Factor Xa Inhibitor Fondaparinux Research Articles

Effectiveness and safety of selective and non - selective factor Xa inhibitors in antiphospholipid syndrome and systemic lupus erythematosus: anti - Xa - activity range

Clinical and laboratory data were analyzed retrospectively in SLE and APS patients who protractedly received low weight molecular heparins (LWMH) and selective factor Xa inhibitors fondaparinux and rivaroxaban. The study included 70 patients in the middle age 39 [31; 43] years: 15/70 (21%) - with SLE, 10/70 (14%) - with APS and 45/70 (65%) - with SLE and APS (SLE+APS). All the patients received anticoagulants: 29 patients - nadroparin (98.3 [67.8; 129.5] IU/kg/day), 29 patients - fondaparinux (5 [5; 7.5] mg/day), 3 patients - enoxaparin (1.2 [0.8; 1.5] mg/day) and 9 patients - rivaroxaban (20 mg/day). All the patients signed informed consents. aXa therapeutic range of 0.1-1.5 IU/ml was found in 43/70 (61%) patients, low aXa - in 14/70 (20%) and high aXa - in 13/70 (19%) patients. Patients with low aXa underwent anticoagulant dose correction. There were not any major bleedings and thrombosis relapses in the study. Increased aXa was more common in patients, who took fondaparinux (31%), than in those, who took nadroparin (7%) and rivaroxaban (23%), p=0.02. Patients with enoxaparin had normal aXa range. In the absence of bleeding in SLE and APS patients, received anticoagulants in standardized therapeutic dose, the next factors influenced the aXa range excess: valvular heart disease (VHD) with the 3rd stage of mitral valve insufficiency as a result of aseptic Libman-Sacks endocarditis (odds ratio - OR 9.02, 95% confidential interval - CI [1.53; 53.12], p=0.015), peripheral artery disease in analogy with arteritis obliterans (AO) (OR 6.86, 95% CI [1.25; 37.71], p=0.027), and also triple - positivity of all types of antiphospholipid antibodies (OR 4.93, 95% CI [1.11; 21.99], p=0.036). According to found logistic regression model, aXa range excess risk can be prognosticated by the next formula: Z = -3.98 + 2.2 × VHD (yes-1/no-0) + 1.9 × AO (yes-1/no-0) + 1.6 × Triple - positivity (yes-1/no-0). Classified function value Z=0.39 defines the patients group with aXa range excess. Thus the value Z>0.39 indicates aXa range excess in the absence of bleeding, herewith sensibility is of 77% and specificity is 86%, positive prognostic value is 84.3%. In SLE and APS patients the next clinical and immunologic manifestations influenced the aXa therapeutic range excess: peripheral artery disease in analogy with AO, earlier aseptic Libman-Sacks endocarditis with the 3rd stage of mitral valve insufficiency and triple - positivity of all types of antiphospholipid antibodies, that does not need LWMH and fondaparinux dose correction. In contrast, anticoagulant dose reduction can cause clinical symptoms progression. Therapeutic aXa range in such patients should be extended.

Novel Anticoagulant Therapy of Venous Thromboembolism: Current Status and Future Directions.

The first-line treatment of venous thromboembolisms (VTE) is anticoagulant therapy, and unfractionated heparin and warfarin are used in Japan. However, as both drugs require dosage adjustments that are difficult, VTE recurrences occur relatively frequently, and hemorrhagic complications are extremely common. The parenteral factor Xa inhibitor fondaparinux and the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and apixaban have recently become available as treatments for VTE in Japan. These novel anticoagulants have more stable effects than traditional therapies and are thus considered safer and more effective than the traditional agents. Especially, DOACs offer improved long-term prevention of recurrence in patients with unprovoked VTE. The initiation of DOAC monotherapy soon after VTE onset leads to shorter hospital stays than required with the older therapies and allows for outpatient treatment. DOACs have additional benefits, such as safer anticoagulant therapy for cancer patients. These novel anticoagulants are extremely promising, but there is a current lack of evidence in areas such as dosing regimens for highly vulnerable patients and dosing for long-term use, and alternative regimens for each DOAC.

Fondaparinux Beats Enoxaparin in NSTEMI Patients

In patients with non–ST-segment elevation myocardial infarction (NSTEMI), the factor Xa inhibitor fondaparinux was noninferior to enoxaparin in reducing ischemic outcomes in the OASIS-5 study. In addition, fondaparinux reduced severe in-hospital bleeding events, leading to both short- and long-term mortality reductions. To see how these trial findings translate to clinical practice, researchers conducted a prospective, multicenter cohort study in Sweden, analyzing data from 40,616 consecutive …

Venous thromboembolism after total hip arthroplasty diagnosed by enhanced computed tomography:comparison of selective thromboprophylaxis and no thromboprophylaxis.

