fondaparinux and Acute-Disease

The initial treatment of haemodynamically stable patients with pulmonary embolism (PE) has dramatically changed since the introduction of low molecular weight heparins (LMWHs). With the recent discovery of the direct oral anticoagulant drugs (DOACs), initial treatment of PE will be simplified even further. In several large clinical trials it has been demonstrated that DOACs are not inferior to standard therapy for the initial treatment of PE, and because of their practicability they are becoming the agents of first choice. However, many relative contraindications to DOACs were exclusion criteria in the clinical trials. Therefore, LMWHs will continue to play an important role in initial PE treatment and in some cases there still is a role for unfractionated heparin (UFH). In this review we will give an overview of the biophysical, pharmacokinetic and pharmacodynamic properties of anticoagulants currently available for the initial management of PE. In addition, we will provide a comprehensive overview of the indications for the use of UFH, LMWHs and DOACs in the initial management of PE from a pharmacokinetic/-dynamic point of view.

Topics: Acute Disease; Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Fibrinolytic Agents; Fondaparinux; Hemodynamics; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Pulmonary Embolism; Treatment Outcome

Direct oral anticoagulants (DOACs) are attractive options for treatment of heparin-induced thrombocytopenia (HIT). We report our continuing experience in Hamilton, ON, Canada, since January 1, 2015 (when we completed our prospective study of rivaroxaban for HIT), using rivaroxaban for serologically confirmed HIT (4Ts score ≥4 points; positive platelet factor 4 [PF4]/heparin immunoassay, positive serotonin-release assay). We also performed a literature review of HIT treatment using DOACs (rivaroxaban, apixaban, dabigatran, edoxaban). We focused on patients who received DOAC therapy for acute HIT as either primary therapy (group A) or secondary therapy (group B; initial treatment using a non-DOAC/non-heparin anticoagulant with transition to a DOAC during HIT-associated thrombocytopenia). Our primary end point was occurrence of objectively documented thrombosis during DOAC therapy for acute HIT. We found that recovery without new, progressive, or recurrent thrombosis occurred in all 10 Hamilton patients with acute HIT treated with rivaroxaban. Data from the literature review plus these new data identified a thrombosis rate of 1 of 46 patients (2.2%; 95% CI, 0.4%-11.3%) in patients treated with rivaroxaban during acute HIT (group A, n = 25; group B, n = 21); major hemorrhage was seen in 0 of 46 patients. Similar outcomes in smaller numbers of patients were observed with apixaban (n = 12) and dabigatran (n = 11). DOACs offer simplified management of selected patients, as illustrated by a case of persisting (autoimmune) HIT (>2-month platelet recovery with inversely parallel waning of serum-induced heparin-independent serotonin release) with successful outpatient rivaroxaban management of HIT-associated thrombosis. Evidence supporting efficacy and safety of DOACs for acute HIT is increasing, with the most experience reported for rivaroxaban.

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Female; Fondaparinux; Heparin; Humans; Male; Middle Aged; Ontario; Polysaccharides; Rivaroxaban; Thrombocytopenia; Treatment Outcome

Topics: Acute Disease; Animals; Anticoagulants; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Humans; Injections, Subcutaneous; Polysaccharides; Pulmonary Embolism; Venous Thrombosis

Approximately 10% of all patients with acute pulmonary embolism (PE) die within the first three months after diagnosis. However, PE is not universally life-threatening, but covers a wide spectrum of clinical severity and death risk. Thrombolytic treatment is indicated patients with acute massive PE who are at high risk for early death, i.e. those patients who present with arterial hypotension and shock. On the other hand, low molecular-weight heparin or fondaparinux is adequate treatment for most normotensive patients with PE. Recombinant tissue plasminogen activator, given as 100 mg infusion over 2 h, is the treatment of choice for patients with PE, although older regimens using urokinase or streptokinase are also efficacious. Beyond the relatively small numbers of patients with massive, high-risk PE as a target population for thrombolysis, there is increasing awareness of the need for risk stratification of normotensive patients and the search for an intermediate-risk group (also called submassive PE). Recent meta-analyses of cohort studies suggest that imaging of the right ventricle or biomarkers of myocardial injury alone may be insufficient for guiding therapeutic decisions. Instead, accumulating evidence appears to support strategies which combine the information provided by an imaging procedure with a biomarker test. These data provide the rationale for a large multinational randomized trial which has set out to determine whether normotensive patients with right ventricular dysfunction, detected by echocardiography or computed tomography, plus evidence of myocardial injury as indicated by a positive troponin test, may benefit from early thrombolytic treatment. This study, which is underway in 13 European countries, will enroll a total of 1000 patients and will be completed in 2012. Together with a parallel trial currently being conducted in the United States, it will hopefully answer the question whether thrombolysis is indicated in submassive PE, thus terminating a 40-year-old debate and filling an important gap in our management concept for acute pulmonary embolism.

