fondaparinux and Hemorrhage

Venous thromboembolism (VTE) is a major complication of trauma. Currently, there are few studies summarising the evidence for prophylaxis in trauma settings. This review provides evidence for the use of VTE prophylactic interventions in trauma patients to produce evidence-based guidelines.. A PRISMA-compliant review was conducted from Sep 2021 to June 2023, using Embase, Medline and Google Scholar. The inclusion criteria were: randomized-controlled trials (RCTs) in English published after 2000 of adult trauma patients comparing VTE prophylaxis interventions, with a sample size higher than 20. The network analysis was conducted using RStudio. The results of the pairwise comparisons were presented in the form of a league table. The quality of evidence and heterogeneity sensitivity were assessed. The primary outcome focused on venous thromboembolism (VTE), and examined deep vein thrombosis (DVT) and pulmonary embolism (PE) as separate entities. The secondary outcomes included assessments of bleeding and mortality. PROSPERO registration: CRD42021266393.. Of the 7,948 search results, 23 studies with a total of 21,312 participants fulfilled screening criteria, which included orthopaedic, spine, solid organ, brain, spinal cord, and multi-region trauma. Of the eight papers comparing chemical prophylaxis medications in patients with hip or lower limb injuries, fondaparinux and enoxaparin were found to be significantly superior to placebo in respect of prevention of DVT, with no increased risk of bleeding. Regarding mechanical prophylaxis, meta-analysis of two studies of inferior vena cava filters failed to provide significant benefits to major trauma patients.. Enoxaparin and fondaparinux are safe and effective options for VTE prevention in trauma patients, with fondaparinux being a cheaper and easier administration option between the two. Inconclusive results were found in mechanical prophylaxis, requiring more larger-scale RCTs.

Topics: Adult; Anticoagulants; Enoxaparin; Fondaparinux; Hemorrhage; Humans; Multiple Trauma; Network Meta-Analysis; Pulmonary Embolism; Venous Thromboembolism

Low molecular weight heparin, enoxaparin, has been one of most used drugs to fight the SARS-CoV-2 pandemic. Pharmacological properties of heparin recognize its specific ability, as with other oligosaccharides and glycosaminoglycan, to bind several types of viruses during their pass through the extracellular matrix of the respiratory tract, as well as its anticoagulant activity to prevent venous thromboembolism. Antithrombotic actions of enoxaparin have been testified both for inpatients with COVID-19 in regular ward and for inpatients in Intensive Care Units (ICUs). Prophylactic doses seem to be able to prevent venous thromboembolism (VTE) in inpatients in the regular ward, while intermediate or therapeutic doses have been frequently adopted for inpatients with COVID-19 in ICU. On the other hand, although we reported several useful actions of heparin for inpatients with COVID-19, an increased rate of bleeding has been recorded, and it may be related to several conditions such as underlying diseases with increased risks of bleeding, increased doses or prolonged administration of heparin, personal trend to bleed, and so on.

Topics: Anticoagulants; COVID-19; Enoxaparin; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Inpatients; Intensive Care Units; Pandemics; SARS-CoV-2; Venous Thromboembolism

The objective of this study is to comprehensively review the efficacy and safety data of low-molecular-weight heparins (LMWHs) and fondaparinux in pediatric patients with obesity.. A comprehensive literature search of PubMed, SCOPUS, CINAHL, Academic Search Complete, PsycInfo, Cochrane Library, and Web of Science databases was conducted (1900 to July 2020). Search terms utilized included. Studies that reported pediatric patients with described overweight or obesity and utilized LMWHs or fondaparinux were considered.. Of 207 studies screened, 12 were included. Average dose reductions of 12.9% to 37.3% from the starting dose were observed with treatment indications of enoxaparin and increased up to 27.3% for prophylactic indications. Trends could not be concluded in the dalteparin and fondaparinux studies. Four thrombotic and 15 bleeding events were reported in the studies.. Pediatric patients with obesity may initially be underdosed or overdosed with enoxaparin compared with children with healthy body weight, depending on the indication.. Pediatric patients with obesity may benefit from proactively adjusting enoxaparin dosing on initiation of therapy. Further studies are needed for dalteparin and fondaparinux in these populations. Clinical controversy exists with the relevance of monitoring these high-risk medications for therapeutic and prophylactic indications. Thrombotic and hemorrhagic events were similar to reported adult outcomes.

Topics: Anticoagulants; Child; Child, Preschool; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Obesity; Retrospective Studies; Thrombosis; Venous Thromboembolism

The aim was to review the relative efficacy and safety of anticoagulation for managing venous thromboembolism (VTE) in patients with cancer.. A systematic review and meta-analysis was carried out. On 17 May 2018 the MEDLINE and Scopus databases were searched for randomised controlled trials (RCTs). Eligible RCTs had to be performed in patients with cancer exclusively or to report results on a subset of patients with cancer. The main study outcomes (efficacy/recurrent VTE and safety/bleeding events) were expressed as risk ratios (RR) with a 95% confidence interval (CI). The quality of evidence was assessed following the GRADE method.. Twenty-three RCTs with 6980 patients were identified. Low molecular weight heparins (LMWHs) were more effective than vitamin K antagonists (VKAs) in preventing recurrent VTE (RR 0.58, 95% CI 0.45-0.75) and deep vein thrombosis (RR 0.44, 95% CI 0.29-0.69) but not pulmonary embolism (PE), bleeding, or overall mortality. Direct oral anticoagulants (DOACs) were more effective than VKAs in preventing recurrent VTE (RR 0.65, 95% CI 0.45-0.95) but not DVT, PE, overall mortality, or bleeding. However, anti-Xa DOACs were more effective (RR for VTE 0.64, 95% CI 0.42-0.97) and caused less bleeding than VKAs, although major bleeding was reduced only with DOACs not requiring initial parenteral anticoagulation (RR 0.45, 95% CI 0.21-0.97). In a direct comparison, DOACs were more effective than LMWHs in preventing VTE recurrence (RR 0.64, 95% CI 0.45-0.90) but caused more major bleeding (RR 1.75, 95% CI 1.10-2.77), with no difference in fatal bleeding and overall mortality. Quality of evidence, where sufficient, was mostly moderate or high.. Compared with VKAs, LMWHs and DOACs are more effective in treating VTE, but the former caused less bleeding. DOACs are more effective than LMWHs in preventing VTE recurrence but may carry a higher risk of major bleeding, pending additional information by ongoing trials.

Topics: Anticoagulants; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oligosaccharides; Pulmonary Embolism; Secondary Prevention; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Compared with people without cancer, people with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE.. To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in people with cancer.. A comprehensive search included a major electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2018, Issue 1), MEDLINE (via Ovid) and Embase (via Ovid); handsearching of conference proceedings; checking of references of included studies; use of the 'related citation' feature in PubMed; and a search for ongoing studies. This update of the systematic review was based on the findings of a literature search conducted on 14 January 2018.. Randomized controlled trials (RCTs) assessing the benefits and harms of LMWH, UFH, and fondaparinux in people with cancer and objectively confirmed VTE.. Using a standardized form, we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interested included all-cause mortality, symptomatic VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach.. Of 15440 identified citations, 7387 unique citations, 15 RCTs fulfilled the eligibility criteria. These trials enrolled 1615 participants with cancer and VTE: 13 compared LMWH with UFH enrolling 1025 participants, one compared fondaparinux with UFH and LMWH enrolling 477 participants, and one compared dalteparin with tinzaparin enrolling 113 participants. The meta-analysis of mortality at three months included 418 participants from five studies and that of recurrent VTE included 422 participants from 3 studies. The findings showed that LMWH likely decreases mortality at three months compared to UFH (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.40 to 1.10; risk difference (RD) 57 fewer per 1000, 95% CI 101 fewer to 17 more; moderate certainty evidence), but did not rule out a clinically significant increase or decrease in VTE recurrence (RR 0.69, 95% CI 0.27 to 1.76; RD 30 fewer per 1000, 95% CI 70 fewer to 73 more; moderate certainty evidence).The study comparing fondaparinux with heparin (UFH or LMWH) did not exclude a beneficial or detrimental effect of fondaparinux on mortality at three months (RR 1.25, 95% CI 0.86 to 1.81; RD 43 more per 1000, 95% CI 24 fewer to 139 more; moderate certainty evidence), recurrent VTE (RR 0.93, 95% CI 0.56 to 1.54; RD 8 fewer per 1000, 95% CI 52 fewer to 63 more; moderate certainty evidence), major bleeding (RR 0.82, 95% CI 0.40 to 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44 more; moderate certainty evidence), or minor bleeding (RR 1.53, 95% CI 0.88 to 2.66; RD 42 more per 1000, 95% CI 10 fewer to 132 more; moderate certainty evidence)The study comparing dalteparin with tinzaparin did not exclude a beneficial or detrimental effect of dalteparin on mortality (RR 0.86, 95% CI 0.43 to 1.73; RD 33 fewer per 1000, 95% CI 135 fewer to 173 more; low certainty evidence), recurrent VTE (RR 0.44, 95% CI 0.09 to 2.16; RD 47 fewer per 1000, 95% CI 77 fewer to 98 more; low certainty evidence), major bleeding (RR 2.19, 95% CI 0.20 to 23.42; RD 20 more per 1000, 95% CI 14 fewer to 380 more; low certainty evidence), or minor bleeding (RR 0.82, 95% CI 0.30 to 2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164 more; low certainty evidence).. LMWH is possibly superior to UFH in the initial treatment of VTE in people with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review. The decision for a person with cancer to start LMWH therapy should balance the benefits and harms and consider the person's values and preferences.

Topics: Anticoagulants; Dalteparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Polysaccharides; Randomized Controlled Trials as Topic; Recurrence; Secondary Prevention; Tinzaparin; Venous Thromboembolism

The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the third update of a review first published in 2007.. To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications.. For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (March 2017), CENTRAL (2017, Issue 2), and trials registries (March 2017). We handsearched the reference lists of relevant papers and conference proceedings.. Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included people with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in a superficial vein.. Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. We assessed the quality of the evidence using the GRADE approach.. We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo-controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low-quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects.. Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Randomized Controlled Trials as Topic; Rivaroxaban; Stockings, Compression; Thrombectomy; Thromboembolism; Thrombophlebitis; Venous Thromboembolism

Standard treatment of deep vein thrombosis (DVT) is based on antithrombotic therapy, initially with parenteral administration of unfractionated heparin or low molecular weight heparins (LMWH) for five to seven days, then subsequent long-term therapy with oral vitamin K antagonists (e.g. warfarin). Pentasaccharides are novel anticoagulants that may be favourable over standard therapy due to their predictable effect, no need for frequent monitoring or re-dosing, and few known drug interactions. Heparin-induced thrombocytopenia, a harmful effect of heparins, appears to be rare during treatment with pentasaccharides.. To assess the efficacy and harms of pentasaccharides for the treatment of deep vein thrombosis.. The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (22 March 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2) (searched 22 March 2017). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles for additional citations.. We included randomised controlled trials in which people 18 years of age or older with a DVT confirmed by standard imaging techniques were allocated to receive a pentasaccharide (fondaparinux, idraparinux, or idrabiotaparinux) for the treatment of DVT in comparison with standard therapy or other treatments.. We extracted data characterising the included trials according to the methods, participants, interventions, and outcomes. We assessed risk of bias using Cochrane's 'Risk of bias' tool and employed the GRADE methodology to evaluate the quality of the evidence.The main primary outcome for efficacy was recurrent venous thromboembolism (VTE), and the main primary outcome for harm was major and clinically relevant bleeding. Since our outcomes were dichotomous, we calculated the risk ratio (RR) with a 95% confidence interval (CI). We combined the effects of different comparisons through a meta-analysis using a fixed-effect model.. We included five randomised controlled trials of 6981 participants comparing pentasaccharides with standard therapy or other pentasaccharides. The quality of the evidence varied depending on the outcome and was judged as of moderate to very low quality. We downgraded the quality of the evidence due to risk of bias or imprecision, or both.Two studies evaluated fondaparinux, at doses of 5.0 mg, 7.5 mg, and 10.0 mg, plus vitamin K antagonist in comparison with standard therapy. A meta-analysis of these two studies showed no clear difference in the risk of recurrent VTE (RR 0.80, 95% CI 0.43 to 1.47; 2658 participants); moderate-quality evidence. The frequencies of major bleeding were similar between interventions in the initial period of treatment (approximately five days) (RR 1.15, 95% CI 0.39 to 3.44; 2645 participants) and at three months' follow-up (RR 1.05, 95% CI 0.64 to 1.71; 2645 participants). We judged the quality of the evidence as moderate.One study (757 participants) compared idrabiotaparinux (3.0 mg) with idraparinux (2.5 mg) and demonstrated no clear difference in the risk of recurrent VTE at six months' follow-up (RR 0.72, 95% CI 0.31 to 1.69); low-quality evidence. Major bleeding during the initial treatment period was not reported. Major bleeding at six-month follow-up was less frequent in participants receiving idrabiotaparinux versus participants treated with idraparinux (RR 0.21, 95% CI 0.06 to 0.71); low-quality evidence.The effect of an initial treatment with LMWH followed by three months of idraparinux (10 mg) showed no clear difference from standard therapy for risk of recurrent VTE (RR 1.51, 95% CI 0.26 to 8.90; 263 participants); very low-quality evidence; one study. Major bleeding during the initial treatment period was not reported. The frequency of major and other clinically relevant bleeding at three months' follow-up ranged from 2% to 15% in participants receiving LMWH and increasing doses of idraparinux of 2.5 mg, 5 mg, 7.5 mg, or 10 mg. When dosage groups were combined, there was no clear difference in major plus other clinically relevant bleeding or in major bleeding alone between the idraparinux treatment group and the standard therapy group (RR 1.30, 95% CI 0.70 to 2.40; 659 participants; RR 3.76, 95% CI 0.50 to 28.19; 659 participants, respectively); very low-quality evidence.One study (2904 participants) compared idraparinux (2.5 mg) to standard therapy. There was no clear difference in the risk of recurrent VTE at thre. We found moderate-quality evidence that the effects of fondaparinux at doses of 5.0 mg, 7.5 mg, and 10.0 mg plus vitamin K antagonist are similar in terms of recurrent VTE and risk of major bleeding compared with standard treatment for DVT.Low-quality evidence suggests equal efficacy of idraparinux at 2.5 mg and the equimolar dose of 3.0 mg of idrabiotaparinux with regard to recurrent VTE, but a higher frequency of major bleeding was observed in participants treated with idraparinux.We judged evidence on the effectiveness of idraparinux compared with standard therapy, with or without initial treatment with LMWH, and on associated bleeding risk to be low to very low quality, therefore we have very limited confidence in the estimated effects.The observed similar effectiveness in terms of recurrent DVT and harmful effects in terms of bleeding risk with fondaparinux plus vitamin K antagonist compared to standard treatment for DVT suggest that it may be an alternative to conventional anticoagulants for the treatment of DVT in certain circumstances.

Topics: Anticoagulants; Biotin; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Oligosaccharides; Polysaccharides; Randomized Controlled Trials as Topic; Recurrence; Time Factors; Venous Thrombosis

Patients with chronic kidney disease (CKD) are at increased risk for both thrombotic events and bleeding. The early stages of CKD are mainly associated with prothrombotic tendency, whereas in its more advanced stages, beside the prothrombotic state, platelets can become dysfunctional due to uremic-related toxin exposure leading to an increased bleeding tendency. Patients with CKD usually require anticoagulation therapy for treatment or prevention of thromboembolic diseases. However, this benefit could easily be offset by the risk of anticoagulant-induced bleeding. Treatment of patients with CKD should be based on evidence from randomized clinical trials, but usually CKD patients are excluded from these trials. In the past, unfractionated heparins were the anticoagulant of choice for patients with CKD because of its independence of kidney elimination. However, currently low-molecular-weight heparins have largely replaced the use of unfractionated heparins owing to fewer incidences of heparin-induced thrombocytopenia and bleeding. We undertook this review in order to explain the practical considerations for the management of anticoagulation in these high risk population.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Platelets; Drug Administration Schedule; Factor Xa; Fondaparinux; Glomerular Filtration Rate; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Renal Insufficiency, Chronic; Thrombin; Thrombocytopenia; Thrombosis

Venous thromboembolism (VTE) is a common and potentially fatal complication of arthroplasty.. We reviewed randomized trials to determine which anticoagulant has the best safety and efficacy in hip and knee arthroplasty patients. We searched PubMed, MEDLINE, and EMBASE through January 2016.. Compared to enoxaparin (most commonly dosed 40 mg once daily), the relative risk (RR) of VTE was lowest for edoxaban 30 mg once daily (0.49; 95% confidence interval [CI], 0.32-0.75), fondaparinux 2.5 mg once daily (0.53; 95% CI, 0.45-0.63), and rivaroxaban 10 mg once daily (0.55; 95% CI, 0.46-0.66), and highest for dabigatran 150 mg once daily (1.19; 95% CI; 0.98-1.44). The RR of major/clinically relevant bleeding was lowest for apixaban 2.5 mg twice daily (0.84; 95% CI; 0.70-0.99) and highest for rivaroxaban (1.27; 95% CI, 1.01-1.59) and fondaparinux (1.64; 95% CI, 0.24-11.35). Fondaparinux was the only agent that was more effective than enoxaparin 30 mg twice daily (VTE RR = 0.58; 95% CI, 0.43-0.76).. With the possible exception of apixaban, newer anticoagulants that lower the risk of postoperative VTE increase bleeding.

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Dabigatran; Enoxaparin; Fondaparinux; Hemorrhage; Humans; Morpholines; Polysaccharides; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Pharmacologic prophylaxis of deep vein thrombosis and venous thromboembolism (VTE) is an important aspect of medical care, particularly in the inpatient setting. Low-molecular weight heparins, heparin, and fondaparinux are commonly used agents to prevent VTE, each of which has well established dosing regimens in patients with normal body mass index. Dosing of these medications in morbidly obese populations (BMI > 40 kg/m(2)) is not as clearly defined in guidelines. This article reviews published data to support specific dosing regimens and monitoring strategies of these agents in this population. The most validated parenteral agent to prevent VTE in morbidly obese hospitalized patients is enoxaparin, dosed at 40 mg subcutaneously (SC) twice daily. If unfractionated heparin is utilized for prophylaxis in morbidly obese patients, a dose of 7500 units SC three times daily should be considered. Monitoring of anti-factor Xa levels to guide prophylactic dosing is an option, although the utility of this lab test is limited, as target anti-Xa ranges for VTE prophylaxis have not been universally defined and trials have not shown a clear link between anti-factor Xa levels and bleeding or thrombotic events. Additional studies are needed to clearly define the most appropriate dosing strategies in patients with moderate obesity (BMI 35-40 mg/m(2)) and those with extreme obesity (BMI > 60 mg/m(2)).

Topics: Factor Xa; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Obesity, Morbid; Polysaccharides; Venous Thromboembolism; Venous Thrombosis

A number of studies have evaluated the efficacy and safety of fondaparinux versus low-molecular-weight heparin (LMWH) in patients with acute coronary syndrome (ACS), but the findings were not consistent across these studies.. Electronic databases and article references were searched for studies that assessed fondaparinux versus LMWH in ACS patients.. Six studies met the inclusion criteria. There was a lower risk of major adverse cardiac events (MACE) with fondaparinux-based regimens both in randomized controlled trials (RCT; risk ratio, RR: 0.91, p = 0.04) and observational studies (RR: 0.85, p < 0.0001). Mortality decreased in fondaparinux-treated patients in RCT (RR: 0.84, p = 0.02), but not in observational studies (RR: 1.44, p = 0.64). For the analysis of myocardial infarction (MI), recurrent ischemia and stroke, none of the studies showed significant results. In addition, fondaparinux lowered the risk of major bleeding in RCT (RR: 0.62, p < 0.0001) and observational studies (RR: 0.65, p < 0.0001). The net clinical outcome also favored fondaparinux over LMWH in RCT (RR: 0.82, p < 0.0001) and observational studies (RR: 0.84, p < 0.0001).. Among ACS patients, a fondaparinux-based regimen presented advantages regarding MACE and major bleeding, and a net clinical benefit compared with LMWH, although the benefit is minimal regarding MACE. For death, MI, recurrent ischemia and stroke, fondaparinux has not shown significant benefits.

Topics: Acute Coronary Syndrome; Anticoagulants; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Myocardial Infarction; Polysaccharides; Randomized Controlled Trials as Topic; Stroke; Treatment Outcome

Despite widespread diffusion of pharmacological prophylaxis, deep venous thrombosis (DVT) is still a common cause of morbidity after major orthopedic surgery (total hip replacement--THR--and total knee replacement--TKR). At present, clear evidence has been provided that pharmacological primary prophylaxis with low molecular weight heparin (LMWH) is associated with a significant decrease in the incidence of venous thromboembolism. The main limitation of LMWH prophylaxis however is the need for parenteral administration with a not negligible drop-out of treatment. Newer oral anticoagulants (NAOs) dabigatran, rivaroxaban, apixiban and edoxaban may be valid alternatives in elective surgery. Several studies have demonstrated the efficacy and safety of NAOs after THR and TKR. The research for new compounds and their antidote is under continuous development Aim of this paper was to review the indications and clinical results of DVT prophylaxis with NAO in patients undergoing major orthopaedic surgery.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Enoxaparin; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Orthopedic Procedures; Polysaccharides; Rivaroxaban; Venous Thromboembolism

Several new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50 % less intracranial bleeding than VKAs. Nevertheless, they are still associated with bleeding complications. Bleeding can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. This review summarises the current options and strategies in development to antagonise anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antithrombins; Benzamides; Clinical Trials as Topic; Dabigatran; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Hemostatics; Heparin; Humans; Infusions, Parenteral; Intracranial Hemorrhages; Polysaccharides; Protamines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Thrombosis; Vitamin K

The introduction of venography into patient care was a major advance because it was the first accurate method for the diagnosis of DVT. Compression ultrasound has since become the preferred test for patients with suspected DVT because, unlike venography, it is simple, non-invasive and widely available. Venography has facilitated the development and approval of new anticoagulants and remains widely used as an efficacy outcome in trials of venous thromboembolism prevention. Most thrombi detected by screening venography are, however, small and unimportant for patients. In order to calculate the trade-off between an asymptomatic thrombus and a bleed we require an estimate of the number of asymptomatic thrombi that must be prevented to avoid a patient-important thrombus. A credible estimate of this ratio is not available. Therefore when used as a measure of efficacy in trials of thromboprophylaxis, venography has limitations for comparing the relative effects of alternative antithrombotic agents on outcomes important to patients.

Topics: Anticoagulants; Cardiology; Clinical Trials as Topic; Contrast Media; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Phlebography; Polysaccharides; Reproducibility of Results; Thrombosis; Treatment Outcome; Venous Thrombosis

Heparin, one of the common anticoagulants, is clinically used to prevent and treat venous thromboembolism (VTE). Though it has been the drug of choice for many advanced medical and surgical procedures with a long history, the adverse events, such as bleeding, heparin-induced thrombocytopenia (HIT), allergic reactions, follow. Therefore, low molecular weight heparins (LMWHs) and ultra low molecular weight heparins (ULMWHs), with lower molecular weights, higher anti-FXa activity, longer half-life times and lower incidence of adverse events than unfractionated heparin (UFH), were researched and developed. Fondaparinux, a chemically synthesized ULMWH of pentasaccharide, has the same antithrombin III (AT-III)-binding sequence as found in UFH and LMWH. In addition, AVE5026 and RO-14, another two ULMWHs, are obtained by selective chemical depolymerization. In this paper, we review the preparation process, pharmacological effects and clinical applications of fondaparinux, AVE5026 and RO-14.

Topics: Animals; Anticoagulants; Blood Coagulation; Drug Design; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Half-Life; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Molecular Structure; Molecular Weight; Polysaccharides; Structure-Activity Relationship; Venous Thromboembolism

To investigate the relative benefits of unfractionated heparin, low molecular weight heparin(LMWH), fondaparinux, and bivalirudin as treatment options for patients with ST segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI).. Mixed treatment comparison and direct comparison meta-analysis of randomized trials in the era of stents and P2Y12 inhibitors.. A search of Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) for randomized trials comparing unfractionated heparin plus glycoprotein IIb/IIIa inhibitor(GpIIb/IIIa inhibitor), unfractionated heparin, bivalirudin, fondaparinux, or LMWH plus GpIIb/IIIa inhibitor for patients undergoing primary PCI.. The primary efficacy outcome was short term (in hospital or within 30 days) major adverse cardiovascular event; the primary safety outcome was short term major bleeding.. We identified 22 randomized trials that enrolled 22,434 patients. In the mixed treatment comparison models, when compared with unfractionated heparin plus GpIIb/IIIa inhibitor, unfractionated heparin was associated with a higher risk of major adverse cardiovascular events (relative risk 1.49 (95% confidence interval 1.21 to 1.84), as were bivalirudin (relative risk 1.34 (1.01 to 1.78)) and fondaparinux (1.78 (1.01 to 3.14)). LMWH plus GpIIb/IIIa inhibitor showed highest treatment efficacy, followed (in order) by unfractionated heparin plus GpIIb/IIIa inhibitor, bivalirudin, unfractionated heparin, and fondaparinux. Bivalirudin was associated with lower major bleeding risk compared with unfractionated heparin plus GpIIb/IIIa inhibitor (relative risk 0.47 (0.30 to 0.74)) or unfractionated heparin (0.58 (0.37 to 0.90)). Bivalirudin, followed by unfractionated heparin, LMWH plus GpIIb/IIIa inhibitor, unfractionated heparin plus GpIIb/IIIa inhibitor, and fondaparinux were the hierarchy for treatment safety. Results were similar in direct comparison meta-analyses: bivalirudin was associated with a 39%, 44%, and 65% higher risk of myocardial infarction, urgent revascularization, and stent thrombosis respectively when compared with unfractionated heparin with or without GpIIb/IIIa inhibitor. However, bivalirudin was associated with a 48% lower risk of major bleeding compared with unfractionated heparin plus GpIIb/IIIa inhibitor and 32% lower compared with unfractionated heparin alone.. In patients undergoing primary PCI, unfractionated heparin plus GpIIb/IIIa inhibitor and LMWH plus GpIIb/IIIa inhibitor were most efficacious, with the lowest rate of major adverse cardiovascular events, whereas bivalirudin was safest, with the lowest bleeding. These relationships should be considered in selecting anticoagulant therapies in patients undergoing primary PCI.

Topics: Anticoagulants; Antithrombins; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Integrin beta3; Myocardial Infarction; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Purinergic P2Y Receptor Antagonists; Recombinant Proteins; Stents; Thrombosis; Treatment Outcome

Venous thromboembolism (VTE) is a frequent complication among acutely ill medical patients hospitalized for congestive heart failure, acute respiratory insufficiency, rheumatologic disorders, and acute infectious and/or inflammatory diseases. Based on robust data from randomized controlled studies and meta-analyses showing a reduced incidence of VTE by 40% to about 60% with pharmacologic thromboprophylaxis, prevention of VTE with low molecular weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux is currently recommended in all at-risk hospitalized acutely ill medical patients. In patients who are bleeding or are at high risk for major bleeding, mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression may be suggested. Thromboprophylaxis is generally continued for 6 to 14 days or for the duration of hospitalization. Selected cases could benefit from extended thromboprophylaxis beyond this period, although the risk of major bleeding remains a concern, and additional studies are needed to identify patients who may benefit from prolonged prophylaxis. For hospitalized acutely ill medical patients with renal insufficiency, a low dose (1.5 mg once daily) of fondaparinux or prophylactic LMWH subcutaneously appears to have a safe profile, although proper evaluation in randomized studies is lacking. The evidence on the use of prophylaxis for VTE in this latter group of patients, as well as in those at higher risk of bleeding complications, such as patients with thrombocytopenia, remains scarce. For critically ill patients hospitalized in intensive care units with no contraindications, LMWH or UFH are recommended, with frequent and careful assessment of the risk of bleeding. In this review, we discuss the evidence for use of thromboprophylaxis for VTE in acutely ill hospitalized medical patients, with a focus on (low-dose) fondaparinux.

