fondaparinux and Renal-Insufficiency

Heparin, whose discovery goes back one hundred years, was first detected as a thromboplastin from liver tissue, and its anticoagulant action was only identified later. The procoagulant action of heparin, which was later characterized as an immunologic reaction by binding to platelet-factor IV, presenting as heparin-induced thrombocytopenia, remains as a side effect. For more than 60 years heparin has been the immediate anticoagulant of choice in many clinical indications. Further development of heparins resulted in the production of low-molecular weight heparins and Fondaparinux, which substituted heparin for many indications and has received many more new indications, including administration for non-anticoagulant purposes. This development is still ongoing and has resulted in more than 300 registered clinical trials at the end of 2015. All types of heparins are still investigated in patients with impairment of renal function to improve the safety of treatment. New therapeutic strategies for the prevention and treatment of thromboembolism, as well as of the non-anticoagulant actions of natural and modified types of heparins, are studied intensively. The clinical study designs include treatment with vitamin-K and non-vitamin K oral anticoagulants. Consequently, heparins, low-molecular weight heparins and Fondaparinux play an important role in the human health care system.

Topics: Anticoagulants; Clinical Trials as Topic; Drug Design; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Renal Insufficiency; Thromboembolism; Vitamin K

Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra®) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients.. Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence-based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Blood Coagulation Tests; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; International Normalized Ratio; Liver Failure; Metabolic Clearance Rate; Morpholines; Perioperative Care; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes; Thrombocytopenia; Thrombosis; Vitamin K

Proper administration of antithrombotic and antiplatelet drugs after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and renal insufficiency is a challenging task. In this study, we utilized Fondaparinux and Tirofiban (either separately or combined) to treat post-PCI patients with ACS and concurrent renal insufficiency. The patients were followed-up for 1 year. We observed that combined treatment led to a higher number of significant therapeutic effects and better reduced the frequency of bleeding events. Our findings indicate that combined antithrombotic and antiplatelet treatment improves the prognosis in patients with ACS and renal insufficiency who received PCI treatment.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Drug Combinations; Female; Fondaparinux; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Polysaccharides; Postoperative Complications; Renal Insufficiency; Tirofiban; Tyrosine

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

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 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

Fondaparinux is an antithrombin-dependent factor Xa inhibitor that is used for thromboprophylaxis of patients undergoing hip fracture surgery, hip or knee replacement, or abdominal surgery. It is cleared by the kidney and should be used with caution in patients with renal impairment and avoided in patients with severe renal insufficiency. Recently, several studies have demonstrated that a lower dose of fondaparinux in patients with moderate renal impairment appears to be safe and effective. The purpose of this study was to obtain pharmacokinetic and clinical data on the use of prophylactic fondaparinux in patients with renal insufficiency undergoing major abdominal surgery for cancer (n=8) or orthopedic surgery (n=1). Anti-factor Xa levels were obtained, and a published population pharmacokinetic model for fondaparinux was fit to the data. The data were analyzed using NONMEM software. Fondaparinux did not appear to accumulate in these patients, even when the drug was administered for up to twelve days. Pharmacokinetic analysis revealed that the apparent clearance in this population, who were primarily undergoing cancer surgery, was similar to prior studies in orthopedic surgery patients. In contrast, lower estimates were obtained for volume of distribution and absorption rate constant parameters. None of the patients sustained a hemorrhagic complication attributable to fondaparinux. One patient developed hypoxia in the setting of transient atrial fibrillation and clinical suspicion for pulmonary embolism, but this was not confirmed radiographically. These results support the use of 1.5mg of fondaparinux every 24hours for thromboprophylaxis in patients with renal insufficiency undergoing high-risk surgical procedures.

