Treatment Of Thromboembolic Events Research Articles

WARFARIN TOXICITY PRESENTING AS RUPTURED OVARIAN TUMOUR WITH HEMOPERITONEUM: A CASE REPORT

Warfarin, a coumarin derivative, is commonly used in prevention and treatment of thromboembolic events in various clinical situations. Although, a safe drug, its toxicity may result into intraperitoneal bleeding. Warfarin induced intraperitoneal bleeding is dose dependent and may have fatal outcome. A case is reported here, who presented with massive intraperitoneal haemorrhage secondary to warfarin toxicity. She had undergone mitral valve replacement six months before the episode. Clinical and imaging suggested a pelvic mass mimicking ruptured ovarian tumour. Her prothrombin time INR was 1.1 at the time of admission. Emergency laparotomy revealed a large organised blood clot in the pouch of Douglas extending to adnexal region, mimicking ruptured ovarian tumour. Warfarin was withdrawn for few days. Patient was transfused with fresh frozen plasma and fresh whole blood. Post operative recovery was uneventful. Warfarin in low dose was restarted for thromboembolic prophylaxis.

Edoxaban Versus Enoxaparin for the Prevention of Venous Thromboembolism: Pooled Analysis of Venous Thromboembolism and Bleeding From STARS E-3 and STARS J-V

Abstract 208 Introduction:Edoxaban is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events. Two randomized, double-blind, double-dummy, phase 3 studies (STARS E-3 and STARS J-V) have been conducted to evaluate the efficacy and safety of edoxaban compared with enoxaparin for the prevention of venous thromboembolism (VTE) after total knee (TKA) or hip arthroplasty (THA). The objective of this pooled analysis was to investigate the effects of edoxaban on VTE and bleeding in key subgroups. Methods:Patients (N=1326) undergoing TKA or THA in Japan and Taiwan were randomized to receive oral edoxaban 30 mg once daily (qd) or subcutaneous enoxaparin 2000 IU twice daily (bid, equivalent to 20 mg bid) for 11–14 days. Edoxaban was initiated 6–24 hours after surgery and enoxaparin was initiated 24–36 hours after surgery, which is the standard of care in Japan. The primary efficacy outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE). The principal safety outcome was the incidence of major and clinically relevant nonmajor (CRNM) bleeding. Results:A total of 1307 patients received at least 1 dose of edoxaban or enoxaparin. There were no clinically relevant differences in baseline characteristics between the treatment groups. The mean age was 68 years and mean body weight was 58.8 kg. Over 70% of patients received physiotherapy (intermittent pneumatic compression, elastic stocking). Overall, edoxaban significantly reduced the incidence of the composite of symptomatic and asymptomatic DVT and PE compared with enoxaparin (5.1% vs 10.7%, P<0.001). Subgroup analysis showed that edoxaban numerically reduced the incidence of the composite efficacy endpoint regardless of age or body weight. The effect was statistically significant in patients <75 years of age and in those <70 kg. Edoxaban was also significantly more effective than enoxaparin in the presence or absence of concomitant physiotherapy. The incidence of major and CRNM bleeding events was 4.6% vs 3.7% in the edoxaban and enoxaparin groups, respectively (P=0.427). Subgroup analysis of major and CRNM bleeding indicated no significant difference between edoxaban and enoxaparin in any of the patient subgroups evaluated, based on age, weight, or creatinine clearance. Conclusion:Edoxaban 30 mg qd is superior to enoxaparin 20 mg bid in the prevention of VTE events following TKA and THA without a statistically significant increase in bleeding in important patient subgroups likely to receive this treatment. Disclosures:Fuji:Daiichi Sankyo: Consultancy; Astellas: Consultancy; Showa Ikakogyo: Consultancy; Bayer: Consultancy. Fujita:Astellas: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy. Tachibana:Daiichi Sankyo: Consultancy. Kawai:Daiichi Sankyo: Consultancy; Toyama Chemical: Consultancy; Bayer: Consultancy.

