Excessive anticoagulation with vitamin K antagonists is a serious condition with a substantial risk of an adverse outcome. We thus found it of interest to review a large case series to characterize the underlying causes of excessive anticoagulation.. Patients were identified both retrospectively and prospectively. The inclusion criteria were an international normalized ratio (INR) > 6.5 or INR > 3.5 and significant bleeding. Patient charts were reviewed for a predefined set of possible causes: Drug-drug interactions, alcohol abuse, disease, start-up or recent change in dosage and dosage errors.. In 86 of 107 admissions one or more causal event were identified. The two most common causes of excessive anticoagulation were disease and drug-drug interactions. The two most common drug-drug interactions were with paracetamol and tramadol. In 44 admissions, a single cause was identified; in 42, two or more causes were identified.. Although it is difficult to identify single initiatives that may reduce the number of admissions due to excessive anticoagulation, interesting areas include a stronger focus on frequent INR control during the various states of disease and heightened attention to drug-drug interactions.. Not relevant.

Topics: Aged; Aged, 80 and over; Anticoagulants; Drug Interactions; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Phenprocoumon; Vitamin K; Warfarin

Claims databases are an important source for pharmacoepidemiological studies although they often lack information on some confounders. Two-phase methodology was used to estimate the bleeding risk in patients treated with phenprocoumon from claims data combined with additional information on body mass index (BMI) and smoking.. We conducted a nested case-control study using claims data from 2004 to 2007 (phase 1). Additional information was obtained from interviews in a subset of 505 insurants (phase 2). Adjusted bleeding OR were calculated using logistic regression using data from the complete case-control dataset. Furthermore, a two-phase analysis was conducted, taking into consideration phase 2 data on BMI and smoking.. The phase 1 sample included 1248 cases and 24,960 controls. In phase 1, we observed an adjusted bleeding ORs of 3.93 (95%CI: 2.75-5.61) for male subjects aged 55 years taking phenprocoumon. The bleeding risk associated with phenprocoumon use decreased with increasing age. The two-phase analysis revealed smoking and a high BMI as risk factors for bleeding. The OR for phenprocoumon obtained from the two-phase analysis was of similar size as the phase 1 estimate.. Phase 2 data added valuable information on smoking and BMI. However, phase 1 results did not change dramatically after accounting for phase 2 information, which is reassuring for the validity of database studies.

Topics: Adult; Age Factors; Aged; Anticoagulants; Body Mass Index; Case-Control Studies; Databases, Factual; Female; Hemorrhage; Humans; Logistic Models; Male; Middle Aged; Pharmacoepidemiology; Phenprocoumon; Risk Factors; Smoking

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

Phenprocoumon is the most frequently used vitamin K antagonist in Germany. The aim of this study was to estimate the risk of serious bleeding as a result of the use of drugs with potential interaction with phenprocoumon.. We conducted a nested case-control study in a cohort of 246,220 phenprocoumon users in the German Pharmacoepidemiological Research Database. Cases were patients hospitalised for haemorrhage of different kinds. Ten controls were matched to each case by health insurance, birth year and sex using incidence density sampling. Odds ratios (OR) with 95% confidence intervals (CI) of the risk of serious bleeding associated with combined use of phenprocoumon and potentially interacting drugs versus phenprocoumon alone were estimated using conditional logistic regression analysis. Our analyses considered multiple risk factors, such as bleeding history, other comorbidities or co-medication.. Our study included 2,553 cases and 25,348 matched controls. An increased risk of bleeding was observed for the combined use of phenprocoumon and clopidogrel vs phenprocoumon use alone (OR: 1.83, 95% CI: 1.41-2.36). Antibiotic drugs associated with an increased risk of haemorrhage in the population of phenprocoumon users included the group of quinolones with ORs ranging from 2.74 (95% CI: 1.80-4.18) for ciprofloxacin to 4.40 (95% CI: 2.45-7.89) for levofloxacin, amoxicillin plus clavulanic acid (OR: 2.99, 95% CI: 1.39-6.42) and cotrimoxazole (OR 3.57, 95% CI: 2.36-5.40). Among non-steroidal anti-inflammatory drugs (NSAIDs), ketoprofen and naproxen were associated with the highest risks.. Significantly elevated risks of major bleeding were mainly observed for drugs with known pharmacodynamic interaction with phenprocoumon, and less for drugs with possible pharmacokinetic interaction.