Topics: Anticoagulants; Critical Illness; Dose-Response Relationship, Drug; Fondaparinux; Hemorrhage; Hospitalization; Humans; Intensive Care Units; Polysaccharides; Randomized Controlled Trials as Topic; Risk Factors; Venous Thromboembolism

For more than 50 years, heparin(s) and warfarin have been the most important anticoagulant agents, and clinicians are accustomed to their specific antidotes (protamine sulfate and vitamin K/plasma [or factor concentrates], respectively). Recently, there has been an explosion of novel anticoagulant development: ideally, these newer agents should have advantages over traditional anticoagulants, such as fewer side effects, a more predictable pharmacokinetic profile (and potentially no need for monitoring), minimal drug-drug interactions, and so forth. But, unlike the older agents, the newer anticoagulants do not have specific antidotes. There is increasing focus on the use of nonspecific procoagulants, such as non-activated and activated prothrombin complex concentrates (PCCs) and recombinant factor VIIa (rFVIIa), to manage major bleeding or need for emergency invasive procedures. This paper reviews several of the novel anticoagulants and presents the available evidence for their "reversal". Based on extrapolation from animal models, clinical anecdote, and an understanding of their mechanism of action, we recommend treating major bleeding complications of DTIs, as follows (in descending order of preference): activated PCCs; rFVIIa; and (non-activated) PCCs. For management of fondaparinux-associated bleeding, rFVIIa has some rationale (for which we provide an illustrative case). The increasing use of novel anticoagulants will require physicians to have an understanding of rational approaches to "reverse" their anticoagulant effects when true antidotes do not exist.

Topics: Animals; Anticoagulants; Blood Coagulation Factors; Factor VIIa; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Humans; Oligosaccharides; Platelet Aggregation Inhibitors; Polysaccharides; Warfarin

New anticoagulants promise to have better efficacy, more safety and/or a better manageability than traditional anticoagulants. However, knowledge is limited regarding special situations such as renal insufficiency, obesity, pregnancy, long-term therapy, heparin-induced thrombocytopenia, treatment in patients with mechanical heart valves, use for children, and in patients with a high risk of thromboembolic complications. These situations have rarely or even never been the objective of randomised controlled trials. The purpose of the present article is to summarize and discuss available data on efficacy and safety in these special situations for one of the first new anticoagulants, the indirect factor-Xa inhibitor fondaparinux. Furthermore, we discuss safety in licensed indications and management of bleeding complications and comment on measuring of drug concentration in plasma.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Evidence-Based Medicine; Factor X; Female; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Pregnancy; Thrombosis

High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices.. The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.. Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education.. We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Topics: Administration, Oral; Decision Support Systems, Clinical; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Humans; Infusions, Intravenous; International Normalized Ratio; Long-Term Care; Patient Education as Topic; Polysaccharides; Randomized Controlled Trials as Topic; Self Care; Societies, Medical; Thrombosis; United States; Vitamin K

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Fondaparinux; Hemorrhage; Heparin; Humans; Polysaccharides; Practice Guidelines as Topic; Preoperative Care; Thrombosis; Warfarin

Anticoagulation is an integral part of both fibrinolytic therapy and percutaneous intervention (PCI) in the reperfusion treatment of ST-segment elevation AMI (STEMI).. This article reviews the choices of adjunctive anticoagulation regimens. Readers will appreciate the complexities of anticoagulation and the variable risk of clotting with ischemic/thrombotic complications versus that of bleeding. Antiplatelet therapy with aspirin and clopidogrel is recommended with fibrinolysis and PCI. Newer P2Y(12) inhibitors such as prasugrel and ticagrelor have been shown to reduce cardiovascular death, myocardial infarction (MI), stroke and stent thrombosis, as compared with clopidogrel. Ticagrelor has also been shown to reduce mortality. Glycoprotein IIb/IIIa inhibitors, by blocking the final pathway of platelet clumping with each other through bridging with fibrinogen, have the ability to disaggregate platelets, hence the potential for reducing thrombotic complications as well as increasing bleeding in patients undergoing PCI bleeding risks. Enoxaparin reduces death and MI compared with unfractionated heparin (UFH) with fibrinolytic therapy. There was a trend for a reduction in death, MI procedural failure or non-coronary artery bypass grafting (CABG) major bleeding compared with UFH in primary PCI. In primary PCI, bivalirudin has the advantage over UFH of inhibiting clot bound thrombin and reduces bleeding and mortality compared with the use of UFH plus glycoprotein IIb/IIIa inhibitors. Combinations of P2Y(12) antagonists and bivalirudin need to be tested to optimize the balance between efficacy and bleeding.. This field is rapidly evolving with multiple appropriate approaches.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Thrombosis; Electrocardiography; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Polysaccharides; Thrombolytic Therapy

Newer therapeutic options available in the prevention of postoperative thromboembolism, currently focused on fondaparinux, rivaroxaban and dabigatran warrant an overall therapeutic assessment. The constitutive comparisons with enoxaparin are based on a combined outcome measure solely driven by the incidence of "asymptomatic deep vein thrombosis". Its validity as a clinically relevant endpoint is missing if antithrombotics of different classes are compared. This is because they target different phases of thrombogenesis i. e. ahead and beyond the asymptomatic stage of thrombosis. Additional concerns refer to the dosing-regimens and their practical administration: Fondaparinux, rivaroxaban and dabigatran are dosed to achieve maximum effects very close to their limits of tolerance whereas wide dosing spectra for the low molecular weight herparin (LMWH)'s indicate the potential for dose adaptation and increase. The other disadvantage to the control-heparin originates in the timing for the 1st administration which doesn't fit in with the "just-in-time" principle. So the enoxaparin-regimen is lacking in benchmark-quality - with the consequence that the meaning of the Phase III-trials does'nt go beyond a mere technical demarcation from the marketed variant of the product as defined by the stipulations in the package insert. As to tolerance the selective anticoagulants exhibit an increased risk of major and other clinically relevant bleeding, exceeding that of enoxaparin by 30% (P<0.001). The outcome of the meta-analyses on fondaparinux, rivaroxaban and dabigatran is supported by product-specific calculations and assessments of the European Medicine Equivalence Agency (EMEA). Rivaroxaban and dabigatran show significant age-dependent renal accumulation. Because the dose-finding studies were restricted to patients over 60 year old the regimens definitely established are not applicable to younger patients. The reason for the limited therapeutic index of the selective anticoagulants originates in their monovalent activity as such not adequately matching the complexity of thrombogenesis and early thrombus extension. Their class-specific limitations are compensated through more intensive dosage-regimens which result in accentuated bleeding complications. Connotatively the hypothesis emerged that antiXa- and IIa-effects interact synergistically which translates into enhanced efficacy and tolerance. Experimental studies on hirudin with pentasaccharide and hirudin with "lo

Topics: Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Evidence-Based Medicine; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Morpholines; Polysaccharides; Practice Guidelines as Topic; Rivaroxaban; Thiophenes; Treatment Outcome; Venous Thromboembolism

Recent studies have highlighted the critical importance of bleeding complications on prognosis in patients with acute coronary syndromes (ACS). In fact, the hazard for an adverse cardiovascular event associated with bleeding is similar to that of a myocardial infarction. Several bleeding risk scores are now available that reliably quantify the probability of an ACS patient experiencing a bleeding complication. Consistent and strong correlates of bleeding include older age, female sex, renal impairment, and an invasive management approach. Although patients who tend to bleed are usually more morbid compared with their non-bleeding counterparts, several lines of experimental and clinical evidence suggest an independent and causal pathway for bleeding-associated cardiovascular risk. Given the frequency and adverse prognosis associated with bleeding, interventions that might reduce such complications are now a major emphasis in the current era of ACS treatment. Recent trials have shown that several novel antithrombotics, bivalirudin and fondaparinux, reduce bleeding risk while maintaining efficacy in reducing ischemic events during ACS. Other promising strategies that continue to be tested include the use of vascular closure devices and transradial arterial access during percutaneous coronary intervention.

Topics: Acute Coronary Syndrome; Anticoagulants; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Hirudins; Humans; Incidence; Peptide Fragments; Platelet Aggregation Inhibitors; Polysaccharides; Prognosis; Recombinant Proteins; Risk Assessment; Risk Factors

The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In the case of severe bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, it may be useful to reverse anticoagulant treatment. Conventional anticoagulants such as vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates, whereas heparin and heparin derivatives can be counteracted by protamine sulphate. The anti-hemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors as well as new antiplatelet agents have been introduced and these drugs show promising results in clinical studies. A limitation of these new agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although experimental studies show hopeful results for some of these agents.

Topics: Anticoagulants; Antithrombins; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Heparin Antagonists; Humans; International Normalized Ratio; Platelet Aggregation Inhibitors; Polysaccharides; Risk Factors; Vitamin K; Warfarin

The prevalence of obesity has increased substantially over recent years. Clinicians are increasingly being challenged with making uncertain anticoagulant dosing decisions, as the optimal dosing strategy for most anticoagulants in the obese patient population remains unknown. Research published to date suggests that the clearance of anticoagulants increases with weight. As obesity is associated with an increased risk of venous thromboembolism and arterial disease, there is an urgent need to establish appropriate anticoagulation regimens for this patient group. Research studies applying the method of pharmacokinetic-pharmacodynamic modelling and simulation could establish an appropriate evidence base and provide direction and reassurance to prescribing clinicians.

Topics: Acute Coronary Syndrome; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Double-Blind Method; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Humans; Morpholines; Multicenter Studies as Topic; Obesity; Polysaccharides; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Venous Thrombosis; Warfarin

Dabigatran is an oral direct thrombin inhibitor with a rapid onset. Patients on dabigatran do not require coagulation monitoring. Recent prospective randomized trials have shown the efficacy of dabigatran for the prevention of venous thromboembolism after knee or hip arthroplasty and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Because dabigatran is cleared principally by the kidneys, dosage adjustments are required in the setting of renal dysfunction. There currently is no reversal agent for dabigatran although hemodialysis can facilitate its rapid removal in life-threatening circumstances. The management of severe bleeding associated with dabigatran also may include the administration of a procoagulant, such as recombinant activated factor VII. Based on recent guidelines, regional anesthesia should be used cautiously in patients taking this novel oral thrombin inhibitor.

Topics: Anesthesia, Conduction; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Chemistry, Pharmaceutical; Dabigatran; Fondaparinux; Heart Valve Prosthesis Implantation; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Randomized Controlled Trials as Topic; Thrombin; Venous Thromboembolism; Vitamin K

A thorough understanding of the pharmacology, pharmacokinetics, and pharmacodynamics of the most commonly prescribed anticoagulants is necessary to ensure optimal therapeutic outcomes and patient safety. Evidence is available to guide some, but not all aspects of anticoagulation therapy initiation. Issues related to the initiation of anticoagulation therapy, including the resumption of therapy following interruption of anticoagulation for invasive procedures, are reviewed. Initiating unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux is challenging for patients with renal dysfunction and obesity. UFH is preferred in patients with severe renal dysfunction. Morbidly obese patients may require higher than usual prophylactic doses of LMWH. Therapeutic doses of LMWH should be based on actual body weight, even in obese patients. Currently available evidence does not demonstrate the superiority of one initial warfarin dose over another. All anticoagulants increase the risk of bleeding and should therefore only be initiated in appropriately selected patients with sufficiently low underlying bleeding risk.

Topics: Anticoagulants; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Polysaccharides

Chronic kidney disease (CKD) is prevalent and affects an ever-increasing proportion of patients presenting with acute coronary syndrome (ACS). Patients with CKD have a higher risk of ACS and significantly higher mortality, and are also predisposed to increased bleeding complications. Antiplatelet and antithrombotic drugs form the bedrock of management of patients with ACS. Most randomized trials of these drugs exclude patients with CKD, and current guidelines for management of these patients are largely based on these trials. We aim to review the safety and efficacy of these drugs in patients with CKD presenting with ACS.

Topics: Acute Coronary Syndrome; Adenosine; Aspirin; Chronic Disease; Clinical Trials as Topic; Clopidogrel; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; Kidney Diseases; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Prasugrel Hydrochloride; Recombinant Proteins; Thiophenes; Ticagrelor; Ticlopidine; Uremia

To evaluate the use of recombinant factor VIIa (rFVIIa) to reverse major bleeding from newer parenteral anticoagulant therapy.. MEDLINE/PubMed was searched from January 2000 through December 2009 using the terms recombinant factor VIIa, rFVIIa, NovoSeven, enoxaparin, argatroban, fondaparinux, lepirudin, bivalirudin, idraparinux, nadroparin, hirudin, and desirudin. References of identified articles were reviewed.. Data evaluating the role of rFVIIa to reverse major bleeding from newer parenteral anticoagulant therapy is limited to case reports and small laboratory investigations. Laboratory investigations suggest that rFVIIa may be effective in reversing the hemostatic effects of newer parenteral anticoagulants. In most case reports analyzed, standard interventions for bleeding (eg, fresh frozen plasma, packed red blood cells) were attempted prior to using rFVIIa. Sixteen published cases describe the use of rFVIIa to reverse major bleeding from low-molecular-weight heparins, synthetic pentasaccharides, and direct thrombin inhibitors. Initial doses ranged from 20 to 120 mug/kg. rFVIIa was considered effective or partially effective based upon clinical response in 13 cases. Use was not effective in 3 cases because of a thrombotic event, no change in hemostasis, and death from bleeding complications. As thrombosis is the major safety concern, an individualized risk-benefit assessment is required prior to the use of rFVIIa therapy to restore hemostasis.. rFVIIa may be considered to manage major refractory bleeding from newer parenteral anticoagulant agents when the benefit is thought to outweigh the thrombotic risk.

Topics: Anticoagulants; Factor VIIa; Fondaparinux; Hemorrhage; Hemostatics; Heparin, Low-Molecular-Weight; Humans; Oligosaccharides; Polysaccharides; Recombinant Proteins; Thrombin

Antithrombotic therapy constitutes the basis of the management of acute coronary syndromes. It combines antiplatelet and anticoagulant therapy. Antiplatelet agents should combine aspirin and agents acting through the ADP pathway such as clopidogrel; newer antiplatelet agents such as prasugrel or ticagrelor have superior anti-ischemic efficacy, compared with clopidogrel. Intravenous glycoprotein IIb/IIIa inhibitors may be used in selected patients at high risk undergoing percutaneous coronary interventions. Unfractionated heparin constitutes the reference anticoagulant treatment. Enoxaparin provides slightly better anti-ischemic efficacy. Newer agents, such as bivalirudin or fondaparinux, reduce bleeding complications, with no improvement in anti-ischemic efficacy. The combination of antiplatelet and anticoagulant agents should be chosen according to the patients' characteristics and the management strategy of the acute coronary syndrome.

Topics: Acute Coronary Syndrome; Adenosine; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Clopidogrel; Disease Management; Drug Synergism; Drug Therapy, Combination; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Recombinant Proteins; Thiophenes; Ticagrelor; Ticlopidine

An increasing number of patients receive anticoagulant therapy to prevent and treat arterial or venous thromboembolism. The major complication of anticoagulant therapy is the increase of the individual bleeding risk. All anticoagulant drugs can cause haemorrhages, that can sometimes be life-threatening. Although heparins and the vitamin K antagonists have been the most widely used anticoagulants for decades, the correct management of bleeding complications associated with these agents has been poorly studied. More recently, new anticoagulant drugs, both parenteral and oral, have been approved for clinical use. Currently, none of these new agents has a specific antidote, and little advise can be given on how to manage a major bleeding event. The aim of this article is to describe the haemorrhagic risk and the management of bleeding complications associated with the principal anticoagulant drugs.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Factor VIIa; Fondaparinux; Hemorrhage; Heparin; Humans; Morpholines; Polysaccharides; Protamines; Recombinant Proteins; Risk Factors; Rivaroxaban; Thiophenes; Vitamin K

Bleeding is a strong predictor of death in patients hospitalized for arterial thrombosis who are treated with antithrombotic therapy, but the prognostic importance of bleeding in patients receiving antithrombotic prophylaxis for venous thromboembolism is uncertain.. Using Cox proportional hazards modeling, we examined the association between major bleeding and death at 30 days using pooled individual patient data from 8 large randomized controlled trials (n=13 085) comparing fondaparinux with control (low-molecular-weight heparin or placebo) for the prophylaxis of venous thromboembolism in hospitalized surgical or medical patients. Patients who developed major bleeding were older, were more likely to be male, had a lower body weight and lower creatinine clearance, and were more likely to be receiving fondaparinux. At 30 days, the risk of death was 7-fold higher among patients with a major bleeding event (8.6% versus 1.7%; adjusted hazard ratio, 6.96; 95% confidence interval, 4.60 to 10.51). There was a consistent pattern of reduced mortality in patients treated with fondaparinux irrespective of whether patients experienced major bleeding (6.8% versus 11.4%; hazard ratio, 0.58; 95% confidence interval, 0.27 to 1.23) or no major bleeding (1.5% versus 1.9%; hazard ratio, 0.77; 95% confidence interval, 0.59 to 1.02; P for heterogeneity=0.47).. Major bleeding in hospitalized surgical and medical patients participating in venous thromboembolism prevention trials is a strong predictor of mortality.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Clinical Trials, Phase III as Topic; Female; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Polysaccharides; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Factors; Sex Factors; Time Factors; Venous Thromboembolism

Idraparinux is an analogue of fondaparinux binding with high affinity to antithrombin. It was designed for weekly, rather than daily, administration, with an exceptionally long half-life. One potential problem with small heparin-like fragments of this type is the difficulty of neutralising excessive activity in the case of side-effects or overdose. The efficacy of idraparinux was was proven in clinical studies with patients suffering from venous thromboembolism (VTE) or atrial fibrillation. Due to major bleeding events during treatment for more than six months the development of idraparinux was stopped. Idrabiotaparinux has an attached biotin moiety at the non-reducing end unit, which allows its neutralisation with avidin, an egg-derived protein with low antigenicity. This compound is currently investigated in clinical trials for prevention of recurrent VTE in patients with acute pulmonary embolism. The future of idrabiotaparinux depends also on the safety and efficacy of avidin.

Topics: Animals; Anticoagulants; Antithrombin III; Atrial Fibrillation; Avidin; Biotin; Carbohydrate Conformation; Carbohydrate Sequence; Drug Design; Drug Evaluation, Preclinical; Fondaparinux; Hemorrhage; Heparin Antagonists; Humans; Molecular Sequence Data; Molecular Structure; Oligosaccharides; Polysaccharides; Randomized Controlled Trials as Topic; Structure-Activity Relationship; Thrombosis; Treatment Outcome

Disseminated intravascular coagulation (DIC) is the physiologic result of pathologic overstimulation of the coagulation system. Despite multiple triggers, a myriad of laboratory abnormalities, and a clinical presentation ranging from gross hemostatic failure to life-threatening thrombosis, or even both simultaneously, a simplified clinical approach augmented by a few readily available tests allows prompt identification of the process and elucidation of treatment opportunities. Platelet counts in DIC may be low, especially in acute sepsis-associated DIC, yet increased in malignancy-associated chronic DIC. Thrombotic risk is not a function of the platelet count, and thrombocytopenia does not protect the patient from thrombosis. The stratification of both thrombotic risk and hemorrhagic risk will be addressed.

Topics: Adenocarcinoma; Aged; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Esophageal Neoplasms; Fatal Outcome; Fondaparinux; Foodborne Diseases; Hemorrhage; Heparin; Hepatitis C, Chronic; Humans; Male; Middle Aged; Multiple Organ Failure; Polysaccharides; Postoperative Complications; Thrombocytopenia; Thrombophlebitis; Thrombosis; Vibrio Infections; Vibrio vulnificus; Young Adult

The overall thromboembolic risk is the resultant of patient-related risk and surgical risk. The surgical risk is decreasing, especially with the introduction of new procedures (fast-track surgery). The value of prophylaxis has been firmly established. Mechanical prophylaxis is to be used as first-line prophylaxis when there is a risk of bleeding. Combining this with drugs increases the antithrombotic efficacy. However, the effectiveness of prophylaxis on pulmonary embolism and mortality has not been demonstrated. Renal function needs to be evaluated when low molecular weight heparins, fondaparinux, rivaroxaban or dabigatran are prescribed. An age of over 75 years and low body weight (<50 kg) have to be taken into account. There is a risk of spinal or epidural hematoma in patients receiving anticoagulants. Caution should be taken especially when administering the newer agents. Patients undergoing surgery that involves a moderate or high overall risk should receive prophylaxis until full mobilization. Patients who have undergone a total hip replacement, surgery for hip fracture, or major abdominal surgery should receive prophylaxis for about 5 weeks longer. The relevance of distal vein thromboses is debated. Surrogate venographic end-points should be gradually replaced by a combination of ultrasound and clinical criteria. The new antithrombotic agents will probably modify prevention in the years to come but currently there are very few long-term data for these products for which - it should be reminded - no antagonists are available.

Topics: Adult; Aged; Anticoagulants; Combined Modality Therapy; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Middle Aged; Morpholines; Polysaccharides; Postoperative Complications; Preanesthetic Medication; Pulmonary Embolism; Risk Factors; Rivaroxaban; Stockings, Compression; Thiophenes; Thromboembolism; Thrombophlebitis; Vitamin K

Fondaparinux sodium (Arixtra) is a synthetic, sulfated pentasaccharide, selective factor Xa inhibitor that is indicated in Europe for preventing thrombus formation in patients with acute coronary syndromes (ACS; the focus of this review), including those with ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina.The large (n = 20,078), well designed OASIS-5 trial showed that subcutaneous fondaparinux 2.5 mg/day for 12,000) OASIS-6 trial. There were no differences in the incidence of major bleeding between these groups, resulting in a benefit : risk balance favoring fondaparinux. The specificity and selectivity of fondaparinux, combined with its long half-life and 100% bioavailability, allows once-daily anticoagulation without the need for monitoring activated clotting time. Subcutaneous fondaparinux was noninferior to enoxaparin treatment in patients with unstable angina or NSTEMI, and was more effective than usual care in those with STEMI. Fondaparinux has a favorable tolerability profile, particularly with regard to the risk of major bleeding, and limited data suggest that it is more cost effective than enoxaparin in the short term. Thus, overall, clinical evidence suggests that fondaparinux has a valuable place in the treatment of patients with ACS.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Anticoagulants; Clinical Trials as Topic; Drug Interactions; Fondaparinux; Hemorrhage; Humans; Polysaccharides

The increasing incidence of patients who develop acute coronary syndrome (ACS) stresses the importance of effective initial treatment to reduce morbidity and mortality. The recommended initial therapeutic regimen for patients with ACS includes both anticoagulants and antiplatelet agents to prevent excessive coronary thrombosis, stroke, and further coronary events. Most commonly, unfractionated heparin (UFH) is used for initial antithrombotic treatment of ACS, despite limited published evidence regarding effectiveness and safety (bleeding complications). Therefore, this treatment regimen is primarily based upon expert opinion rather than evidence-based medicine. Studies addressing the dilemma of effectiveness and increased risk of bleeding when using UFH and low molecular weight heparin (LMWH) in patients with ACS showed superior clinical outcome in patients treated with LMWH. Nevertheless, the concurrent increased risk of bleeding while using anticoagulants is a severe problem and negatively impacts upon clinical outcome. Furthermore, non-hemorrhagic side effects of heparin such as heparin-induced thrombocytopenia (HIT), and skin reactions at the site of subcutaneous injection are reduced but not abolished by replacing UFH with LMWH. The limitations of UFH and LWMH as outlined above provided the impetus for the development of a pentasaccharide, called fondaparinux, which inhibits factor Xa selectively. Fondaparinux has been shown to be as effective as enoxaparin in the prevention of thrombosis in patients undergoing orthopedic surgery and showed similar results compared to enoxaparin or UFH in patients with deep-vein-thrombosis or pulmonary embolism. Recently, a large clinical study addressed the dilemma of the effectiveness and adverse effects of anticoagulation in ACS by comparing fondaparinux and LMWH such as enoxaparin in patients with unstable angina or non ST-segment elevation myocardial infarction (NSTEMI).

Topics: Acute Coronary Syndrome; Angina, Unstable; Anticoagulants; Enoxaparin; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; Myocardial Infarction; Polysaccharides

Topics: Angina, Unstable; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Morpholines; Myocardial Infarction; Peptide Fragments; Polysaccharides; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Thrombosis; Warfarin

The anticoagulant properties of heparin were discovered in 1916, and by the 1930s researchers were evaluating its therapeutic use in clinical trials. Treatment of unstable angina with unfractionated heparin (UFH), in addition to aspirin, was introduced into clinical practice in the early 1980s. UFH was combined with aspirin to suppress thrombin propagation and fibrin formation in patients presenting with acute coronary syndromes (ACS) or patients undergoing percutaneous coronary intervention (PCI). However, UFH stimulates platelets, leading to both activation and aggregation, which may further promote clot formation. Clinical trials have demonstrated that newer agents, such as the low-molecular-weight heparins (LMWHs), are superior to UFH for medical management of unstable angina or non-ST-segment elevation myocardial infarction. Increasingly, the LMWHs have been used as the anticoagulant of choice for patients presenting with ACS. For patients undergoing PCI, LMWH provides no sub-stantial benefit over UFH for anticoagulation; however, direct thrombin inhibitors (DTIs) have demonstrated safety and efficacy in this setting. UFH is likely to be replaced by more effective and safer antithrombin agents, such as DTIs. DTIs have antiplatelet effects, anticoagulant action, and most do not bind to plasma proteins, thereby providing a more consistent dose-response effect than UFH. The FDA has approved 4 parenteral DTIs for various indications: lepirudin, argatroban, bivalirudin, and desirudin. The antiplatelet, anticoagulant, and pharmacokinetic properties of bivalirudin support its use as the anticoagulant of choice for both lower- and higher-risk patients, including those undergoing PCI.

Topics: Acute Disease; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Models, Molecular; Molecular Structure; Myocardial Ischemia; Peptide Fragments; Pipecolic Acids; Platelet Activation; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombosis

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

The antithrombin binding sequence of heparin, a pentasaccharide, has been synthesized as fondaparinux, an indirect, selective, and reversible factor Xa inhibitor. It can be administered subcutaneously, is well absorbed, and has a half-life of c. 17 hours permitting once-daily injection. It has been evaluated in an extensive study program in major orthopedic surgery, including hip fracture, and in major abdominal surgery with a large proportion of surgery for cancer. The effect is at least as effective as for low-molecular-weight heparins and it has also been shown effective for extended prophylaxis in hip fracture patients. Several thousands of patients have been studied and the substance is safe, although a slightly higher frequency of bleedings is found than in patients on low-molecular-weight heparins. There is no specific antidote but if necessary, recombinant activated factor VII can be used. Other side-effects are rare. Fondaparinux is cost saving and sometimes cost neutral when compared with enoxaparin.

Topics: Abdomen; Anticoagulants; Cost-Benefit Analysis; Drug Costs; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Orthopedic Procedures; Polysaccharides; Surgical Procedures, Operative; Thromboembolism; Treatment Outcome; Venous Thrombosis

The death rate of patients with ST-segment elevation myocardial infarction (STEMI) remains substantial. Fondaparinux is a synthetic selective Factor Xa inhibitor with a high efficacy and good safety, in terms of bleeding risk, in the prevention and treatment of venous thromboembolism, and in the treatment of non-ST elevation acute coronary syndromes (OASIS-5). The OASIS-6 trial was a randomized, double-blind trial comparing fondaparinux 2.5 mg once daily with standard therapy, either placebo or unfractionated heparin according to the indication, in 12092 patients with STEMI. At day 30, fondaparinux significantly reduced the occurrence of the primary efficacy outcome (death or recurrent myocardial infarction) by 14% (p = 0.008). Consistent reductions in both death and recurrent MI were observed at 6-month follow-up. The benefits were significant in patients who received no reperfusion therapy or a thrombolytic agent, but not in patients undergoing primary percutaneous coronary interventions. There was a trend (p = 0.13) towards fewer severe bleeds in the fondaparinux group (1.0% vs 1.3% in the control group). In conclusion, fondaparinux significantly reduced mortality without increasing severe bleeding in patients with STEMI. Overall, the data from the OASIS studies showed that fondaparinux 2.5 mg may represent a new anticoagulant standard in patients with acute coronary syndromes.