Total hip arthroplasty (THA) is the most effective treatment for advanced or end-stage hip osteoarthritis. However, venous thromboembolism (VTE) remains one of its unresolved complications. We reviewed the records of 322 patients undergoing primary THA and investigated the efficacy of anticoagulant prophylaxis for VTE. Our study cohort consisted of 60 patients who received no anticoagulants, 100 patients who received a factor Xa inhibitor (fondaparinux), 100 patients who received low molecular weight heparin (enoxaparin), and 62 patients who selectively received no anticoagulant prophylaxis due to perioperative bleeding, weight, and/or hemoglobin concentration. Enhanced 64-slice multidetector row computed tomography was performed postoperatively for 7 days in all cases. The incidence of VTE in the four groups was 15%, 9.0%, 6.0%, and 6.4%, respectively. The incidence of VTE was significantly lower in the groups receiving anticoagulant prophylaxis and the group selectively receiving no anticoagulant prophylaxis than in the group receiving no anticoagulants. Complications of fondaparinux therapy included hepatic dysfunction in 4 cases (4.0%), minor bleeding in 2 cases (2.0%), persistent wound drainage in 3 cases (3.0%), and eruption in 1 case (1.0%). The complications of enoxaparin therapy were persistent wound drainage in 1 case (1.0%) and progression of anemia in 1 case (1.0%). The incidence of VTE was low in patients who selectively received no anticoagulant prophylaxis, so we conclude that anticoagulant prophylaxis should be used selectively in THA cases.

Antithrombotic and anticoagulant effects of direct factor Xa inhibitor darexaban in rat and rabbit models of venous thrombosis

The oral direct factor Xa inhibitor darexaban administered intraduodenally prevented venous thrombus formation in both rats and rabbits with no effect on bleeding. The indirect parenteral Factor Xa inhibitor fondaparinux exerted similar properties, only prolonging bleeding time at extremely high doses. In contrast, the thrombin inhibitor ximelagatran and low-molecular-weight heparin enoxaparin prolonged bleeding time at antithrombotic doses. Studies using human platelets showed darexaban glucuronide, a darexaban metabolite that predominantly determines darexaban antithrombotic effects in vivo, had no effect on platelet activation and aggregation, while heparin and enoxaparin activated platelets. Melagatran, heparin, and enoxaparin all inhibited thrombin-induced platelet aggregation at clinically relevant concentrations. Taken together, these results suggest that thrombin-inhibiting drugs may increase the risk of bleeding, while darexaban may have potential as an orally available antithrombotic agent with a wide therapeutic window.

1697P - Semuloparin Efficiently Inhibits Thrombin Generation Triggered by Pancreas Adenocarcinoma Cells BXPC3. Distinct Roles of Anti-XA and Anti-IIA Activity

ABSTRACT Background Venous thromboembolism (VTE) is a common complication in patients with cancer receiving chemotherapy. Currently no anticoagulant is approved for VTE prophylaxis in this setting. Semuloparin is an ultra-LMWH generated through a highly selective depolymerization of heparin which protects the antithrombin (AT) binding site in order to improve the benefit/risk ratio compared to existing anitcoagulants. Aims We studied in vitro the mechanism of action of semuloparin on the inhibition of thrombin generation (TG) of human platelet poor plasma (PPP) triggered by human pancreatic cancer cells BXPC3. We compared the antithrombotic efficiency of semuloparin to that of enoxaparin and the specific AT-dependent factor Xa inhibitor fondaparinux. Materials and methods BXPC3 cells were suspended in PPP spiked with clinically relevant concentrations of semuloparin, enoxaparin and fondaparinux. The endogenous thrombin potential (ETP) and the mean rate index (MRI) of the propagation phase of TG were monitored with the CAT assay (Stago France) as described previously (Gerotziafas et al Thromb Res 2011). Anti-Xa and anti-IIa specific activities were assessed assays obtained from Diagnostica Stago. Results Both semuloparin and enoxaparin, at the concentration of 0.4 anti-Xa IU/ml, completely abrogated TG. Total inhibition of TG occured in the presence of 0.002 anti-IIa IU/ml of semuloparin and 0.05 anti-IIa IU/ml of enoxaparin. Fondaparinux, even at concentrations higher than 2 µg/ml, reduced the MRI but did not significantly affect the ETP and did not completely inhibited TG,. The IC50 for the ETP of the anti-IIa activity of enoxaparin was 37-fold higher as compared to that of semuloparin. Conclusion In a cancer cell model of hypercoagulability, semuloparin reduced efficiently thrombin generation. The unique anticoagulant profile of semuloparin based on its high AT-affinity differentiates it from enoxaparin and fondaparinux. The residual anti-IIa activity of semuloparin amplifies its antithrombotic efficacy. This profile is expected to translate into an improved benefit/risk ratio. Disclosure All authors have declared no conflicts of interest.