Topics: Aged; Anticoagulants; Case-Control Studies; Cohort Studies; Databases, Factual; Drug Interactions; Drug Prescriptions; Female; Germany; Hemorrhage; Hospitalization; Humans; Logistic Models; Male; Phenprocoumon; Risk; Vitamin K

Topics: Administration, Oral; Anticoagulants; Cardiovascular Diseases; Elective Surgical Procedures; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Perioperative Period; Phenprocoumon; Risk Factors; Thromboembolism; Vitamin K

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

The authors discuss a rare case of hemorrhage in a filum terminale ependymoma presenting with acute paraparesis and transient hydrocephalic dementia in association with long-term phenprocoumon anticoagulation. The CT scan of the brain revealed the presence of blood in both occipital horns and communicating hydrocephalus. The symptoms gradually resolved after tumor removal and there was no need for shunting. This is a complex clinical presentation of a spinal cord tumor associated hemorrhage, which further illustrates the possibility of retrograde passage of blood from the lumbosacral region to the ventricles.

Topics: Aged; Anticoagulants; Cauda Equina; Cerebral Ventricles; Dementia, Vascular; Ependymoma; Female; Hemorrhage; Humans; Hydrocephalus; Paraparesis; Phenprocoumon; Spinal Cord Neoplasms; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Aspirin; Atrial Fibrillation; Clopidogrel; Coronary Disease; Coronary Restenosis; Drug Interactions; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Phenprocoumon; Proton Pump Inhibitors; Stents; Thromboembolism; Ticlopidine

Oral anticoagulants are broadly used in cardiology. However, it is still necessary to evaluate their use in clinical practice.. To describe the differences in the maintenance of anticoagulation control, as well as the incidence of hemorrhagic and thromboembolic events among users of warfarin and phenprocoumon.. Non-concurrent cohort study of 127 patients using oral anticoagulation.. Phenprocoumon was the most frequently used anticoagulant in 60% of the patients. The prevalence of RNI<2 at the last medical appointment was higher among warfarin users (46% vs. 19.5%; p<0.001). During the follow-up, Phenprocoumon users were within the therapeutic range during 60.7% of the period, in comparison with 45.6% of warfarin users (OR:1.84; 95%CI:1.59-2.13; P<0.001). The incidence of bleeding was 5.3/100 patients/year in the phenprocoumon group versus 18.8/100 patients/year in the warfarin group (RR: 3.5; 95%CI: 1.87-6.48; P<0.001).. Patients that used Warfarin remained at subtherapeutic levels for a longer period; however, they also presented more hemorrhagic events. Phenprocoumon users were younger and had been using oral anticoagulation for longer periods, presenting fewer drug-related adverse events.

Topics: Administration, Oral; Ambulatory Care Facilities; Anticoagulants; Brazil; Epidemiologic Methods; Female; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Prothrombin; Time Factors; Treatment Outcome; Warfarin

Low molecular weight heparin is widely used during the interruption of long-term oral anticoagulation in patients undergoing surgery. The optimal dose is still a matter of debate. The 8th ACCP Guidelines primarily recommend therapeutic-dose or low-dose low molecular weight heparin after stratification of the thromboembolic risk. We investigated the efficacy and safety of a standardized bridging therapy with enoxaparin in a half-therapeutic dose in patients with a target INR of 2,0 to 3,0.. In our prospective registry we studied 198 consecutive patients receiving oral anticoagulant therapy with phenprocoumon and a planned surgery. Phenprocoumon was stopped 7 days before surgery and after reaching an INR less than 2,0 all patients received enoxaparin in a half-therapeutic dose (1 x 1 mg / kg body weight (bw)/day) until the day before surgery. Enoxaparin was continued with the same dose split into 2 x 0,5 mg / kg bw / day after the procedure. Phenprocoumon was resumed within day 1 to 14 after surgery depending on the bleeding risk as determined by the surgeon. All patients were followed up for 28 days after surgery.. Major surgery was performed in 148 patients (75 %). 175 patients (88 % of the total) had an intermediate thromboembolic risk. On average, enoxaparin was administered for 19,5 days. One patient (0,5 %) experienced arterial thrombosis after surgery, and one patient (0,5 %) required a second surgical intervention due to severe bleeding.. In patients receiving oral anticoagulant therapy with a target INR of 2,0-3,0 and at an intermediate risk of thromboembolic events who require interruption of oral anticoagulant therapy a half therapeutic dose of enoxaparin seems to be safe and effective for bridging.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Blood Loss, Surgical; Enoxaparin; Female; Germany; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Phenprocoumon; Postoperative Hemorrhage; Prospective Studies; Registries; Risk Assessment; Risk Factors; Surgical Procedures, Operative; Thromboembolism; Time Factors

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

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Dose-Response Relationship, Drug; Hemorrhage; Humans; Phenprocoumon; Pyridines; Randomized Controlled Trials as Topic; Stroke; Vitamin K

Topics: Anticoagulants; Clinical Competence; Evidence-Based Medicine; Hemorrhage; Humans; Phenprocoumon; Platelet Count; Practice Guidelines as Topic; Preoperative Care; Thrombocytopenia