Heparin Impairs Angiogenesis through Inhibition of MicroRNA-10b

Heparin, which has been used as an anticoagulant drug for decades, inhibits angiogenesis, whereas thrombin promotes tumor-associated angiogenesis. However, the mechanisms underlying the regulation of angiogenesis by heparin and thrombin are not well understood. Here, we show that microRNA-10b (miR-10b) is down-regulated by heparin and up-regulated by thrombin in human microvascular endothelial cells (HMEC-1). Overexpression of miR-10b induces HMEC-1 cell migration, tube formation, and angiogenesis, and down-regulates homeobox D10 (HoxD10) expression via direct binding of miR-10b to the putative 3' UTR of HoxD10. In addition, HMEC-1 cell migration and tube formation are induced by HoxD10 knockdown, whereas angiogenesis is arrested when HoxD10 expression is increased after anti-miR-10b or heparin treatments. Furthermore, expression of miR-10b and its transcription factor Twist are up-regulated by thrombin, whereas HoxD10 expression is impaired by thrombin. Using quartz crystal microbalance analysis, we show that heparin binds to thrombin, thereby inhibiting thrombin-induced expression of Twist and miR-10b. However, the expression of miR-10b is not attenuated by heparin any more after thrombin expression is silenced by its siRNA. Interestingly, we find that heparin attenuates miR-10b expression and induces HoxD10 expression in vivo to inhibit angiogenesis and impair the growth of MDA-MB-231 tumor xenografts. These results provide insight into the molecular mechanism by which heparin and thrombin regulate angiogenesis.

Melatonin stimulates release of tissue factor pathway inhibitor from the vascular endothelium

We previously found an association between the circadian variation of free tissue factor pathway inhibitor (TFPI) and melatonin in able-bodied males and in men with complete cervical spinal cord injuries. We therefore examined whether melatonin modifies production and/or secretion of TFPI in endothelial cells. We sampled supernatants from cultures of primary human umbilical vein endothelial cells (HUVECs) and of human coronary artery endothelial cells (HCAECs), that had been exposed to varying doses (0-300 pg/ml) of melatonin for 0.5-24 h. We then measured the protein concentrations of free TFPI, tissue factor and plasminogen activator inhibitor type 1 (PAI-1). We also measured endothelial TFPI, tissue factor and PAI-1 transcripts using quantitative real-time PCR. Melatonin dose dependently increased free TFPI levels about 25-30-fold in supernatants of both HUVEC and HCAEC, and independent of incubation duration. In contrast, TF and PAI-1 remained unaltered upon increasing doses of melatonin. Neither TFPI mRNAs nor tissue factor mRNAs nor PAI-1-mRNAs were changed in cell cultures added melatonin. The ratio of free TFPI in cell supernatants to free TFPI in cell lysates about doubled upon addition of melatonin, indicating that melatonin increased release from intracellular storages of free TFPI or from membrane-bound free TFPI. Our data indicate that melatonin stimulates vascular endothelial cells to secrete TFPI without altering transcription of the TFPI gene. If melatonin increases TFPI release in a similar fashion in vivo as in vitro, this could have potential clinical implications in both prophylaxis and treatment of thromboembolic events.

Les nouveaux anticoagulants oraux

For years, prevention and treatment of thromboembolic events have been restricted to the use of heparins and vitamin K antagonists. These treatments, in spite of their unquestioned efficacy, present numerous limits (hemorrhagic risk, need for regular laboratory controls). These limits call for the development of new antithrombotic drugs. This review briefly reports on three new molecules, in very advanced phases of clinical research: dabigatran (Pradaxa®), rivaroxaban (Xarelto®) and apixaban. These molecules represent new oral anticoagulants, which directly inhibit a coagulation factor (thrombin for dabigatran, factor Xa for rivaroxaban and apixaban) and do not need regular anticoagulant monitoring or dose adjustment. The approval is still restricted in France to the prophylaxis of venous thromboembolism in orthopaedics. Dabigratran will be soon available in the prevention of stroke in atrial fibrillation. With the forthcoming phase III studies to prevent and treat venous thromboembolism, anticoagulant therapy management will be most probably improved in the coming years.