Investigating the benefit of adding a vena cava filter to anticoagulation with fondaparinux sodium in patients with cancer and venous thromboembolism in a prospective randomized clinical trial

The benefit of adding a vena cava filter to anticoagulation in treating cancer patients with venous thromboembolism remains controversial. We initiated this study as the first prospectively randomized trial to evaluate the addition of a vena cava filter placement to anticoagulation with the factor Xa inhibitor fondaparinux sodium in patients with cancer. Sixty-four patients with deep vein thrombosis (86 %) and/or pulmonary embolism (55 %) were randomly assigned to receive anticoagulation with fondaparinux sodium with or without a vena cava filter. Endpoints included rates of complications by treatment arm, recurrent thromboembolism, complete resolution of thromboembolism, and survival rates. No patient had a recurrent deep vein thrombosis; two (3 %) patients had new pulmonary emboli, one in each randomized cohort. Major bleeding occurred in three patients (5 %). Two patients on the vena cava filter arm (7 %) had complications from the filter. Median survivals were 493 days in the anticoagulation only arm and 266 days for anticoagulation + vena cava filter (p < 0.57). Complete resolution of venous thromboembolism occurred in 51 % of patients within 8 weeks of initiating anticoagulation. No advantage was found for placement of a vena cava filter in addition to anticoagulation with fondaparinux sodium in terms of safety, recurrent thrombosis, recurrent pulmonary embolism, or survival in this prospective randomized trial evaluating anticoagulation plus a vena cava filter in cancer patients. Favorable complete resolution rates of thrombosis were observed on both study arms.

Documenting the complete resolution rates of venous thromboemboli (VTE) with the factor Xa inhibitor fondaparinux sodium (FS) in patients with cancer.

9130 Background: Cancer patients have a significant risk of VTE. Recurrent VTE rates of 9-17% occur (Lee NEJM 2003) despite the use of therapeutic anticoagulation (AC). Low molecular weight heparins (LMWH) afford several advantages over warfarin. Nevertheless, even with LMWHs more than 20% of patients have VTE propagation. Completeresolution and partial resolution of DVTs occur in up to 38% and 54%, respectively, after 6 months of AC (Prandoni Ann Intern Med 2002, Piovella Haematologica 2002), and thrombi remaindetectable in half of non-cancer patients after a year (Kearon Circulation 2003). Recently, Factor Xa inhibitors have become available and require further study to determine if they offer therapeutic improvements in this patient population. As part of the CAT (Cancer and Thrombosis) trial, we prospectively evaluated complete resolution rates with the Factor Xa inhibitor fondaparinux sodium (FS). Methods: Inclusion criteria included an acute VTE (DVT and/or PE) in patients with cancer and creatinine clearance > 30 mL/min. Patients received FS [5mg SC for pts <50 kg or age >65, 7.5mg SC for pts 50–100 kg and 10mg SC for pts >100 kg]. Imaging studies after baseline were repeated on days 14, 30, and 56 for DVTs, and on day 56 for PEs. Results: 64 patients were entered and 63 evaluated. Cancer types included: Lung (25%); Breast (18%), Colon (14%), Pancreas (14%), Lymphoma (8%), Ovarian (6%), and 15% with other cancers. Findings included: 107 DVT sites and 43 PEs. No patient had a recurrent DVT; 2 (3%) patients had new asymptomatic PEs. Major bleeding occurred in 3 patients (5%); minor bleeding occurred in 4 patients (6%). VTE resolution results are seen in the table. Conclusions: 1) The VTE complete resolution rate documented in this prospective trial with FS is among the highest reported in patients with cancer, and occurred within 8 weeks of starting AC. 2) VTE resolution could help tailor the duration of AC. These favorable results support future randomized trials to compare resolution rates of FS with LMWHs, and to evaluate if the optimal duration of AC depends on VTE resolution. % with complete resolution day 56 (95% CI) DVTs (n=107) 51% (40.6%-60.3%) PEs (n = 43) 47% (31.2%-62.3%)