An 84-year-old woman was admitted to the emergency room with hemoptysis consisting of relevant amounts of fresh blood. She was treated with phenprocoumon for 11 years following mechanical aortic valve replacement without any complication. Laboratory results revealed phenprocoumon over dosage with international normalized ratio over 6. Chest radiograph showed diffuse alveolar infiltrates conformable to diffuse alveolar hemorrhage. Besides the pulmonary complication no other bleeding occurred. She needed noninvasive ventilatory support for 24 h to cope with the symptoms of an acute respiratory failure. After substitution of vitamin K dependent blood clot factors resulting in a normalized coagulation hemoptysis which persisted for another 3 days followed by a slow recovery. Other causes of diffuse alveolar hemorrhage were excluded in our patient. This case report presents a rare case with diffuse alveolar hemorrhage as the leading and sole symptom due to phenprocoumon overdose.

Topics: Aged, 80 and over; Drug Overdose; Female; Hemorrhage; Humans; International Normalized Ratio; Phenprocoumon; Pulmonary Alveoli; Respiratory Distress 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

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

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

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

According to their code of professional conduct, German physicians are obliged to report suspected cases of adverse drug reactions (ADRs) to the Drug Commission of the German Medical Association (AkdA). On the basis of an agreement between the German Medical Association and the Federal Institute for Drugs and Medical Devices (BfArM) a common pharmacovigilance database within the German spontaneous reporting system was created. A user-friendly application program developed in-house enables the user to conduct searches about reported ADRs covering a wide variety of questions within a short period of time. ADRs caused by anticoagulants and by antiplatelet drugs still belong to the most reported adverse events. The most frequently reported suspected drugs are heparins, followed by ticlopidine, phenprocoumon, acetylsalicylic acid, and clopidogrel. Bleeding complications are the most often described ADR symptoms of any anticoagulation therapy, especially of phenprocoumon and acetylsalicylic acid. Another serious ADR is heparin-induced thrombocytopenia or changes in blood counts (CBC) due to ticlopidine and clopidogrel. During the past few years a reduction in severe reactions, such as cerebral hemorrhage, especially with fatal outcome was detectable because of better clinical management of oral anticoagulant therapy and of adverse events concerning heparin.

Topics: Administration, Oral; Adverse Drug Reaction Reporting Systems; Anticoagulants; Aspirin; Association; Blood Cell Count; Cerebral Hemorrhage; Clopidogrel; Databases, Factual; Drug Information Services; Germany; Hemorrhage; Heparin; Humans; Phenprocoumon; Platelet Aggregation Inhibitors; Product Surveillance, Postmarketing; Thrombocytopenia; Ticlopidine; Time Factors; Treatment Outcome; Vitamin K

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

Topics: Aged; Diagnosis, Differential; Hemorrhage; Humans; Male; Paraplegia; Phenprocoumon; Spinal Cord Vascular Diseases

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

Two patients with severe bleeding complications under oral anticoagulant treatment are presented, in one case caused by pharmacokinetic drug interference (phenylbutazone), in the other by genetic predisposition to bleeding induced by coumarin anticoagulants. Another patient with decreasing INR due to drug interference (rifampicin) is presented as well. The possibility of drug interferences with coumarin anticoagulants has to be anticipated, whenever the medication of an orally anticoagulated patient is changed. A founder mutation of the factor IX propeptide constitutes a genetic predisposition to bleeding in patients put on coumarins. Its presence should be excluded in any patient suffering from hemorrhagic complications after starting anticoagulation when INR values are in the target range.

Topics: Administration, Oral; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aortic Valve; Blood Coagulation Tests; Drug Interactions; Follow-Up Studies; Genetic Predisposition to Disease; Heart Valve Prosthesis; Hematoma; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Iatrogenic Disease; Injections, Intramuscular; Low Back Pain; Male; Middle Aged; Mitral Valve; Phenprocoumon; Phenylbutazone; Thrombophlebitis; Time Factors