Topics: Anticoagulants; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Myocardial Infarction; Polysaccharides; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Research Design; Secondary Prevention; Treatment Outcome

Extending the period of anticoagulation is an active area of investigation in both primary and secondary prevention of venous thromboembolic disease. In orthopaedic surgery, particularly in patients undergoing hip surgery, there is a growing interest in using extended anticoagulation beyond that traditionally given in the postoperative period using low-molecular weight heparin, oral anticoagulants, or newer agents such as fondaparinux sodium. Most studies show a benefit to extending anticoagulation without a considerable increase in major bleeding. There have been several large clinical trials addressing the question of extending oral anticoagulation in secondary prevention of venous thromboembolism (VTE). Just how long anticoagulation should be given in the treatment of venous thromboembolic disease remains an open question, depending on the nature of the initial VTE, associated patient risk factors and the risks of major bleeding. Future directions include the use of newer agents for anticoagulation as well as methods of better defining who will benefit most from extended anticoagulation based on an identification of risk factors with the aid of markers such as D-dimer or residual vein thrombosis.

Topics: Anticoagulants; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Postoperative Care; Secondary Prevention; Venous Thrombosis

Fondaparinux is the first synthetic selective Factor Xa inhibitor. Along with its antithrombotic efficacy, the safety of fondaparinux has been documented in several Phase II and III clinical trials, including the prevention of venous thromboembolism in patients undergoing major orthopaedic surgery or high-risk abdominal surgery, or in acutely ill medical patients with restricted mobility, and the treatment of patients with deep-vein thrombosis and pulmonary embolism. In all these indications, the safety of fondaparinux used according to its registered regimen was similar to that of reference comparators. In conclusion, due to its superior efficacy and satisfactory safety, fondaparinux may substantially improve the prevention and treatment of venous thrombosis.

Topics: Anticoagulants; Clinical Trials as Topic; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Risk Factors; Thromboembolism; Venous Thrombosis

Aging itself is a risk factor for venous thromboembolism, and the prevalence in the elderly of additional risk factors (e.g. cancer, orthopedic surgery, immobility) increase its intrinsic risk. Many in the medical community are reluctant to prescribe anticoagulation (for primary and secondary prevention of venous thromboembolism) to their geriatric patients for the fear that bleeding complications may outweigh the benefits. A thorough analysis of the data support the concept that the under-use of heparin in primary prevention in the elderly is more related to medical beliefs than to facts. The risk of bleeding due to oral anticoagulants (secondary prevention) is greatly reduced by keeping the International Normalized Ratio (INR) values within therapeutic ranges and carefully avoiding conditions/drugs that may interfere with such treatment. The oral direct thrombin inhibitor ximelagatran has been studied for primary (hip and knee replacement surgery) and for secondary prophylaxis of venous thromboembolism, and for acute venous thromboembolism treatment. The selective factor Xa inhibitor fondaparinux has been approved for primary prophylaxis of venous thromboembolism in hip and knee replacement surgery and in hip fracture surgery. Studies on the latter drugs, where most of the patients were > 65 years of age, further show that the fear of bleeding complications due to anticoagulation in the elderly is largely unjustified.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; International Normalized Ratio; Polysaccharides; Risk Factors; Thromboembolism; Time Factors; Venous Thrombosis

Inhibition of activated coagulation factor X (FXa) is an attractive target for antithrombotic treatment strategies, because of the central position of FXa in the coagulation cascade. Most of the now available anticoagulant drugs have inhibitory effects not only on FXa, but also on thrombin. With the development of pentasaccharides, a new class of antithrombotic agents has emerged that acts by specific inhibition of FXa and lacks activity against FIIa. Fondaparinux, the first synthetic short-acting pentasaccharide, has been evaluated, in a large phase II and III clinical programme concerning prophylaxis and treatment of venous thromboembolism and also in phase II studies in patients with acute coronary syndromes. Idraparinux, the long-acting pentasaccharide, has been studied in a dose-finding study in patients with established deep-vein thrombosis and phase III studies are now planned in patients with venous thromboembolism and in patients with atrial fibrillation.

Topics: Acute Disease; Anticoagulants; Blood Coagulation; Coronary Disease; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Thrombosis; Venous Thrombosis

Venous thromboembolism (VTE) prophylaxis is indicated while in the hospital after major surgery. There is evidence that the prevalence of asymptomatic deep-vein thrombosis, detected by routine venography after major orthopedic surgery, is lower at hospital discharge in patients who have received 10 days rather than 5 days of prophylaxis. This observation supports the current American College of Chest Physicians (ACCP) recommendation for a minimum of 7 to 10 days of prophylaxis after hip and knee replacement, even if patients are discharged from the hospital within 7 days of surgery. As risk of VTE persists for up to 3 months after surgery, patients at high risk for postoperative VTE may benefit from extended prophylaxis (eg, an additional 3 weeks after the first 7 to 10 days). Extended prophylaxis with low-molecular-weight heparin (LMWH) reduces the frequency of postdischarge VTE by approximately two thirds after hip replacement; however, the resultant absolute reduction in the frequency of fatal pulmonary embolism is small (ie, estimated at 1 per 2,500 patients). Indirect evidence suggests that, compared with LMWH, efficacy of extended prophylaxis after hip replacement is greater with fondaparinux, similar with warfarin, and less with aspirin. Extended prophylaxis is expected to be of less benefit after knee than after hip replacement. In keeping with current ACCP recommendations, at a minimum, extended prophylaxis should be used after major orthopedic surgery in patients who have additional risk factors for VTE (eg, previous VTE, cancer). If anticoagulant drug therapy is stopped after 7 to 10 days, an additional month of prophylaxis with aspirin should be considered.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Aspirin; Drug Administration Schedule; Fondaparinux; Hemorrhage; Heparin; Humans; Polysaccharides; Postoperative Complications; Prevalence; Radiography; Risk Factors; Time Factors; Venous Thrombosis; Warfarin

Topics: Clinical Trials, Phase III as Topic; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Survival Rate; Therapeutic Equivalency; Thromboembolism; Treatment Outcome; Venous Thrombosis

We aimed to assess the safety and efficacy of fondaparinux (FPNX) for patients undergoing laparoscopic colorectal surgery (LAC).. Patients scheduled for LAC received once-daily subcutaneous injections of FPNX 1.5-2.5 mg for 4-8 days. The primary endpoint was the incidence of bleeding events. The secondary endpoint was the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE).. Among 128 patients evaluable for efficacy, 119 patients were administered FPNX. Nine patients were excluded owing to intraoperative events, including conversion to open surgery among others. Thirteen patients discontinued treatment owing to anastomotic bleeding (n = 5), anastomotic leakage (n = 3), bleeding at drain insertion site (n = 2), subcutaneous bleeding (n = 1), drug-induced rash (n = 1), and sepsis (n = 1). Among the FPNX discontinuations, there were eight cases of bleeding (6.7%), and two cases of major bleeding (1.7%). In multivariate analysis, operative time >300 min was identified as a risk factor for bleeding events (p = 0.001) secondary to FPNX. The incidence rate of DVT was 2.5% (3/119 cases); these patients were asymptomatic.. There were no cases of PE. It is necessary to establish strict criteria for VTE prophylaxis with FPNX after LAC for Japanese patients considering the incidence of bleeding events.

Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Laparoscopy; Male; Middle Aged; Polysaccharides; Postoperative Complications; Prospective Studies; Thromboembolism; Venous Thrombosis

XALIA assessed the safety and effectiveness of rivaroxaban for deep vein thrombosis (DVT) treatment in routine clinical practice. This substudy describes the clinical characteristics and outcomes of 'early switchers' - patients who received heparin or fondaparinux for >2-14days and/or a vitamin K antagonist (VKA) for 1-14days before switching to rivaroxaban.. Patients with DVT (latterly with concomitant pulmonary embolism) received rivaroxaban or standard anticoagulation (initial treatment with heparin or fondaparinux, usually overlapping with and followed by a VKA). Patients administered rivaroxaban alone, or heparin or fondaparinux for ≤48h pre-enrollment were included in the rivaroxaban cohort. Therapy type, dose, and duration were at the physician's discretion. Primary outcomes were major bleeding, recurrent venous thromboembolism (VTE), and all-cause mortality.. In 368 early switchers, recurrence or bleeding risk factors were more prevalent versus the rivaroxaban cohort, including creatinine clearance<50mL/min (6.5% vs. 3.9%), previous major bleeding (4.6% vs. 1.4%), active cancer (8.2% vs. 5.6%), and concomitant pulmonary embolism (20.9% vs. 8.4%). Crude incidence rates were numerically higher versus the rivaroxaban cohort for major bleeding (1.4% vs. 0.7%), recurrent VTE (2.2% vs. 1.4%), and all-cause mortality (0.8% vs. 0.5%).. Patients who switched to rivaroxaban early in the treatment process had a higher frequency of risk factors for bleeding and recurrent VTE than patients treated with rivaroxaban; reflected by the higher risk of adverse events in that group during follow-up.

Topics: Adult; Aged; Anticoagulants; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Polysaccharides; Rivaroxaban; Treatment Outcome; Venous Thrombosis

Superficial-vein thrombosis can lead to deep-vein thrombosis and pulmonary embolism. Rivaroxaban, an oral factor Xa inhibitor, might simplify treatment compared with fondaparinux because it does not require daily subcutaneous injection and is cheaper. We compared efficacy outcomes in patients with superficial-vein thrombosis and additional risk factors given either rivaroxaban or fondaparinux to assess whether rivaroxaban is non-inferior to fondaparinux in the prevention of thromboembolic complications.. In this open-label, masked endpoint, randomised, non-inferiority phase 3b trial, we recruited patients aged 18 years or older with symptomatic superficial-vein thrombosis from 27 sites (academic, community hospitals, and specialist practices) in Germany. We randomly assigned patients (1:1) to receive 10 mg oral rivaroxaban or 2·5 mg subcutaneous fondaparinux once a day for 45 days. Patients were eligible if they had symptomatic thrombosis (at least 5 cm in a supragenual superficial-vein segment) and at least one additional risk factor (older than 65 years, male sex, previous venous thromboembolism, cancer, autoimmune disease, thrombosis of non-varicose veins). Main exclusion criteria were: symptoms for longer than 3 weeks, thrombus within 3 cm of the sapheno-femoral junction, indication for full-dose anticoagulation therapy, and substantial hepatic or renal impairment. Randomisation was done with a central block randomisation process. The primary efficacy outcome was a composite of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality at 45 days in the per-protocol population (all randomly assigned patients without major protocol violations). We used a non-inferiority margin of 4·5% (absolute difference between rivaroxaban and fondaparinux). The main safety outcome was major bleeding. This study is registered with ClinicalTrials.gov, number NCT01499953.. Between April 25, 2012, and Feb 18, 2016, 485 patients were enrolled in the study and 472 were randomly assigned to the rivaroxaban group (n=236) or the fondaparinux group (n=236). In the 435 patients included in the per-protocol analysis set, the primary efficacy outcome occurred in seven (3%) of 211 patients (95% CI 1·6-6·7) in the rivaroxaban group and in four (2%) of 224 patients (0·7-4·5) in the fondaparinux group (hazard ratio [HR] 1·9, 95% CI 0·6-6·4; p=0·0025 for non-inferiority) at day 45. There were no major bleeds in either group. There was one death in the rivaroxaban group; this patient died from cardiogenic shock on day 50 after a type A aortic dissection, not related to treatment.. Rivaroxaban was non-inferior to fondaparinux for treatment of superficial-vein thrombosis in terms of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality, and was not associated with more major bleeding. Therefore, rivaroxaban could offer patients with symptomatic superficial-vein thrombosis a less burdensome and less expensive oral treatment option instead of a more expensive subcutaneous injection.. GWT-TUD and Bayer Vital.

Topics: Aged; Aged, 80 and over; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Polysaccharides; Pulmonary Embolism; Rivaroxaban; Thrombosis; Venous Thrombosis

Fondaparinux is an alternative to low molecular weight heparin (LMWH) for non-ST-elevation myocardial infarction (NSTEMI) with levels of recommendation that differ according to guidelines. The aim of this study was to assess outcomes in real world practice in NSTEMI patients participating in the French Registry of ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) 2010 according to the use of fondaparinux, in comparison with patients receiving enoxaparin.. FAST-MI 2010 is a nationwide French registry that included 4,169 patients with acute myocardial infarction at the end of 2010 in 213 centres (76% of active centres in France); 1,734 had NSTEMI, with 240 receiving fondaparinux and 1,027 enoxaparin. Patients receiving enoxaparin vs. fondaparinux had essentially characteristics with a similar GRACE (Global Registry of Acute Coronary Events) score. Invasive strategy was used in 69% in both groups. In-hospital bleeding was similar with both anticoagulant strategies and 1-year survival was 94.6% and 91.7%, respectively. Using fully adjusted Cox multivariate analysis, the use of fondaparinux was not associated with a reduced risk of death (hazard ratio: 1.35; 95% confidence interval: 0.70-2.51). After propensity score matching (207 patients per group), 1-year survival was similar with both strategies. There was, however, an interaction between fondaparinux and unfractionated heparin, with higher survival in fondaparinux-treated patients who received UFH, compared with those who did not.. In this French cohort of NSTEMI patients, predominantly managed invasively, there was no evidence that fondaparinux was superior to enoxaparin as regards bleeding events or 1-year mortality (FAST-MI 2010; NCT01237418).

Topics: Aged; Anticoagulants; Enoxaparin; Female; Fondaparinux; France; Heart Conduction System; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Polysaccharides; Prospective Studies; Registries; Treatment Outcome

We aimed to determine the optimal adjunctive anticoagulation regimen for percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS) initially treated with fondaparinux. The optimal adjunctive anticoagulation regimen for PCI in these patients is unclear. In this open-label, prospective, randomized, multicenter pilot study, we compared treatment with unfractionated heparin (UFH) versus bivalirudin in patients with non-ST-segment elevation ACS initially treated with fondaparinux and undergoing early invasive strategy. The randomized population consisted of 100 patients (62.7 ± 12.7 years, 68% men), all of whom were on clopidogrel. During the angioplasty, patients were randomized to either bivalirudin or UFH therapy in a 1:1 fashion. Baseline clinical and angiographic characteristics were similar except for a higher body mass index in the UFH group (29.4 ± 4.7 vs. 27.3 ± 4.2, P = 0.02). Major bleeding was the primary outcome; a major bleeding event was documented in only 1 patient from the bivalirudin group (2%) and in none from the UFH group (P = 0.49). There was no death, Q-wave MI, or acute revascularization in either group. There was no documentation of stent thrombosis, reinfarction, and catheter thrombus. Data from this prospective, multicenter pilot study suggest that bivalirudin, compared to standard-dose UFH, has a similar safety profile in terms of peri-PCI bleeding and thrombotic events and can be used safely in ACS patients initially treated with upstream fondaparinux who undergo PCI.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Female; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Percutaneous Coronary Intervention; Pilot Projects; Polysaccharides; Prospective Studies; Recombinant Proteins; Treatment Outcome

We evaluated hemostatic markers in patients who underwent major orthopedic surgery, including total hip and total knee arthroplasty, and were treated for the prophylaxis of deep vein thrombosis (DVT) with or without fondaparinux (anti-Xa group, n = 98 and without anti-Xa group, n = 20). The frequency of DVT was significantly higher in the without anti-Xa group than in the anti-Xa group, but the reduction of hemoglobin and fibrinolytic marker levels was significantly lower in the without anti-Xa group than in the anti-Xa group. Eighteen patients in the anti-Xa group showed a reduction in hemoglobin of more than 2 g/dl, and those individuals were considered to be the increased bleeding (IB) group. The concentration of fibrinolytic markers in the anti-Xa group was significantly higher in the IB group than in the non-IB group. There were also no significant differences in the levels of anti-Xa activity, plasminogen activator inhibitor-I, soluble fibrin and antithrombin between the IB and non-IB groups. In conclusion, elevated fibrinolysis induced by increased bleeding may lead to further increases in bleeding in patients receiving thromboprophylaxis with fondaparinux following major orthopedic surgery.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Biomarkers; Factor Xa Inhibitors; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Polysaccharides; Postoperative Complications; Venous Thrombosis

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.

Topics: Aged; Aged, 80 and over; Anticoagulants; Combined Modality Therapy; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Polysaccharides; Prospective Studies; Recurrence; Survival Rate; Treatment Outcome; Vena Cava Filters; Venous Thromboembolism

Fondaparinux (FPX), a selective inhibitor of factor Xa, is widely used for the prophylaxis of venous thromboembolism (VTE) after total joint arthroplasty. However, the association between plasma FPX concentration and adverse events and the occurrence of VTE has not been clarified thus far. We aimed to prospectively evaluate these associations by measuring anti-Xa activity of FPX in patients undergoing total hip arthroplasty (THA) and investigate whether factors such as age, body weight, and renal function influence the anti-Xa levels. We enrolled 85 patients who underwent primary THA. All patients received subcutaneous FPX (2.5 mg/day for 14 days) after surgery. Anti-Xa activity was measured on postoperative days 1, 3, 7, and 14. To assess VTE, multidetector row computed tomography was performed in all patients at 1 week after surgery. The median levels of anti-Xa activity increased as follows (medians with 95 % confidence interval): 0.00 (0.00-0.01) mg/L, 0.13 (0.11-0.14) mg/L, 0.19 (0.17-0.20) mg/L, and 0.24 (0.22-0.25) mg/L on postoperative days 1, 3, 7, and 14, respectively. The plasma accumulation of FPX was more likely in patients with renal impairment than in those with normal renal function. In contrast, a poor correlation was observed between the plasma levels of anti-Xa activity and age or body weight. No differences were observed in the anti-Xa activity in patients with and without postoperative VTE or bleeding. Substantial increase in the levels of anti-Xa activity was observed, especially in patients with renal impairment, after subcutaneous administration of FPX 2.5 mg after THA.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Body Weight; Factor Xa; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Polysaccharides; Prospective Studies; Time Factors; Venous Thromboembolism

Renal impairment is common, affecting around 40% of acutely ill medical patients, and is associated with an increased risk of both venous thromboembolism (VTE) and bleeding. The clinical benefit of effective thromboprophylactic strategies may be outweighed in these patients by an excessive rate of hemorrhage.. To assess the safety and efficacy of lower prophylactic doses of fondaparinux in acutely ill medical patients with renal impairment.. We carried out a multicenter, investigator-initiated, prospective cohort study. Patients at risk of VTE with a creatinine clearance between 20 and 50 mL min(-1) were treated with fondaparinux 1.5 mg qd for a minimum of 6 to a maximum of 15 days. The primary outcome was the incidence of major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB) and symptomatic VTE.. We enrolled 206 patients with a mean age of 82 years, mean creatinine clearance of 33 mL min(-1) , and a mean Charlson co-morbidity index of 8.2. One patient had major bleeding (0.49%, 95% confidence interval [CI] 0.03-3.10), eight had CRNMB (3.88%, 95% CI 1.81-7.78) and three developed symptomatic VTE (1.46%, 0.38-4.55). Twenty-three patients (11.17%, 7.36-16.48) died. No independent predictors of bleeding were found at univariate analysis.. The addition of moderate to severe renal impairment to patients with traditional risk factors for VTE identified a population of very elderly acutely ill medical patients potentially at high risk of both VTE and bleeding complications. The recently approved lower prophylactic dose of fondaparinux appears to be a safe and relatively effective strategy in these patients.

Topics: Aged; Aged, 80 and over; Anticoagulants; Creatinine; Female; Fondaparinux; Hemorrhage; Humans; Incidence; Male; Middle Aged; Polysaccharides; Prospective Studies; Pulmonary Embolism; Renal Insufficiency; Risk Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

Unfractionated heparin (UFH) is the standard drug for the initial treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT) in Japan, whereas fondaparinux is the standard drug in Europe and the United States. Here, we examine the efficacy and safety of fondaparinux in Japanese patients.. In 2 randomized, open-label, multicenter studies, 80 Japanese patients with acute PE or DVT received either subcutaneous fondaparinux or intravenous UFH as a non-comparative reference, in a 3:1 ratio, for 5-10 days. Concomitant warfarin therapy was continued until Day 90. Multidetector-row computed tomography-based assessment showed that 57.9% and 45.9% of the patients with acute PE and acute proximal DVT had proximal DVT and PE as a complication, respectively. There was no recurrence of symptomatic venous thromboembolism. In the fondaparinux group, the respective improvement rates at the end of the initial treatment and follow-up periods were 71.4% and 86.8% for 42 patients with PE, and 57.8% and 83.3% for 46 patients with DVT; similar results were noted in the UFH group. One patient in the fondaparinux group experienced major bleeding during the initial treatment, but no such episode in the UFH group.. Once-daily, subcutaneous fondaparinux is as effective and safe without monitoring as adjusted-dose intravenous UFH for the initial treatment of acute PE and DVT in Japanese patients.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Anticoagulants; Asian People; Contrast Media; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Infusions, Intravenous; Injections, Subcutaneous; Japan; Male; Middle Aged; Polysaccharides; Predictive Value of Tests; Pulmonary Embolism; Recurrence; Risk Assessment; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Venous Thrombosis; Warfarin; Young Adult

In patients with acute coronary syndromes (ACS), the negative impact of baseline haemoglobin levels on ischaemic events, particularly death, is well established, but the association with bleeding risk is less well studied. The aim of this study was to assess the impact of baseline haemoglobin levels on major bleeding complications.. Pooled analysis of OASIS 5 and 6 data involving 32 170 patients with ACS with and without ST-segment elevation was performed. The association between baseline haemoglobin and major bleeding or ischaemic events was examined using multiple regression model.. were 30-day rates of major bleeding, death, and death/myocardial infarction (MI) analysed according to baseline haemoglobin levels. Baseline haemoglobin level independently predicted the risk of overall, procedure-related, and non-procedure-related major bleedings at 30 days [odds ratio (OR) 0.94, 95% CI 0.90-0.98; OR 0.94, 95% CI 0.90-0.99; and OR 0.89, 95% CI 0.83-0.95, respectively, per 1 g/dL haemoglobin increment above 10 g/dL]. In addition, a curvilinear relationship between baseline haemoglobin levels and death at 30 days was observed with a 6% decrease in the risk for every 1 g/dL haemoglobin increment above 10 g/dL up to 15.9 g/dL (OR 0.94, 95% CI 0.90-0.98) and a 19% increase above this value (OR 1.19, 95% CI, 0.98-1.43). A similar relationship for the composite outcome of death/MI was observed.. A low baseline haemoglobin level is an independent predictor of the risk of major bleeding in ACS as well as of the risk of death and death and MI. Among other predictors of bleeding risk, baseline haemoglobin should be taken into account in patients presenting with ACS.. ClinicalTrials.gov number, NCT00139815. http://clinicaltrials.gov/ct2/show/NCT00139815?term=NCT00139815&rank=1.

Topics: Acute Coronary Syndrome; Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Anticoagulants; Double-Blind Method; Enoxaparin; Female; Fondaparinux; Hemoglobins; Hemorrhage; Heparin; Humans; Male; Middle Aged; Polysaccharides; Treatment Outcome

In the OASIS-5 trial, fondaparinux reduced major bleeding with similar short-term efficacy as enoxaparin but lowered death and stroke during long-term follow-up. The mechanism of lower bleeding and improved efficacy with fondaparinux is uncertain.. We compared the anti-Xa concentration (reflecting drug levels), Xa clot time (reflecting anticoagulant effect) and endogenous thrombin potential (ETP; a global test of hemostatic function) in plasma samples collected 6, 24 and 72 h after the first dose of the study drug in 48 patients randomly assigned fondaparinux 2.5 mg day(-1) and 42 patients assigned enoxaparin 1 mg kg(-1) twice daily in the OASIS-5 trial. Patients assigned to fondaparinux compared with enoxaparin had a significantly lower mean anti-Xa level [0.52 IU mL(-1) (SD 0.22 IU mL(-1)) vs. 1.2 IU mL(-1) (SD 0.45 IU mL(-1)), P<0.0001] and Xa clot time [64.9 s (SD 17.7 s) vs. 111.8 s (SD 29.6 s), P<0.0001], and significantly higher ETP area under the curve (AUC) [386.7 mA (SD 51.5 mA) vs. 206.4 mA (SD 90.6 mA), P<0.001] at 6 h, and these differences remained evident at 24 and 72 h. There was significantly less variability of the results of anti-Xa levels, Xa clot time and ETP AUC for fondaparinux compared with enoxaparin at 6 h (P<0.001 for each comparison).. Fondaparinux 2.5 mg day(-1) compared with enoxaparin 1 mg kg(-1) twice daily produces less variable anticoagulant effect and lower mean anticoagulant intensity. These results most likely explain the reduced risk of bleeding seen with fondaparinux compared with enoxaparin in the OASIS-5 trial and suggest that a lower intensity of anticoagulation than used in the past may be sufficient to prevent recurrent ischemic events and death in patients with ACS who are concurrently treated with aspirin and clopidogrel.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Blood Coagulation; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Enoxaparin; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; Injections, Subcutaneous; Middle Aged; Partial Thromboplastin Time; Platelet Aggregation Inhibitors; Polysaccharides; Risk Assessment; Risk Factors; Secondary Prevention; Thrombin; Time Factors; Treatment Outcome

The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain.. To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux.. Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010.. Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT).. Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30.. The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15).. Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications.. clinicaltrials.gov Identifier: NCT00790907.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Catheters, Indwelling; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Polysaccharides

The efficacy and safety of anticoagulant treatment for patients with acute, symptomatic superficial-vein thrombosis in the legs, but without concomitant deep-vein thrombosis or symptomatic pulmonary embolism at presentation, have not been established.. In a randomized, double-blind trial, we assigned 3002 patients to receive either fondaparinux, administered subcutaneously at a dose of 2.5 mg once daily, or placebo for 45 days. The primary efficacy outcome was a composite of death from any cause or symptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superficial-vein thrombosis at day 47. The main safety outcome was major bleeding. The patients were followed until day 77.. The primary efficacy outcome occurred in 13 of 1502 patients (0.9%) in the fondaparinux group and 88 of 1500 patients (5.9%) in the placebo group (relative risk reduction with fondaparinux, 85%; 95% confidence interval [CI], 74 to 92; P<0.001). The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group, except for the outcome of death (0.1% in both groups). The rate of pulmonary embolism or deep-vein thrombosis was 85% lower in the fondaparinux group than in the placebo group (0.2% vs. 1.3%; 95% CI, 50 to 95; P<0.001). Similar risk reductions were observed at day 77. A total of 88 patients would need to be treated to prevent one instance of pulmonary embolism or deep-vein thrombosis. Major bleeding occurred in one patient in each group. The incidence of serious adverse events was 0.7% with fondaparinux and 1.1% with placebo.. Fondaparinux at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with acute, symptomatic superficial-vein thrombosis of the legs and did not have serious side effects. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00443053.)