Evaluating the need for a practical risk score to predict major bleeding in acute coronary syndromes

The incidence of recurrent adverse ischemic events and death after acute coronary syndromes (ACS): unstable angina, ST-segment elevation myocardial infarction [STEMI] and non-STEMI [NSTEMI]) has been significantly reduced by advances in antithrombotic therapy and invasive treatment strategies [1–4]. However, the use of multiple antiplatelet agents (i.e., aspirin, P2Y12 inhibitors, and glycoprotein IIb/IIIa inhibitors [GPIs]) and antithrombotic therapies (i.e., unfractionated heparin [UFH], lowmolecular weight heparin, factor-Xa inhibitors and direct thrombin inhibitors), in combination with an early invasive approach has increased the risk of bleeding. The incidence of hemorrhagic complications after treatment of ACS ranges from 1 to 10%, depending on differences in patient characteristics, antithrombotic therapies, timing of event reporting and bleeding definitions [5–8]. Despite this heterogeneity, numerous studies have demonstrated that bleeding is associated with an increased risk for both shortand long-term adverse outcomes [5,7–12]. Although the exact mechanisms causing this increased risk after bleeding complications are not fully understood, a number of factors are likely to contribute, such as the cessation of evidence-based therapies (i.e., antiplatelet agents, b-blockers and statins) in patients who bleed, adverse effects of blood transfusion, detrimental effects of acute anemia and a greater prevalence of comorbidities in patients who bleed. In contemporary practice, cardiologists have a wide variety of antiplatelet and antithrombin agents from which to choose. Each individual drug has a different profile of clinical efficacy (suppression of ischemic complications from the ACS event itself, or from the treatments subsequently required, most commonly percutaneous coronary intervention [PCI]) versus complications (principally bleeding). Large randomized clinical trials have demonstrated that treatment strategies that reduce bleeding while effectively suppressing ischemia are associated with improved survival in patients with ACS. The Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial randomized 20,078 patients with non-STelevation ACS to the low-molecular weight heparin enoxaparin or the factor-Xa inhibitor fondaparinux [13]. Fondaparinux was noninferior to enoxaparin in terms of the primary end points of death, myocardial infarction or refractory ischemia at 9 days. Moreover, fondaparinux was associated with significantly reduced rates of major bleeding at 9 days (2.2 vs 4.1%; p < 0.01) and significantly reduced rates of mortality at 30 days (2.9 vs 3.5%; p = 0.02) and 6 months (5.8 vs 6.5%; p = 0.05). The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONSAMI) trial randomized 3602 STEMI patients undergoing primary PCI to treatment with either UFH plus a GPI or the direct thrombin inhibitor bivalirudin. In HORIZONS-AMI, bivalirudin compared with UFH plus a GPI was associated with significantly reduced major bleeding (4.9 vs 8.3%; p < 0.01) at 30-day follow-up, and mortality at 30 days (2.1 vs 3.1%; p = 0.047) and 1 year (3.5 vs 4.8%; p = 0.04) [14,15].

Heparininduzierte Thrombozytopenie

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction that carries an increased risk of thromboembolic complications. HIT is caused by platelet-activating antibodies directed against a complex of platelet factor4 (PF4) and heparin. HIT typically manifests in the second week after initiation of heparin therapy with a platelet count reduction of more than 50% of the highest level after the start of heparin administration as well as thromboembolic events. The clinical probability can be calculated by the 4 T's score. The laboratory diagnosis of HIT is based on confirmation of PF4/heparin antibodies or on functional tests that provide evidence of heparin-dependent platelet-activating antibodies. A low 4 T's score and negative HIT test virtually rule out the presence of HIT. Patients with acute HIT require anticoagulation with a compatible anticoagulant in a therapeutic dose. The drugs currently available for this include the direct thrombin inhibitors argatroban, lepirudin, bivalirudin, and desirudin and the indirect factor Xa inhibitors danaparoid and fondaparinux.