In patients on oral anticoagulation with warfarin, genetic variations of the cytochrome P 450-CYP2C9 have recently been associated with very low warfarin requirements. Patients needing low doses had an increased risk for bleeding complications. In Germany, phenprocoumon (having a similar metabolic pathway) is the most commonly employed vitamin K antagonist. Treatment is usually monitored by general practitioners (GPs).. To determine whether CYP2C9 variant alleles can serve as risk markers in general-practice patients anticoagulated with phenprocoumon.. All adult anticoagulated patients in 12 teaching general practices and one university outpatient clinic were to be recruited. Blood samples were taken from 185 patients during routine anticoagulation controls and tested for CYP2C9 mutations. Subjects answered a questionnaire concerning bleeding complications, drug intolerance, and personal and family medical history. Phenprocoumon dosages required for stable anticoagulation were recorded. Odds ratios (OR) with 95% confidence intervals (CI) were calculated based on 2-way cross-tabulations and multivariate logistic regression models, t-tests used where appropriate.. Bleeding was reported by 19% of the patients, 2.2% of whom had suffered life-threatening bleeding. CYP2C9 variants were carried by 26.3% of 179 patients tested (17.9% *1/*2, 7.8% *1/*3, 0.6% *2/*3). While presence of a *2 allele was not associated with an increased risk (OR 0.35, CI 0.10-1.24), carriers of the rare *3 alleles had a higher risk of bleeding (OR 3.10, CI 1.02-9.40). With regard to bleeding, carrying CYP2C9*3 was highly specific (94%), though sensitivity was low at 17%; post-test probability of bleeding was 40%.. CYP2C9*3 variants are associated with an increased bleeding risk in patients anticoagulated with phenprocoumon. Screening can identify patients with a high risk of bleeding. Appropriate clinical consequences (restricted indication for anticoagulation, careful induction, adjustment of target INR, closer monitoring or self-testing of INR) as well as the cost-effectiveness of screening for variant CYP2C9 with regard to patient outcomes should be subject of further research.

Topics: Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Blood Coagulation; Cross-Sectional Studies; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Female; Genetic Markers; Genotype; Hemorrhage; Humans; Middle Aged; Phenprocoumon; Polymorphism, Genetic; Risk Assessment; Sensitivity and Specificity

We report on two men with severe and recurrent bleeding episodes under well performed phenprocoumon therapy. Both patients showed an INR value within the therapeutic/subtherapeutic range with an inappropriately prolonged activated partial thromboplastin time (aPTT). The vitamin K-dependent coagulation factors were in the expected range, except for factor IX, which was as low as in moderate haemophilia B. After substitution of vitamin K, factor IX and the aPTT recovered completely in one case. In the other case factor IX was not measured but aPTT normalized. Diagnosis of an increased sensitivity of factor IX to phenprocoumon was assumed and proven in both cases by the demonstration of a missense mutation at ALA-10 in the factor IX propeptide.

Topics: Administration, Oral; Aged; Anticoagulants; Aortic Valve; Arthroplasty, Replacement, Hip; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon

Topics: Anticoagulants; Hemorrhage; Humans; Injections, Intramuscular; Injections, Subcutaneous; Phenprocoumon; Risk Factors; Vaccination

Topics: Anticoagulants; Colonoscopy; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Phenprocoumon; Practice Guidelines as Topic; Risk Factors; Thromboembolism; United States

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

Two cases of massive iliopsoas muscle bleeding leading to fatal exsanguination are presented. Both patients (two women, 61 and 74 years old, respectively) received oral anticoagulation with phenprocoumon. The intramuscular bleeding occurred spontaneously in women of relatively good physical condition. Intriguingly, phenprocoumon concentrations were within the therapeutic range (1.55 microg/ml and 1.26 microg/ml, respectively) as detected by toxicologic analysis. These cases demonstrate that severe bleeding in the iliopsoas muscle has to be considered in all patients receiving anticoagulant medication, even in those who have coagulation parameters within the therapeutic range. Especially in older patients with a high degree of comorbidity or in patients receiving analgesic drugs, the potential of fatal outcome of iliopsoas muscle bleeding seems to be of clinicopathologic relevance.

Topics: Aged; Anticoagulants; Fatal Outcome; Female; Hemorrhage; Humans; Middle Aged; Muscular Diseases; Phenprocoumon; Psoas Muscles

Topics: Ambulatory Care; Germany; Hemorrhage; Humans; Internal Medicine; International Normalized Ratio; Malpractice; Phenprocoumon; Prothrombin Time; Quality Control; Reagent Kits, Diagnostic

To investigate long-term clinical and morphological outcome of patients with subclavian-axillary vein thrombosis treated with systemic thrombolysis compared to anticoagulation in a retrospective, nonrandomised study.. We studied 95 consecutive inpatients with subclavian-axillary vein thrombosis treated either with systemic urokinase thrombolysis and subsequent oral anticoagulation (n=33) or with anticoagulation only (n=62). Anticoagulation was performed with heparin and phenprocoumon. Patients were followed for median 40 months (IQR 14 to 94) for symptomatic upper extremity post-thrombotic syndrome and for venous recanalisation by duplex ultrasound.. Primary technical success rate of the systemic thrombolysis was 88% (n=29) with seven peri-intervention bleeding complications (21%). No complication was observed in patients with anticoagulation only (p<0.0001). At the time of follow-up, duplex sonography showed a thrombotic subclavian vein in 40 of 83 patients (48%), but only 9 of 95 patients (10%) had a symptomatic upper extremity post-thrombotic syndrome. Patients with systemic thrombolysis exhibited a 60% adjusted reduced risk for a thrombotic subclavian vein at the time of follow-up compared to patients with anticoagulation only (95% CI: 0.2 to 0.9, p=0.03). However, the frequency of symptomatic post-thrombotic syndrome after thrombolysis and anticoagulation was similar (adjusted p=0.6).. Systemic thrombolysis of subclavian-axillary vein thrombosis has an acceptable primary technical success rate and improves venous recanalisation rates compared to anticoagulation. However, the high rate of complications during thrombolysis and the lack of clinical benefit suggest that conservative treatment may be favoured.