Topics: Aged; Aged, 80 and over; Anticoagulants; Fondaparinux; Humans; Male; Middle Aged; Polysaccharides; Postoperative Period; Prospective Studies; Renal Insufficiency; Risk Factors; Thromboembolism

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

Fondaparinux, a selective activator factor X (factor Xa) inhibitor, is effective and safe for preventing venous thromboembolism after major orthopaedic surgery (MOS) at the once-daily subcutaneous dose of 2.5 mg. As the drug is mainly eliminated by the kidneys, a reduced dosage (1.5 mg once daily) was developed for patients with renal impairment.. We studied the pharmacokinetics (PK) of this dosage regimen using data from a real-world cohort of 442 patients with renal impairment (creatinine clearance 20-50 ml/min) undergoing MOS. Data were analysed using NON-linear Mixed Effect Modelling software (NONMEM) software. Fondaparinux PK was modelled using a two-compartment model with first-order absorption.. This analysis confirmed the relationship between renal function and fondaparinux PK profiles. The mean predicted steady-state area under the plasma concentration time curve, peak and trough plasma concentrations of fondaparinux were lower by 15.6 %, 13.0 % and 10.3 %, respectively, in patients with renal impairment treated with 1.5 mg compared with patients with normal renal function treated with 2.5 mg (p < 0.01).. Although administration of 1.5 mg fondaparinux in patients with renal impairment resulted in a predicted exposure slightly lower than that achieved with 2.5 mg in patients with normal renal function, fondaparinux 1.5 mg is a valuable thromboprophylactic option in MOS patients with renal impairment who are at risk of bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Area Under Curve; Cohort Studies; Drug Administration Schedule; Factor Xa Inhibitors; Female; Fondaparinux; Humans; Kidney; Male; Orthopedic Procedures; Polysaccharides; Renal Insufficiency; Venous Thromboembolism

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

Initial treatment of venous thromboembolic events is currently based on antithrombotics. This treatment is validated and identical for deep vein thrombosis (DVT) and pulmonary embolism. For distal DVT, this treatment has still to be validated. This reference therapeutic strategy is firstly parenteral and based on low-molecular-weight heparins (LMWH) or fondaparinux, subcutaneously prescribed at fixed dosage based on body weight without any systematic dose adjustment on hemostasis tests. Unfractionated heparin is steel the reference treatment in case of severe renal insufficiency. This parenteral treatment has to be relieved by vitamin K antagonists (VKA). VKA has to be co-administrated for at least 3 days, without any loading dose and can be early initiated. VKA dose needs to be adjusted in order to maintain INR between 2 and 3. However, in case of cancer, LMWH have to be carried on for 6 months. A part this antithrombotic treatment, thrombolytics are recommended in case of massive PE and vena cava filter should be used in case of recurrence despite adequate antithrombotic treatment or in case of contraindication to antithrombotic.

Topics: Anticoagulants; Antifibrinolytic Agents; Factor X; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections, Intravenous; Injections, Subcutaneous; International Normalized Ratio; Polysaccharides; Pulmonary Embolism; Renal Insufficiency; Thromboembolism; Vena Cava Filters; Venous Thrombosis; Vitamin K

Venous thromboembolism (VTE) is a common complication among hospitalized patients. Pharmacological thromboprophylaxis has emerged as the cornerstone for VTE prevention. As trials on thromboprophylaxis in medical patients have proven the efficacy of both low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH), all acutely medical ill patients should be considered for pharmacological thromboprophylaxis. Unlike in the surgical setting where the risk of associated VTE attributable to surgery is well recognized, and where widespread use of pharmacological thromboprophylaxis and early mobilization has resulted in significant reductions in the risk of VTE, appropriate VTE prophylaxis is under-used in medical patients. Many reasons for this under-use have been identified, including low perceived risk of VTE in medical patients, absence of optimal tools for risk assessment, heterogeneity of patients and their diseases, and fear of bleeding complications. A consistent group among hospitalized medical patients is composed of elderly patients with impaired renal function, a condition potentially associated with bleeding. How these patients should be managed is discussed in this review. Particular attention is devoted to LMWHs and fondaparinux and to measures to improve the safety and the efficacy of their use.

Topics: Aged; Anticoagulants; Drug Monitoring; Fondaparinux; Guideline Adherence; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Practice Guidelines as Topic; Renal Insufficiency; Venous Thromboembolism