Primary prevention of venous thromboembolism in medical and surgical oncology patients

Recent data suggest that patients with a malignancy have a seven-fold increased risk for venous thromboembolism (VTE) compared with those without cancer, suggesting that these patients may benefit from thromboprophylaxis. Mechanisms for the prevention of thromboembolism can be divided into two broad categories: mechanical and pharmacological. Although generally used in combination with pharmacotherapy, little evidence exists for the efficacy of mechanical modalities either in the broader population of patients at risk for VTE or for patients with cancer specifically. A recent study using graduated compression stockings (GCS) for thromboprophylaxis showed no support for the use of stockings in acute stroke patients. Established pharmacological modalities, including warfarin, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the factor Xa inhibitor fondaparinux, have been shown to reduce risk for VTE in general medical and surgical populations. In medical cancer patients, only limited data are available for the efficacy of thromboprophylaxis. In contrast, considerable evidence indicates that thromboprophylaxis is warranted in patients undergoing cancer surgery. The most recent evidence suggests that catheter-related thrombosis is not prevented by current pharmacological modalities. On 22 May 2009, a group of clinicians based in the United Kingdom (UK) met in London, UK, to evaluate recent data on cancer thrombosis. This article (the second of four) briefly reviews key data on the prevention of VTE in medical and surgical oncology patients, providing context for a brief transcript of the surrounding discussion and a consensus statement, developed by meeting attendees, on the implications of this information for UK clinical practice.

Assessment of laboratory assays to measure rivaroxaban – an oral, direct factor Xa inhibitor

Although there is no need for routine coagulation monitoring with rivaroxaban--an oral, direct factor Xa inhibitor--a haemostasis assay might be valuable to measure its pharmacodynamic effects. This study aimed to find assays, among those commercially available, to measure rivaroxaban pharmacodynamics. Several global conventional clotting tests, as well as clotting or chromogenic assays to measure anti-factor Xa activity, were studied. A thrombin generation test using calibrated automated thrombogram was also done. Tests were performed with the indirect factor Xa inhibitor fondaparinux for comparison. A concentration-dependent prolongation of prothrombin time (PT), dilute PT, and activated partial thromboplastin time was observed with rivaroxaban. The results varied depending on the reagents. This variability cannot be standardised with the international normalised ratio system commonly used for vitamin K antagonists. Using a standard calibration curve, PT test results can be expressed in plasma concentrations of rivaroxaban rather than PT seconds or ratio. Standard methods for HepTest and two-step prothrombinase-induced clotting time (PiCT) resulted in a paradoxical response, with low concentrations of rivaroxaban reducing clotting times. This was not observed with shorter incubation times, or when antithrombin-deficient (immunodepleted) plasma was used. The chromogenic tests found a dose-dependent relationship between anti-factor Xa activity and rivaroxaban concentration. Modified specific factor Xa chromogenic assays are being further investigated. One-step PiCT and HepTest with shortened incubation times, as well as the widely available PT assay (using a rivaroxaban calibrator) could be useful to monitor the pharmacodynamic effects of rivaroxaban accurately. Finally, all clotting and chromogenic assays showed a concentration-dependent effect induced by rivaroxaban.

Tissue Factor and Factor V Involvement in Rat Peritoneal Fibrosis

Fibrin deposition on the peritoneum has been frequently observed in peritoneal fibrosis induced by long-term peritoneal dialysis. The present study was conducted to clarify the contribution of factor Xa through tissue factor and factor V expression in peritoneal fibrosis. Wistar rats were intraperitoneally injected with chlorhexidine gluconate (CG) every day. For the interventional study, the factor Xa inhibitor fondaparinux was subcutaneously administered. After 28 days of CG injection, peritoneal specimens were examined by immunohistochemical analyses and in situ hybridization. The peritoneal submesothelial compact zone was observed to be markedly thicker in the CG-injected groups than in the normal group, and that thickness was dose dependent. Immunohistochemical study revealed massive fibrin, fibronectin, and type IV collagen depositions in the CG-injected groups, which was markedly higher than that in the normal group. Macrophage infiltration and staining for tissue factor, factor V, factor X, and protease-activated receptor-2 were intense in the CG-injected groups and negative/trace in the normal group. Tissue factor and factor V mRNAs were abundant in cells in the thickened peritoneum. A double-labeling experiment revealed that tissue factor was observed mainly in macrophages, and factor V was abundantly distributed in the fibrotic tissue together with macrophages. Fondaparinux treatment decreased the thickness of submesothelial fibrotic tissue, and size and number of CD31-positive vessels. These results suggest that expression of tissue factor and factor V in infiltrated macrophages, together with factor X deposition, may progress angiogenesis and accumulation of extracellular matrix components, partly via profibrotic and procoagulant mechanisms in the peritoneum after inflammatory stimulation.