Topics: Adult; Anticoagulants; Axillary Vein; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Male; Middle Aged; Phenprocoumon; Postphlebitic Syndrome; Retrospective Studies; Subclavian Vein; Thrombolytic Therapy; Treatment Outcome; Ultrasonography; Upper Extremity; Urokinase-Type Plasminogen Activator; Venous Thrombosis

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

A 66-year-old patient presented to our clinic with extensive left arm and left flank haematomas, anaemia, a prolonged activated partial thromboplastin time (aPTT), and reduced factor IX activity 6 weeks after prosthetic mechanical aortic valve implantation.. Treatment with both vitamin K and a single injection of factor IX concentrate led to normalization of the activated partial thromboplastin time and factor IX activity, which remained constant for several days. No acquired factor IX inhibitor was detectable. Analysis of exon 2 of the factor IX gene revealed a C-->T mutation in codon 10 of the propeptide region, resulting in the substitution of alanine by valine. Echocardiography revealed a significant paravalvular leak.. The substitution of valine for alanine in the factor IX propeptide leads to an impaired affinity of factor IX to the vitamin K-carboxylase complex. In this situation, treatment with coumarin derivatives can profoundly reduce factor IX activity and result in severe bleeding episodes. This patient was re-exposed to warfarin under close hematological monitoring. After 4 days factor IX activity had decreased to 15%, which was associated with an increase of the aPTT and a mild decrease of the prothrombin time. Due to rapid progression of the paravalvular leak and almost impossible long-term orale anticoagulation with coumarin derivatives, we recommended replacement of the prosthetic mechanical valve with a biological device.. The development of severe bleeding in the context of initiating warfarin therapy raises the suspicion of a factor IX propeptide mutation. The initial screening test is the activated partial thromboplastin time, which is elevated in the presence of the mutation. If concomitantly diminished factor IX activity is found the factor IX propeptide mutation should be excluded. Use of lifelong coumarin derivatives is contraindicated in patients with this mutation. However, a general screening of the activated partial thromboplastin time after coumarin initiation is not justified by cost/benefit analysis.

Topics: Aged; Alanine; Anticoagulants; Aortic Valve; Echocardiography; Factor IX; Heart Valve Prosthesis; Hemorrhage; Humans; Partial Thromboplastin Time; Phenprocoumon; Point Mutation; Protein Precursors; Valine; Vitamin K

Overdose or bleeding with oral anticoagulation requires gradual antagonization of the drugs. Minor bleedings are most commonly managed by temporarily discontinuing treatment and by giving vitamin K to antagonize the coumarin derivative effects. Major bleedings, in contrast, especially intracranial hemorrhages, require immediate antagonization of anticoagulation. This is also necessary in required major surgery of anticoagulated patients. Instant normalization of hemostasis in such cases is achieved by the administration of clotting factors, in particular prothrombin complex concentrates. The use of fresh frozen plasma, instead, is less useful. The treatment with prothrombin complex concentrates requires a strict risk-benefit estimation and laboratory monitoring is recommended to optimize dosage adjustment. A 2-year follow-up of 45 out-patients receiving phenprocoumon at our center revealed a total of 11 bleeding complications (11.6/100 treatment-years, 10 minor and 1 major bleeding). Discontinuing or reducing oral anticoagulation together with vitamin K were the methods most frequently used to efficiently manage hemorrhages, whereas prothrombin complex concentrates were only used in one case with major bleeding. Oral anticoagulation appeared to be an enhancing factor for an otherwise existing bleeding diathesis rather than a genuine cause for hemorrhages.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Thrombosis

In a patient on oral anticogulation with sudden onset of loin pain, the possibility of spontaneous bleeding in the retroperitoneum must be considered in the differential diagnosis of renal colic. This rare pathology can be life-threatening, and rapid diagnosis with ultrasound and computerized tomography of the abdomen must be made. If the patient is hemodynamically stable, a conservative approach is justified. Otherwise, emergency nephrectomy may be needed. As patients become older and indications for anticoagulant therapy become more common, we will probably have to face more of these rare bleeding complications in the future. We report such a case.