Topics: Acute Disease; Anticoagulants; Double-Blind Method; Female; Fondaparinux; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Polysaccharides; Pulmonary Embolism; Recurrence; Risk; Treatment Outcome; Venous Thrombosis

Bleeding in patients with coronary artery disease has been linked with adverse outcomes. We examined the incidence and outcomes after bleeding in 20 078 patients with acute coronary syndromes (ACS) enrolled in the OASIS-5 trial who were treated with fondaparinux or the low-molecular weight heparin, enoxaparin.. Nine hundred and ninety (4.9%) patients developed major bleeding and 423 (2.1%) developed minor bleeding. Fondaparinux compared with enoxaparin reduced fatal bleeding [0.07 vs. 0.22%, relative risk (RR) 0.30, 95% CI: 0.13-0.71], non-fatal major bleeding (2.2 vs. 4.2%, RR 0.52, 95% CI: 0.44-0.61), minor bleeding (1.1 vs. 3.2%, RR 0.34, 95% CI: 0.27-0.42), and need for transfusion (1.8 vs. 3.1%, RR 0.56, 95% CI: 0.47-0.61) during the first 9 days. One of every six deaths during the first 30 days occurred in patients who experienced bleeding. Cox proportional hazards model revealed that major bleeding was associated with about a four-fold increased hazard of death, myocardial infarction, or stroke during the first 30 days and about a three-fold increased hazard during 180 days of follow up.. Bleeding in patients with ACS is a powerful determinant of fatal and non-fatal outcomes. Reducing the risk of bleeding using a safer anticoagulant strategy during the first 9 days is associated with substantial reductions in morbidity and mortality.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Enoxaparin; Female; Fondaparinux; Hemorrhage; Humans; Male; Myocardial Infarction; Myocardial Revascularization; Polysaccharides; Risk Factors; Stroke; Treatment Outcome

No data are available on the efficacy and safety of a combination of fondaparinux and thrombolysis in the setting of high to intermediate risk pulmonary embolism (PE). Patients submitted to thrombolysis and fondaparinux, presenting with > or =1 of the following criteria were included: (1) cardiogenic shock, (2) syncope, (3) > or =1 proximal thrombo-embolus at CT scan, (4) positive troponin test, (5) echocardiographic findings indicating right ventricular (RV) dysfunction. In-hospital results included death, recurrent PE, persistent RV dysfunction at 48 h echocardiography, bleeding complications. Twenty seven patients were included; 22 received a 2 h infusion of rt-PA and 5 received a 2 h infusion of streptokinase. Ten patients presented with cardiogenic shock (37%), 8 with syncope (30%), all had RV dysfunction. 82% of patients had an uneventful in-hospital course. One patient died during hospital stay from refractory shock. Thrombolysis failed in 2 patients (7%), requiring successful rescue surgical embolectomy. Bleeding events occurred in 2 patients (7%), of whom 1 required blood transfusion. Despite the small sample size, our data suggest that fondaparinux procures adequate tolerability compared to standard current therapy in combination with thrombolysis in high to intermediate risk PE.

Topics: Aged; Chemotherapy, Adjuvant; Combined Modality Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Phenindione; Polysaccharides; Pulmonary Embolism; Risk; Streptokinase; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome

The OASIS-5 (Organization to Assess Strategies in Ischemic Syndromes-5) trial demonstrated that fondaparinux was noninferior to enoxaparin while reducing the risk of bleeding by 50%. The objectives of our study were to assess the effects of fondaparinux compared to enoxaparin in patients stratified by their Global Registry of Acute Coronary Events (GRACE) score and to examine the ability of the GRACE score to predict bleeding in patients with acute coronary syndromes (ACS).. We analyzed efficacy and safety according to the GRACE admission risk score.. The impact of fondaparinux versus enoxaparin on the primary outcome of death, myocardial infarction, and refractory ischemia at 180 days was similar in the low-, intermediate-, and high-risk groups: 7.0% versus 7.7% (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.75-1.08), 10.2% versus 11.3% (HR 0.89, 95% CI 0.77-1.03), and 20.1% versus 21.1% (HR 0.95, 95% CI 0.85-1.06). Major bleeding rates were higher with increasing GRACE risk scores: 2.2%, 3.2%, and 4.1% in the low, intermediate, and high-risk groups. Six-month mortality was 2.2%, 4.2%, and 12.3% in the 3 groups. The risk of major bleeding was substantially lower with fondaparinux in all groups: 1.6% versus 2.9% (HR 0.55, 95% CI 0.39-0.77), 2.2% versus 4.1% (HR 0.53, 95% CI 0.40-0.70), 2.8% versus 5.5% (HR 0.50, 95% CI 0.38-0.64).. The GRACE score predicted both bleeding and mortality in patients with ACS. The efficacy and safety of fondaparinux were consistent in all risk groups supporting its use in a broad range of ACS patients.

Topics: Acute Coronary Syndrome; Anticoagulants; Enoxaparin; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Prognosis; Risk Assessment; Treatment Outcome

The Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) trials evaluated fondaparinux, a synthetic factor Xa inhibitor, in patients with non-ST- and ST-segment elevation acute coronary syndromes, respectively. Combined results for these 2 trials on major efficacy and safety outcomes and data on the effects of fondaparinux in relation to interventional management strategy have not been previously reported.. We performed an individual patient-level combined analysis of 26 512 patients from the OASIS 5 and 6 trials who were randomized in a double-blind fashion to fondaparinux 2.5 mg daily or a heparin-based strategy (dose-adjusted unfractionated heparin or enoxaparin). Results were stratified according to whether an early invasive, a delayed invasive, or an initial conservative management strategy was performed. Fondaparinux was superior to heparin in reducing the composite of death, myocardial infarction, or stroke (8.0% versus 7.2%; hazard ratio [HR], 0.91; P=0.03) and death alone (4.3% versus 3.8%; HR, 0.89; P=0.05). Fondaparinux reduced major bleeding by 41% (3.4% versus 2.1%; HR, 0.59; P<0.00001) and had a more favorable net clinical outcome than heparin (11.1% versus 9.3%; HR, 0.83; P<0.0001). In 19 085 patients treated with an invasive strategy, fondaparinux suppressed ischemic events to an extent similar to heparin and reduced major bleeding by more than one-half, resulting in a superior net clinical outcome (10.8% versus 9.4%; HR, 0.87; P=0.008). A similar benefit also was observed in those treated with a conservative strategy (HR, 0.74; 95% confidence interval, 0.64 to 0.85; P<0.001).. Compared with a heparin-based strategy, fondaparinux reduced mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and was associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Enoxaparin; Female; Fondaparinux; Hemorrhage; Heparin; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Polysaccharides; Stroke; Treatment Outcome

At least one quarter of ST-segment elevation myocardial infarction (STEMI) patients do not receive reperfusion therapy, and these patients are at high risk for new ischaemic events. We evaluated fondaparinux treatment vs. usual care, i.e. placebo or unfractionated (UF) heparin, in a pre-specified subgroup of 2867 (out of 12 092) patients not receiving reperfusion treatment in the OASIS-6 trial.. In all, 1458 patients were randomized to fondaparinux 2.5 mg once daily subcutaneously up to 8 days and 1409 patients to usual care (control). Randomization was stratified by indication for UF heparin (stratum II, n = 1226) or not (stratum I, n = 1641) based on the investigator's judgment.. The proportion of patients who suffered death or myocardial re-infarction at 30 days (primary outcome) was 12.2% in the fondaparinux vs. 15.1% in the control group, hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.65-0.98. There was no increase in severe bleedings, HR 0.82; CI 0.44-1.55, or strokes, HR 0.62; CI 0.29-1.33. Consequently, the composite of death, myocardial re-infarction, or severe bleeding were significantly reduced at 30 days, HR 0.81; CI 0.67-0.99. Reductions in death or myocardial re-infarction at 30 days were consistent in stratum I with fondaparinux vs. placebo, HR 0.88; 95% CI 0.65-1.19, and in stratum II with fondaparinux vs. UF heparin infusion for 24-48 h (n = 806), HR 0.74; CI 95% 0.57-0.97, P = 0.41 for heterogeneity.. In STEMI patients not receiving reperfusion treatment, fondaparinux reduces the composite of death or myocardial re-infarction without an increase in severe bleedings or strokes as compared to placebo or UF heparin.

Topics: Aged; Anticoagulants; Double-Blind Method; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Myocardial Infarction; Polysaccharides; Secondary Prevention; Survival Analysis; Time Factors

Heparin-induced thrombocytopenia (HIT) is a life-threatening immune response to heparin that is associated with a high risk of thromboembolic complications. We prospectively treated seven subjects with acute HIT with fondaparinux and compared the results to a similar historical control population from the same hospital. Six of the seven fondaparinux-treated subjects were transitioned to warfarin, beginning after platelet count recovery occurred. Ten historical controls were treated with a direct thrombin inhibitor (DTI), eight of which were transitioned to warfarin. The primary study outcome was platelet count recovery which was defined as an increase from baseline by at least 30% of nadir to greater than 100,000/mm(3) by day seven. Seven subjects were prospectively treated with fondaparinux for a median of eight days. Six of the seven had HIT with thrombosis at the time of enrollment. All fondaparinux treated subjects had a complete platelet count recovery, and none experienced a new thromboembolic complication, major bleeding or death by week four. One subject underwent limb amputation. Ten historical controls were treated with a DTI for a median duration of eleven days. Platelet count recovery occurred in eight of the ten historical controls. No new thromboembolic complications or major bleeds occurred but limb gangrene occurred in four controls. The development of limb gangrene in the historical controls may have been a result of delayed recognition of HIT and/or inappropriately early institution of warfarin in the historical controls. This pilot study suggests that fondaparinux may be useful in patients with acute HIT.

Topics: Acute Disease; Aged; Anticoagulants; Blood Coagulation; Case-Control Studies; Factor Xa Inhibitors; Feasibility Studies; Female; Fondaparinux; Hemorrhage; Heparin; Humans; International Normalized Ratio; Male; Pilot Projects; Platelet Count; Polysaccharides; Prospective Studies; Thrombocytopenia; Time Factors; Treatment Outcome; Venous Thrombosis; Warfarin

No antithrombotic therapy has been shown to reduce mortality when used with thrombolytics in acute myocardial infarction (AMI). In the OASIS-6 trial, fondaparinux significantly reduced mortality and reinfarction without increasing bleeding in 12 092 patients with acute ST elevation MI.. We report the results of a subgroup analysis in the 5436 patients (45%) receiving thrombolytics. According to local practice, 4415 patients did not have an indication for unfractionated heparin (stratum 1) and 1021 did (stratum 2). Fondaparinux reduced the primary study outcome of death or MI at 30 days [Hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.68-0.92] with consistent reductions in both mortality (HR and CI) and reinfarction (HR and CI). There was a non-significantly lower rate of stroke (HR 0.77, CI 0.48-1.25). The risk of severe bleeding was significantly reduced (HR 0.62, CI 0.40-0.94), and thus the balance of benefit and risk (death, MI and severe haemorrhage) was clearly reduced by fondaparinux (HR 0.77, 95% CI 0.67-0.90). Results were consistent in the two strata, by the different types of thrombolytics and across various time intervals from symptom onset to treatment.. In STEMI patients treated with thrombolytic agents (predominantly streptokinase), fondaparinux significantly reduced the risk of death, re-MI and severe bleeds.

Topics: Anticoagulants; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Polysaccharides; Randomized Controlled Trials as Topic; Risk Factors; Secondary Prevention; Survival Analysis; Time Factors; Treatment Outcome

Selecting initial anticoagulant dose by patient weight for acute pulmonary embolism and deep vein thrombosis has clinical credibility; however, uncertainty remains regarding how to dose obese patients with newer anticoagulants because outcome data are sparse.. To use the Matisse trials' comparison of sc fondaparinux once daily with control heparin therapies (intravenous unfractionated heparin for pulmonary embolism, sc enoxaparin 1 mg/kg b.i.d. for deep vein thrombosis) for initial treatment in order to compare primary outcomes (venous thromboembolism recurrence and major bleeding) in obese patients.. Primary outcomes were compared in subsets composed of patients weighing < or = and > 100 kg and with body mass index (BMI) < 30 and > or = 30 kg/m(2). Medians and ranges for weight and BMI were compared for patients suffering either recurrence or major bleeding.. Twenty-two thousand and one patients received fondaparinux and 2217 received enoxaparin or unfractionated heparin. Four hundred and ninety-six patients (11%) weighed > 100 kg and 1216 (28%) had a BMI > or = 30. Treatment groups had similar characteristics. The upper limit in subject weight for recurrence was 166 kg (BMI 58), and for major bleeding 120 kg (BMI 39). The incidences of recurrence and major bleeding were similar for each patient subset of weight and BMI for both fondaparinux and heparin treatment groups. Among patients with a primary outcome, median weights and BMIs were also similar.. The current recommended doses of fondaparinux and heparins for the treatment of venous thromboembolism appear to provide similar protection against recurrence and major bleeding to one another and to obese and non-obese patients.

Topics: Adult; Aged; Anticoagulants; Enoxaparin; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Obesity; Polysaccharides; Recurrence; Thromboembolism; Treatment Outcome; Venous Thrombosis

A recent randomized, controlled trial, the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS 5) trial, reported that major bleeding was 2-fold less frequent with fondaparinux than with enoxaparin in acute coronary syndromes (ACS). Renal dysfunction increases the risk for major bleeding.. To compare the efficacy and safety of fondaparinux and enoxaparin over the spectrum of renal dysfunction observed in the OASIS 5 trial.. Subgroup analysis of a randomized, controlled trial.. Patients presenting to the hospital with non-ST-segment elevation ACS.. 19,979 of the 20,078 patients in the OASIS 5 trial in whom creatinine was measured at baseline.. Death, myocardial infarction, refractory ischemia, and major bleeding were evaluated separately and as a composite end point at 9, 30, and 180 days. Glomerular filtration rate (GFR) was calculated by using the Modification of Diet in Renal Disease formula.. The absolute differences in favor of fondaparinux (efficacy and safety) were most marked in patients with a GFR less than 58 mL/min per 1.73 m2; the largest differences occurred in major bleeding events. At 9 days, death, myocardial infarction, or refractory ischemia occurred in 6.7% of patients receiving fondaparinux and 7.4% of those receiving enoxaparin (hazard ratio, 0.90 [95% CI, 0.73 to 1.11]); major bleeding occurred in 2.8% and 6.4%, respectively (hazard ratio, 0.42 [CI, 0.32 to 0.56]). Statistically significant differences in major bleeding persisted at 30 and 180 days. The rates of the composite end point were lower with fondaparinux than with enoxaparin in all quartiles of GFR, but the differences were statistically significant only among patients with a GFR less than 58 mL/min per 1.73 m2.. Subgroup analyses warrant caution; the study was powered to detect noninferiority at 9 days. Fondaparinux is not approved for use in patients with ACS in the United States.. The benefits of fondaparinux over enoxaparin when administered for non-ST-segment elevation ACS are most marked among patients with renal dysfunction and are largely explained by lower rates of major bleeding with fondaparinux.

Topics: Aged; Aged, 80 and over; Angina Pectoris; Anticoagulants; Coronary Disease; Death, Sudden, Cardiac; Double-Blind Method; Enoxaparin; Female; Fondaparinux; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Male; Middle Aged; Myocardial Infarction; Polysaccharides; Syndrome

Topics: Adult; Anticoagulants; Drug Administration Schedule; Feasibility Studies; Female; Fondaparinux; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Pilot Projects; Polysaccharides; Prospective Studies; Secondary Prevention; Treatment Outcome; Venous Thromboembolism

To determine the efficacy and safety of the anticoagulant fondaparinux in older acute medical inpatients at moderate to high risk of venous thromboembolism.. Double blind randomised placebo controlled trial.. 35 centres in eight countries.. 849 medical patients aged 60 or more admitted to hospital for congestive heart failure, acute respiratory illness in the presence of chronic lung disease, or acute infectious or inflammatory disease and expected to remain in bed for at least four days.. 2.5 mg fondaparinux or placebo subcutaneously once daily for six to 14 days.. The primary efficacy outcome was venous thromboembolism detected by routine bilateral venography along with symptomatic venous thromboembolism up to day 15. Secondary outcomes were bleeding and death. Patients were followed up at one month.. 425 patients in the fondaparinux group and 414 patients in the placebo group were evaluable for safety analysis (10 were not treated). 644 patients (75.9%) were available for the primary efficacy analysis. Venous thrombembolism was detected in 5.6% (18/321) of patients treated with fondaparinux and 10.5% (34/323) of patients given placebo, a relative risk reduction of 46.7% (95% confidence interval 7.7% to 69.3%). Symptomatic venous thromboembolism occurred in five patients in the placebo group and none in the fondaparinux group (P = 0.029). Major bleeding occurred in one patient (0.2%) in each group. At the end of follow-up, 14 patients in the fondaparinux group (3.3%) and 25 in the placebo group (6.0%) had died.. Fondaparinux is effective in the prevention of asymptomatic and symptomatic venous thromboembolic events in older acute medical patients. The frequency of major bleeding was similar for both fondaparinux and placebo treated patients.

Topics: Acute Disease; Aged; Anticoagulants; Bed Rest; Chronic Disease; Disease-Free Survival; Double-Blind Method; Female; Follow-Up Studies; Fondaparinux; Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Polysaccharides; Thromboembolism; Treatment Outcome; Venous Thrombosis

The combined use of anticoagulants, antiplatelet agents, and invasive coronary procedures reduces ischemic coronary events but also increases bleeding in patients with acute coronary syndromes. We therefore assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding.. We randomly assigned 20,078 patients with acute coronary syndromes to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg per kilogram of body weight twice daily) for a mean of six days and evaluated death, myocardial infarction, or refractory ischemia at nine days (the primary outcome); major bleeding; and their combination. Patients were followed for up to six months.. The number of patients with primary-outcome events was similar in the two groups (579 with fondaparinux [5.8 percent] vs. 573 with enoxaparin [5.7 percent]; hazard ratio in the fondaparinux group, 1.01; 95 percent confidence interval, 0.90 to 1.13), satisfying the noninferiority criteria. The number of events meeting this combined outcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 days (805 vs. 864, P=0.13) and at the end of the study (1222 vs. 1308, P=0.06). The rate of major bleeding at nine days was markedly lower with fondaparinux than with enoxaparin (217 events [2.2 percent] vs. 412 events [4.1 percent]; hazard ratio, 0.52; P<0.001). The composite of the primary outcome and major bleeding at nine days favored fondaparinux (737 events [7.3 percent] vs. 905 events [9.0 percent]; hazard ratio, 0.81; P<0.001). Fondaparinux was associated with a significantly reduced number of deaths at 30 days (295 vs. 352, P=0.02) and at 180 days (574 vs. 638, P=0.05).. Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long term mortality and morbidity. (ClinicalTrials.gov number, NCT00139815.).

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Enoxaparin; Female; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Polysaccharides; Recurrence; Stroke; Survival Analysis; Treatment Outcome

Despite many therapeutic advances, mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) remains high. The role of additional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy.. To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care (placebo in those in whom unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI.. Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12,092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment.. Composite of death or reinfarction at 30 days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months).. Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73-0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced throughout the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P = .08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P = .008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days.. In patients with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes.. ClinicalTrials.gov Identifier NCT00064428.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Double-Blind Method; Factor X; Female; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Polysaccharides; Recurrence; Risk Assessment; Survival Analysis

Factor Xa plays a central role in the generation of thrombin, making it a novel target for treatment of arterial thrombosis. Fondaparinux is a synthetic factor Xa inhibitor that has been shown to be superior to standard therapies for the prevention of venous thrombosis. We performed a randomized trial to determine the safety and feasibility of fondaparinux in the percutaneous coronary intervention (PCI) setting.. A total of 350 patients undergoing elective or urgent PCI were randomized in a blinded manner to receive unfractionated heparin (UFH), 2.5 mg fondaparinux IV, or 5.0 mg fondaparinux IV. Randomization was stratified for planned or no planned use of glycoprotein (GP) IIb/IIIa antagonists. The primary safety outcome was total bleeding, which was a combination of major and minor bleeding events. The incidence of total bleeding was 7.7% in the UFH group and 6.4% in the combined fondaparinux groups (hazard ratio, 0.81; 95% confidence interval, 0.35 to 1.84; P=0.61). Bleeding was less common in the 2.5-mg fondaparinux group compared with the 5-mg fondaparinux group (3.4% versus 9.6%, P=0.06). The composite efficacy outcome of all-cause mortality, myocardial infarction, urgent revascularization, or need for a bailout GPIIb/IIIa antagonist was 6.0% in the UFH group and 6.0% in the fondaparinux group, with no significant difference in efficacy among the fondaparinux doses compared with UFH. Coagulation marker analysis at 6 and 12 hours after PCI demonstrated that fondaparinux was superior to UFH in inducing a sustained reduction in markers of thrombin generation, as measured by prothrombin fragment F1.2 (P=0.02).. In this pilot study of patients undergoing contemporary PCI, factor Xa inhibition with the synthetic anticoagulant fondaparinux in doses of 2.5 and 5.0 mg was comparable to UFH for clinical safety and efficacy outcomes. These data form the basis for further evaluation of fondaparinux in arterial thrombosis.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Emergencies; Factor Xa Inhibitors; Feasibility Studies; Female; Fondaparinux; Hemorrhage; Heparin; Hospital Mortality; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Pilot Projects; Polysaccharides; Single-Blind Method; Stents; Treatment Outcome

The current standard initial therapies for deep venous thrombosis are low-molecular-weight heparin and unfractionated heparin. In a dose-ranging study of patients with symptomatic deep venous thrombosis, fondaparinux had efficacy and a safety profile similar to those of low-molecular-weight heparin (dalteparin).. To evaluate whether fondaparinux has efficacy and safety similar to those of enoxaparin in patients with deep venous thrombosis.. Randomized, double-blind study.. 154 centers worldwide.. 2205 patients with acute symptomatic deep venous thrombosis.. Fondaparinux, 7.5 mg (5.0 mg in patients weighing <50 kg and 10.0 mg in patients weighing >100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body weight, subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0.. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolic complications. The main safety outcomes were major bleeding during initial treatment and death. An independent, blinded committee adjudicated all outcomes.. 43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, -0.15 percentage point [95% CI, -1.8 to 1.5 percentage points]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively.. Follow-up was incomplete in 0.4% of fondaparinux-treated patients and 1.0% of enoxaparin-treated patients.. Once-daily subcutaneous fondaparinux was at least as effective (not inferior) and safe as twice-daily, body weight-adjusted enoxaparin in the initial treatment of patients with symptomatic deep venous thrombosis.

Topics: Aged; Body Weight; Cause of Death; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Kidney; Male; Middle Aged; Polysaccharides; Recurrence; Treatment Outcome; Venous Thrombosis; Vitamin K

In this dose-finding study, we sought to compare fondaparinux with enoxaparin in patients with acute coronary syndromes (ACS).. Fondaparinux is a synthetic pentasaccharide that selectively inhibits activated clotting factor X. It has been demonstrated as effective in preventing thromboembolic complications in orthopedic surgery.. Four doses fondaparinux (2.5, 4, 8, or 12 mg once daily) and enoxaparin (1 mg/kg twice daily) were compared, both given for three to seven days, in patients with ACS without persistent ST-segment elevation.. The rates of the combined primary end point of death, myocardial infarction, or recurrent ischemia after nine days were 27.9%, 35.9%, 34.7%, 30.3%, and 35.7% in patients allocated to fondaparinux doses of 2.5, 4, 8, and 12 mg and enoxaparin, respectively (p = NS). In the per-protocol analysis (929 patients who received adequate study drug and had adequate ST-segment monitoring), these figures were 30.0%, 43.5%, 41.0%, 34.8%, and 40.2%. Again, no dose response was observed. The lowest event rates were observed in the 2.5-mg fondaparinux group, which had significantly lower rates than the enoxaparin group as well as for 4 and 8 mg fondaparinux in the per-protocol analysis (p < 0.05). Bleeding rates were low and not different among the patient groups. No differences were observed in fondaparinux concentrations in patients with or without death, myocardial infarction, recurrent ischemia, or bleeding events.. This dose-finding study revealed no dose response for different fondaparinux doses ranging from 2.5 to 12 mg subcutaneously and suggests that the efficacy and safety of fondaparinux may be similar to that of enoxaparin. Further studies with fondaparinux in ACS might include the lowest dose (2.5 mg) investigated in this study.

Topics: Acute Disease; Adrenergic beta-Antagonists; Adult; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Coronary Artery Bypass; Coronary Disease; Creatine Kinase; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Enoxaparin; Female; Fibrinolytic Agents; Follow-Up Studies; Fondaparinux; Hemorrhage; Humans; Hypolipidemic Agents; Isoenzymes; Male; Middle Aged; Polysaccharides; Survival Analysis; Syndrome; Treatment Outcome; Troponin T

The standard initial treatment of hemodynamically stable patients with pulmonary embolism is intravenous unfractionated heparin, requiring laboratory monitoring and hospitalization.. We conducted a randomized, open-label trial involving 2213 patients with acute symptomatic pulmonary embolism to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux with those of unfractionated heparin and to document noninferiority in terms of efficacy. Patients received either fondaparinux (5.0, 7.5, or 10.0 mg in patients weighing less than 50, 50 to 100, or more than 100 kg, respectively) subcutaneously once daily or a continuous intravenous infusion of unfractionated heparin (ratio of the activated partial-thromboplastin time to a control value, 1.5 to 2.5), both given for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio above 2.0. The primary efficacy outcome was the three-month incidence of the composite end point of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent deep-vein thrombosis.. Forty-two of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent), for an absolute difference of -1.2 percent in favor of fondaparinux (95 percent confidence interval, -3.0 to 0.5). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups. Of the patients in the fondaparinux group, 14.5 percent received the drug in part on an outpatient basis.. Once-daily, subcutaneous administration of fondaparinux without monitoring is at least as effective and is as safe as adjusted-dose, intravenous administration of unfractionated heparin in the initial treatment of hemodynamically stable patients with pulmonary embolism.

Topics: Aged; Drug Administration Schedule; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Polysaccharides; Pulmonary Embolism; Secondary Prevention; Single-Blind Method

Surgery for hip fracture carries a high risk of venous thromboembolism, despite the use of current thromboprophylactic treatments. Fondaparinux, a synthetic pentasaccharide, is a new antithrombotic agent that may reduce this risk.. In a double-blind study, were randomly assigned 1711 consecutive patients undergoing surgery for fracture of the upper third of the femur to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily, initiated postoperatively, or 40 mg of enoxaparin once daily, initiated preoperatively, for at least five days. The primary efficacy outcome was venous thromboembolism up to postoperative day 11. Venous thromboembolism was defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The main safety outcomes were major bleeding and mortality from all causes. The duration of follow-up was six weeks.. The incidence of venous thromboembolism by day 11 was 8.3 percent (52 of 626 patients) in the fondaparinux group and 19.1 percent (119 of 624 patients) in the enoxaparin group (P<0.001). The reduction in risk with fondaparinux was 56.4 percent (95 percent confidence interval, 39.0 to 70.3 percent). There were no significant differences between the two groups in the incidence of death or clinically relevant bleeding.. In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism and equally safe.

Topics: Aged; Double-Blind Method; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Hip Fractures; Humans; Incidence; Injections, Subcutaneous; Male; Mortality; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

Despite thromboprophylaxis, major knee surgery carries a high risk of venous thromboembolism. Fondaparinux, the first of a new class of synthetic antithrombotic agents, may reduce this risk.. In a double-blind study, we randomly assigned 1049 consecutive patients undergoing elective major knee surgery to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily or 30 mg of enoxaparin twice daily, with both treatments initiated postoperatively. The primary efficacy outcome was venous thromboembolism up to postoperative day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The primary safety outcome was major bleeding.. The primary efficacy outcome was assessed in 724 patients. The fondaparinux group had a significantly lower incidence of venous thromboembolism by day 11 (12.5 percent [45 of 361 patients]) than the enoxaparin group (27.8 percent [101 of 363 patients]; reduction in risk, 55.2 percent; 95 percent confidence interval, 36.2 to 70.2; P<0.001). Major bleeding (including overt bleeding with a bleeding index of 2 or more) occurred more frequently in the fondaparinux group (P=0.006), but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ.. In patients undergoing elective major knee surgery, postoperative treatment with 2.5 mg of fondaparinux once daily was significantly more effective in preventing deep-vein thrombosis than 30 mg of enoxaparin twice daily.