The HIT treatment in a cardiac surgery patient

Heparin-induced thrombocytopenia (HIT) occurs in 1 to 3% of patients after cardiac surgery. In patients with suspected or confirmed HIT, the standard of care is withheld of heparin, and an alternative, non-heparin anticoagulant substituted. An established fact is that currently only direct thrombin inhibitors (lepirudin, bivalirudin and argatroban) and heparinoids like danaparoid are approved for alternative anticoagulation in HIT patients. Herein, we report the case of a patient who developed HIT after coronary artery bypass grafting (CABG) and who was successfully treated by the factor Xa inhibitor fondaparinux. Danaparoid is our first line alternative anticoagulant to treat HIT patients. Normally the recovery from thrombocytopenia began within 24 h. In the present patient, however, platelet counts continued to fall for 3 more days. Discontinuation of danaparoid and anticoagulation with fondaparinux clearly improved platelet counts which normalized. The present patient has been treated for 26 consecutive days, and we have not observed any subsequent fall in platelet counts and any further bleeding or thrombotic complications.

Abstract 6048: An Indirect Comparison of the Efficacy and Safety of Factor Xa Inhibitors with Thrombin Inhibitors nn Preventing Venous Thromboembolism after Hip or Knee Surgery

Introduction Selective factor Xa inhibitors and thrombin inhibitors are effective in the prevention of venous thromboembolism (VTE) after hip or knee surgery, but they have not been compared directly against each other. We performed an indirect comparison of the relative efficacy and safety of these two classes of inhibitors, from meta-analyses of randomized controlled trials (RCTs) of these agents, in which a low molecular heparin (LMWH) was used as a common comparator. Methods Relevant RCTs were identified by searching MEDLINE (Ovid MEDLINE® 1950 to March week 1, 2008), EMBASE (1980 to 2008, week 10) and the Cochrane Central Register of Controlled Trials (1 st quarter 2008), supplemented by hand searching and screening meeting websites. We restricted our search to the five agents (ximelagatran, dabigatran, fondaparinux, idraparinux and rivaroxaban) that have been evaluated in phase III trials. Trials were included if the study drug was compared against a LMWH and was administered in the pre- and/or postoperative (12–24hrs from surgery) period, to patients undergoing elective, hip or knee replacement surgery. The outcomes assessed were total VTE, symptomatic VTE, major bleeding and the need for blood transfusions. We obtained summary estimates (RR and 95% CI) for each outcome for the Xa and thrombin inhibitor studies, using a random-effects model. We then performed indirect comparisons between these estimates using standard statistical methods. Results We included 12 trials (18110 patients) of factor Xa inhibitors (fondaparinux, rivaroxaban) and 10 trials (17777 patients) of thrombin inhibitors (ximelagatran, dabigatran). These agents were compared with enoxaparin, except in two studies where dalteparin was the control agent. On indirect comparison, factor Xa inhibitors were significantly better than thrombin inhibitors in preventing total VTE (RR 0.54, 95% CI 0.40 – 0.75) and symptomatic VTE (RR 0.49, 95% CI 0.25– 0.97). There was no difference in the risk of major bleeding (RR 1.17, 95% CI 0.71–1.93) or the number of transfusions (RR 1.02, 95% CI 0.94–1.11). Conclusion Based on this indirect comparison, selective factor Xa inhibitors appear to be more effective than thrombin inhibitors, for the prevention of VTE after elective hip or knee surgery.

The Medical Management of Acute Coronary Syndromes and Potential Roles for New Antithrombotic Agents

Antithrombic therapy is recommended to prevent ischemic complications in patients with high-risk non-ST-segment elevation acute coronary syndromes, including patients with unstable angina/non-ST-segment elevation myocardial infarction and patients with ST-segment elevation myocardial infarction undergoing fibrinolysis with fibrin-specific agents. Ischemic benefit from these agents must be balanced against an increased risk of bleeding, which may itself carry adverse long-term consequences. Recent trials suggest that the low-molecular-weight heparin enoxaparin may be superior to unfractionated heparin for preventing ischemic complications, although it also may be associated with an increase in bleeding risk. In two other contemporary trials, the Factor Xa inhibitor fondaparinux improved mortality and morbidity in patients with unstable angina/non-ST-segment elevation myocardial infarction and in patients with ST-segment elevation myocardial infarction undergoing fibrinolytic reperfusion, without increasing bleeding risk. These data underscore the promise of new antithrombotic agents to improve outcomes in acute coronary syndrome (ACS) patients being medically managed.