Topics: Administration, Oral; Adult; Anticoagulants; Female; Hemorrhage; Humans; Phenprocoumon; Retroperitoneal Space

A serious retroperitoneal bleeding occurred in a 56-year-old male patient receiving unfractionated heparin due to multiple pulmonary embolism. After reducing the heparin dose, the patient developed a new pulmonary embolism and a large thrombus in the right atrium. Concomitantly, the platelet count dropped to a value of 29 g/l. Heparin-induced thrombocytopenia (HIT) was confirmed by a functional assay, the heparin-induced platelet activation (HIPA) assay, whereas the results of a platelet factor 4/heparin complex ELISA were repeatedly negative. This indicated that the patient's HIT antibodies were directed towards an antigen other than platelet factor 4/heparin complexes. For treatment of the atrial thrombus, an ultra-low-dose lysis with rt-PA (2 mg/h, intravenously) was administered for a period of 52 h, overlapping with systemic treatment with recombinant hirudin (Lepirudin, Refludan, 0.06-0.14 mg/kg/h intravenously). The aim was to enhance lysis of the thrombus without increasing the haematoma, and at the same time keep the risk of fulminant pulmonary embolism due to thrombus fragmentation as low as possible. The cardiac thrombus disappeared within 48 h, without new signs of pulmonary embolism. Platelet counts normalized within nine days.

Topics: Anticoagulants; Arrhythmias, Cardiac; Autoimmune Diseases; Heart Atria; Heart Diseases; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Phenprocoumon; Plasminogen Activators; Pulmonary Embolism; Recombinant Proteins; Retroperitoneal Space; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator; Vena Cava Filters

Two male patients with severe and recurrent bleeding episodes under phenprocoumon therapy are reported. Both patients exhibited a strong decrease of their factor IX activities below 1% of normal, whereas the activities of the vitamin K-dependent factors prothrombin, VII, and X were found to be within or above the expected therapeutic ranges of 20-40%. Upon removal of phenprocoumon and substitution with vitamin K, the factor IX activities increased to 85% and 55%, respectively. Reexposition to phenprocoumon in one patient confirmed the rapid and selective decrease of the factor IX activity. These findings provide the first report of an abnormally high sensitivity of factor IX activity to oral anticoagulant therapy.

Topics: Adult; Aged; Anticoagulants; Factor IX; Hemorrhage; Humans; Male; Phenprocoumon; Postoperative Hemorrhage

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

By administering a questionnaire to 253 patients with cardiac-valve prostheses (89.3% responding), and another to 136 of their attending dentists (79% responding), the level of knowledge among both groups of anticoagulant therapy in connection with dental treatment was investigated. The cardiothoracic department monitored all anticoagulation therapies. Of the anticoagulated patients, 96.6% were able to state their medication (94.1% received phenprocoumon); and of 86 dentists with patients on anticoagulation treatment, 94% were aware of their patients' medication. All 20 dentists stating that their patients did not receive anticoagulants were correct. The great majority (98%) of the dentists employed a special measure to reduce the risk of bleeding associated with invasive dental procedures, most commonly (86%) referring patients to their general practitioner or hospital department for adjustment of the anticoagulant therapy. Around 60% of the dentists considered extractions and operations to require measures to reduce the risk of bleeding complications. We recommend referral of patients to the attending physician for adjustment of anticoagulation to a target International Normalized Ratio (INR) of 4.0 or possibly 3.0 before undergoing dental procedures involving the risk of bleeding. Additional reduction of the bleeding risk can be obtained by local application of an inhibitor of fibrinolysis (tranexamic acid).

Topics: Adult; Aged; Aged, 80 and over; Attitude of Health Personnel; Attitude to Health; Blood Coagulation Tests; Dental Care; Dentist-Patient Relations; Dentists; Female; Heart Valve Prosthesis; Hemorrhage; Hemostatic Techniques; Humans; Male; Middle Aged; Phenprocoumon; Referral and Consultation