Topics: Acute Disease; Biomarkers; Clinical Trials as Topic; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Pulmonary Embolism; Radiography; Risk Factors; Streptokinase; Thrombolytic Therapy; Tissue Plasminogen Activator; Troponin; Urokinase-Type Plasminogen Activator; Ventricular Dysfunction, Right

Anticoagulants are the mainstay of treatment of venous thromboembolic and acute coronary events. Improvements of new over established anticoagulants are targeted to achieve more favorable pharmacokinetics, minimal hemorrhagic side effects, a predictable dose response that obviates the need for coagulation monitoring, and more appropriate dose selection for the indication of interest. New parenteral anticoagulants are free of the complications of HIT, can be selected so that they are safe in patients with impaired renal or hepatic function, and can be administered once daily without the need for coagulation monitoring. Drug development has been focused on two key targets: factor Xa and factor IIa (thrombin). Fondaparinux is the first selective inhibitor of the coagulation factor Xa which is commercially available for clinical use. It has been approved for the prevention of venous thromboembolism in patients undergoing orthopedic surgery, abdominal surgery and for the initial therapy of deep venous thrombosis and venous thromboembolism. Fondaparinux sodium injection has been accepted for priority review by the United States Food and Drug Administration based on positive results from two pivotal, Phase III trials (OASIS 5 and 6) that evaluated its role in the treatment of a broad spectrum of patients with acute coronary syndromes (ACS). In this article, we review the available literature that provides evidence for the efficacy of fondaprinux in management of thromboembolic disease as well as acute coronary syndromes.

Topics: Acute Disease; Animals; Anticoagulants; Coronary Disease; Fondaparinux; Humans; Polysaccharides; Thromboembolism

Topics: Acute Disease; Algorithms; Anticoagulants; Echocardiography, Transesophageal; Fibrin Fibrinogen Degradation Products; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Pulmonary Embolism; Risk Assessment; Tomography, X-Ray Computed; Vitamin K

The clinical presentation of pulmonary embolism (PE) varies widely, ranging from only limited symptoms to severe cardiogenic shock. Treatment of PE comprises initial therapy--with low-molecular-weight heparin (LMWH), fondaparinux, or unfractionated heparin--and long-term treatment, most commonly with vitamin-K antagonists (VKAs). Methods of risk stratification, to determine whether a patient will benefit from thrombolysis, are currently under investigation. However, at present, insufficient evidence exists that hemodynamically stable patients who demonstrate echocardiographic right ventricular strain (submassive PE) benefit from thrombolysis. By contrast, thrombolysis is a widely accepted treatment strategy for patients with hemodynamic shock (massive PE). The duration of VKA treatment is commonly 3-12 months and depends on the type of PE and on the balance between the risks of recurrent PE, major bleeding, and the patient's preference. In patients with a malignancy, treatment with LMWH during the first 6 months after diagnosis of PE is recommended. Several new oral anticoagulants, such as factor IIa and factor Xa inhibitors, are now being investigated. For prevention of recurrent PE in situations where anticoagulation is contraindicated, a temporary inferior vena cava filter might be useful. Some patients with PE can be safely treated at home, but few outcome studies in this setting have been published.