Dose-Dependent Antithrombotic Effects of Apixaban, an Oral Direct Factor Xa Inhibitor, in Prevention and Treatment of Thrombosis in Rabbit Models of Arteriovenous-Shunt and Venous Thrombosis at Doses That Preserve Hemostasis.

Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor, which is currently in late stage clinical development for the prevention and treatment of thromboembolic diseases. The dose-dependent antithrombotic and antihemostatic profile of apixaban was determined in the rabbit models of arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), and cuticle bleeding time (BT), and compared to those of the direct thrombin inhibitor lepirudin, the indirect FXa inhibitor fondaparinux and the oral anticoagulant warfarin. We induced the formation of thrombus in the AVST and VT models by placing threads in the extracorporeal shunt and vena cava, respectively, and bleeding by the incision of cuticles in anesthetized rabbits. In the AVST and VT prevention models, apixaban (0.03 to 3 mg/kg/h), lepirudin (0.006 to 0.75 mg/kg/h) and fondaparinux (0.01 to 1 mg/kg/h) were infused IV 30–60 min before the initiation of thrombosis. Warfarin (0.1 to 3 mg/kg/day) was administered orally for 4 days before the study. Control thrombus weight averaged 290±11 mg and 64±2 mg in AVST and VT, respectively, and control BT averaged 179±5 s (n=6 per group). Apixaban exhibited similar dose-related efficacy as lepirudin, fondaparinux, and warfarin in preventing AVST and VT. At doses that prevented 80 to 90% of thrombus formation in AVST and VT, apixaban, fondaparinux, lepirudin and warfarin increased BT by 20±2, 30±5, 500±10, 502±20%, respectively (n=6 per group). Doses for 50% reduction of control thrombus weight in AVST, VT were 0.27±0.03, 0.11±0.02 mg/kg/h IV for apixaban, 0.04±0.01, 0.05±0.01 mg/kg/h IV for lepirudin, 0.05±0.01, 0.05±0.005 mg/kg/h IV for fondaparinux and 0.53±0.04, 0.27±0.02 mg/kg PO for warfarin, respectively. To increase BT by 3-fold required higher doses of apixaban and fondaparinux (>3 mg/kg/h IV), lepirudin (0.24±0.05 mg/kg/h IV) and warfarin (0.70±0.07 mg/kg PO). In a VT treatment model, apixaban, lepirudin and fondaparinux, administered IV as a bolus injection supplemented with a continuous infusion after thrombus formation, were all able to arrest thrombus growth. However clot regression was only observed following administration of apixaban (0.6 mg/kg+0.87 mg/kg/h IV) where the preformed thrombus decreased from an initial weight of 38±2 mg (n=6) to 26±4 mg (n=6; P<0.05). In summary, apixaban and fondaparinux were effective in the prevention and treatment of experimental thrombosis at doses that preserve hemostasis in rabbits. Warfarin and lepirudin also prevented thrombus formation but with greater increases in BT. Furthermore, these standard anticoagulant agents have well-known limitations including narrow therapeutic index, frequent laboratory monitoring, or the requirement of parenteral administration. The favorable preclinical antithrombotic and antihemostatic profile of apixaban demonstrated here is consistent with clinical efficacy and safety results in recent Phase II trials, and indicates that direct inhibition of FXa with apixaban is a promising approach for the prevention and treatment of venous thromboembolism.