Five hundred and four St. Jude Medical valves (SJM) were implanted in 435 patients between September 1978 and March 1982. There were 234 females and 201 males with a mean age of 52.8 +/- 10.1 years (range 12-83 years), who underwent 204 aortic, 163 mitral, 67 mitral plus aortic and one triple valve replacements. All patients were followed prospectively. Follow up was 100% complete and averaged 122.2 +/- 1.1 months for operative survivors. The total follow up for aortic patients was 1968.5, for mitral patients 1520.4, and for double valve replacement 573.9 pty. For the entire patient population the total follow up was 4080.8 pty. Early mortality was 2% after aortic, 4.3% after mitral and 5.9% after mitral plus aortic valve replacement. There were 68 late deaths representing a linearized incidence of 1.37%/pty in the aortic, 1.71%/pty in the mitral and 2.61%/pty in the double valve replacement groups. The corresponding cumulative survival after ten years at risk was 85% in the aortic, 78% in the mitral and 72% in the double valve replacement groups. The ten year event-free survival was 64% in the aortic, 57% in the mitral and 47% in the double valve replacement groups. The linearized incidence for thromboembolic events was 3.71%/pty taking all events into account, and 2.67%/pty taking only the first or most severe of several events into account for aortic, 5.1%/pty and 4.08%/pty for mitral, and 6.62%/pty and 5.40%/pty for double replacements, respectively. There were two cases of valve thrombosis, both with proven inadequate anticoagulation. When the prothrombin times measured with the different thromboplastize used in this patient group were converted to INR, the so far homogeneous values could be separated into three groups: INR = 3.0 to 4.5, 2.5 to 3.2 and 1.8 to 2.7. Low INR values caused only a marginal increase in the rate of embolism but a highly significant decrease in the rate of bleeding. These results suggest that the generally recommended INR of 3.0 to 4.5 is too high for the SJM. A large, multicenter, prospective randomized study is therefore proposed to establish the safe INR levels with low intensity anticoagulation after SJM implantation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Female; Follow-Up Studies; Heart Valve Diseases; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Postoperative Complications; Prosthesis Design; Prosthesis Failure; Prothrombin; Prothrombin Time; Survival Rate; Thromboembolism

1051 extremities with arterial reconstruction and anticoagulant prophylaxis were followed for at least 15 to 25 years. The results as to patency rate were best in patients with anticoagulation permanently in the therapeutic range. Interruption of the prophylaxis led to occlusions in half of the patients, most within the first year. 42 bleeding complications occurred in 37 patients, 0.005 per treatment year, 0.002 gastrointestinal, 0.0004 cerebral, 0.0001 with fatal outcome. Most bleedings occurred within the first ten years, 0.6 per treatment year in the first, 0.38 between the third and the seventh year, reaching a steady level of 0.46 at twelve years. Prophylaxis after arterial reconstruction for peripheral arterial disease should be restricted to patients without contraindications, in whom an optimal anticoagulation can be achieved within the first year.

Topics: Arterial Occlusive Diseases; Combined Modality Therapy; Follow-Up Studies; Hemorrhage; Heparin; Humans; Ischemia; Leg; Long-Term Care; Phenprocoumon; Postoperative Care; Prothrombin Time

One thousand and ten patient years of oral anticoagulant therapy with vitamin-K-antagonists were reviewed with regard to major bleeding complications. The incidence of bleeding that necessitated hospital admission was 2.7% per year (95% confidence limits, 1.7-3.7%). The major source of bleeding was the alimentary tract, whereas no cases of intracranial bleeding were found. Various factors with potential effects on the bleeding risk were evaluated by multivariate statistical analysis, and the following independent risk factors were identified: age greater than 75 years and hypertension increased the bleeding risk by 10.5% and 4.5%, respectively. Each recorded prothrombin value significantly below the therapeutic range increased the bleeding risk by 3.9%, and each year of treatment increased the risk by 2.0%. These figures may be used to estimate the risk of major bleeding in an individual patient. Current treatment with thiazide diuretics was found to increase the bleeding risk by 5.2%. However, this observation requires further documentation and analysis. Although no lethal episodes of bleeding occurred, the developing field of indications for oral anticoagulant therapy should be considered on the basis of a continuous substantial risk of major bleeding.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Ambulatory Care; Anticoagulants; Cimetidine; Drug Interactions; Female; Hemorrhage; Humans; Male; Middle Aged; Multivariate Analysis; Phenprocoumon; Retrospective Studies; Risk Factors; Vitamin K; Warfarin