Topics: Aged; Double-Blind Method; Drug Administration Schedule; Elective Surgical Procedures; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Incidence; Injections, Subcutaneous; Knee; Male; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

The literature recommends against the use of fondaparinux in patients with kidney failure and dialysis as it may, with repeated dosing, accumulate and put patients at risk of bleeding. The management of patients with thrombosis in the presence of heparin-induced thrombocytopenia HIT requires the introduction of an alternative anticoagulant like bivalirudin or argatroban. When these drugs are not available, fondaparinux, remains the only alternative. In similar scenarios, there are few studies addressing how to administer it.  METHODS: We developed a protocol for fondaparinux in patients with renal failure where pharmacokinetic parameters are altered, and levels changed only after hemodialysis or in cases of residual renal activity. Patients received a full first dose except for high risk of bleeding. We targeted a peak anti-factor Xa activity level of 0.6-1.3 units/ml and changed the subsequent dose accordingly. Furthermore, we monitored the patients for signs of bleeding, a drop in hemoglobin level, or clinical signs of thrombosis.  DISCUSSION: We described 10 patients with kidney failure and suspected HIT taking fondaparinux. All the patients achieved therapeutic anti-factor Xa activity levels. However, one developed new-onset venous thromboembolism (VTE) despite therapeutic anti-factor Xa levels. Another patient experienced a bleeding episode. We believe that these two patients developed complications due to their medical conditions rather than the use of fondaparinux.. Fondaparinux can be safely used in kidney failure using our protocol. However, despite its safety profile and relative success, this case series was small. More robust studies need to be conducted prior to drawing conclusions.. New Fondaparinux Protocol to Reduce the Risk of Blood Thickening and Blood Clots Formation in Adults with Kidney Disease and Heparin-induced Thrombocytopenia (drop in platelets after the use of heparin): A Test Study.Fondaparinux is a drug used to treat patients suffering from thrombosis (clot in blood) and prevent vessels occlusions. When patients have kidney disease, the ideal treatment for thrombosis would be heparin; and, in case of Heparin Induced Thrombocytopenia (HIT), an unexpected drop in platelets after the use of heparin, the ideal treatment would be argatroban or bivalirudin. Fondaparinux can be used for HIT. However, studies recommend against its use in kidney disease as it might accumulate and cause bleeding.We were put in a challenging situation where we had patients with life-threatening thrombosis, kidney disease, HIT and unavailability of both argatroban and bivalirudin. Our only option was fondaparinux. We had to devise a safe and efficient protocol. The starting dose was the one used had the patient had a normal kidney function. Then, anti-Factor Xa activity was regularly measured with the target level 0.6-1.3units/ml 4 h after a dose. The dose was individualized, changed based on the Factor Xa activity result, the risk of bleeding or thrombosis, the overall kidney function and the need for dialysis.Our protocol was tested on 10 patients. All our patients could reach the target and safe Factor Xa activity. We had 2 exceptions. The first had a clotting event despite having therapeutic Factor Xa activity and the second was a very sick cancer patient who was bleeding despite skipping many doses of fondaparinux. We consider that these 2 cases developed complications due to their medical conditions rather than the use of fondaparinux.We concluded that fondaparinux can be safely used in patients with kidney disease, granted that Factor Xa activity is measured, the risk of bleeding is weighed to the risk of thrombosis and the dose is individualized. However, our sample size is small and further studies with a larger number of patients are needed to draw a conclusion.

Topics: Adult; Anticoagulants; Fondaparinux; Hemorrhage; Heparin; Humans; Renal Insufficiency; Retrospective Studies; Thrombocytopenia; Thrombosis

Fondaparinux is a synthetic anticoagulant that inhibits thrombosis by suppressing factor Xa. The efficacy of fondaparinux for orthopedic surgeries has been revealed by several foreign studies; however, relevant evidence in Chinese patients is lacking. This study intended to investigate the occurrence rate and risk factors of in-hospital venous thromboembolism (VTE), major bleeding, and death in patients receiving fondaparinux after orthopedic surgery or trauma surgery.. Totally, 1258 patients who received fondaparinux after orthopedic surgery or trauma surgery were retrospectively enrolled. Meanwhile, in-hospital VTE, major bleeding, and death were obtained for assessment. Besides, adverse events were recorded.. The occurrence rates of in-hospital VTE, major bleeding, and death were 2.5%, 21.8%, and 0.0%, respectively. The multivariate logistic regression analysis revealed that only age (> 60 years vs. ≤ 60 years) (odd ratios (OR) = 3.380, P = 0.013) was independently correlated with increased risk of in-hospital VTE. Additionally, osteoarthritis diagnosis (OR = 3.826, P < 0.001), femoral head necrosis diagnosis (OR = 1.809, P = 0.034), hip replacement (vs. internal fracture fixation) (OR = 2.199, P = 0.007), knee replacement (vs. internal fracture fixation) (OR = 2.781, P = 0.002), and serum creatinine (abnormal vs. normal) (OR = 1.677, P = 0.012) were independently linked to a higher risk of in-hospital major bleeding. Moreover, the common adverse events included pain (56.6%), wound bleeding (23.0%), increased drainage (5.2%), etc. CONCLUSION: Fondaparinux realizes low occurrence rates of in-hospital VTE and major bleeding with tolerable adverse events in patients receiving orthopedic surgery or trauma surgery.

Topics: Anticoagulants; Fondaparinux; Fracture Fixation, Internal; Hemorrhage; Humans; Middle Aged; Orthopedic Procedures; Polysaccharides; Retrospective Studies; Risk Factors; Venous Thromboembolism; Venous Thrombosis

Long term incidence of symptomatic venous thromboembolism (VTE) and bleeding events in patients with superficial vein thrombosis (SVT) was investigated.. In this prospective, observational study, patients with acute SVT were treated at the discretion of the responsible physician. The primary efficacy outcome was symptomatic VTE including deep vein thrombosis (DVT), pulmonary embolism (PE), and recurrent or extending SVT. The primary safety outcome was clinically relevant bleeding, recorded at periodic clinic visits over a 12 month period.. The mean age of 872 patients with 12 month follow up was 60.6 ± 14.5 years, 64.5% were female, 80.1% had chronic venous disease (defined as chronic venous insufficiency and or varicose veins), and 41.9% had a history of VTE. They were receiving fondaparinux in 62.1% (mean duration 34.9 ± 15.7 days), low molecular weight heparin (LMWH) in 25.0% (mean duration 26.2 ± 23.2 days), any other anticoagulants in 6.2%, and no anticoagulant in 6.7%. At 12 months, 108 patients (14.3%) achieved the primary efficacy outcome. The most common VTE event was recurrent or extending SVT in 11.0%, followed by symptomatic DVT in 2.7%, symptomatic PE in 2.4%, hospitalisation due to VTE in 1.8%, and death in 1.1%. Clinically relevant bleeding events occurred in 2.1% of patients, and major bleedings in 0.3%. By drug, the rate of the primary efficacy outcome was highest in the LMWH group (22.4%) and lowest in the fondaparinux group (10.4%). In a multivariable model, patients with events between three months and 12 months were significantly more likely to have higher BMI (hazard ratio [HR] 1.06; p = .002), history of VTE (HR 2.89; p = .002), and severe systemic infections (HR 7.59; p = .006).. The risk of symptomatic VTE remained elevated over 12 months of follow up. Therefore, anticoagulation beyond 45 days may be considered in patients with risk factors. [ClinicalTrials.gov identifier: NCT02699151.].

Topics: Aged; Anticoagulants; Female; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Varicose Veins; Venous Thromboembolism; Venous Thrombosis

Low-dose parenteral anticoagulation has demonstrated its efficacy for venous thromboembolism prophylaxis in randomized trials. However, current practice is not widely documented. In ambulatory settings, we aimed to provide an overview of the clinical use of low-dose parenteral anticoagulation in France and to assess the incidence of major bleeding and death rates.. A population-based prospective cohort study using the French national health data system (SNIIRAM) identified 142,815 adults living in five well-defined geographical areas who had a course of low-dose parenteral anticoagulants (a total of 150,389 courses) in the period 2013-2015. The main outcome measures were the types of low-dose parenteral anticoagulant, the duration and the clinical context. Adjusted incidence rate ratios (IRR) were derived from Poisson models.. Enoxaparin was the most frequently prescribed anticoagulant (58.9%) followed by tinzaparin (27.3%) and fondaparinux (10.9%). Patients receiving unfractionated heparin (N = 766, 0.53%) were older, more frequently had renal disease (48.75%) and had a higher modified HAS-B(L)ED score (≥ 3 in 61.6%) than patients receiving low-molecular weight heparin (LMWH). Surgical thrombo-prophylaxis was the most frequent indication (47.6%), followed by medical prophylaxis (29.9%). Course durations were in line with regulatory agency specifications. Only 43 (0.028%) major bleeding events and 478 (0.32%) deaths were observed. Adjusted IRRs for major bleeding or death were not significantly different for dalteparin/nadroparin, tinzaparin or fondaparinux compared to enoxaparin.. Very low incidence rates of major bleeding and all-cause mortality were observed. Our study confirms the safety of LMWHs and fondaparinux in thrombo-prophylaxis in ambulatory settings.. ClinicalTrials.gov identifier: NCT02886533.

Topics: Adult; Anticoagulants; Cohort Studies; Enoxaparin; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Incidence; Polysaccharides; Prospective Studies; Tinzaparin; Venous Thromboembolism

The present real-world study aimed to compare the efficacy and safety between fondaparinux sodium (FPX) and low molecular weight heparin (LMWH) for venous thromboembolism (VTE) prophylaxis in Chinese patients with major orthopedic surgery or trauma.. A total of 2429 patients, with major orthopedic surgery or trauma, underwent FPX (n = 1177) or LMWH (n = 1252) for VTE prophylaxis and were retrospectively reviewed. Primary outcomes, including in-hospital VTE and in-hospital major bleeding incidences, as well as the secondary outcomes, including in-hospital minor bleeding, in-hospital death, and VTE/bleeding/death within 2 months after discharge, were analyzed. Inverse probability of treatment weighting (IPTW) was conducted.. FPX group exhibited lower in-hospital VTE (0.1% vs. 0.8%; P = 0.032, crude OR = 0.11 before IPTW; P = 0.046, weighted OR = 0.12 after IPTW) and in-hospital minor bleeding (17.8% vs. 26.8%; P < 0.001, crude OR = 0.59 before IPTW; P < 0.001, weighted OR = 0.67 after IPTW) compared to LMWH group. Furthermore, no difference of in-hospital major bleeding, in-hospital death, and VTE/bleeding/death within 2 months after discharge was observed between FPX group and LMWH group (all P > 0.05). Further subgroup analyses identified, in specific cluster of patients such as older age, renal function impairment, hypertension and so on, in-hospital VTE was declined in FPX group compared to LMWH group (all P < 0.001).. FPX is probable to exhibit a superior thromboprophylaxis efficacy compared with LMWH in in-hospital patients with major orthopedic surgery or trauma, especially in some special patients such as older age, renal function impairment, hypertension, etc.

Topics: Anticoagulants; China; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Hospital Mortality; Humans; Hypertension; Orthopedic Procedures; Retrospective Studies; Venous Thromboembolism

Aim      To study specific features of the parenteral anticoagulant therapy for acute myocardial infarction (MI) in the Russian Federation and to evaluate the consistency of the prescribed parenteral anticoagulant therapy with the effective clinical guidelines.Material and methods  REGION-MI, the Russian rEGIstry for acute myOcardial iNfarction, is a multicenter observational study. This registry includes all patients admitted to hospitals with a documented diagnosis of ST-elevation acute MI (STEMI) and non-ST-elevation acute MI (NSTEMI) based on the criteria of the Forth Universal Definition of MI of the European Society of Cardiology. Risk of bleeding was assessed with the Academic Research Consortium for High Bleeding Risk (ARC-HBR) scale, and risk of major bleeding in patients with NSTEMI was additionally assessed with the CRUSADE scale.Results From November 01, 2020 through April 03, 2022, 5025 patients were included into the REGION-MI registry. At primary vascular departments, 70.5% of patients were administered unfractionated heparin (NFH); at regional vascular centers, 37.1 % of patients were administered NFH, 29.6 % enoxaparin, 20,2% NFH in combination with enoxaparin, 6.8 % fondaparinux, 4.2 % NFH in combination with fondaparinux, and 1.9 % nadroparin. At the prehospital stage, NFH was used as an anticoagulant support for the thrombolytic therapy (TLT) in 84% of patients, and low-molecular heparins (LMH) were used in 16 %. At the hospital stage, UFH was administered to 64.4 % of patients, and enoxaparin was administered to 23.9 % of patients. Among the patients who had undergone primary percutaneous coronary intervention (PCI), 40 % received NFH, 25 % enoxaparin, 22 % NFH in combination with enoxaparin, 7 % fondaparinux, and 4 % NFH in combination with fondaparinux. In conservative and invasive tactics of therapy for NSTEMI, NFH was also administered more frequently (43 and 43 %, respectively), followed by (according to frequency of administration) enoxaparin (36 and 34 %, respectively), NFH in combination with enoxaparin (10 and 16 %, respectively), fondaparinux (7 and 6 %, respectively), and NFH in combination with fondaparinux (3 and 1 %, respectively).Conclusion      According to the Russian registry of acute MI, REGION-MI, with all strategies for the treatment of MI, parenteral anticoagulants are not prescribed in full consistency with clinical guidelines. The most frequently used parenteral anticoagulant is NFH. Despite the high efficacy a

Topics: Anticoagulants; Enoxaparin; Fondaparinux; Hemorrhage; Heparin; Humans; Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Treatment Outcome

COVID-19 became a widespread infectious disease in late 2019. Indonesia currently has the highest COVID-19 mortality rate in Asia, between 4-5 percent. Interestingly, COVID-19-associated coagulopathy characterized by an increase of several procoagulant factor levels, including fibrinogen and D-dimer, that has been associated with higher mortality and unfavorable outcomes. We report a case of a 30-year-old male admitted to the hospital with a profuse vomiting and worsening fever, cough and shortness of breath, and was diagnosed with COVID-19-associated coagulopathy. Seven days after admission, he became deteriorated with significant reduction of oxygen saturation and his coagulation parameter levels were increased with highly suspicion of pulmonary embolism. He was treated with azithromycin, isoprinosine, lopinavir, and fondaparinux with thromboprophylaxis dosage since admission. The role of increased fondaparinux dosage at the time of clinical deterioration was then followed by clinical improvement and reduced D-dimer level. Anticoagulant therapy, mainly with fondaparinux, showed a better prognosis in patients with markedly elevated D-Dimer. Fondaparinux needs to be monitored appropriately to prevent bleeding and adverse. The patient was discharged from the hospital in an improved condition and normal D-Dimer levels. There was no bleeding event nor other major side effects had been found in this case. The decision for increasing dose of anticoagulant may be determined on individual basis, considering risks, benefits, and also the most important is clinical findings.

Topics: Adult; Antiviral Agents; Azithromycin; Clinical Deterioration; COVID-19; COVID-19 Drug Treatment; Dose-Response Relationship, Drug; Drug Monitoring; Factor Xa Inhibitors; Fibrin Fibrinogen Degradation Products; Fondaparinux; Hemorrhage; Humans; Inosine Pranobex; Lopinavir; Male; Pulmonary Embolism; SARS-CoV-2; Thrombophilia; Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a highly thrombogenic condition. Cancer patients are already at high risk of thrombosis. The treatment and outcomes of HIT in cancer patients are not well established. We retrospectively identified patients with active cancer who were diagnosed with HIT at our institution. Only patients with a positive HIT assay and intermediate to high 4Ts score were included. We assessed patients for baseline characteristics, HIT characteristics, non-heparin agent usage, and outcomes (recurrent thrombosis, bleeding, and death) up to 180 days after diagnosis of HIT. Between November 1, 2006 and December 31, 2016, 39 patients with active cancer received a diagnosis of HIT. Of these, 35.9% had thrombotic complications at diagnosis. Gastrointestinal cancer was the most common solid organ malignancy while myeloproliferative neoplasm (MPN) was the most common hematological malignancy. Fondaparinux was the most often used parenteral agent at any point of follow-up (87.2%), followed by argatroban (41.0%). Less than half the patients transitioned to an oral agent. The recurrent thrombosis rate was 17.9%, the bleeding rate was 20.5%, the major bleeding rate was 10.3%, and the mortality rate was 15.4% in the entire cohort. HIT in cancer patients is associated with poor outcomes.

Topics: Aged; Anticoagulants; Arginine; Canada; Female; Fondaparinux; Gastrointestinal Neoplasms; Hematologic Neoplasms; Hemorrhage; Heparin; Humans; Male; Patient Acuity; Pipecolic Acids; Platelet Count; Retrospective Studies; Risk Adjustment; Sulfonamides; Thrombocytopenia

There is no specific evidence on the antithrombotic management of survivors of out-of-hospital cardiac arrest (OHCA) due to acute myocardial infarction (AMI). We sought to compare the short-term outcome of unfractioned heparin (UFH) vs fondaparinux in OHCA survivors due to AMI admitted in our Institution in the last decade.. We performed a retrospective cohort study on survivors of OHCA due to AMI managed with UFH or fondaparinux during the hospitalization. The primary outcome was the occurrence of any bleeding, all-cause mortality, cerebrovascular accidents, re-MI, and unplanned revascularization at 1 month. A propensity-score matching was performed to compare the outcome between UFH and fondaparinux.. Out of 2083 AMI patients undergoing successful PCI, OHCA was present in 94 (4.5%): 41 (43.6%) treated with UFH and 53 (56.4%) with fondaparinux. At clinical follow-up, the incidence of the primary outcome was 65.9% in UFH and 35.8% in fondaparinux group (p = 0.007). More than half of the events included in the primary outcome were related to bleeding complications. In the matched cohort of 56 patients, the primary outcome occurred in 46.4% and 25.0% (p = 0.16), while bleeding was present in 32.1% and 7.1% (p = 0.04), in the UFH and fondaparinux group, respectively.. The present analysis suggests that fondaparinux is safer than UFH in the management of OHCA due to AMI by reducing early bleeding complications at one month.

Topics: Anticoagulants; Fondaparinux; Hemorrhage; Heparin; Humans; Myocardial Infarction; Out-of-Hospital Cardiac Arrest; Percutaneous Coronary Intervention; Retrospective Studies

Management and outcomes of superficial vein thrombosis (SVT) are highly variable and not well described. Therefore, the INvestigating SIGnificant Health TrendS in the management of SVT (INSIGHTS-SVT) study collected prospective data under real life conditions.. Prospective observational study of objectively confirmed acute isolated SVT. The primary outcome was a composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), and extension or recurrence of SVT at three months. The primary safety outcome was clinically relevant bleeding.. A total of 1 150 patients were included (mean age 60.2 ± 14.7 years; 64.9% women; mean BMI 29.4 ± 6.3 kg/m. At three month follow up, patients with isolated SVT are at risk of thromboembolic complications (mainly recurrent or extended SVT), despite anticoagulation. In this real life study, about one third had received either heparins, oral anticoagulants, or no anticoagulation.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Leg Ulcer; Lower Extremity; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Recurrence; Risk Factors; Stockings, Compression; Treatment Outcome; Varicose Veins; Venous Insufficiency; Venous Thrombosis

Our previous study showed that parenteral anticoagulation therapy (PACT) in the context of aggressive antiplatelet therapy failed to improve clinical outcomes in patients undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome (NSTE-ACS). However, the role of PACT in patients managed medically remains unknown. This observational cohort study enrolled patients with NSTE-ACS receiving medical therapy from November 2014 to June 2017 in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. Eligible patients were included in the PACT group and non-PACT group. The primary outcomes were in-hospital all-cause mortality and major bleeding. The secondary outcome included minor bleeding. Among 23,726 patients, 8,845 eligible patients who received medical therapy were enrolled. After adjusting the potential confounders, PACT was not associated with a lower risk of in-hospital all-cause mortality (adjusted odds ratio (OR), 1.25; 95% confidence interval (CI), 0.92-1.71; P = 0.151). Additionally, PACT did not increase the incidence of major bleeding or minor bleeding (major bleeding: adjusted OR, 1.04; 95% CI, 0.80-1.35; P = 0.763; minor bleeding: adjusted OR, 1.27; 95% CI, 0.91-1.75; P = 0.156). The propensity score analysis confirmed the primary analyses. In patients with NSTE-ACS receiving antiplatelet therapy, PACT was not associated with a lower risk of in-hospital all-cause mortality or a higher bleeding risk in patients with NSTE-ACS receiving non-invasive therapies and concurrent antiplatelet strategies. Randomized clinical trials are warranted to reevaluate the safety and efficacy of PACT in all patients with NSTE-ACS who receive noninvasive therapies and current antithrombotic strategies.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Angina, Unstable; Anticoagulants; China; Dual Anti-Platelet Therapy; Female; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hospital Mortality; Humans; Infusions, Parenteral; Injections; Ischemic Stroke; Male; Middle Aged; Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Recurrence

The present article addresses clinical challenges associated with the choice of the anticoagulant agent, the definition of the duration of anticoagulant treatment and the assessment of the risk-to-benefit ratio of prolonged anticoagulation for patients with pulmonary embolism (PE).Anticoagulation is performed with unfractionated heparin (UFH) in hemodynamically unstable patients and with low molecular weight heparins (LWMH) or fondaparinux in normotensive patients. In patients with high or intermediate clinical probability of pulmonary embolism, anticoagulation should be initiated without delay while awaiting the results of diagnostic tests. LMWH and fondaparinux are preferred over UFH in the initial anticoagulation of PE since they are associated with a lower risk of bleeding.All patients with PE require therapeutic anticoagulation for at least three months. The current 2019 guidelines of the European Society of Cardiology (ESC) recommend that all eligible patients should be treated with a non-vitamin K antagonist oral anticoagulant (NOAC) in preference to a vitamin K antagonist (VKA). In patients with active cancer, Apixaban, Edoxaban and Rivaroxaban are effective alternatives to treatment with LMWH.The decision on the duration of anticoagulation should consider both, the individual risk of PE recurrence and the individual risk of bleeding. The risk for recurrent PE after discontinuation of treatment is related to the features of the index PE event. While patients with a strong transient risk factor have a low risk of recurrence and anticoagulation can be discontinued after three months, patients with strong persistent risk factor (such as active cancer) have a high risk of recurrence and thus should receive anticoagulant treatment of indefinite duration. Given the favourable safety profile of NOACs (especially if a reduced dosage of Apixaban or Rivaroxaban is initiated after at least six months of therapeutic anticoagulation), extended oral anticoagulation of indefinite duration should be considered for all patients with intermediate risk of recurrence.

Topics: Acute Disease; Dalteparin; Dose-Response Relationship, Drug; Drug Administration Schedule; Fibrinolytic Agents; Fondaparinux; Guideline Adherence; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Neoplasms; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Recurrence; Risk Assessment; Risk Factors; Rivaroxaban; Thiazoles

Topics: Aged; Aged, 80 and over; Anticoagulants; COVID-19; COVID-19 Drug Treatment; Enoxaparin; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Italy; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Thrombosis; Treatment Outcome; Venous Thromboembolism

The use of heparin has been shown to decrease the mortality in hospitalized patients with severe COVID-19. The aim of our study was to evaluate the clinical impact of venous thromboembolism prophylaxis with fondaparinux versus enoxaparin among 100 hospitalized COVID-19 patients. The incidence of pulmonary embolism, deep venous thrombosis, major bleeding (MB), clinically relevant non-MB, acute respiratory distress syndrome, and in-hospital mortality was compared between patients on fondaparinux versus enoxaparin therapy. The 2 groups were homogeneous for demographic, laboratory, and clinical characteristics. In a median follow-up of 28 (IQR: 12-45) days, no statistically significant difference in venous thromboembolism (14.5% vs. 5.3%; P = 0.20), MB and clinically relevant non-MB (3.2% vs. 5.3%, P = 0.76), ARDS (17.7% vs. 15.8%; P = 0.83), and in-hospital mortality (9.7% vs. 10.5%; P = 0.97) has been shown between the enoxaparin group versus the fondaparinux group. Our preliminary results support the hypothesis of a safe and effective use of fondaparinux among patients with COVID-19 hospitalized in internal medicine units.

Topics: Aged; Anticoagulants; Antithrombins; Coronavirus Infections; COVID-19; Enoxaparin; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Hospital Mortality; Humans; Incidence; Male; Middle Aged; Pandemics; Pneumonia, Viral; Pulmonary Embolism; Retrospective Studies; Venous Thromboembolism; Venous Thrombosis

The off-label use of fondaparinux in patients with heparin-induced thrombocytopenia with thrombosis (HITT) has historically been controversial. We present a case of successful fondaparinux use to treat HITT confirmed by the serotonin-release assay in the setting of other significant clotting and bleeding risk factors.. We report a 19-year-old male with a history of Factor V Leiden and recent neurosurgery treated with fondaparinux after developing HITT confirmed by the serotonin-release assay (SRA). The patient achieved full platelet recovery on fondaparinux and was successfully transitioned to warfarin therapy without further thrombotic nor bleeding complications.. This case demonstrates a clear example of success of fondaparinux use to treat SRA-confirmed HITT in the setting of complicating factors and adds to the existing literature supporting the use of fondaparinux for HIT.

Topics: Adult; Anticoagulants; Blood Coagulation; Factor V; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Serotonin; Thrombocytopenia; Thrombosis; Young Adult

Portal vein thrombosis (PVT) is a frequent complication of cirrhosis. Benefit, safety, and duration of anticoagulant treatment in this setting are controversial issues. The aim of this study was to analyze the course of PVT in a large cohort of cirrhotic patients undergoing or not anticoagulation therapy.. The data of 182 patients who presented between January 2008 and March 2016 with cirrhosis and PVT with at least 3 months of follow-up after the first PVT detection were analyzed. Eighty-one patients received anticoagulants and 101 were untreated per physician discretion.. The extension of the thrombosis decreased by >50% in 46 (56.8%, with complete recanalization in 31/46) patients under anticoagulation and in 26 (25.7%) untreated patients. Of the 46 patients who underwent recanalization, 17 (36%) suffered recurrent thrombosis after stopping anticoagulation therapy. Kaplan-Meier analysis showed a higher survival rate in the treated group (p = 0.010). At multivariate analysis, anticoagulation was an independent factor associated with longer survival (HR:0.30, CI:0.10-0.91, p = 0.014). The Child-Turcotte-Pugh classes B/C negatively influenced survival (hazard ratio, (HR):3.09, confidence interval (CI):1.14-8.36, p = 0.027 for Child-Turcotte-Pugh B and HR:9.27, CI:2.67-32.23, p < 0.001 for Child-Turcotte-Pugh C). Bleeding complications occurred in 22 (21.8%) untreated and 16 (19.7%) treated patients, but in only four cases was it judged to be related to the anticoagulant treatment. No death was reported as a consequence of the bleeding events.. Anticoagulant treatment is a safe and effective treatment leading to partial or complete recanalization of the portal venous system in 56.8% of cases, improving the survival of patients with cirrhosis and PVT. Discontinuation of the therapy is associated with a high rate of PVT recurrence.

Topics: Aged; Anticoagulants; Esophageal and Gastric Varices; Female; Fondaparinux; Gastrointestinal Hemorrhage; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Venous Thrombosis

Many strategies for venous thromboembolism (VTE) prophylaxis following hip and knee arthroplasty exist, with extensive controversy regarding the optimum strategy to minimize risk of VTE and bleeding complications. Data from the American Board of Orthopedic Surgery Part II (oral) Examination case list database was analyzed to determine efficacy, complication rates, and prescribing patterns for different prophylactic strategies.. The American Board of Orthopedic Surgery case database was queried utilizing Current Procedural Terminology codes 27447 and 27130 for primary total knee and hip arthroplasty, respectively. Geographic region, patient age, gender, deep vein thrombosis prophylaxis strategy, and complications were obtained. Less aggressive prophylaxis patterns were considered if only aspirin and/or sequential compression devises were utilized. More aggressive VTE prophylaxis patterns were considered if any of low-molecular-weight heparin (enoxaparin), warfarin, rivaroxaban, fondaparinux, or other strategies was used.. In total, 22,072 cases of primary joint arthroplasty were analyzed from 2014 to 2016. The national rate of less aggressive VTE prophylaxis strategies was 45.4%, while more aggressive strategies were used in 54.6% of patients. Significant regional differences in prophylactic strategy patterns exist between the 6 regions. The predominant less aggressive prophylaxis pattern was aspirin with sequential compression devises at 84.8% with 14.8% receiving aspirin alone. Use of less aggressive prophylaxis strategy was significantly associated with patients having no complications (95.5% vs 93.0%). Use of more aggressive prophylaxis patterns was associated with higher likelihood of mild thrombotic (0.9% vs 0.2%), mild bleeding (1.3% vs 0.4%), moderate thrombotic (1.2% vs 0.4%), moderate bleeding (2.7% vs 2.1%), severe thrombotic (0.1% vs 0.0%), severe bleeding events (1.2% vs 0.9%), infections (1.9% vs 1.3%), and death within 90 days (0.7% vs 0.3%). Similar results were found in subgroup analysis of total hip and knee arthroplasty patients.. It was not possible to ascertain the individual rationale for use of more aggressive VTE prophylaxis strategies; however, more aggressive strategies were associated with higher rates of bleeding and thrombotic complications. Less aggressive strategies were not associated with a higher rate of thrombosis.. Therapeutic Level III.. All views expressed in the study are the sole views of the authors and do not represent the views of the American Board of Orthopedic Surgery.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Aspirin; Databases, Factual; Enoxaparin; Female; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Orthopedic Procedures; Orthopedics; Practice Patterns, Physicians'; Risk Factors; Rivaroxaban; United States; Venous Thromboembolism; Venous Thrombosis; Warfarin

Inferior vena cava (IVC) thrombosis is an under-recognized entity that is associated with a mortality rate approaching twice that of lower extremity deep venous thrombosis (DVT). Thrombolytic therapy not only results in greater lysis, but also results in higher complication rates than anticoagulation alone. Catheter-directed thrombolysis (CDT), which is effective in accomplishing local resolution whilst reducing bleeding complications, has been established as an alternative treatment for patients with extensive DVT.. We report the case of a 70-year-old man who was admitted due to warmness, pain, and swelling in his left leg and a feeling of gait disturbance.. Contrast-enhanced computed tomography and venous ultrasonography revealed a pulmonary embolism and extensive DVT spreading to the IVC.. First, the patient was treated with fondaparinux. Since this was inadequate, he underwent CDT using a Fountain infusion catheter. Then, CDT was switched to direct oral anticoagulant (DOAC) treatment.. Both CDT and subsequent DOAC treatments dramatically improved the DVT. His subjective symptoms have disappeared, and no recurrence of thrombosis has been identified.. The present case showed the therapeutic effect of CDT, which preceded DOAC treatment, on an extensive DVT.

