fondaparinux and Critical-Illness

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

Venous thromboembolism (VTE) is a frequent complication in cancer patients, and represents an important cause of morbidity and mortality. Especially in those patients who have a poor life expectancy, preventing death from pulmonary embolism is the mainstay of treatment. Critically ill patients should promptly be administered thrombolytic drugs. Except for selected patients requiring aggressive therapy, the initial VTE treatment should be conducted with adjusted-dose unfractionated heparin, fixed-dose low-molecular-weight heparin (LMWH) or fondaparinux. LMWHs and fondaparinux have the potential to greatly simplify the initial treatment of VTE, making the treatment of suitable patients feasible in an outpatient setting. During anticoagulant therapy, cancer patients have a twofold to fourfold higher risk of recurrent VTE and major bleeding complications when compared to non-cancer patients. The long-term administration of LMWH should be considered as an alternative to anti-vitamin K drugs in patients with advanced disease and in those with conditions limiting the use of oral anticoagulants. Prolongation of anticoagulation should be considered for as long as the malignant disorder is active.

Topics: Anticoagulants; Critical Illness; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Polysaccharides; Risk Assessment; Secondary Prevention; Venous Thromboembolism

In trauma patients, pulmonary embolism occurs in up to 4% of cases and carries a mortality of 20-50%. The incidence of deep vein thrombosis (DVT) varies from 5 to 63% depending on patients' risk factors, modality of prophylaxis, and methods of detection. For these reasons, trauma patients require adequate DVT prophylaxis.. Spinal fracture or cord injury patients are at particular risk. Increasing injury severity, head injury, older age, lower limb injuries, and obesity are other risk factors. The current standard of care for DVT prophylaxis is enoxaparin (a low molecular weight heparin) as long as anticoagulation is not contraindicated. Unfractionated heparin alone does not provide sufficient protection against DVT. Selective factor Xa inhibitors such as fondaparinux are showing promising results. Other strategies for pulmonary embolism prevention include: graduated compression stockings, sequential compression devices, continuous passive motion, and prophylactic inferior vena cava filter. There is lack of consensus regarding the optimal DVT prophylaxis in trauma patients and few level I recommendations exist.. Best practice in thromboprophylaxis for trauma patients will remain on the basis of recommendations until definitive risk-benefit ratios are determined to justify the use of various mechanical and pharmacological measures, in combination or alone.

Topics: Anticoagulants; Critical Illness; Enoxaparin; Factor Xa Inhibitors; Fondaparinux; Humans; Incidence; Polysaccharides; Pulmonary Embolism; Risk Factors; Time Factors; Venous Thrombosis; Wounds and Injuries

Fondaparinux, as a factor Xa-inhibitor, is used off label to manage heparin-induced thrombocytopenia (HIT), but little experience with HIT patients has been reported in the literature. Moreover, the use of fondaparinux for full anticoagulation in critically ill patients with HIT and renal insufficiency is limited.. A trauma patient, who had received low molecular weight heparin (LMWH) and heparin to treat venous thromboembolism, developed thrombocytopenia and multiple organ dysfunction in the intensive care unit (ICU). Also, her deep venous thromboembolism (DVT) continued to progress.. The final diagnosis was HIT.. Fondaparinux was temporarily used for anticoagulation treatment of DVT for 7 days when another anticoagulant (argatroban) was unavailable. Although the patient had kidney dysfunction, a full therapeutic dose of 7.5 mg fondaparinux was administered every morning through subcutaneous injection for consecutive 7 days.. The patient's thrombocytopenia and thrombosis were successfully treated without bleeding complications during therapeutic fondaparinux administration.. This is the first case reporting the successful use of fondaparinux for full anticoagulation for DVT in a critically ill patient with HIT and renal insufficiency. Our experience suggests that fondaparinux might be an alternative for anticoagulation treatment in patients with HIT and kidney dysfunction if another anticoagulant (argatroban) is unavailable.

Topics: Aged, 80 and over; Anticoagulants; Critical Illness; Factor Xa Inhibitors; Female; Fondaparinux; Heparin; Humans; Polysaccharides; Thrombocytopenia; Venous Thromboembolism