Efficacy and Safety of Edoxaban Versus Enoxaparin for the Prevention of Venous Thromboembolism Following Total Hip Arthroplasty: STARS J-V trial

AbstractAbstract 3320 Introduction:Edoxaban is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events. The aim of this non-inferiority trial was to determine the efficacy and safety of edoxaban compared with enoxaparin sodium (enoxaparin) after total hip arthroplasty (THA) in Japan. Methods:This was a randomized, double-blind, double-dummy, enoxaparin-controlled, multicenter trial. Patients were randomized to oral edoxaban 30 mg once daily (QD) or subcutaneous enoxaparin 2,000 IU, equivalent to 20 mg, twice daily (BID) for 11 to 14 days. Edoxaban was initiated 6–24 hours after surgery and enoxaparin was initiated 24–36 hours after surgery which is the Japanese standard of care. The primary efficacy outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT), and pulmonary embolism (PE). The primary safety outcome was the incidence of major and clinically relevant non-major bleeding. Results:A total of 610 patients were randomized. There were no clinically relevant differences in baseline characteristics between the treatment groups. The mean age was 62.8 years and mean body weight was 57.4 kg (Efficacy analysis set). The primary efficacy outcome occurred in 6 of 255 (2.4%) patients receiving edoxaban and 17 of 248 (6.9%) patients receiving enoxaparin (relative risk reduction=65.7%; absolute risk difference -4.5%, 95% CI, -8.6% to -0.9%; P<0.001 for non-inferiority; P=0.0157 for superiority). The thromboembolic events were all asymptomatic DVT (Table). No symptomatic DVT or PE was observed in both treatment groups. The incidence of major and clinically relevant non-major bleeding events was 2.6% (8/303) vs 3.7% (11/301) in the edoxaban and enoxaparin groups, respectively (P=0.475). Major bleeding occurred in 0.7% of the edoxaban group and 2.0% of the enoxaparin group. The rates of elevated serum aminotransferase levels of more than 3 times the upper limit of normal was 2.6% with edoxaban versus 10% with enoxaparin. Conclusions:The STARS J-V trial demonstrated that oral edoxaban 30 mg QD has efficacy superior to enoxaparin 2,000 IU BID in the prevention of thromboembolic events following THA and is associated with a similar incidence of major and clinically relevant non-major bleeding events. Disclosures:Fuji:Astellas: Consultancy; Showa Ikakogyo: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy. Fujita:Daiichi Sankyo: Consultancy; Astellas: Consultancy; GlaxoSmithkline: Consultancy. Tachibana:Daiichi Sankyo: Consultancy. Kawai:Daiichi Sankyo: Consultancy; Toyama Chemical: Consultancy. Koretsune:Daiichi Sankyo: Consultancy, National Lead Investigator. Yamashita:Daiichi Sankyo: Consultancy, National Lead Investigator; Otsuka Pharmaceutical: Paid instructor; Sanofi-aventis: Paid instructor; Teijin Pharma: Paid instructor. Nakamura:Daiichi Sankyo: Consultancy; GlaxoSmithkline: Consultancy; Astellas: Consultancy.

A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty.

Edoxaban (the free base of DU-176b) is an oral, direct factor (F)Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events. The aim of the present study was to evaluate the efficacy and safety of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA). This was a randomized, double-blind, placebo-controlled, multicenter study conducted in Japan. A total of 523 Japanese patients were assigned to receive edoxaban 5, 15, 30 or 60 mg once daily or placebo for 11-14 days. A placebo control was used as neither low-molecular-weight heparin (LMWH) nor fondaparinux had been approved for thromboprophylaxis at the time of the study in Japan. The primary efficacy outcome was the incidence of VTE (lower-extremity deep vein thrombosis, symptomatic pulmonary embolism or symptomatic deep vein thrombosis). The primary safety outcome was the incidence of major and clinically relevant non-major bleeding. Edoxaban produced a significant dose-related reduction in VTE: the incidence of VTE was 29.5%, 26.1%, 12.5% and 9.1% in the edoxaban 5-, 15-, 30- and 60-mg treatment groups vs. 48.3% in the placebo group. The incidence of major and clinically relevant non-major bleeding was similar across all groups without any significant differences among edoxaban doses or between edoxaban and placebo. Edoxaban demonstrated significant dose-dependent reductions in VTE in patients undergoing TKA with a bleeding incidence similar to placebo. [This trial is registered with JAPIC, JapicCTI-060283 (ja).].

Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children

Low molecular weight heparins (LMWHs) are commonly used in paediatric tertiary institutions for primary prophylaxis and treatment of thromboembolic events. Despite this widespread use, the therapeutic and prophylactic guidelines for LMWH therapy in children are extrapolated from adult guidelines. In fact, there is very little information regarding the pharmacokinetics, clinical effectiveness, adverse event profile and optimal dose schedule for LMWH therapy in children. This study was designed to determine whether paediatric-specific dosage requirements for LMWH are justified, by investigating the doses required to achieve target therapeutic ranges. Patients who were treated with enoxaparin between October 2003 and July 2007 were identified for inclusion in this study. One hundred forty patients had an anti-activated factor X assay result with a total of 55 (39%) patients achieving therapeutic levels 4-6 h post dose. Children younger than 1 year required the highest dose of enoxaparin/kg and highest number of dose changes to achieve the target therapeutic range. Major bleeding occurred in one patient, equating to 0.7%, with complete clot resolution recorded in 16 (11%) patients. This study demonstrated a 2-3-fold variation in individual dose requirements for LMWH in children <or=5 years of age, and further mandates the need for age-specific dosage requirements in children receiving enoxaparin.

Venous thromboembolism in multiple myeloma: Current perspectives in pathogenesis

Patients with multiple myeloma are at increased risk of venous thromboembolism (VTE) compared to the general population. The introduction of immunomodulatory agents, such as thalidomide and lenalidomide, substantially increases the incidence of VTE in multiple myeloma patients, especially when used in combination with high-dose dexamethasone and/or anthracycline-based chemotherapy. Thromboprophylaxis is recommended for reducing VTE in patients receiving immunomodulatory agent-based regimens. On the other hand, bortezomib, a proteasome inhibitor, is not associated with an increased risk of VTE, as observed by a very low incidence of thrombotic complications in the absence of thromboprophylaxis. Currently, the mechanisms underlying the impact of these agents on VTE are not well-understood. Further studies to investigate the pathogenesis of VTE in multiple myeloma are warranted. These studies may not only yield greater insight into the pathogenesis of disease but may also define novel targets for the prevention and treatment of thromboembolic events in patients with multiple myeloma.

Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements

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.

Anti-cancer properties of low-molecular-weight heparin: Preclinical evidence

Malignant conditions are frequently associated with a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Heparin and, its pharmacokinetically improved versions, low-molecular-weight heparins (LMWH) are effective in the prevention and treatment of thromboembolic events in cancer patients. There are several lines of preclinical evidence suggesting potential benefits of LMWH in hypercoagulation and thrombosis as well as in various processes involved in tumour growth and metastasis. Tinzaparin is a LMWH produced by controlled enzymatic depolymerisation of unfractionated heparin. The efficacy of tinzaparin has been documented in several clinical trials across various conditions and in special patient populations. The main objective of this review is to present the existing knowledge on the preclinical anti-cancer properties of tinzaparin and other LMWH. The evidence for tinzaparin, as well as other LMWH, regarding interference with cancer-induced hypercoagulation, cancer cell proliferation, degradation of extra-cellular matrix, angiogenesis, selectin-mediated binding of platelet and cancer cells, chemokine signalling, tumour progression, and metastasis are reviewed. Certain clinical trials suggest improved survival of cancer patients with deep venous thrombosis treated with LMWH versus unfractionated heparin and when added to the promising preclinical anti-cancer properties of LMWH this warrants further investigations in prospective, randomised, controlled clinical trials in cancer patients. The benefits of LMWH in cancer might at least in part, be independent from its anti-coagulant activities, but may still be partially dependent on its anti-coagulant activities.