Topics: Aged; Anticoagulants; Catheterization, Peripheral; Fondaparinux; Hemorrhage; Humans; Male; Polysaccharides; Thrombolytic Therapy; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography, Interventional; Vena Cava, Inferior; Venous Thrombosis

There are numerous studies discussing thromboprophylaxis after total joint arthroplasty (TJA), with varying conclusions. Patient inclusion criteria may be different for each study, which may lead to selection bias and misrepresentation of data. This study aimed to investigate if industry funding impacted patient demographics and overall reported outcomes of studies analyzing venous thromboembolism (VTE) prevention after TJA.. Electronic searches were completed using Ovid, PubMed, and Embase databases. Studies were included if (1) they are published in the English language between 2000 and 2016; (2) they included patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA); and (3) they evaluated prevention and control of postoperative VTE with at least one of the following thromboprophylactic agents: aspirin, enoxaparin, dalteparin, dabigatran, apixaban, rivaroxaban, dabigatran, ximelagatran, fondaparinux, or coumadin. Data were extracted and analyzed via mixed-effect logistic regression.. Fifty-seven studies were included; 29 were industry funded, and 28, nonfunded. There were no significant differences between patient's age, body mass index, or revision exclusions between funded and nonfunded studies. Funded studies reported less pulmonary embolisms, fewer events of major bleeding, and significantly less 90-day mortality compared with nonfunded studies.. Industry-funded studies reported less pulmonary embolisms, major bleeding, and mortality compared with nonfunded studies. Detailed demographic data were missing from the literature, and we were unable to demonstrate the cause of different reported outcomes between industry-funded and nonfunded studies. Further investigations should be aimed toward understanding how funded studies report less adverse outcomes in analyzing VTE after TJA.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Aspirin; Conflict of Interest; Dabigatran; Enoxaparin; Female; Fondaparinux; Health Care Sector; Hemorrhage; Humans; Male; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism; Warfarin

Essentials Critically ill cancer patients require pharmacologic prophylaxis for venous thromboembolism (VTE). Patients from 566 hospitals in the United States between 2010 and 2014 were included. Low-molecular-weight heparin (LMWH) prophylaxis was not associated in a reduction of VTE rates. LMWH prophylaxis was associated with a reduction in bleeding and heparin induced thrombocytopenia. SUMMARY: Background Critically ill patients with cancer are at increased risk of venous thromboembolism (VTE) from physical and cellular factors, requiring pharmacologic prophylaxis to reduce the risk of VTE. Objectives To assess whether low-molecular-weight heparin (LMWH) prophylaxis reduces in-hospital rates of VTE or improves clinical outcomes compared with unfractionated heparin (UFH) prophylaxis in critically ill patients with cancer. Methods We used a propensity-matched comparative-effectiveness cohort from the Premier Database. Patients aged 18 years or older with a primary diagnosis of cancer, intensive care unit admission and VTE prophylaxis within 2 days of admission between 1 January 2010 and 31 December 2014 were included. Patients were divided into LMWH or UFH prophylaxis groups. Results A total of 103 798 patients were included; 75 321 (72.6%) patients received LMWH and 28 477 (27.4%) patients received UFH. Propensity analysis matched (2 : 1) 42 343 LMWH patients and 21 218 UFH patients. Overall, LMWH was not associated with a decreased incidence of VTE (5.32% vs. 5.50%). LMWH prophylaxis was associated with a reduction in pulmonary embolism (0.70% vs. 0.99%), significant bleeding (13.3% vs. 14.8%) and heparin-induced thrombocytopenia (HIT) (0.06% vs. 0.19%). In non-metastatic solid disease, LMWH was associated with decreased VTE (4.27% vs. 4.84%) and PE (0.47% vs. 0.95%). Conclusions The use of an LMWH for VTE prophylaxis was not associated with a reduction in the incidence of in-hospital VTE as compared with UFH, but was associated with significant reductions in PE, clinically important bleeding events, and incidence of HIT in critically ill patients with cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Comparative Effectiveness Research; Critical Illness; Databases, Factual; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Risk Factors; Thrombocytopenia; Time Factors; Treatment Outcome; United States; Venous Thromboembolism; Young Adult

Which treatments for lower extremity superficial thrombophlebitis (ST) are associated with lower rates of venous thromboembolic events (VTEs) vs placebo?. A dose of 2.5 mg of fondaparinux administered subcutaneously once daily for 45 days is associated with fewer cases of symptomatic VTE without an increase in major bleeding vs placebo. Low-molecular-weight heparin (LMWH) and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with lower rates of ST extension or recurrence vs placebo, but data regarding symptomatic VTE remain inconclusive. Oral rivaroxaban requires further evaluation.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Lower Extremity; Male; Randomized Controlled Trials as Topic; Review Literature as Topic; Stockings, Compression; Thrombophlebitis; Venous Thromboembolism

Rates of venous thromboembolism in contemporary studies of primary total knee arthroplasty (TKA) have been reported to be as high as 3.5%. Although drug prophylaxis is effective, the best option among these regimens is not well established. The purpose of this study was to evaluate the comparative effectiveness and safety of aspirin, low-molecular-weight heparin, synthetic pentasaccharide factor Xa inhibitors, and vitamin K antagonist.. Data were from a US total joint replacement registry, with 30,499 patients receiving unilateral TKA from May 16, 2006, to December 31, 2013. Patients received either aspirin (324-325 mg daily), enoxaparin (40-60 mg daily), fondaparinux (2.5 mg daily), or warfarin (all doses) and were followed up 90 days postoperatively on several outcomes: deep vein thrombosis, pulmonary embolism, major bleeding, wound complications, infection, and death.. There was no evidence that fondaparinux, enoxaparin, or warfarin were superior to aspirin in the prevention of pulmonary embolism, deep vein thrombosis, or venous thromboembolism or that aspirin was safer than these alternatives. However, enoxaparin was found to be as safe as aspirin with respect to bleeding, and fondaparinux was as safe as aspirin for risk of wound complications.. Among TKA patients, we did not find evidence for decreased effectiveness or increased safety with use of aspirin, but enoxaparin had comparable safety to aspirin for bleeding and fondaparinux had comparable safety to aspirin for wound complications.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Aspirin; Cohort Studies; Enoxaparin; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Polysaccharides; Pulmonary Embolism; Venous Thromboembolism; Venous Thrombosis; Warfarin

Endovenous heat-induced thrombosis (EHIT) and deep venous thrombosis (DVT) are well-known complications after superficial endovenous thermoablation. We investigated the efficacy of rivaroxaban in preventing EHIT and DVT after endovenous laser ablation (EVLA).. We retrospectively analyzed a consecutive series of patients presenting with truncal varicosis class C. Between February 2009 and December 2015, 391 patients (473 limbs) were treated with EVLA of the truncal saphenous vein. The primary end point occurred in 13 of 166 (7.8%) and 14 of 225 (6.2%) after 1 week and in 13 of 166 (7.8%) and 15 of 225 (6.7%) after 4 weeks comparing the rivaroxaban and fondaparinux groups (P = .659). EHIT class 1 was observed in 20 patients (5.1%) and EHIT class 2 in five (1.3%). No patients had EHIT class 3 or 4. The incidence of DVT was one of 166 (0.6%) in the rivaroxaban group and two of 225 (0.9%) in the fondaparinux group (P = .750). Minor bleeding events occurred in 17 of 166 patients (10.2%) and in 20 of 225 patients (8.9%), respectively (P = .652). No major bleeding events were observed. Paresthesia was observed in 12.5% in the rivaroxaban group and in 17.8% in the fondaparinux group. No skin burns were observed.. Rivaroxaban offers an oral medication approach showing no difference in preventing EHIT and DVT compared with fondaparinux, without increased bleeding risk.

Topics: Administration, Cutaneous; Administration, Oral; Endovascular Procedures; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Laser Therapy; Male; Middle Aged; Polysaccharides; Retrospective Studies; Rivaroxaban; Saphenous Vein; Treatment Outcome; Varicose Veins; Venous Insufficiency; Venous Thrombosis

Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label.. The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT.. In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings.. Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed "true" HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux.. Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238).

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Hospital Mortality; Hospitalization; Humans; Male; Necrosis; Off-Label Use; Partial Thromboplastin Time; Patient Safety; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Registries; Retrospective Studies; Sulfonamides; Thrombocytopenia; Thromboembolism; Treatment Outcome

Topics: Anticoagulants; Fondaparinux; Hemorrhage; Humans; Intraoperative Complications

The factor Xa inhibitors have been widely used for the treatment and prevention of venous thromboembolism (VTE). However, the efficacy of factor Xa inhibitors in Japanese patients with VTE has not been well examined. In this study, we investigated the effect of the sequential use of two factor Xa inhibitors in patients with acute VTE.. We conducted an observational study of 87 consecutive patients diagnosed with VTE. As an initial treatment, we administered subcutaneous fondaparinux to the patients for 7-10 days, and then switched to oral rivaroxaban. The symptoms and findings were assessed after the initial treatment and after using rivaroxaban for 7-14 days. We evaluated the deep vein thrombosis (DVT) in the legs using our own scoring system [quantitative ultrasound thrombosis (QUT) score].. Of the 87 patients, 33% had symptoms, half had pulmonary embolism (PE), and 95% had DVT of the legs. Out of the 87 patients, VTE worsened during the administration of fondaparinux in 4 patients. All of them had experienced malignancy, and died within 6 months. Of two patients developing bleeding, one patient required a transfusion. Eventually, this strategy was effective in 80 patients and had no change in one. The D-dimer level was significantly reduced by fondaparinux (17.8μg/ml±16.0μg/ml vs. 8.3μg/ml±7.2μg/ml, p<0.0001), followed by rivaroxaban (8.3μg/ml±7.2μg/ml vs. 5.5μg/ml±4.9μg/ml, p<0.0001). Similarly, the QUT score was improved by fondaparinux (4.7±2.6 vs. 2.5±2.5, p<0.0001), and further reduced by rivaroxaban (2.5±2.5 vs. 1.9±1.8, p<0.0001).. A treatment strategy using subcutaneous fondaparinux followed by oral rivaroxaban is effective for treating acute VTE in Japanese patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Polysaccharides; Pulmonary Embolism; Rivaroxaban; Venous Thromboembolism; Venous Thrombosis

Fondaparinux (FPX), a synthesized factor Xa inhibitor, is one of the most popular anticoagulants for the prevention of postoperative venous thromboembolism (VTE). Although routine monitoring is not required, the bleeding adverse events cannot be neglected, and the measurement of anti-Xa activity is expected to be monitored. The primary purpose of this study is to evaluate the performances of 2 chromogenic assays for the detection of anti-Xa activity. Furthermore, the pharmacokinetics of FPX was examined using chromogenic assays. Anti-Xa activity was measured using 2 FPX-based chromogenic substrates (S2222 and STA-Liquid Anti-Xa). The reproducibility, detection limits, linearity, and correlations between the substrates were examined using normal plasma doped with low and high concentrations of FPX formulation. In addition, anti-Xa activity in 235 clinical samples from 164 cases treated was measured, and the pharmacokinetics of FPX was evaluated. Both of the tested substrates were capable of accurately measuring the anti-Xa activity of FPX, with a lower limit of 0.05 μg/mL and a coefficient of variation of less than 10%. The repeated administration of FPX induced a gradual but significant increase in the anti-Xa activity, which was negatively correlated with body weight and estimated glomerular filtration rate. No significant correlation between the anti-Xa activity and the occurrence of postoperative VTE or bleeding event was observed. Anti-Xa activity can be successfully determined using 2 chromogenic assays and automated biochemical analyzers. The clinical significance of anti-Xa activity monitoring should be examined in the future study.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Body Weight; Chromogenic Compounds; Clinical Chemistry Tests; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Fondaparinux; Glomerular Filtration Rate; Hemorrhage; Humans; Male; Middle Aged; Polysaccharides; Postoperative Complications; Venous Thromboembolism

The prevalence of medical conditions representing a risk for thromboembolic complications and requiring antithrombotic therapy increases gradually with age. Two cases of fatal noncritical organ bleeding complication that occurred during the conversion period from initial fondaparinux to vitamin K antagonist are presented. An 81-year-old obese female patient (body mass index 43 kg/m(2)) with previous postoperative thrombosis underwent uneventful total knee replacement under spinal anesthesia. She presented with popliteal hematoma during conversion to oral anticoagulant. A 92-year-old female patient (body mass index 33 kg/m(2)) with left lower limb thrombosis was referred to our orthopedics department from her senior citizens' home for right lower limb hematoma and ischemia that occurred during conversion to oral anticoagulant. Thromboembolic and bleeding events in the elderly are real public health problems. Specific guidelines dedicated to this particular population are needed, which will improve the management of anticoagulation and decrease risk of complications.

Topics: Age Factors; Aged, 80 and over; Anticoagulants; Fatal Outcome; Female; Fondaparinux; Hemorrhage; Humans; Obesity; Polysaccharides; Risk Factors; Thromboembolism; Thrombosis; Vitamin K

The efficacy and safety of the anticoagulant rivaroxaban for the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism has been shown in phase 3 trials. However, data about rivaroxaban use in routine clinical practice are needed.. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was a multicentre, international, prospective, non-interventional study of patients with deep-vein thrombosis, done in hospitals and community care centres in 21 countries. The study investigated the safety and effectiveness of rivaroxaban compared with standard anticoagulation therapy (initial treatment with unfractionated heparin, low-molecular-weight heparin, or fondaparinux, usually overlapping with and followed by a vitamin K antagonist) for at least 3 months. Eligible patients were adults (aged ≥18 years) with an objectively confirmed diagnosis of deep-vein thrombosis, and an indication to receive anticoagulation treatment for at least 3 months. Following approval of rivaroxaban for the pulmonary embolism indication, patients with deep-vein thrombosis and concomitant pulmonary embolism were also eligible; however, those with isolated pulmonary embolism were not included. Type, dose, and duration of therapy for each patient were at the physician's discretion. The primary effectiveness and safety outcomes were major bleeding, recurrent venous thromboembolism, and all-cause mortality. Propensity score-adjusted analyses were done to account for potential imbalances between groups. This study is registered with ClinicalTrials.gov, number NCT01619007.. Between June 26, 2012, and March 31, 2014, 5142 patients were enrolled. The safety population (all patients who received at least one dose of the anticoagulant of interest) comprised 2619 patients in the rivaroxaban group and 2149 in the standard anticoagulant therapy group. Patients in the rivaroxaban group were younger and fewer had active cancer or concomitant pulmonary embolism than those in the standard anticoagulation group. In the propensity score-adjusted population, the frequency of major bleeding was 0·8% (19/2505) in the rivaroxaban group and 2·1% (43/2010) in the standard anticoagulation group, with a propensity score-adjusted hazard ratio (HR) of 0·77 (95% CI 0·40-1·50); p=0·44. The frequency of recurrent venous thromboembolism was 1·4% (36/2505) in the rivaroxaban group and 2·3% (47/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·91 [95% CI 0·54-1·54], p=0·72). The all-cause mortality frequency was 0·4% (11/2505) in the rivaroxaban group and 3·4% (69/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·51 [95% CI 0·24-1·07], p=0·074). The incidence of treatment-emergent adverse events in the safety population was similar between the two groups (944 [36·0%] of 2619 in the rivaroxaban group vs 805 [37·5%] of 2149 in the standard anticoagulation group).. In routine clinical practice, rivaroxaban-treated patients had a lower risk profile at baseline than those treated with standard anticoagulation. Propensity score-adjusted results confirm that rivaroxaban is a safe and effective alternative to standard anticoagulation therapy in a broad range of patients. Rates of major bleeding and recurrent venous thromboembolism were low in rivaroxaban-treated patients and consistent with phase 3 findings.. Bayer HealthCare Pharmaceuticals and Janssen Research & Development, LLC.

Topics: Aged; Anticoagulants; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Polysaccharides; Prospective Studies; Pulmonary Embolism; Rivaroxaban; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

Recent studies have shown fondaparinux's superiority over enoxaparin in patients with non-ST elevation acute coronary syndrome (ACS), especially in relation to bleeding reduction. The description of this finding in a Brazilian registry has not yet been documented.. To compare fondaparinux versus enoxaparin in in-hospital prognosis of non-ST elevation ACS.. Multicenter retrospective observational study. A total of 2,282 patients were included (335 in the fondaparinux group, and 1,947 in the enoxaparin group) between May 2010 and May 2015. Demographic, medication intake and chosen coronary treatment data were obtained. Primary outcome was mortality from all causes. Secondary outcome was combined events (cardiogenic shock, reinfarction, death, stroke and bleeding). Comparison between the groups were done through Chi-Square test and T test. Multivariate analysis was done through logistic regression, with significance values defined as p < 0.05.. With regards to treatment, we observed the performance of a percutaneous coronary intervention in 40.2% in the fondaparinux group, and in 35.1% in the enoxaparin group (p = 0.13). In the multivariate analysis, we observed significant differences between fondaparinux and enoxaparin groups in relation to combined events (13.8% vs. 22%. OR = 2.93, p = 0.007) and bleeding (2.3% vs. 5.2%, OR = 4.55, p = 0.037), respectively.. Similarly to recently published data in international literature, fondaparinux proved superior to enoxaparin for the Brazilian population, with significant reduction of combined events and bleeding.. Estudos recentes têm apresentado superioridade do fondaparinux em relação à enoxaparina em pacientes com síndrome coronariana aguda (SCA) sem supradesnivelamento de ST, principalmente relacionada à redução de sangramentos. A descrição desse achado em registro brasileiro ainda não foi documentada.. Comparar fondaparinux versus enoxaparina no prognóstico intrahospitalar em SCA sem supradesnivelamento de ST.. Estudo retrospectivo, multicêntrico e observacional. Foram incluídos 2.282 pacientes (335 no grupo fondaparinux e 1.947 no grupo enoxaparina) entre maio de 2.010 e maio de 2.015. Foram obtidos dados demográficos, medicações utilizadas e tratamento coronariano adotado. O desfecho primário foi mortalidade por todas as causas. O desfecho secundário foi eventos combinados (choque cardiogênico, reinfarto, morte, acidente vascular cerebral e sangramentos). A comparação entre os grupos foi realizada por meio de Q-quadrado e teste-T. A análise multivariada foi realizada por regressão logística, sendo considerado significativo p < 0,05.. Em relação ao tratamento, observou-se realização de intervenção coronária percutânea em 40,2% no grupo fondaparinux e 35,1% no grupo enoxaparina (p = 0,13). Na análise multivariada, observaram-se diferenças significativas entre os grupos fondaparinux e enoxaparina em relação a eventos combinados (13,8% vs. 22%, OR = 2,93, p = 0,007) e sangramentos (2,3% vs. 5,2%, OR = 4,55, p = 0,037), respectivamente.. Semelhante aos dados recentemente publicados na literatura mundial, fondaparinux mostrou-se superior à enoxaparina para a população brasileira, com redução significativa de eventos combinados e sangramentos.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Brazil; Enoxaparin; Female; Fondaparinux; Hemorrhage; Hospital Mortality; Humans; Logistic Models; Male; Middle Aged; Polysaccharides; Reproducibility of Results; Retrospective Studies; Risk Factors; Statistics, Nonparametric; Treatment Outcome

To assess the frequency of platelet monitoring and bleeding risks associated with the use of injectable anticoagulants in a real life setting and to estimate the associated costs.. An analysis of the 2013 data from a random sample of ≈600,000 patients registered in the French National Health Insurances reimbursement database was conducted to identify platelet counts performed during injectable anticoagulants exposure period and treatment interruptions due to heparin-induced thrombocytopenia or transfusion. Events were then valued to establish associated costs.. Overall 15,985 adult patients representing a cumulated injectable anticoagulants exposure time of 12,264 months were selected. Treatment sequences involved unfractionated heparin (2.8%), low molecular weight heparin (86.9%), and fondaparinux (13.1%). Patients treated with unfractionated heparin were older (77 vs. 57 and 59 years) with longer treatment duration (32.6 vs. 25.1 and 21 days). After statistical adjustment, the average monthly number of platelet counts was 1.36-fold lower in patients treated with fondaparinux compared to low molecular weight heparin (P<0.0001). No difference was found between low molecular weight heparin and fondaparinux regarding the incidence of bleeding with transfusion (P=0.76) or hospitalized thrombocytopenia (P=0.82). Extrapolated for the whole country, the estimated costs for biological monitoring were € 21.6 million for low molecular weight heparin and € 0.9 million for fondaparinux.. Significantly fewer platelet counts were performed among patients treated with fondaparinux than among patients receiving low molecular weight heparin without additional bleeding risk. This finding should be taken into account when assessing the costs of such treatments.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Costs and Cost Analysis; Environmental Monitoring; Female; Fondaparinux; France; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections; Male; Middle Aged; Platelet Count; Polysaccharides; Risk Factors; Thrombocytopenia

EP217609 is a new synthetic parenteral dual-action anticoagulant combining a direct thrombin inhibitor (α-NAPAP analog), an indirect factor Xa inhibitor (fondaparinux analog) and a biotin moiety allowing its neutralisation. EP217609 exhibited similar in vitro anticoagulant properties as its parent compounds. On the basis of dose-response curves, we identified low and moderate doses of EP217609 resulting in similar ex vivo prolongation of the APTT as α-NAPAP analog and comparable ex vivo anti-FXa activity as fondaparinux. The effects of EP217609 were compared to those of its parent compounds used alone or in combination in two models of experimental thrombosis induced by FeCl3 injury of the carotid artery or mechanical injury of atherosclerotic plaques in ApoE-deficient mice. When administered at low doses increasing the APTT by only 1.1 fold, EP217609 significantly reduced the thrombus area in both models as compared to α-NAPAP analog or fondaparinux alone, but not to the combination of these drugs. In contrast, at higher doses increasing the APTT 1.5 times, EP217609 was not superior to either parent compound. Low doses of EP217609 did not prolong the tail bleeding time or increase the volume of blood loss, although a tendency towards an increased blood loss was observed in five out of 12 mice. Finally, the effects of EP217609 could be neutralised in vivo by injection of avidin. The pharmacological profile of EP217609, its performance in arterial thrombosis models and its possible neutralisation make it an interesting molecule and a potential candidate as an antithrombotic drug.

Topics: Animals; Anticoagulants; Arteries; Avidin; Biotin; Bleeding Time; Blood Coagulation; Dose-Response Relationship, Drug; Factor Xa; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oligosaccharides; Polysaccharides; Prothrombin; Thrombosis

Fondaparinux has an increased bleeding risk in patients with a CrCl ≤ 50 mL/min and is contraindicated if CrCl < 30 mL/min. Data regarding dosing and anti-Xa monitoring are lacking in this population.. To describe dosing, monitoring, and safety outcomes of prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment, including renal replacement therapy (RRT).. Retrospective analysis from October 2006 to November 2012 of patients ≥ 18 years old who received fondaparinux for ≥ 72 hours with ≥ 1 dose in an intensive care unit and a CrCl ≤ 50 mL/min or RRT during therapy. Participants were divided into 4 cohorts: moderate impairment (CrCl = 30-50 mL/min), severe impairment (CrCl < 30 mL/min), hemodialysis (HD), or continuous venovenous hemofiltration (CVVH). Outcomes included the incidence of clinically significant bleeding and thromboembolic events. Fondaparinux dose, dosing frequency, and anti-Xa level monitoring are described. Pharmacokinetic modeling was performed to assess drug accumulation.. In all, 95 patients met inclusion criteria: 64 (67.4%) with moderate impairment, 10 (10.5%) with severe impairment, 5 (5.3%) with HD, and 16 (16.8%) with CVVH. The median defined daily doses in the moderate, severe, HD, and CVVH cohorts were 2.5, 2.5, 0.9, and 1.9 mg. Anti-Xa monitoring occurred in 19 (20%) patients, although few concentrations were peaks. Clinically significant bleeding occurred in 4 (4.2%) patients. A pharmacokinetic model demonstrated drug accumulation.. Empirical dose adjustments may be prudent in critically ill patients with renal dysfunction; however, the optimal fondaparinux dosage in this population remains unknown. Peak anti-Xa concentrations may help guide therapy.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Chemoprevention; Critical Illness; Female; Fondaparinux; Hemofiltration; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Intensive Care Units; Male; Middle Aged; Monitoring, Physiologic; Polysaccharides; Renal Dialysis; Renal Insufficiency; Renal Replacement Therapy; Retrospective Studies; Severity of Illness Index; Young Adult

Current guidelines for heparin-induced thrombocytopenia (HIT) management recommend heparin cessation and switching to a nonheparin anticoagulant (ie, argatroban, danaparoid) upon clinical suspicion. Fondaparinux may be effective but information supporting its use is limited. We retrospectively evaluated 239 patients who received a nonheparin anticoagulant (fondaparinux = 133, danaparoid = 59, and argatroban = 47) for suspected or confirmed HIT. A propensity score was constructed based on age, gender, creatinine, 4T scores, and comorbidity index, and used to match 133 patients to 60 controls. Outcomes were thrombosis or thrombosis-related death and major bleeding. In the matched population there were 22 (16.5%) episodes of thromboses in the fondaparinux group and 13 (21.4%) in the control group (χ(2) P = .424). Bleeding was observed in 28 (21.1%) patients in the fondaparinux group compared with 12 (20%) in the control group (χ(2) P = .867). Survival analysis, and subgroup and unmatched analyses showed similar results. In the fondaparinux group, 60% of patients received prophylactic doses. Fondaparinux has similar effectiveness and safety as argatroban and danaparoid in patients with suspected HIT. Prophylactic fondaparinux doses seem to be effective if no indication for full anticoagulation exists.