Topics: Acute Disease; Anticoagulants; Biomarkers; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Prothrombin; Pulmonary Embolism; Risk Assessment; Shock, Cardiogenic; Vitamin K

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

Fondaparinux (Arixtra, Sanofi-Synthelabo, Paris, France) is a pentasaccharide that selectively inhibits factor Xa; it is the first of a new class of synthetic antithrombotic agents. Fondaparinux has a linear pharmacokinetic profile allowing once-daily subcutaneous administration. Absence of metabolism, complete bioavailability, and lack of nonspecific binding in plasma contribute to the predictability of its effect. Fondaparinux has been approved for use in the prophylaxis of venous thromboembolism following orthopedic surgery. In this setting, it was found to reduce VTE risk by more than 50% in comparison with the low molecular weight heparin enoxaparin, with an incidence of clinically important bleeding not significantly different from that of standard low molecular weight heparin regimens. Furthermore, 4 weeks of prophylaxis with fondaparinux after hip fracture surgery was shown to reduce the risk of venous thromboembolism by 96% compared with 1-week prophylaxis. Finally, the efficacy and safety of fondaparinux in the treatment of venous thromboembolism and acute coronary syndromes appears promising.

Topics: Acute Disease; Antithrombin III; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Coronary Disease; Double-Blind Method; Female; Fondaparinux; Humans; Injections, Subcutaneous; Male; Meta-Analysis as Topic; Orthopedic Procedures; Polysaccharides; Pregnancy; Pregnancy Complications, Cardiovascular; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome; 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

No studies have compared treatment efficacy between subcutaneous (SC) fondaparinux and oral edoxaban, which are categorized as factor Xa inhibitors, for venous thromboembolism (VTE) in the acute phase, and only a limited number of imaging-based quantitative studies have evaluated treatment.Methods and Results:In this open-label, randomized study, 50 patients with acute non-massive pulmonary embolism (PE) and/or deep-vein thrombosis (DVT) were assigned to fondaparinux or edoxaban groups. Lower-limb venous ultrasonography (US), and chest computed tomography (CT) were compared before and 7 days after treatment. Thrombus volume in DVT was calculated using quantitative ultrasound thrombosis (QUT) score on US. For evaluation of PE thrombus volume, lung perfused blood volume (PBV) on CT was calculated. The measurements before and after treatment, respectively, were as follows: QUT score: fondaparinux, 8.1±7.3 to 4.1±4.5; edoxaban, 7.7±6.3 to 4.4±4.3, both significant decreases (P=0.001, P<0.001, respectively); lung PBV: fondaparinux, 32.0±7.8 to 32.1±8.2 HU; edoxaban, 34.2±8.6 to 38.5±11.8 HU (P=0.732, P=0.426, respectively). On subjective CT-based evaluation, all pulmonary artery-related filling defects decreased/disappeared after treatment in both groups (P=NS).. Both SC fondaparinux and oral edoxaban are effective in acute VTE. Effects on thrombus regression on imaging-based quantitative measurement did not differ between the 2 drugs.

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Cyclophosphamide; Female; Fondaparinux; Humans; Injections, Subcutaneous; Male; Middle Aged; Polysaccharides; Prospective Studies; Tomography, X-Ray Computed; Ultrasonography; Venous Thromboembolism

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

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

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

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

There remains considerable controversy regarding optimal initial warfarin dosing in patients with acute venous thromboembolism. Therefore, an open-label, randomized trial comparing 2 warfarin initiation nomograms (5 vs 10 mg) was conducted in patients with acute venous thromboembolism. All participants received fondaparinux for > or = 5 days as a "bridge" to warfarin. The primary end point was defined as the number of days necessary to achieve 2 consecutive international normalized ratio laboratory test values > 1.9. A total of 50 patients were enrolled and randomly assigned to each of the treatment arms. The median time to 2 consecutive international normalized ratios was 5 days in the 2 groups. There was no statistical difference in achieving the primary end point using either the 5- or the 10-mg nomogram (p = 0.69). These results should provide clinicians with increased warfarin dosing options in patients presenting with acute venous thromboembolism.