Improving Heparin Safety: A Multidisciplinary Invited Conference

Heparin is widely used in a variety of settings for prevention and treatment of thromboembolic events. Data from a number of sources indicate that it is also one of the drugs most frequently associated with adverse events and medication errors, many of which are serious. National media attention has focused on recent events involving heparin and The Joint Commission has included heparin in its 2009 National Patient Safety Goal to reduce patient harm from anticoagulants. Heparin safety is on the national agenda and health care organizations are struggling to improve it. Health care providers in clinical, management, and executive roles must work together to improve heparin safety. Over 40 anticoagulation experts and practitioners came together in San Diego on March 13 through 14, 2008 to share information, offer perspectives, and address issues on the topic improving heparin safety. These individuals represented The Joint Commission, United States Pharmacopoeia, the Institute for Safe Medical Practices, academic institutions, large health care systems, and small hospitals who participated in a day and a half of presentations and round-table discussions. This article summarizes 21 presentations with a primary focus on types and frequency of heparin errors as well as identified opportunities to improve heparin safety. The conference was sponsored by Cardinal Health's Center for Safety and Clinical Excellence.

In Vitro Evaluation of the Effect of rFVIIa on Anti Coagulated Human Whole Blood Treated with Abciximab Using Thromboelastography (TEG).

Abciximab inhibits platelet aggregation by binding to GPIIb/IIIa. Thus, Abciximab is effective in prevention and treatment of thromboembolic events. Although major bleeding complications are rare, Abciximab has the potential to increase bleeding which often is managed by temporary discontinuation of administration of drug. However, an effective and instant haemostatic intervention may be needed in some cases of acute serious bleeding. The aim of this study was to investigate 1) the effect of in vitro addition of Abciximab to whole blood (WB) from 8 healthy donors, 2) to determine the haemostatic potential of ex vivo addition of 10, 25 (25nM≈90ug/kg), and 100nM rFVIIa (NovoSeven®, Novo Nordisk) to WB treated with 4μg/ml of Abciximab (ReoPro®, Lilly) and 3) to compare the response of rFVIIa in TEG assays containing tissue factor (TF, Innovin 1:42500) or Kaolin (standard initiator provided by Haemsoscope) with or without tPA (0.75nM). TEG Platelet Mapping was performed on all Abciximab-treated blood samples before conducting TEG demonstrating 70–100% inhibition of ADP-induced platelet aggregation. The following TEG parameters were used: Reaction time (R-time), Maximum Thrombin generation (MTG), Maximum Amplitude (MA) and Area under the TEG fibrinolysis curve calculated from MA (AUC lysis). The statistical analysis was performed by a two-way ANOVA model. A significant effect of adding rFVIIa (10 nM) to Abciximab-treated blood was observed for all clot formation parameters and with both TF and Kaolin as initiator. rFVIIa demonstrated a significant dose-dependent improvement of the TEG parameters in the assay containing kaolin, in kaolin+tPA (except MA) and in TF (except for MTG). rFVIIa showed significant dose-dependent protection against clot lysis (AUC lysis) in the assay containing kaolin+tPA, whereas no significant effect on clot lysis was observed in the assay containing TF. In conclusion, addition of rFVIIa to WB treated with Abciximab significantly improves most of the TEG parameters. Comparison of Abciximab+rFVIIa TEG parameters with TEG parameters obtained in normal WB (n=59) showed normalization of the R-value, however, none of the other TEG parameters reached normal values although a significant effect was observed after addition of rFVIIa. The TEG assay using kaolin as initiator showed significant dose-dependent effect of rFVIIa on all TEG parameters. In contrast, in the TEG assay initiated with TF the dose-dependent response of rFVIIa was only significant for some of the parameters. This may be due to a strong initiating effect of TF in the assay thus lowering the sensibility to rFVIIa. In contrast, in the assay initiated with Kaolin only TF-independent effects of rFVIIa are measured. The design of a TEG assay therefore seems to be important for evaluating the in vitro effect of rFVIIa. The clinical relevance of these findings is currently unknown and needs to be evaluated further.TEG values (±SD) using the kaolin assayR (sec)MTG (mm×100/sec)MA (mm)Lysis AUC (+tPA) (mm2)Normal value359±6314.4±2.260±631707Abciximab treated527±567.6±2.333±1014725±5110rFVIIa 10nM458±76*8.3±2.1*35±10*15837±4634*rFVIIa 25nM413±42*9.2±2.7*37±11*16120±4969*rFVIIa 100nM383±41*9.0±2.2*37±10*18658±5693**: Significant effect compared to the Abciximab treated blood sample. P<0.05