Meta-analysis of venous thromboembolism prophylaxis in medically Ill patients

Background: Venous thromboembolism (VTE) prophylaxis in medically ill patients has received a level 1A recommendation in previously published clinical guidelines. Pharmacologic prophylaxis for VTE includes unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux. Few direct comparisons between anticoagulants exist in medically ill patients. Objective: This meta-analysis was conducted to assess UFH and LMWH (including the selective factor Xa inhibitor fondaparinux) in the reduction of in-hospital VTE in unselected medically ill patients. Methods: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry databases from January 1981 through September 2007 (English language) for randomized controlled trials using the following terms: dalteparin, enoxaparin, fondaparinux, nadroparin, and heparin. References of included articles and key review papers for additional studies were also searched. Data from studies were included in the analysis if the studies included medically ill patients with risk factors for VTE who had been followed up for 7 to 21 days. Results: A total of 12,391 patients (of whom 8357 were in placebo-controlled trials) from 9 studies were included. Mean age for the entire cohort was 72.8 years; mean (SD) body mass index, 25.6 kg/m2; and mean (SD) actual body weight, 68.2 kg. Deep vein thrombosis (DVT) was significantly reduced with the addition of an LMWH compared with placebo (odds ratio [OR], 0.60; 95% CI, 0.47-0.75; P ≤ 0.001), but rates of DVT were similar when comparing LMWH with UFH (OR, 0.92; 95% CI, 0.56-1.52). No significant differences in pulmonary embolism (PE) or death were found among the UFH, LMWH, and placebo groups. LMWH was associated with a significant increased risk for minor bleeding compared with placebo (OR, 1.64; 95% CI, 1.18-2.29; P = 0.003). However, no significant difference was found between LMWH and UFH (OR, 0.68; 95% CI, 0.27-1.70). Major bleeding events were similar among all groups: LMWH/fondaparinux versus placebo, OR, 1.65 (95% CI, 0.8-3.4); LMWH/fondaparinux versus UFH, OR, 0.69 (95% CI, 0.29-1.68); LMWH/fondaparinux versus UFH or placebo, OR, 1.16 (95% CI, 0.66-2.04). Conclusions: This analysis suggests that VTE prophylaxis with an LMWH (including fondaparinux) or UFH is effective in reducing the rate of DVT, but this benefit did not extend to enhanced protection against PE. Additionally, LMWH and UFH had similar bleeding outcomes.

Use of newer anticoagulants in patients with chronic kidney disease

The current indications, dosing, and practical considerations for use of newer anticoagulants in patients with various degrees of renal impairment who do not require dialysis are reviewed. Kidney function should generally be evaluated in all patients commencing anticoagulant therapy. As in the general population, hospitalized patients with impaired renal function most often have impairment that is mild to moderate in severity. Drug dosing in patients with chronic kidney disease may require that adjustment be made to the usual loading or maintenance dose of a drug. Newer anticoagulants with labeling approved by the Food and Drug Administration for venous thromboembolism (VTE) prophylaxis, treatment, or both include the low-molecular-weight heparins (LMWHs) and the factor Xa inhibitor fondaparinux. Some LMWHs are also indicated for the management of patients with acute coronary syndrome (ACS). All of the newer anticoagulants currently available for the management of VTE and ACS have approved labeling for use in patients with mild-to-moderate renal impairment. Currently available LMWHs, factor Xa inhibitors, and direct thrombin inhibitors (excluding argatroban) are eliminated primarily by the kidneys, so dosing in patients with severe renal impairment may require cautious dosage reduction or increased monitoring for bleeding and thromboembolic complications or both. Unfractionated heparin is the preferred anticoagulant for use in most of these patients. Newer anticoagulants should be used with caution in patients with mild-to-moderate renal impairment. Unfractionated heparin remains the preferred anticoagulant in most patients with severe renal impairment even though its use is associated with increased bleeding in this population. Dosing of newer anticoagulants, except argatroban, requires cautious dosage reduction and increased monitoring for complications.

Neue Antikoagulanzien: Von der präklinischen Entwicklung zum klinischen Einsatz - Einfache, orale Applikation bei guter Wirksamkeit und Verträglichkeit

Ein besseres Nutzen-/Risiko-Profil und eine einfachere Anwendung als sie Heparin oder Vitamin-K-Antagonisten bieten können, waren die Zielsetzung bei der Entwicklung selektiver Inhibitoren der Gerinnungsfaktoren Xa und IIa. Die erste Substanz in dieser Reihe ist der selektive Faktor-Xa-Inhibitor Fondaparinux. Dieses Pentasaccharid wurde bereits vor einigen Jahren zur Prävention und Therapie venöser Thromboembolien zugelassen und steht mittlerweile auch für den Einsatz beim akuten Koronarsyndrom zur Verfügung. Trotz einiger Fortschritte hinsichtlich Wirksamkeit und Verträglichkeit bleibt jedoch auch bei diesem Antikoagulans der Nachteil der parenteralen Anwendung bestehen. Derzeit konzentriert sich die Forschung daher auf oral verfügbare Substanzen. Am weitesten vorangeschritten sind bislang die klinischen Entwicklungsprogramme des Faktor-X-Inhibitors Rivaroxaban und des Thrombininhibitors Dabigatran - zwei nach den bisherigen klinischen Studienergebnissen außerordentlich vielversprechende Optionen zur Gerinnungshemmung. Sie lassen nochmals eine signifikante Verbesserung der antithrombotischen Therapie erwarten, sowohl in der Klinik als auch bei der ambulanten Patientenversorgung.