One thousand six hundred and sixty-eight consecutive patients who underwent isolated mitral valve replacement (MVR) from 1963 to 1984 were evaluated retrospectively. Thromboembolism occurred with a linearised rate of 2.5% +/- 0.2%/patient-year (PY) for Starr-Edwards disc prosthesis Model 6520, 2.4% +/- 0.3%/PY for Bjørk-Shiley plane prosthesis, 3.0% +/- 0.8%/PY for Bjørk-Shiley convexo-concave 60 degrees prosthesis, 3.0% +/- 0.8%/PY for St. Jude Medical prosthesis and 3.4% +/- 0.5%/PY for Carpentier-Edwards tissue valve without the differences reaching significance. In the SJM group, the incidence of thromboembolism was significantly higher (P less than 0.025) in smaller sizes (less than M29) probably due to a more turbulent flow. The linearised rate for major haemorrhage was 1.6% +/- 0.1%/PY. Twenty-three percent of the thromboembolic and 18% of the bleeding events were fatal. Sixty-eight percent of the emboli involved the central nervous system and bleeding apart from fatalities was predominantly non-cerebral (81%). Whereas thromboembolism was a time-related event with more than twice as high a risk in the first postoperative year (4.2% +/- 0.5% vs. 1.7% +/- 0.8%, P less than 0.01), bleeding occurred with a constant rate over time (0.9% +/- 0.4%). Adequacy of anticoagulation was an important risk factor for postoperative embolism with the prothrombin time (PT) exceeding the therapeutic range in 65% of all events. A preoperative history of embolism was the only additional patient-related risk factor for postoperative embolism (18.3% vs. 9.6%, P less than 0.001). In 30% of all haemorrhage, the PT was below 15%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Bioprosthesis; Blood Loss, Surgical; Female; Follow-Up Studies; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Mitral Valve Stenosis; Phenprocoumon; Postoperative Complications; Prosthesis Design; Risk Factors; Thromboembolism

Topics: 4-Hydroxycoumarins; Adult; Antithrombin III Deficiency; Female; Hemorrhage; Humans; Necrosis; Phenprocoumon; Skin Diseases; Thrombophlebitis; Toes

Topics: 4-Hydroxycoumarins; Aged; Drug Interactions; Female; Hemorrhage; Humans; Metoclopramide; Phenprocoumon

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

In a 5-year retrospective study (1982-1978) in a well defined population of 332 patients (representing greater than or equal to 2140 anticoagulation years) from a heart specialist's practice, the question was studied whether optimum anticoagulation (Quick test between 18-29%, INR 4.0-2.75, Geigy thromboplastin, capillary blood method) with minimum complications could be achieved. In the qualitative study it was found that 75% of Quick determinations were in the optimum range for phenprocoumon, 71.6% for clorindion, 62% for acenocoumarol and 72% for all anticoagulants. 77% of phenprocoumon patients were optimally anticoagulated for more than 3 years. With phenprocoumon there was no difference in intensity of anticoagulation between the oldest and youngest patient groups, as all mean Quick values ranged over 20% (means Q% 1982-1978 = 25, INR = 3.0). It was also shown that after 6 months' anticoagulant therapy it is clearly recognizable whether optimum anticoagulation is feasible or not: at that moment the criteria for halting or continuing anticoagulant therapy can and should be reviewed.

Topics: Aged; Ambulatory Care; Anticoagulants; Blood Coagulation Tests; Cardiovascular Diseases; Female; Hemorrhage; Humans; Longitudinal Studies; Male; Middle Aged; Phenprocoumon; Retrospective Studies; Switzerland

The incidence of arterial embolism (AE) and pulmonary embolism (PE) during treatment with oral anticoagulants (OA) or without OA therapy was studied in 38 patients with dilated cardiomyopathy (DCMP). AE/PE occurred in 17 patients (44.7%) before initiation of OA treatment. The severity of DCMP was a risk factor for AE/PE, but not the presence of atrial fibrillation or intracardial thrombi. No AE/PE episodes occurred during the period of OA therapy. No major bleeding complications were seen, probably due to the moderate intensity of OA therapy (therapeutic range 5-15% Thrombotest [TT], 2.1-4.8 International Normalized Ratio [INR], median TT value 11%, median INR 2.6). Recurrence of AE was observed in 4 of 5 patients in whom treatment with OA had been discontinued.

Topics: 4-Hydroxycoumarins; Administration, Oral; Adult; Aged; Arteries; Cardiomyopathy, Dilated; Embolism; Female; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Pulmonary Embolism; Retrospective Studies; Risk

Topics: 4-Hydroxycoumarins; Adrenal Gland Diseases; Adrenal Glands; Anticoagulants; Female; Hemorrhage; Humans; Middle Aged; Phenprocoumon

Successful prevention of the progression of incipient hemorrhagic skin necrosis by timely administration of vitamin K1 in a woman treated with phenprocoumon is presented. From a critical review of the literature strong evidence emerges that coumarin necrosis does only occur in cases with severe initial drug induced hypocoagulability. Non- recognition thusfar of its importance is due to insufficient knowledge of the biological activities of thromboplastin preparations presently used in the laboratory control of oral anticoagulation. All well documented cases with apparently adequate Quick values were monitored with Faktor VIII insensitive thromboplastin. Therefore, such preparations should no longer be used in anticoagulant control.

Topics: 4-Hydroxycoumarins; Female; Hemorrhage; Humans; Middle Aged; Necrosis; Phenprocoumon; Skin; Skin Diseases; Thromboplastin; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Hemorrhage; Humans; Naphthoquinones; Phenprocoumon; Retinoids; Vitamin K; Vitamin K 1