The Bad Oeynhausen Concept of INR Self-Management

A significant number of patients depend on the intake of vitamin K antagonists for prevention and treatment of thromboembolic events. The development of portable anticoagulation monitors has enabled self-testing and self-adjustment of anticoagulation therapy. To describe the principles of a training course to learn INR self-management and to illustrate reliability of our concept. The training is divided into an early postoperative training, an ambulatory training six months later, and a 24 hours care and consultation. According to our concept, each patient who depends on long-term anticoagulation therapy is able to learn INR self-management. Reliability of our concept has been proved in two prospective, randomized clinical trials. A study with 1,155 patients has demonstrated that INR values lie more often in the predetermined target range in the INR self-management group if compared to the conventional group (79.2% vs. 64.9%; P < 0.001). Moreover, this study has demonstrated that self-management can lead to a reduction of thromboembolism (1.5% vs. 2.8%; P < 0.05), and to a lower lethality if compared to conventional INR management (3.5% vs 6.0%; P < 0.025). A second study with 1,816 patients has confirmed that INR self-management results in a high percentage of INR values in the target range (76%), even though target INR-range is reduced and narrowed. Thus, low dose INR self-management did not increase the risk of thromboembolism while avoiding the zone of higher risk for bleeding, beginning from INR > 3.5. The Bad Oeynhausen concept of INR self-management is a promising tool to achieve low hemorrhagic complications without increasing the risk of thromboembolic complications. It can thus be successfully applied to patients with an indication for permanent anticoagulation therapy.

Bleeding profiles of anticoagulants, including the novel oral direct thrombin inhibitor ximelagatran: definitions, incidence and management.

Ximelagatran is a novel oral direct thrombin inhibitor (oral DTI) that is currently in advanced clinical development for the prevention and treatment of thromboembolic events in a wide range of patient populations and indications. The clinical development of novel anticoagulant therapies requires that treatments be assessed according to both their clinical benefit (reduction of risk of thromboembolic events) and safety profile (primarily bleeding). Definition and assessment of bleeding severity is thus an important factor in clinical trial design. Lack of consistency in bleeding definitions used in different clinical trial programmes makes comparison of bleeding event data difficult. Standard bleeding definitions would be required to make fair comparisons between clinical trials possible. The definitions of bleeding events used in clinical trials of ximelagatran are broadly consistent with those used in many other major trials. Results of phase II and III trials comparing ximelagatran with currently available anticoagulant therapies demonstrate that ximelagatran can be used with fixed dosing with no coagulation monitoring, dose titration, or dose adjustment, without compromising efficacy or safety. The incidences of major bleeding events in clinical trials of ximelagatran have been low and similar to those with other anticoagulant drugs. Adequate treatment in case of emergency situations such as serious bleeding should include cessation of treatment and maintenance of adequate diuresis.

Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis

Introduction: Ximelagatran is a novel, oral direct thrombin inhibitor that is currently being investigated for the prophylaxis and treatment of thromboembolic events. This study evaluated the pharmacokinetics, pharmacodynamics, and clinical effects of melagatran, the active form of ximelagatran, in patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE). Materials and methods: In this open-label study, 12 patients received a fixed dose of 48 mg oral ximelagatran twice daily for 6–9 days. Plasma samples were collected for determination of melagatran concentrations and scintigraphic changes and adverse events were recorded. Results: Peak plasma concentrations of melagatran were attained approximately 2 h after administration of ximelagatran. Melagatran plasma concentration profiles were similar on Days 1, 2, and 6–9. Plasma activated partial thromboplastin time increased following administration of ximelagatran and reached a peak that was approximately twofold higher than the predose activated partial thromboplastin time and correlated with melagatran plasma concentrations ( R 2=0.69). All but one patient (with malignancy) showed regressed or unchanged lung scintigraphic findings, and six of these demonstrated no, or only minor, perfusion defects at central evaluation after 6–9 days of ximelagatran treatment. Clinical symptoms, including chest pain, dyspnoea, cough, and oedema, and pain in the affected leg, were improved. Ximelagatran was well tolerated with no deaths or severe bleeding events reported during treatment. Conclusion: Treatment with a fixed dose of oral ximelagatran, used without routine coagulation monitoring, showed reproducible pharmacokinetics and pharmacodynamics with a rapid onset of action and promising clinical results in patients with pulmonary embolism.