Topics: Acute Disease; Anticoagulants; Dose-Response Relationship, Drug; Factor X; Female; Fondaparinux; Humans; Male; Middle Aged; Polysaccharides; Thromboembolism; Treatment Outcome; Warfarin

Factor Xa plays a central role in the generation of thrombin, making it a novel target for treatment of arterial thrombosis. Fondaparinux, a synthetic pentasaccharide, is a factor Xa inhibitor, which has been shown to be superior to enoxaparin for the prevention of venous thrombosis. We designed a large, phase III, randomized trial to evaluate the efficacy and safety of fondaparinux compared with enoxaparin in acute coronary syndromes.. The OASIS-5 trial is a randomized, double-blind trial of fondaparinux versus enoxaparin in 20,000 patients with unstable angina or non-ST-segment elevation myocardial infarction. The primary objective is to determine whether fondaparinux is noninferior to enoxaparin in preventing the composite of death, new myocardial infarction, and refractory ischemia at 9 days (primary outcome) and at 30 days (secondary outcome) after randomization. There will be additional follow-up of all patients for 3 to 6 months after randomization. If noninferiority is established at 9 days, superiority will be tested. The primary safety outcome is to evaluate the rates of major bleeds in the 2 groups with the balance of benefit and risk assessed by comparing the impact on the composite of the primary and safety outcomes. Secondary outcomes are each component of the composite primary outcome separately at days 9, 30, and up to 6 months. The TIMACS, a major substudy using a partial 2x2 factorial design evaluating whether early angiography and intervention (within 24 hours) are superior to a more delayed approach (after 36 hours) in reducing major ischemic events at 6 months after randomization.. The MICHELANGELO OASIS 5 program will provide a comprehensive and reliable evaluation of fondaparinux in a broad spectrum of patients with ACS.

Topics: Acute Disease; Aged; Angina, Unstable; Anticoagulants; Coronary Disease; Double-Blind Method; Enoxaparin; Female; Fondaparinux; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Patient Selection; Polysaccharides

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 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

Heparin-induced thrombocytopenia (HIT) is a pro-thrombotic side effect of heparin therapy caused by HIT antibodies with platelet-activating properties. Recent advances in understanding of spontaneous HIT syndrome, which can occur even without any heparin exposure despite its clinical and serological characteristics being similar to those of HIT, reveal the following HIT clinical features atypical for an immune-mediated disease. Heparin-naïve patients can develop IgG antibodies as early as day 4, as in a secondary immune response. Evidence for an anamnestic response upon heparin re-exposure is lacking. In addition, HIT antibodies are relatively short-lived, unlike those in a secondary immune response. Antigen immunoassays are commonly used worldwide for serological diagnosis of HIT. However, such assays do not indicate whether HIT antibodies have platelet-activating properties, leading to low diagnostic specificity for HIT. The detection of platelet-activating antibodies using a washed platelet activation assay is crucial for making a HIT diagnosis. These atypical clinical and serological features should be carefully considered while appropriately diagnosing HIT, which leads to appropriate therapy such as immediate administration of an alternative anticoagulant for preventing thromboembolic events and re-administration of heparin during surgery involving cardiopulmonary bypass when HIT antibodies are no longer detectable.

Topics: Acute Disease; Animals; Fondaparinux; Heparin; Humans; Platelet Factor 4; Polysaccharides; Thrombocytopenia

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

to assess the current use of anticoagulants and implementation of International Guidelines in venous thromboembolism (VTE) prophylaxis in hospitalized patients with acute medical illnesses in Jakarta, Indonesia.. a multicenter, prospective, disease registry, recruiting patients diagnosed as acutely ill medical diseases and other medical conditions at risk of VTE, with in-hospital immobilization for at least 3 days.. of 401 patients, 46.9% received anticoagulants which included unfractionated heparin (64.4%), fondaparinux (11.7%), enoxaparin (9.6%), warfarin (3.7%), and combination of anticoagulants (10.6%). VTE prophylaxis using physical and mechanical method was used in 81.3% of patients, either as a single modality or in combination with anticoagulants. During hospitalization, VTE were found in 3.2% patients; 10 patients (2.5%) had lower limb events and 3 patients (0.75%) had a suspected pulmonary embolism. The main reference international guidelines used were AHA/ASA 2007 (47.4%), followed by ACCP 2008 (21.7%).. the study showed underutilization of prophylaxis anticoagulants in which mechanical thromboprophylaxis either alone or combination with anticoagulants was the most commonly used. Unfractionated heparin was the preferable choice. The most commonly used guideline was AHA/ASA 2007. VTE thromboprophylaxis in medically ill patients needs to be encouraged.