Topics: Aged; Anticoagulants; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Polysaccharides; Propensity Score; Retrospective Studies; Thrombocytopenia; Thrombosis; Treatment Outcome

Fondaparinux was associated with reduced major bleeding events and improved survival compared with low-molecular-weight heparin (LMWH) in a large randomized clinical trial involving patients with non-ST-segment elevation myocardial infarction (NSTEMI). Large-scale experience of the use of fondaparinux vs LMWH in a nontrial setting is lacking.. To study the association between the use of fondaparinux vs LMWH and outcomes in patients with NSTEMI in Sweden.. Prospective multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry involving 40,616 consecutive patients with NSTEMI who received fondaparinux or LMWH between September 1, 2006, through June 30, 2010, with the last follow-up on December 31, 2010.. In-hospital treatment with fondaparinux or LMWH during the hospital stay.. In-hospital severe bleeding events and death and 30- and 180-day death, MI, stroke, and major bleeding events. Logistic regression models adjusted for calendar time, admitting hospital, baseline characteristics, and in-hospital revascularization.. In total, 14,791 patients (36.4%) were treated with fondaparinux and 25,825 (63.6%) with LMWH. One hundred sixty-five patients (1.1%) in the fondaparinux group vs 461 patients (1.8%) in the LMWH group experienced in-hospital bleeding events (adjusted odds ratio [OR], 0.54; 95% CI, 0.42-0.70). A total of 394 patients (2.7%) in the fondaparinux group died while in the hospital vs 1022 (4.0%) in the LMWH group (adjusted OR, 0.75; 95% CI, 0.63-0.89). The differences in major bleeding events and mortality between the 2 treatments were similar at 30 and 180 days. There were no significant differences in the number of recurrent MI and stroke events at 30 or 180 days among the 2 treatment groups.. In routine clinical care of patients with NSTEMI, fondaparinux was associated with lower odds than LMWH of major bleeding events and death both in-hospital and up to 180 days afterward.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Electrocardiography; Female; Fondaparinux; Glomerular Filtration Rate; Hemorrhage; Heparin, Low-Molecular-Weight; Hospital Mortality; Humans; Kidney Diseases; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Polysaccharides; Registries; Sweden

Topics: Blood Coagulation; Drug Administration Schedule; Drug Interactions; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Risk Factors; Thromboembolism; Treatment Outcome; Venous Thrombosis

To evaluate the average duration of in-hospital treatment with fondaparinux 2.5mg prescribed for venous thromboprophylaxis in acutely ill medical patients and to describe the treatment population.. Prospective, observational, national, multicentre, epidemiological study, performed in France at the request of the Transparency Commission of the French National Health Authority (Haute Autorité de Santé). This is part of a larger study program that also included a study with similar design in the general practice setting. The hospital practice part of the study was conducted by hospital pharmacists who were asked to include the first 15 adult subjects hospitalized in a non-surgical ward for whom fondaparinux 2.5mg was initiated for prophylaxis.. Fifty-three pharmacists (49.5%) included a total of 718 patients. The average age was 71 ± 16 years (47%<75 years old); 54% were women. For 41% of patients, duration of fondaparinux 2.5mg administration ranged from 6 to 14 days. Eighty-five percent of patients had at least one acute illness related to the prescription of fondaparinux 2.5mg for thromboprophylaxis. Ten percent of the population had at least one risk factor listed on the Case Report Form. Characteristics of patients from the hospital practice study differ from those included in the general practice part of the ArchiMed Study program.. The hospital practice part of the ArchiMed Study, which is similar to "audits of practices", shows that the real-life conditions of prescription of fondaparinux 2.5mg in patients hospitalized are generally in line with guidelines with respect to indication for thromboprophylaxis in acute medical illness.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Bed Rest; Body Mass Index; Creatinine; Diagnosis-Related Groups; Drug Utilization; Female; Fondaparinux; France; Hemorrhage; Hospital Departments; Humans; Length of Stay; Male; Middle Aged; Pharmacy Service, Hospital; Polysaccharides; Postoperative Complications; Practice Guidelines as Topic; Prospective Studies; Risk Factors; Socioeconomic Factors; Thrombophilia; Venous Thromboembolism; Young Adult

Acute coronary syndrome (ACS) refers to a spectrum of life-threatening cardiac diseases usually due to coronary artery plaque rupture, subsequent thrombin generation plaque activation and thrombus formation. To date, no economic analyses have been published about the use of fondaparinux in NSTE-ACS patients in Canada. The purpose of our study is to estimate the lifetime cost-effectiveness of fondaparinux compared to enoxaparin for non-ST-elevation acute coronary syndrome (NSTE-ACS) patients in a Canadian hospital setting.. As an extension of a previous published economic analysis for US patients, an event-based decision analytic model was constructed using clinical and resource use data from OASIS-5, a randomized trial of 20,078 patients from 41 countries. A public payer perspective in the hospital setting was adopted. Resource use data from the trial were valued using Canadian costs. A cost regression model was developed to estimate the mean cost of managing the clinical events over the 180 day period. Annual costs of long-term care for ACS patients were added after 180 days until death. Long-term survival was incorporated using Canadian life tables with further adjustment for additional risks associated with NSTE-ACS. Quality-of-life (utility) decrements from published sources were applied to clinical events. Lifetime costs (2009 CAD$) and quality-adjusted life-years (QALYs), discounted annually at 5 %, were estimated for the typical patient in OASIS-5 (i.e., at mean covariate values).. The trial data showed that fondaparinux is protective against all clinical events observed in the trial. The model showed that: over 180 days, fondaparinux dominates enoxaparin, producing similar estimates of QALYs gained and saving $439; over a patient's lifetime, fondaparinux yields an ICER of $4293/QALY. Based on PSA, the probabilities that fondaparinux dominates enoxaparin (less costly and more effective) and that is cost-effective at a $50,000 threshold were 42 % and 96 %, respectively.. In the Canadian hospital setting, fondaparinux is cost-effective when compared to enoxaparin for the treatment of NSTE-ACS. This result holds both in the immediate post-event period and over the lifetimes of patients.

Topics: Acute Coronary Syndrome; Anticoagulants; Canada; Cost-Benefit Analysis; Decision Support Techniques; Drug Costs; Enoxaparin; Fondaparinux; Hemorrhage; Hospital Costs; Humans; Models, Economic; Polysaccharides; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Treatment Outcome

There is scarce evidence to identify which acutely ill medical patients might benefit from prophylaxis against venous thromboembolism (VTE).. The Spanish National Discharge Database was used to identify predictors of bleeding and VTE during hospitalization for an acute medical illness.. Of 1,148,301 patients, 3.10% bled, 1.21% were diagnosed with VTE, and 8.64% died. The case-fatality rate was: 20.8% for bleeding and 19.7% for VTE. Eight clinical variables were independently associated with an increased risk for VTE and bleeding, one with a decreased risk for both events, 4 with an increased risk for VTE and a decreased risk for bleeding, 2 with an increased risk for bleeding but a decreased risk for VTE, and 1 with a decreased risk for bleeding. When all these variables were considered, we composed a risk scoring system, in which we assigned points to each variable according to the ratio between the odds ratio for bleeding and for VTE. Overall, 21% of patients scored less than 0 points and had a bleeding vs. VTE ratio of 1.19; 55% scored 0 to 1.0 points and had a ratio of 2.13; and 24% scored over 1.0 points and had a ratio of 6.10.. A risk score based on variables documented at admission can identify patients with different ratios (near 1.0; about 2.0; and >6.0) between the rate of bleeding and of VTE.

Topics: Acute Disease; Aged; Aged, 80 and over; Anticoagulants; Chemoprevention; Comorbidity; Databases, Factual; Female; Fondaparinux; Heart Failure; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Male; Middle Aged; Polysaccharides; Pulmonary Embolism; Respiratory Insufficiency; Risk Assessment; Risk Factors; Spain; Venous Thromboembolism; Venous Thrombosis

Thromboprophylaxis is recommended for preventing postoperative venous thromboembolism (VTE) after abdominal surgery; however, its use after major hepatobiliary-pancreatic surgery is typically avoided as it increases the risk of bleeding. We conducted this study to evaluate the safety of thromboprophylaxis after major hepatobiliary-pancreatic surgery.. We analyzed the rates of postoperative bleeding, VTE, morbidity, and prolonged hospital stay in 349 patients who underwent major hepatobiliary-pancreatic surgery, such as pancreaticoduodenectomy, hemihepatectomy or greater, and hepatopancreaticoduodenectomy.. Chemical thromboprophylaxis was associated with significantly increased rates and risks of overall bleeding events vs. no chemical thromboprophylaxis (26.6 vs. 8.5%, respectively). The rate of minor hemorrhage was significantly higher in patients who received chemical thromboprophylaxis (21.7 vs. 3.5%); however, there were no differences in the rate of major hemorrhage requiring blood transfusion or hemostatic intervention between the groups (4.8 vs. 4.9%). The postoperative VTE rate was also significantly decreased by chemical thromboprophylaxis (2.9 vs. 7.7%). However, chemical thromboprophylaxis did not affect the rate of SSI, severe morbidity, or duration of the postoperative hospital stay.. We consider that chemical thromboprophylaxis is beneficial and can be safely used even after major hepatobiliary-pancreatic surgery.

Topics: Aged; Anticoagulants; Asian People; Enoxaparin; Female; Fondaparinux; Hemorrhage; Hepatectomy; Humans; Length of Stay; Male; Middle Aged; Morbidity; Pancreaticoduodenectomy; Polysaccharides; Postoperative Complications; Risk; Safety; Treatment Outcome; Venous Thromboembolism

Venous thromboembolism (VTE) is one of the leading causes of morbidity and mortality in acutely ill medical patients. Fondaparinux is recommended for the prevention of VTE in this setting, but little information is available on its safety and effectiveness in unselected, "real world" patients. The aim of this paper was to assess the safety and efficacy of fondaparinux in elderly acutely ill medical patients.. Single center, retrospective study. All patients >60 years, admitted for acute medical disease, bedridden for at least four days and treated with fondaparinux were evaluated. Occurrence of objectively documented, symptomatic VTE, and of bleeding events during the treatment period and follow-up were reported.. Two hundred and ten patients (median age 81 years) were treated with fondaparinux. Seventy patients received fondaparinux 1.5 mg daily, 140 received the 2.5 mg daily dose. However, 29 patients in the first group (with a CrCl≥50 mL/min) and 84 patients in the last group (with a CrCl<50 mL/min) did not receive the correct dose of fondaparinux. During treatment, one episode (0.48%, 95% CI 0.1% to 2.6%) of major bleeding and 6 episodes (2.86%, 95% CI 1.3% to 6.1%) of clinically relevant non major bleeding were recorded. Only one thromboembolic event (0.48%, 95% CI 0.1% to 2.6%) was documented. Thirty-nine patients died; no death was related to VTE, unlike one death was due to major bleeding. Cancer was the only significant predictor of bleeding at statistical analysis.. In elderly acutely ill hospitalized medical patients, thromboprophylaxis with fondaparinux 2.5 or 1.5mg daily is safe and effective in preventing VTE without increasing bleeding risk.

Topics: Acute Disease; Aged; Aged, 80 and over; Anticoagulants; Drug Administration Schedule; Female; Fondaparinux; Hemorrhage; Humans; Incidence; Inpatients; Italy; Male; Medical Records; Polysaccharides; Renal Insufficiency, Chronic; Retrospective Studies; Venous Thromboembolism

The incidence of venous thrombotic events (VTE) and use of anticoagulants in children have both risen over time. It is imperative that safety and efficacy studies of newer anticoagulants include children.. The purpose of this study was to investigate the long-term safety, dosing, and efficacy of fondaparinux in children.. The study included children 1-18 years old treated with fondaparinux at Children's Hospital Los Angeles. Descriptive statistics were used to present our findings.. Data from 35 patients were collected and analyzed. Fourteen of 22 evaluable patients (63.6%) had complete resolution of their thrombus, 6/22 (27.3%) had partial resolution, and 2/22 (9.1%) had no change. Ten patients needed a total of 16 dose adjustments over a median 152 days treatment duration to achieve therapeutic levels. Two patients (9.1%) had VTE recurrence. There were 3 major (intracranial hemorrhage- prior to initiation of fondaparinux, pulmonary hemorrhage, and subretinal hemorrhage) and 6 minor (2 with blood in stool, 1 with injection site, 1 CVC site, 1 tracheostomy bleed, 1 epistaxis) bleeding events.. In this long-term follow-up study on children treated with fondaparinux for VTE, 90.9% of patients had either complete or partial resolution while the recurrence rate was in line with previous studies. There were 9 bleeding events (3 major and 6 minor), though only 1 event required the discontinuation of fondaparinux. Given the advantages of fondaparinux over other anticoagulants, this study suggests that fondaparinux could be considered a safe and effective alternative for the management of VTE in children.

Topics: Adolescent; Age Factors; Anticoagulants; Child; Child, Preschool; Drug Administration Schedule; Drug Dosage Calculations; Female; Follow-Up Studies; Fondaparinux; Hemorrhage; Hospitals, Pediatric; Humans; Infant; Los Angeles; Male; Polysaccharides; Prospective Studies; Recurrence; Retrospective Studies; Time Factors; Treatment Outcome; Venous Thromboembolism

Topics: Anticoagulants; Cardiology; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hospitalization; Humans; International Cooperation; Neoplasms; Polysaccharides; Renal Insufficiency; Societies, Medical; Thrombocytopenia; Venous Thromboembolism

Venous thromboembolism (VTE) causes significant morbidity and mortality in surgical patients. Despite strong evidence that thromboprophylaxis reduces the incidence VTE, guidelines for prophylaxis in otolaryngology are not well established. Key to the development of VTE prophylaxis recommendations are effective VTE risk stratification and evaluation of the benefits and harms of prophylaxis.. To evaluate the effectiveness and safety of VTE chemoprophylaxis among a population of otolaryngology patients stratified by risk.. Retrospective cohort study of 3498 adult patients admitted for otolaryngologic surgery at a single-institution academic tertiary care medical center between September 1, 2003, and June 30, 2010.. Patients were stratified into 2 groups based on whether they received VTE chemoprophylaxis.. Incidence of VTE and bleeding-related complications within 30 days after surgery.. Of 1482 patients receiving VTE chemoprophylaxis, 18 (1.2%) developed a VTE compared with 27 of 2016 patients (1.3%) who did not receive prophylaxis (P = .75). Patients with Caprini VTE risk scores greater than 7 were less likely to have a VTE with perioperative chemoprophylaxis (5.3% vs 10.4%; P = .06). Of patients with VTE chemoprophylaxis, 3.5% developed a bleeding complication compared with 1.2% of patients without prophylaxis (P < .001). Bleeding complications were associated with concomitant use of antiplatelet medications and chemoprophylaxis. Among patients undergoing free tissue transfer, chemoprophylaxis significantly decreased the incidence of VTE (2.1% vs 7.7%; P = .002) and increased bleeding complications (11.9% vs 4.5%; P = .01). In all other patients, VTE chemoprophylaxis did not significantly influence the likelihood of VTE (1.0% vs 0.6%; P = .12) or bleeding (1.5% vs 0.9%; P = .15).. Effectiveness and safety of VTE chemoprophylaxis differed between patient subgroups, defined by Caprini risk score and by procedure. Effectiveness was most evident in patients with high Caprini risk scores and microvascular free tissue reconstruction. Bleeding complications were associated with VTE chemoprophylaxis administered in close proximity to potent antiplatelet therapy. The Caprini risk assessment model appears to be an effective tool to stratify otolaryngology patients by risk for VTE. Patients undergoing free tissue reconstruction merit further study before developing recommendations for VTE prophylaxis because of their higher risk of both VTE and bleeding.

Topics: Anticoagulants; Enoxaparin; Fondaparinux; Free Tissue Flaps; Hemorrhage; Heparin; Humans; Incidence; Otolaryngology; Otorhinolaryngologic Surgical Procedures; Polysaccharides; Retrospective Studies; Risk Assessment; Venous Thromboembolism

Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.

Topics: Animals; Anticoagulants; Antidotes; Benzamides; Dose-Response Relationship, Drug; Enoxaparin; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Hemostasis; Male; Mice; Mice, Inbred C57BL; Morpholines; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Rabbits; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Rivaroxaban; Thiophenes

Heparin and its analogs, mediating their anticoagulant activity through antithrombin (AT) activation, remain largely used for the preventive and curative treatment of thrombosis. The major adverse reaction of these drugs is the bleeding risk associated with overdose. Unfractionnated heparin (UFH) can be efficiently and rapidly neutralized by protamine sulfate, but this reversal partially neutralizes low-molecular-weight heparin (LMWH) and is inefficient in reversing fondaparinux. To secure administration of AT-mediated anticoagulants and counteract bleeding disorders, we previously designed a recombinant inactive AT as an antidote to heparin derivatives.. To get around the limited production level of recombinant AT, we propose in this study an alternative strategy to produce a chemically modified inactive AT, exhibiting increased heparin affinity, as an antagonist of heparin analogs.. Plasma-derived AT was chemically modified with 2,3 butanedione, a diketone known to specifically react with the arginine side chain. The chemical reaction was conducted in the presence of heparin to preserve basic residues within the heparin binding site from modifications.. AT treated by butanedione and selected for its high heparin affinity (AT-BD) was indeed modified on reactive Arg393 and thus exhibited decreased anticoagulant activity and increased heparin affinity. AT-BD was able to neutralize anticoagulant activity of heparin derivatives in vitro and in vivo and was devoid of intrinsic anticoagulant activity, as assessed by activated partial thromboplastin time assay.. AT-BD appears to be as efficient as protamine to neutralize UFH in vivo but could be more largely used because it also reverses fondaparinux and LMWH.

Topics: Animals; Anticoagulants; Antithrombins; Arginine; Diacetyl; Drug Design; Female; Fondaparinux; Hemorrhage; Heparin; Heparin Antagonists; Humans; Mass Spectrometry; Mice; Partial Thromboplastin Time; Polysaccharides; Recombinant Proteins; Risk

To assess adherence to French guidelines for curative treatment of thromboembolism in cancer patients, and to identify factors limiting their implementation.. Retrospective analysis of the medical files of cancer patients diagnosed with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in one site between January 1st, 2010 and June 30th, 2011. Central venous catheter thrombosis and superficial vein thrombosis were excluded.. The series included 145 patients, among whom 113 (78%) had solid tumors (at a metastatic stage in 68% of cases) and 33 (22%) had hematologic malignancies. Low molecular weight heparin (LMWH) was prescribed as long-term treatment (>10 days) for 83 patients (57.2%) and a vitamin K antagonist (VKA) for 33 patients (22.7%). Bleeding required treatment modifications or discontinuation in 11 (7.5%) and 10 (6.8%) patients respectively. After 6 months, LMWH, VKA and fondaparinux were prescribed for 28, 27 and six (19.3%, 18.6% et 4.1%) patients respectively. Mean duration of anticoagulation was 176.8 days. Treatment was not affected by a history of venous thromboembolism, the presence of pulmonary embolism or proximal deep vein thrombosis but it was significantly shorter in case of thrombosis limited to muscular veins (115.5 vs 182.3 days, P<0.05). Overall, guidelines were fully implemented in only 68 (46.9%) patients, with regards to the choice of pharmacological class and duration of treatment.. Adherence to national guidelines is insufficient and actions must be taken to improve the management of venous thromboembolism in cancer patients.

Topics: 4-Hydroxycoumarins; Adult; Aged; Aged, 80 and over; Anticoagulants; Drug Administration Schedule; Drug Utilization; Female; Fondaparinux; France; Guideline Adherence; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Polysaccharides; Practice Patterns, Physicians'; Pulmonary Embolism; Retrospective Studies; Thrombophilia; Thrombophlebitis; Ultrasonography, Doppler; Venous Thrombosis

Accelerated vascular calcification and increased risk of calciphylaxis can be a reason to restrict the use of vitamin K antagonists in dialysis patients. We describe the use of fondaparinux, a prototype indirect factor Xa inhibitor, as an alternative anticoagulant to coumarin derivatives in dialysis patients.. In this case series, we included six chronic haemodialysis patients treated with vitamin K antagonists. Low-molecular-weight heparin given as anticoagulant during dialysis was replaced by fondaparinux. Anti-Xa activity was regularly measured pre- and postdialysis to adapt the dose of fondaparinux. Adequate continuous anticoagulation and circuit patency were registered by evaluating clotting in the bubble trap and dialyser membrane at the end of dialysis.. Anticoagulation with fondaparinux at a starting dose of 2.5 mg resulted in an effective anticoagulation in the majority of dialysis sessions. Although median predialysis anti-Xa levels were significantly lower [0.36 IU/mL (0.30-0.42 IU/mL) (P < 0.0001)] than postdialysis levels [0.75 IU/mL (0.65-0.80 IU/mL)], predialysis anti-Xa levels were sufficient to limit the risk of thromboembolism. After an initial period of gradually increasing anti-Xa levels due to accumulation of fondaparinux, stable levels were achieved. Haemodialysis without clotting problems was possible in 96% of the sessions (clotting score ≤1), whereas two episodes (2/459 dialysis sessions) of major clotting were observed, defined as clotting of the extracorporeal circuit necessitating premature termination of the procedure.. We demonstrated that fondaparinux is a valuable anticoagulant for patients dialysed with low-flux membranes in need of continuous anticoagulation.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Contraindications; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Male; Polysaccharides; Renal Dialysis; Vitamin K; Warfarin

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Contraindications; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; Kidney Failure, Chronic; Polysaccharides; Renal Dialysis; Thromboembolism; Vascular Calcification; Vitamin K; Warfarin

Topics: Anesthesia; Animals; Anticoagulants; Arteries; Blood Pressure; Factor VIIa; Fondaparinux; Hemorrhage; Hemostasis; Male; Polysaccharides; Prothrombin; Rats; Rats, Wistar; Recombinant Proteins; Thrombin; Time Factors

The pentasaccharide fondaparinux is widely approved for prophylaxis and treatment of thromboembolic diseases and therapy of acute coronary syndrome. It is also used off-label in patients with acute, suspected or antecedent heparin-induced thrombocytopenia (HIT). The aim of this prospective observational cohort study was to document fondaparinux' prescription practice, tolerance and therapy safety in a representative mixed German single-centre patient cohort.. Between 09/2008 - 04/2009, 231 consecutive patients treated with fondaparinux were enrolled. Medical data were obtained from patient's records. The patients were clinically screened for thrombosis (Wells score), sequelae of HIT (4T's score), and bleeding complications (ISTH-criteria) and subjected to further assessment (i.e. sonography, HIT-diagnostics), if necessary. The mortality rate was assessed 30 days after therapy start.. Overall, 153/231 patients had a prophylactic, 74/231 patients a therapeutic, and 4/231 patients a successive prophylactic/therapeutic indication. In 11/231 patients fondaparinux was used due to suspected/antecedent HIT, in 5/231 patients due to a previous cutaneous delayed-type hypersensitivity to heparins. Other indications were rare. Three new/progressive thromboses were detected. No cases of HIT, major bleedings, or fatalities occurred.. Fondaparinux was well tolerated and was safe in prophylaxis and therapy; prescriptions mostly followed the current approval guidelines and were rarely related to HIT-associated indications (<5% of prescriptions), which is in contrast to previous study results in the U.S. (>94% of prescriptions were HIT-associated). A trend towards an individualised fondaparinux use based on the compound's inherent properties and the patients' risk profiles, i.e., antecedent HIT, bone fractures, heparin allergy, was observed.

Topics: Adult; Aged; Anticoagulants; Drug Hypersensitivity; Drug Prescriptions; Female; Fondaparinux; Germany; Hemorrhage; Heparin; Hospitals, University; Humans; Male; Middle Aged; Polysaccharides; Prospective Studies; Risk Assessment; Risk Factors; Thrombocytopenia; Thrombosis; Time Factors; Treatment Outcome

Prophylactic use of anticoagulants for septic patients in intensive care unit is a standard therapy for the prevention of venous thrombosis. Moreover, recent studies have demonstrated the anti-inflammatory effects of anticoagulants such as Factor Xa inhibitors and heparins. However, there have been no studies to examine the effects of fondaparinux and enoxaparin when applied in a sepsis model. Therefore, we examined the anti-inflammatory effects and bleeding events when these agents are applied in a lipopolysaccharide challenge model.. Wistar rats received lipopolysaccharides followed by a bolus infusion of fondaparinux, enoxaparin, or placebo. Microscopic observation of the mesenteric microcirculation for endothelial damage and measurement of bleeding area after vascular puncture was performed (n = 6 in each group). In another series, blood samples were taken, and blood cell counts, coagulation markers, and organ damage markers were measured (n = 6 in each).. Both leukocyte adherence to vascular endothelium and endothelial damage were reduced in fondaparinux and enoxaparin groups. The bleeding area was markedly increased in the fondaparinux group. Coagulation markers were maintained better in the enoxaparin group. Levels of organ damage markers were significantly suppressed in both fondaparinux and enoxaparin groups (p < 0.01, compared with control, each).. Fondaparinux and enoxaparin reduce organ dysfunction by decreasing endothelial damage. However, bleeding was more prominent in the fondaparinux group compared with the enoxaparin group at an equipotent dose for anti-Xa activity. Because the setting of this experiment is different from the clinical use, further study is required for the comparison of both pharmaceuticals.

Topics: Animals; Anticoagulants; Endothelium, Vascular; Endotoxemia; Enoxaparin; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Leukocytes; Lipopolysaccharides; Male; Polysaccharides; Rats; Rats, Wistar

This guideline addressed VTE prevention in hospitalized medical patients, outpatients with cancer, the chronically immobilized, long-distance travelers, and those with asymptomatic thrombophilia.. This guideline follows methods described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.. For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) and suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B). For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B). For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C). For critically ill patients, we suggest using LMWH or LDUH thromboprophylaxis (Grade 2C). For critically ill patients who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases (Grade 2C). In outpatients with cancer who have no additional risk factors for VTE we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B).. Decisions regarding prophylaxis in nonsurgical patients should be made after consideration of risk factors for both thrombosis and bleeding, clinical context, and patients' values and preferences.

Topics: Ambulatory Care; Combined Modality Therapy; Critical Care; Evidence-Based Medicine; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Immobilization; Intermittent Pneumatic Compression Devices; Neoplasms; Polysaccharides; Randomized Controlled Trials as Topic; Risk Factors; Societies, Medical; Stockings, Compression; Travel; Venous Thromboembolism

This article addresses the treatment of VTE disease.. We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence.. For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C).. Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences.

Topics: Administration, Oral; Anticoagulants; Diagnostic Imaging; Drug Administration Schedule; Evidence-Based Medicine; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Infusions, Intravenous; International Normalized Ratio; Long-Term Care; Polysaccharides; Pulmonary Embolism; Risk Factors; Societies, Medical; United States; Venous Thrombosis; Vitamin K

Despite the need for effective and safe thromboprophylactic drugs for patients with renal impairment, clinical trial data on anticoagulant agents are limited in this population. The study aim was to assess in the real-world setting the use of the once-daily 1.5 mg reduced dosage regimen of fondaparinux available for this context. In this prospective cohort study, patients with a creatinine clearance (CrCl) of 20-50 ml/minute, undergoing total hip (THR) or knee (TKR) replacement or hip fracture surgery (HFS) received fondaparinux thromboprophylaxis. Main clinical outcomes were bleeding (major/clinically relevant non-major), symptomatic venous thromboembolism (VTE) and death. Overall, 442 patients (353 women; median age: 82 years; 39.4% in ASA class ≥3; mean ± SD CrCl: 39.0 ± 8.0 ml/minute; 78% with additional risk factors for bleeding), undergoing THR (43.7%), TKR (27.6%), or HFS (28.7%) received fondaparinux 1.5 mg for a mean ± SD duration of 16.0 ± 12.5 days. At postoperative day 10, the rates (95% confidence interval) of major bleeding, clinically relevant bleeding and symptomatic VTE were 4.5% (2.8-6.9), 0.5% (0.1-1.6) and 0.5% (0.05-1.62), respectively; no fatal bleeding, bleeding into a critical organ, pulmonary embolism or proximal deep-vein thrombosis occurred. Corresponding rates at one month were 5.2%, 0.7% and 0.7%. One-month mortality was 2.3% (0.9-3.6). This large clinical prospective study provides for the first time, under conditions reflecting "real-world" routine clinical practice, data on the bleeding and VTE risks of thromboprophylaxis with fondaparinux 1.5 mg after major orthopaedic surgery in renally impaired patients. It shows that these patients constitute a very elderly and fragile population.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Biomarkers; Creatinine; Female; Fondaparinux; Fracture Fixation; France; Hemorrhage; Hip Fractures; Humans; Kidney; Logistic Models; Male; Middle Aged; Multivariate Analysis; Orthopedic Procedures; Polysaccharides; Prospective Studies; Renal Insufficiency; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism

Fondaparinux is an indirect, Factor Xa inhibitor that requires co-administration of another anticoagulant with anti-Factor IIa activity for percutaneous coronary intervention (PCI) per guideline recommendations. In this setting, the use of bivalirudin, a direct Factor IIa inhibitor, is not well established.. Using the Premier hospital database, we identified 971 patients who underwent elective or urgent PCI after receiving fondaparinux as the initial anticoagulant. They were treated with either bivalirudin ± glycoprotein IIb/IIIa inhibitor (GPI) (Group A=618) or unfractionated heparin (UFH) ± GPI (Group B=353) during PCI. A 2:1 propensity score matching (PSM) process was performed to control for patient and hospital level characteristics. The primary endpoints were to determine in-hospital death, bleeding and post-PCI length of stay (LOS) between treatment groups. After PSM, 512 matched patients were analysed (Group A=348 and Group B=174). In-hospital death was 1.4% in Group A vs. 2.9% in Group B (p=0.26). Clinically apparent bleeding occurred in 4.0% of Group A vs. 9.2% of Group B patients (p<0.02). Clinically apparent bleeding requiring transfusion was lower in Group A patients (0.6% vs. 2.9%; p=0.04). Post-PCI LOS was 1.9 ± 3.8 days for Group A and 2.4 ± 5.8 days for Group B (p=0.36). GPI use during PCI occurred in 9.2% of Group A vs. 44.8% of Group B patients (p<0.0001).. After initial administration of fondaparinux, a bivalirudin-based strategy for PCI is associated with significantly reduced bleeding, with similar mortality and post-PCI LOS when compared with an UFH-based strategy.