Hirudin for prophylaxis and treatment of deep vein thrombosis.

Since recombinant hirudin (r-hirudin) has become available, several studies have been published on hirudin for prophylaxis and treatment of thromboembolic complications. Vr-hirudin was shown to be superior even to low-molecular-weight heparin (LMWH) for prophylaxis of deep venous thrombosis (DVT), especially in high-risk patients. Consequently, r-hirudin was expected to be more effective than heparins are in the treatment of thromboembolic events. Vr-hirudin was proved to be safe and efficacious in the therapy of thromboembolic events. However, no benefit could be shown in comparison with heparin. In contrast, in patients suffering from HIT type II, r-hirudin is the drug of choice for the therapy of thromboembolic complications.

Low molecular weight heparin in children.

Low molecular weight heparins potentially have significant advantages over unfractionated heparin and oral anticoagulants for both the prevention and treatment of thromboembolic events in children. Compared to standard heparin, low molecular weight heparins have superior bioavailability, a longer half-life, and a dose-independent clearance, which results in a more predictable anticoagulant response. Low molecular weight heparins are administered subcutaneously and require minimal laboratory monitoring and dose adjustment, offering important benefits to children with poor venous access. In addition, complications including osteoporosis and heparin-induced thrombocytopenia are relatively rare with low molecular weight heparins compared to unfractionated heparin. based on the available data, low molecular weight heparins seem to be an efficient and safe alternative to standard anticoagulation therapy with unfractionated heparin and oral anticoagulants for both treatment and prevention of thromboembolic events in children of varying ages and underlying disorders.

Oral anticoagulation self-management and management by a specialist anticoagulation clinic: a randomised cross-over comparison

Vitamin K antagonist treatment is effective for prevention and treatment of thromboembolic events but frequent laboratory control and dose-adjustment are essential. Small portable devices have enabled patient self-monitoring of anticoagulation and self-adjustment of the dose. We compared this self-management of oral anticoagulant therapy with conventional management by a specialist anticoagulation clinic in a randomised cross-over study. 50 patients on long-term oral anticoagulant treatment were included in a randomised controlled crossover study. Patients were self-managed or were managed by the anticoagulation clinic for a period of 3 months. After this period the alternative strategy was followed for each patient. Prothrombin time (expressed as international normalised ratio [INR]) were measured at intervals of 1-2 weeks in both periods without knowledge of type of management. The primary endpoint was the number of measurements within the therapeutic range (therapeutic target value +/-50.5 INR units). There was no significant difference in the overall quality of control of anticoagulation between the two study periods. Patients were for 55% and for 49% of the treatment period within a range of +/-0.5 from the therapeutic target INR during self-management and anticoagulation clinic management, respectively (p=0.06). The proportion of patients who spent most time in the therapeutic target range was larger during self-management than during anticoagulation clinic-guided management. The odds ratio for a better control of anticoagulation (defined as the period of time in the therapeutic target range) during self-management compared with anticoagulation clinic-guided management was 4.6 (95% CI 2.1-10.2). A patient-satisfaction assessment showed superiority of self-management over conventional care. Self-management of INR in the population in this study is feasible and appears to result in control of anticoagulation that is at least equivalent to management by a specialist anticoagulation clinic. It is also better appreciated by patients. Larger studies are required to assess the effect of this novel management strategy on the incidence of thromboembolic or bleeding complications.

Antithrombotic therapy in children.

Thromboembolic events are an increasingly common secondary complication in children who are successfully treated for serious, life-threatening primary diseases. In contrast to adults, thromboembolic events are rare enough in children to hinder clinical trials assessing optimal use of antithrombotic agents. Currently, pediatric patients are treated according to guidelines extrapolated from adults. However, optimal prevention and treatment of thromboembolic events in children likely differs from such treatment for adults. The following review summarizes the available information on commonly used antithrombotic agents in children, which include standard heparin, low molecular heparin, oral anticoagulants, thrombolytic therapy, antiplatelet agents, antithrombin concentrates, and protein C concentrates. The mechanisms, dosing, monitoring, therapeutic range, factors influencing dose-response relationship, and side effects are discussed.