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

Pharmacologic options for venous thromboembolism (VTE) prophylaxis are often limited in critically ill patients due to thrombocytopenia and multisystem organ dysfunction. Fondaparinux offers potential advantages in the critically ill; however, it is currently contraindicated in severe renal dysfunction (SRD). We evaluated anti-factor Xa levels in critically ill patients with SRD who were receiving an extended interval dosing regimen of fondaparinux for VTE prophylaxis.. A prospective, single-arm, interventional study was conducted at two academic hospitals of the Detroit Medical Center. Eligible patients were in the intensive care unit, had an estimated creatinine clearance of less than 30 ml/minute, and had either acute kidney injury or end-stage renal disease; several patients were taking renal replacement therapy. Fondaparinux was administered at an extended interval dosing regimen of 2.5 mg subcutaneously every 48 hours. Fondaparinux peak and trough anti-factor Xa levels were obtained. Lower extremity venous duplex studies were performed at baseline and study completion to assess for deep vein thrombosis (DVT), and patients were monitored for bleeding complications.. Thirty-two patients were enrolled. Patients received a median of four doses (interquartile range two to five) of fondaparinux. Fondaparinux peak (n=98) and trough (n=86) anti-factor Xa levels were 0.36 ± 0.18 mg/L and 0.17 ± 0.11 mg/L (mean ± SD), respectively, and were similar to levels reported in patients with normal renal function receiving conventional once-daily dosing. No lower extremity DVTs or suspected VTE events occurred. Two (6%) patients had significant bleeding events.. In critically ill patients with SRD, an extended interval fondaparinux dosing regimen of 2.5 mg every 48 hours for VTE prophylaxis achieved peak and trough anti-factor Xa levels similar to those reported in noncritically ill patients with normal renal function receiving once-daily fondaparinux. This regimen offers an alternative for patients with SRD when heparinoids must be avoided.

Topics: Acute Kidney Injury; Critical Illness; Drug Administration Schedule; Drug Monitoring; Factor Xa; Factor Xa Inhibitors; Female; Fondaparinux; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polysaccharides; Prospective Studies; Severity of Illness Index; Venous 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

Venous thromboembolism is a common problem in the intensive care unit (ICU). To decrease its incidence, prophylactic pharmacologic interventions are part of the ICU routine. However, common ICU conditions may impair the bioavailability of subcutaneously administered agents. The present study evaluates the bioavailability of prophylactic subcutaneous fondaparinux to critically ill patients.. The purpose of the study was to evaluate vasopressor effect on the bioavailability of subcutaneously administered fondaparinux.. A 2-center, prospective, observational study was performed. Forty patients were enrolled and divided into 2 groups depending on their vasopressor requirements. All subjects were critically ill patients admitted to a medical ICU for an anticipated stay of more than 72 hours.. All patients received subcutaneous fondaparinux 2.5 mg/d, and serum anti-Xa factor was serially assessed during the first 100 hours of medical ICU stay.. Therapeutic anti-factor Xa levels among patients receiving vasopressors were observed. In hemodynamically normal patients, subtherapeutic concentrations were detected during the first 48 hours of fondaparinux administration.. Vasopressor therapy does not appear to affect fondaparinux bioavailability or to reduce anti-factor Xa levels. Subtherapeutic concentrations were detected during the first 48 hours of fondaparinux administration in hemodynamically stable patients. The clinical significance of reduced levels during the first 2 days of fondaparinux administration remains unknown.

Topics: Anticoagulants; Biological Availability; Critical Illness; Factor Xa Inhibitors; Female; Fondaparinux; Humans; Male; Middle Aged; Polysaccharides; Prospective Studies; Thromboembolism

In critically ill patients, heparin-induced thrombocytopenia (HIT) is estimated to account for approximately 1 to 10% of all causes of thrombocytopenia. HIT exerts a strong procoagulant state. In case of suspected HIT, it is an important clinical decision to stop heparin and start treatment with alternative nonheparin anticoagulation, awaiting the results of laboratory testing for the final diagnosis of HIT (bridging therapy). Fondaparinux acts by factor Xa inhibition and expresses no cross-reactivity with HIT antibodies. Excretion of fondaparinux is mainly renal. We describe our early experience with fixed low-dose fondaparinux bridging therapy and monitoring of anticoagulant activity for safety reasons.. This retrospective cohort study was conducted in a closed format general intensive care unit in a teaching hospital. Consecutive critically ill patients suspected of HIT were treated with fondaparinux after discontinuation of unfractionated heparin or nadroparin. Anti-Xa levels were determined afterwards.. Seven patients were treated with fondaparinux 2.5 mg/day for 1.8 to 6.5 days. Anti-Xa levels varied from 0.1 to 0.6 U/ml. A negative correlation was found between creatinine clearance and mean and maximum anti-Xa levels. No thromboembolic complications occurred. Bleeding complications were only minor during fondaparinux treatment. Transfusion requirements did not differ significantly between treatment episodes with fondaparinux or with heparin anticoagulants.. In this small sample of critically ill patients suspected of HIT, bridging therapy with fixed low-dose fondaparinux resulted in prophylactic and therapeutic anti-Xa levels. Monitoring of anticoagulant activity is advised in patients with renal insufficiency.

Topics: Aged; Aged, 80 and over; Anticoagulants; Chemoprevention; Critical Care; Critical Illness; Dose-Response Relationship, Drug; Drug Monitoring; Female; Fondaparinux; Heparin; Hospitals, Teaching; Humans; Intensive Care Units; Male; Middle Aged; Polysaccharides; Retrospective Studies; Thrombocytopenia