Topics: Aged; Anticoagulants; Antithrombins; Drug Therapy, Combination; Female; Follow-Up Studies; Fondaparinux; Hemorrhage; Heparin; Hirudins; Hospital Mortality; Humans; Incidence; Length of Stay; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Percutaneous Coronary Intervention; Polysaccharides; Prospective Studies; Recombinant Proteins; Retrospective Studies; Treatment Outcome

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Thrombosis; Enoxaparin; Evidence-Based Medicine; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Polysaccharides; Recombinant Proteins; Risk Assessment; Risk Factors; Treatment Outcome

Controversy exists regarding the optimal preventative therapy for venous thromboembolism (VTE) after coronary artery bypass graft (CABG) surgery. We sought to compare the effectiveness and safety of the most commonly used regimens.. We assembled a cohort of 92 699 patients who underwent CABG between 2004 and 2008, using the Premier database. Patients were categorized by method of VTE prevention initiated within 48 hours of surgery, including no preventative therapy (n=55 400), mechanical preventative therapy (n=21 162), subcutaneous unfractio--nated or low-molecular-weight heparin (n=10 718), subcutaneous fondaparinux (n=88), and concurrent mechanical-chemical therapy (n=5331). The incidence of VTE and major bleeding events within 6 weeks of CABG were compared, using multivariable and propensity score adjustment. The overall incidence of VTE for the entire cohort was 0.74%, and the incidence of major bleeding was 1.43%. VTE and bleeding events occurred with similar incidence in each of the patient categories (VTE: 0.70%, 0.79%, 0.81%, 1.14%, and 0.73%; major bleeding: 1.36%, 1.45%, 1.69%, 3.41%, 1.50%; no prevention, mechanical prevention, subcutaneous heparin, subcutaneous fondaparinux, concurrent mechanical-chemical prevention, respectively). Compared with receiving no prevention, the use of mechanical prevention or subcutaneous heparin did not significantly reduce the risk of VTE or change the risk of major bleeding (P=NS).. Venous thromboembolism occurs infrequently after CABG. Compared with the use of no prevention, the administration of chemical or mechanical preventative therapies to CABG patients does not appreciably lower the risk of VTE. These data provide support for the common practice of administering no VTE preventative therapy after CABG, used for nearly 60% of patients within this cohort.

Topics: Aged; Anticoagulants; Cohort Studies; Comorbidity; Coronary Artery Bypass; Databases, Factual; Female; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Polysaccharides; Postoperative Complications; Risk Factors; Stockings, Compression; Venous Thromboembolism

Patients with central nervous system (CNS) malignancies have a substantial risk for developing both thrombotic and bleeding disorders. The risk of venous thromboembolism (VTE) is substantially higher in these patients, both in the perioperative period and throughout their disease course. Patients with CNS malignancy harbor a latent hypercoagulability, which predisposes to VTE, as do postoperative immobility, hemiparesis, and other factors. The management of VTE in these patients is complex, given the significant morbidity and mortality associated with intratumoral hemorrhage. In the past, the perceived risk of intracranial hemorrhage limited the use of anticoagulation for the management of VTE with many favoring nonpharmacologic methods for prophylaxis and treatment. Inferior vena cava (IVC) filters have since lost favor at many centers given significant complications, which appear to be more frequent in patients with CNS malignancy. Recent studies have demonstrated safe and efficacious use of anticoagulation in these patients with a low incidence of intracranial hemorrhage. Treatment of established VTE is now recommended in this population with many centers favoring low-molecular-weight heparin (LMWH) versus oral warfarin for short- or long-term treatment. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, we recommend LMWH in patients with newly diagnosed VTE and a CNS malignancy.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Bevacizumab; Central Nervous System Neoplasms; Fondaparinux; Glioblastoma; Glioma; Hemorrhage; Heparin, Low-Molecular-Weight; Hirudins; Humans; Pipecolic Acids; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Vena Cava Filters; Venous Thromboembolism; Venous Thrombosis; Warfarin

Due to high health care costs of venous thromboembolism (VTE), economic analyses are needed to determine the efficiency of different drug treatments. Consequently, a study was conducted to estimate the budgetary impact for the National Health System (NHS) with apixaban for prevention of venous thromboembolism (VTE) in total hip (THR) or knee (TKR) replacement.. Cost considered: the drugs for the prevention of VTE (apixaban, dabigatran, enoxaparin, fondaparinux, other heparins, rivaroxaban and warfarin) and the complications of VTE in the short term and in 5 years (deep vein thrombosis, pulmonary embolism, bleedings and the post-thrombotic syndrome). The effectiveness of prophylaxis was estimated using a meta-analysis. The VTE rates and death with apixaban are lower in THR and TKR than enoxaparin (-3.5% and -10.0%, respectively) with less bleeding events (-0.7% and -1.6%, respectively). Population data and unit costs were obtained from Spanish sources.. 5 years. All costs were discounted by 3.5% annually. Five years after commercialization, the use of apixaban was estimated to account for 23% of the prophylaxis of VTE and the use of enoxaparin decrease from the 60% to 33%.. Apixaban´s introduction for the prophylaxis of VTE would have a significant impact for the NHS, resulting in a saving of 547,422 Euro over a period of 5 years. In the case of outpatient administration of heparin did not have a cost, the savings for the NHS five years amount to 270,068 Euro.. According to this study, the introduction of apixaban may reduce the rate of VTE and bleeding compared with enoxaparin, decreasing the expenditure of NHS in VTE prophylaxis.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Budgets; Cost Control; Dabigatran; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Morpholines; Polysaccharides; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Spain; State Medicine; Thiophenes; Venous Thromboembolism

As a potent anticoagulant agent, fondaparinux exposes a risk of bleeding. An effective way to reverse its effects is needed. It was the objective to study efficacy and safety of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of fondaparinux in a rabbit model of bleeding and thrombosis. In anaesthetised and ventilated rabbits, the Folts model was applied: a stenosis (75%) and an injury were carried out on the carotid artery, inducing thrombosis. Blood flow decreased as thrombus size increased until the pressure gradient was such that the thrombus was released and local blood flow was suddenly restored. This is known as a cyclic flow reduction (CFR). After the first CFR, rabbits were randomised into three groups: control (saline and saline after 1 minute), fondaparinux (fondaparinux [3 mg.kg-1] and saline), PCC (fondaparinux and PCC [40 UI.kg-1]). Then CFRs were recorded over 20 minutes. The following were measured: ear immersion bleeding time (BT), haemoglobin blood level (Hb1) and thrombelastometric parameters (ROTEM®). Finally, a hepatosplenic section was performed; 15 minutes later, the amount of blood loss was recorded as primary endpoint and Hb2 was measured. Blood loss was increased with fondaparinux and normalised with PCC. Regarding ROTEM® INTEM, fondaparinux increased clotting time and clotting formation time. PCC normalised these parameters. EXTEM and FIBTEM tests were not modified. Regarding safety, PCC did not increase CFRs. PCC reduced bleeding without increasing thrombosis and was effective to reverse the haemorrhagic effect of fondaparinux in this rabbit model.

Topics: Animals; Anticoagulants; Blood Coagulation Factors; Carotid Arteries; Disease Models, Animal; Fondaparinux; Hemorrhage; Polysaccharides; Rabbits; Regional Blood Flow; Thrombosis; Treatment Outcome

Heparin derivative-based therapy has evolved from unfractionated heparin (UFH) to low-molecular-weight heparins (LMWHs) and now fondaparinux, a synthetic pentasaccharide. Contrary to UFH or LMWHs, fondaparinux is not neutralized by protamine sulfate, and no antidote is available to counteract bleeding disorders associated with overdosing. To make the use of fondaparinux safer, we developed an antithrombin (AT) variant as a potent antidote to heparin derivatives. This variant (AT-N135Q-Pro394) combines 2 mutations: substitution of Asn135 by a Gln to remove a glycosylation site and increase affinity for heparins, and the insertion of a Pro between Arg393 and Ser394 to abolish its anticoagulant activity. As expected, AT-N135Q-Pro394 anticoagulant activity was almost abolished, and it exhibited a 3-fold increase in fondaparinux affinity. AT-N135Q-Pro394 was shown to reverse fondaparinux overdosing in vitro in a dose-dependent manner through a competitive process with plasma AT for fondaparinux binding. This antidote effect was also observed in vivo: administration of AT-N135Q-Pro394 in 2.5-fold molar excess versus plasma AT neutralized 86% of the anti-Xa activity within 5 minutes in mice treated with fondaparinux. These results clearly demonstrate that AT-N135Q-Pro394 can reverse the anticoagulant activity of fondaparinux and thus could be used as an antidote for this drug.

Topics: Amino Acid Substitution; Animals; Anticoagulants; Antidotes; Antithrombin Proteins; Antithrombins; Drug Design; Female; Fondaparinux; HEK293 Cells; Hemorrhage; Heparin Antagonists; Humans; Mice; Polysaccharides; Recombinant Proteins

Topics: Anticoagulants; Aortic Valve Stenosis; Aspirin; Drug Therapy, Combination; Fondaparinux; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Obesity; Platelet Aggregation Inhibitors; Polysaccharides; Postoperative Complications; Risk Factors; Thromboembolism; Time Factors; Treatment Outcome

Fondaparinux has a favourable efficacy-safety profile but if major bleeding occurs, reversal of antithrombotic treatment is challenging. We present clinical and biological observations from patients treated with rFVIIa for bleeding under fondaparinux.. Fondaparinux-treated patients with bleeding (>10% haematocrit decrease) and cardiovascular collapse were eligible. Patients received a single 90 μg/kg bolus rFVIIa. Clinical success was defined as clinical bleeding control without thrombotic complication. A biological criterion of successful antagonization was defined as a >100% increase in peak thrombin generation (C(max)).. 8 patients were treated (5 ACS, 3 VTE). Patients received aspirin and clopidogrel (n = 5), eptifibatide (n = 2), fluindione (n = 5). In addition to standard haemostatic methods, all patients received rFVIIa and transfusion. Clinical progression was favourable in 4, with bleeding clinically controlled in <6 h. 1 patient died. Biological success was observed in 4 patients with lowest baseline anti-Xa (0.67-0.92 U/L); ¾ had clinical success. In patients with baseline anti-Xa >1.0 U/L (1.14-1.62 U/L), increase in C(max) was low; ¾ had no clinical bleeding control.. This series is the largest describing rFVIIa use to control bleeding in patients under fondaparinux. rVFIIa was considered efficient in 50%, suggesting inefficacy in the context of elevated anti-Xa.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Anticoagulants; Blood Transfusion; Factor VIIa; Female; Fondaparinux; Hemorrhage; Humans; Male; Middle Aged; Polysaccharides; Prospective Studies; Recombinant Proteins; Treatment Outcome; Venous Thromboembolism

The number of spinal fusion operations in the USA is rapidly rising, but little is known about optimal venous thromboembolism prophylaxis after spinal surgery.. To examine the use of and outcomes associated with venous thromboembolism prophylaxis after spinal fusion surgery in a cohort of 244 US hospitals..  We identified all patients with a principal procedure code for spinal fusion surgery in hospitals participating in the Premier Perspective database from 2003 to 2005, and searched for receipt of pharmacologic prophylaxis (subcutaneous unfractionated heparin, low molecular weight heparin, or fondaparinux) and/or mechanical prophylaxis (compression devices and elastic stockings) within the first 7 days after surgery. We also searched for discharge diagnosis codes for venous thromboembolism and postoperative hemorrhage during the index hospitalization and within 30 days after surgery.. Among 80,183 spinal fusions performed during the time period, cervical fusions were the most common (49.0%), followed by lumbar fusions (47.8%). Thromboembolism prophylaxis was administered to 60.6% of patients within the first week postoperatively, with the most frequent form being mechanical prophylaxis alone (47.6%). Of the 244 hospitals, 26.2% provided prophylaxis to ≥ 90% of their patients undergoing spinal fusion; however, 33.2% provided prophylaxis to fewer than 50% of their patients. The rate of diagnosed venous thromboembolism within 30 days after surgery was 0.45%, and the rate of postoperative hemorrhage was 1.1%..  Substantial variation exists in the use of thromboembolism prophylaxis after spinal fusion surgery in the USA. Nevertheless, overall rates of diagnosed thromboembolism after spinal fusion appear to be low.

Topics: Adult; Aged; Chemoprevention; Cohort Studies; Databases, Factual; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Polysaccharides; Postoperative Complications; Retrospective Studies; Spinal Fusion; Stockings, Compression; Treatment Outcome; Venous Thromboembolism

Hospitalized cancer patients are at an increased risk for venous thromboembolism (VTE) and it is recommended they receive pharmacologic prophylaxis unless otherwise contraindicated. The majority of data supporting this recommendation comes from sub-group analyses and extrapolation of data gathered in general medical/surgical patients. This study seeks to assess the safety and efficacy of VTE prophylaxis in cancer patients admitted to our institution.. Charts of patients 18-89 years of age receiving VTE prophylaxis with unfractionated heparin, low molecular weigh heparin, or fondaparinux while admitted to Karmanos Cancer Center between September and October 2007 were retrospectively reviewed. Risk factors for VTE were assessed and the efficacy/safety of the prophylactic agents was compared.. One-hundred and eighty consecutive patients were identified. The average number of risk factors for developing VTE was 3-4 per hospital admission in addition to an active cancer diagnosis. Three VTEs occurred in the heparin group with two patients experiencing a VTE during their admission and one experiencing a VTE within 1 month after discharge. Four (2.6%) patients receiving heparin had a major bleeding event. Minor bleeding occurred in 14.3, 11.5, and 22.2% of patients receiving heparin, enoxaparin, and fondaparinux, respectively.. This retrospective study showed cancer patients are at increased risk for VTE, typically with 3-4 risk factors per admission. VTEs were uncommon; however, three patients receiving heparin experienced a VTE and four had a major bleeding event. Minor bleeding rates were similar among groups.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Drug Therapy, Combination; Enoxaparin; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Medical Records; Middle Aged; Neoplasms; Polysaccharides; Practice Guidelines as Topic; Pulmonary Embolism; Retrospective Studies; Risk Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Young Adult

Venous thromboembolism (VTE) remains a great challenge because of its frequency and of its potential severity. However, VTE treatment can also lead to iatrogenic complications. We report a case of thigh haematoma by a 83-year-old woman under fondaparinux for a solear thrombosis. Then we discuss the indications of Unfractionated Heparin (UFH), Low-Molecular-Weight Heparins (LMWH) and Fondaparinux, which are the three classes of rapidly acting anticoagulant treatments nowadays available. As their efficacy is comparable, the choice between these classes relies on the risk of adverse effects, which depends on some patient's characteristics. LMWH and fondaparinux are contra-indicated by the patients with a renal clearance under 30 ml/min. Only UFH are authorized during the whole pregnancy even though LMWH are more and more used. Fondaparinux has proven its safety by patients over 100 kg. UFH requires a daily biological management whereas it is optional for LMWH and fondaparinux, as long as their contra-indications are taken into account. No Heparin-induced-thrombocytopenia Syndrome (HIT-Sd) has been proven yet under fondaparinux so that platelets management seems not necessary, contrary to UFH and LMWH which require a twice-weekly platelets count. The accuracy of the therapeutic indication should result in the best benefit/risk assessment.

Topics: Aged, 80 and over; Anticoagulants; Female; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Thrombosis

Fondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Body Weight; Computer Simulation; Creatinine; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Fondaparinux; France; Hemorrhage; Humans; Kidney; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Orthopedic Procedures; Polysaccharides; Prospective Studies; Reproducibility of Results; Treatment Outcome; Venous Thromboembolism; Young Adult

Many acutely ill medical patients are at significant risk for developing venous thromboembolism (VTE) during hospitalization. Venous thromboembolism risk arises from both the presenting clinical condition as well as predisposing risk factors, such as advanced age. Thromboprophylaxis is underprescribed in these patients. Thrombotic risk assessment could encourage the prescribing of thromboprophylaxis and, therefore, improve patient protection against VTE. Current guidelines from the American College of Chest Physicians and the International Union of Angiology (IUA) recommend thromboprophylaxis with low-dose unfractionated heparin (UFH), a low-molecular-weight heparin (LMWH), or fondaparinux for acutely ill medical patients with VTE risk factors. However, the optimal dose regimen for UFH is unclear. The 2006 evidence-based guidelines from the IUA recommend a 3-times-daily dose regimen for UFH. However, UFH is usually administered twice daily despite a lack of evidence for the superiority of this regimen. Both heparin-induced thrombocytopenia and bleeding are associated with UFH, and to a lesser degree with alternative anticoagulants, such as the LMWHs. If utilized, an appropriate prophylaxis regimen in medical patients can reduce the risk of VTE and its burden.

Topics: Anticoagulants; Causality; Drug Administration Schedule; Drug Prescriptions; Drug Utilization; Evidence-Based Medicine; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Incidence; Patient Selection; Polysaccharides; Practice Guidelines as Topic; Practice Patterns, Physicians'; Risk Assessment; Time Factors; Venous Thromboembolism

Topics: Acute Coronary Syndrome; Anticoagulants; Enoxaparin; Fondaparinux; Hemorrhage; Humans; Myocardial Ischemia; Polysaccharides; Risk Assessment

Anticoagulant therapy is widely used for the management of acute coronary syndromes. In order to optimize patient outcomes, anticoagulants should ideally combine high antithrombotic efficacy with a low risk of bleeding. Intravenous unfractionated heparin has been in clinical use for more than 50 years and reduces the risk of recurrent ischemic events in patients with acute coronary syndromes but at the cost of increased bleeding. Enoxaparin, compared with intravenous unfractionated heparin, further reduces the risk of ischemic events but also increases bleeding. Neither of these approaches has been shown to reduce mortality. The synthetic parenteral Factor Xa inhibitor, fondaparinux, is highly effective for the prevention and treatment of venous thromboembolic disease in medical and surgical patients. The Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS) 5 and 6 trials evaluated the efficacy and safety of fondaparinux in more than 32,000 patients with non-ST elevation acute coronary syndromes or ST elevation myocardial infarction. This clinical trial report discusses the findings of these two pivotal trials.

Topics: Acute Coronary Syndrome; Anticoagulants; Double-Blind Method; Enoxaparin; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; Middle Aged; Myocardial Infarction; Polysaccharides; Randomized Controlled Trials as Topic

In the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference -8.3, 95% CI -16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Double-Blind Method; Enoxaparin; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Polysaccharides; Proportional Hazards Models; Pulmonary Embolism; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Secondary Prevention; Time Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Young Adult

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding. Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

Topics: Anticoagulants; Brain Ischemia; Evidence-Based Medicine; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Hirudins; Humans; International Normalized Ratio; Myocardial Infarction; Polysaccharides; Risk Factors; Severity of Illness Index; Thrombolytic Therapy; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Acute Disease; Anticoagulants; Arginine; Blood Coagulation; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Pipecolic Acids; Platelet Count; Polysaccharides; Recombinant Proteins; Research Design; Sulfonamides; Thrombin; Thrombocytopenia; Treatment Outcome; Venous Thrombosis; Warfarin

Deep vein thrombosis (DVT) remains a major burden and fondaparinux represents a new option for DVT therapy. We sought to determine if fondaparinux offered financial advantages over low-molecular weight heparin since it is given as a fixed dose over a wide range of patient weights rather then dosed directly on weight and because fondaparinux is not associated with heparin-induced thrombocytopenia (HIT).. We conducted a cost-minimization analysis comparing fondaparinux to enoxaparin for acute anticoagulation in DVT. We modeled a cohort of 1,000 hypothetical subjects and drew estimates for model inputs from the published literature. We completed multiple sensitivity analyses to asses the significance of our assumptions and used Monte Carlo simulation to estimate the 95% confidence intervals (CIs) around our estimation of the cost differential for the two agents.. In the base case, total disease management costs per patient with fondaparinux are US 472 dollars compared to 769 dollars with enoxaparin. The 95% CI around this difference ranges from US 48 dollars to US 401 dollars. The model was mildly sensitive to the pharmacy acquisition costs of fondaparinux and enoxaparin which was the major driver of overall costs. Neither the rates of nor costs associated with DVT recurrence, major bleeding, nor HIT substantially affected our observations. Breakeven analysis indicated our findings to be robust over a wide range of likely clinical scenarios.. From the perspective of a healthcare system, fondaparinux use offers an attractive economic alternative to other agents for initial DVT therapy. Expanded reliance on fondaparinux could potentially result in savings.

Topics: Body Weight; Costs and Cost Analysis; Enoxaparin; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Models, Economic; Polysaccharides; Recurrence; Thrombosis; Venous Thrombosis

Current anticoagulant therapies for the prevention and treatment of thromboembolic disorders have many drawbacks: vitamin K antagonists interact with food and drugs and require frequent laboratory monitoring, and heparins require parenteral administration. Oral rivaroxaban (BAY 597939) is a new, highly selective and potent direct factor-Xa (FXa) inhibitor with a predictable pharmacodynamic and pharmacokinetic profile and could therefore be an attractive antithrombotic drug. It was the objective of this study to investigate the antithrombotic efficacy of oral rivaroxaban in two rabbit models of experimental venous thrombosis. In the venous stasis (prevention) model, animals were randomized to receive oral rivaroxaban 0.3, 1.0, 3.0 or 10.0 mg/kg or vehicle control. Thrombosis was induced by jugular vein stasis and injection of thromboplastin into the ear vein. In the venous thrombosis (treatment) model, intravenous (1.0 and 3.0 mg/kg) and oral (3.0 mg/kg) rivaroxaban was compared with intravenous nadroparin (40 U bolus and 20 U/h), fondaparinux (42 microg/kg) and vehicle control. Thrombus growth was assessed by measuring the accretion of radiolabelled fibrinogen into preformed clots in the jugular veins. Bleeding was assessed using an ear bleeding model. In the prevention model, rivaroxaban reduced thrombus formation dose-dependently (calculated ED(50) 1.3 mg/kg). In the treatment model, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth to a similar extent to intravenous rivaroxaban (1.0 mg/kg), nadroparin and fondaparinux. Oral rivaroxaban did not prolong bleeding time. In conclusion, the orally available selective, direct FXa inhibitor rivaroxaban is effective in the prevention and treatment of venous thrombosis in two well-established models of experimental thrombosis.

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation Tests; Disease Models, Animal; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Infusions, Intravenous; Injections, Intravenous; Jugular Veins; Ligation; Morpholines; Nadroparin; Polysaccharides; Rabbits; Random Allocation; Rivaroxaban; Thiophenes; Thromboplastin; Venous Thrombosis

Topics: Aged; Anticoagulants; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Polysaccharides; Thromboembolism; Venous Thrombosis

Anticoagulant therapy plays an important role in current medical practice. The main types of anticoagulant agents are: heparins, hirudins and vitamin K antagonists. None of the drugs used as anticoagulants meet the criteria of an ideal anticoagulant because they have side effects and they interact with other compounds. The main side effect of anticoagulant therapy is bleeding. The choice of a certain anticoagulant is made by the doctor based on the clinical context and also on the desired effect.

Topics: Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Polysaccharides; Thrombocytopenia; Vitamin K; Warfarin

Topics: Anticoagulants; Enoxaparin; Fondaparinux; Hemorrhage; Humans; Myocardial Infarction; Polysaccharides

Topics: Angina, Unstable; Anticoagulants; Dose-Response Relationship, Drug; Enoxaparin; Fondaparinux; Hemorrhage; Heparin; Humans; Myocardial Infarction; Polysaccharides

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Artery Bypass; Drug Therapy, Combination; Enoxaparin; Fondaparinux; Hemorrhage; Heparin; Humans; Myocardial Infarction; Polysaccharides; Research Design

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Electrocardiography; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Humans; Intracranial Hemorrhages; Multicenter Studies as Topic; Myocardial Infarction; Polysaccharides; Recurrence; Risk; Treatment Outcome

Topics: Anticoagulants; Factor X; Fondaparinux; Hemorrhage; Humans; Myocardial Infarction; Polysaccharides; Risk

Topics: Anticoagulants; Factor X; Fondaparinux; Hemorrhage; Humans; Myocardial Infarction; Polysaccharides; Risk

Topics: Acute Disease; Anticoagulants; Antithrombin III; Coronary Disease; Drug Therapy, Combination; Electrocardiography; Fondaparinux; Hemorrhage; Heparin; Humans; Incidence; Myocardial Infarction; Platelet Aggregation Inhibitors; Polysaccharides; Registries; Severity of Illness Index; Syndrome; Thrombocytopenia

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a

Topics: Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Myocardial Ischemia; Oligosaccharides; Polysaccharides; Recurrence; Thrombin; Time Factors; Venous Thrombosis; Warfarin

Topics: Aged; Body Weight; Cause of Death; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Kidney; Male; Middle Aged; Polysaccharides; Recurrence; Treatment Outcome; Venous Thrombosis; Vitamin K

Rebound thrombin generation after successful thrombolysis might be related to (i) too short-term anticoagulant therapy and to (ii) the inability of heparin derivatives to inhibit clot-bound thrombin. To meet these shortcomings, a compound was synthesized, which consists of a pentasaccharide conjugated to a direct thrombin inhibitor. This compound (Org 42675) has a 10 times longer half-life compared with the original half-life of the direct thrombin inhibitor, while the thrombin inhibitory activity is maintained. An extra advantage of this product is the inhibitory activity on thrombin generation via antithrombin III (AT)-mediated factor (F)Xa inhibition. Org 42675 inhibited in vitro clot-bound thrombin with similar activity to the direct thrombin inhibitor argatroban. In experimental models in rats, Org 42675 showed on a molar base similar antithrombotic activity to unfractionated heparin, was more active than argatroban and was more active than fondaparinux sodium (AT-mediated FXa inhibitor) in arterial thrombosis. Finally, Org 42675 was far more active than the three reference compounds in an experimental thrombolysis model in rabbits. These properties of Org 42675, with its FXa and (clot-bound) thrombin inhibitory activity in combination with its long half-life, make this compound a powerful drug that is likely to be effective in the prevention of re-occlusion after successful thrombolysis in man.

Topics: Animals; Antithrombin III; Arginine; Blood Coagulation Tests; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Half-Life; Hemorrhage; Heparin; Male; Molecular Structure; Oligosaccharides; Pipecolic Acids; Polysaccharides; Rabbits; Rats; Rats, Wistar; Sulfonamides; Thrombin; Thrombolytic Therapy; Thrombosis

Topics: Arthroplasty, Replacement, Hip; Drug Administration Schedule; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Postoperative Complications; Thromboembolism; Venous Thrombosis

Topics: Arthroplasty; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Postoperative Complications; Venous Thrombosis

Topics: Arthroplasty; Enoxaparin; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Postoperative Complications; Venous Thrombosis

Topics: Anticoagulants; Clinical Trials as Topic; Dose-Response Relationship, Drug; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Injections, Intravenous; Polysaccharides; Postoperative Complications; Venous Thrombosis