Topics: Acute Disease; Aged; Anticoagulants; Drug Therapy, Combination; Enoxaparin; Female; Fondaparinux; Heparin; Hospitalization; Humans; Indonesia; Male; Middle Aged; Polysaccharides; Practice Guidelines as Topic; Prospective Studies; Risk Factors; Venous Thromboembolism; Warfarin

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

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

Topics: Acute Disease; Anticoagulants; Axillary Vein; Chemical and Drug Induced Liver Injury; Child; Fondaparinux; Humans; Polysaccharides; Vascular Malformations

Some patients with acute VTE who may previously have been exposed to heparin products have unrecognized antibodies implicated in heparin-induced thrombocytopenia (HIT). Antibody prevalence and patient consequences upon exposure to heparin, low-molecular-weight heparin, and fondaparinux are uncertain.. In this secondary analysis, we tested patients in the Matisse VTE studies at study entry for heparin-dependent antibodies and further tested patients with enzyme-linked immunosorbent assay (ELISA)-positive results for platelet-activating antibodies. We compared the risk of HIT (> 50% fall in platelet count, heparin-dependent antibodies, no contradicting features) between patients treated with heparin (either unfractionated or low molecular weight [enoxaparin]) vs those who received fondaparinux. Comparison groups for thrombocytopenia occurrence comprised patients with ELISA-positive, platelet-activating, antibody-positive results; ELISA-positive, but platelet-activating antibody-negative results; and randomly selected antibody-negative results.. A total of 127 of 3,994 patients (3.2%) had ELISA-positive results at baseline, but only 14 (0.4%; 95% CI, 0.2%-0.6%) had platelet-activating antibodies. Among these 14, four treated with unfractionated or low-molecular-weight heparin developed HIT compared with zero of 10 fondaparinux-treated patients (OR, 95; 95% CI, 8-1,123; P < .001). This frequency (four of four, 100%) significantly differed from that of both heparin-treated patients whose results were ELISA positive but platelet-activating antibody negative and from heparin-treated antibody-negative control subjects (zero of 15 and zero of 27, respectively; P < .001 for both).. Of patients with VTE, 0.4% had pathologic platelet-activating heparin-dependent antibodies rather than the 3.2% detected by the recommended cutoff of the commercial ELISA. Among study patients with acute VTE who had platelet-activating antibodies, treatment with fondaparinux reduced the risk of precipitating rapid-onset HIT.

Topics: Acute Disease; Antibodies; Anticoagulants; Enzyme-Linked Immunosorbent Assay; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Platelet Factor 4; Polysaccharides; Thrombocytopenia; Venous Thromboembolism

Topics: Acute Disease; Aged; Anticoagulants; Coagulants; Factor VIIa; Fondaparinux; Hematoma, Subdural, Acute; Humans; Male; Polysaccharides; Recombinant Proteins; Stroke

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

Topics: Acute Disease; Anticoagulants; Bed Rest; Disease-Free Survival; Fondaparinux; Humans; Inpatients; Polysaccharides; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome; Venous Thrombosis

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

Fondaparinux sodium (fondaparinux) is a synthetic sulfated pentasaccharide anticoagulant developed from the antithrombin binding moiety of heparin. Through the activation of antithrombin it inhibits Factor Xa, the activation of thrombin, and the subsequent coagulation cascade. Fondaparinux is approved in Europe and the US for the treatment of acute venous thromboembolism (VTE), including both deep vein thrombosis (DVT) and pulmonary embolism (PE), when used in conjunction with warfarin. In phase III clinical trials, subcutaneous fondaparinux was noninferior to subcutaneous enoxaparin or intravenous unfractionated heparin (UFH) in the prevention of recurrent symptomatic VTE in patients with acute DVT and PE, respectively, and equally well tolerated. It thus provides a valuable alternative to UFH and low-molecular weight heparins in the treatment of acute VTE, particularly in the outpatient setting.

Topics: Acute Disease; Anticoagulants; Antithrombin III; Clinical Trials as Topic; Fondaparinux; Humans; Polysaccharides; Venous Thrombosis