Evaluation and Pharmacokinetics of Treatment Dose Enoxaparin in Hospitalized Patients With Morbid Obesity.

BACKGROUND: The pharmacokinetic properties of enoxaparin may lead to supratherapeutic antifactor Xa (anti-Xa) levels and increased bleeding when standard treatment doses are used in patients with morbid obesity. OBJECTIVE: To evaluate the dose of enoxaparin needed to achieve therapeutic anti-Xa levels in a prospective, masked observational cohort of heterogeneous inpatients with morbid obesity and to determine whether patients with morbid obesity treated with 1 mg/kg of enoxaparin are at increased risk of supratherapeutic levels and bleeding events compared to patients receiving lower doses. METHODS: Hospitalized patients with a body mass index ≥40 kg/m(2) or actual body weight ≥140 kg and prescribed treatment doses of enoxaparin >60 mg per day were enrolled and consented to phlebotomy for determination of anti-Xa levels. RESULTS: Forty-one patients were included for data analysis. The dose of enoxaparin that resulted in therapeutic and supratherapeutic anti-Xa levels at steady state was 0.83 mg/kg and 0.98 mg/kg (-0.11; 95% confidence interval [CI] -0.20 to -0.01, P = .02), respectively. Enoxaparin dose as mg/kg of actual body weight was an independent predictor of having a supratherapeutic anti-Xa level. Patients with doses <0.95 mg/kg versus ≥0.95 mg/kg were less likely to have supratherapeutic levels (odds ratio 0.21 [95% CI 0.05-0.84], P = .02) and had similar rates of subtherapeutic levels. Doses <0.95 mg/kg and ≥0.95 mg/kg resulted in similar bleeding rates of 17.9% and 22.2% (P = .71), respectively. CONCLUSION: Patients with morbid obesity required less than the recommended 1 mg/kg enoxaparin dose to achieve therapeutic peak anti-Xa levels; therefore, initiation with lower dosages is prudent and anti-Xa monitoring should guide dosage adjustments.

Prevention and management of venous thromboembolism in the surgical patient: options by surgery type and individual patient risk factors.

BACKGROUND: Current evidence-based guidelines provide recommendations for prophylaxis and treatment of venous thromboembolism (VTE) in a variety of surgical patients. DATA SOURCES: A systematic Ovid Medline search (from 1950 to the present) was conducted for relevant articles using the following search terms: "venous thromboembolism," "thrombophlebitis," "thromboembolism," "pulmonary embolism," "heparin," "low-molecular-weight heparin," "postoperative complications," and "anticoagulants." CONCLUSIONS: Pharmacologic and mechanical approaches are available for VTE prophylaxis, including low-dose unfractionated heparin, low-molecular-weight heparin, vitamin K antagonists, fondaparinux, intermittent pneumatic compression devices, and graduated compression stockings. Permanent inferior vena cava filters are not recommended for primary VTE prophylaxis, although they do have a role in the prevention of pulmonary embolism in patients with recent VTE who cannot have surgery delayed. Retrievable inferior vena cava filters are under investigation for primary VTE prophylaxis in trauma patients. New anticoagulants that inhibit factor Xa and thrombin will soon be available for the prevention and treatment of VTE in surgical patients.

Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.

Dabigatran, an oral once-daily unmonitored thrombin inhibitor, has been tested elsewhere using enoxaparin 40 mg once daily. We used the North American enoxaparin 30 mg BID regimen as the comparator. This was a double-blind, centrally randomized trial. Unilateral total knee arthroplasty patients were randomized to receive oral dabigatran etexilate 220 or 150 mg once daily, or enoxaparin 30 mg SC BID after surgery, blinded. Dosing stopped at contrast venography, 12 to 15 days after surgery. Among 1896 patients, dabigatran 220 and 110 mg showed inferior efficacy to enoxaparin (venous thromboembolism rates of 31% [P = .02 vs enoxaparin], 34% [P < .001 vs enoxaparin], and 25%, respectively). Bleeding rates were similar, and no drug-related hepatic illness was recognized. Dabigatran, effective compared to once-daily enoxaparin, showed inferior efficacy to the twice-daily North American enoxaparin regimen, probably because of the latter's more intense and prolonged dosing.

Factors associated with thromboprophylaxis for orthopedic patients and their impact on outcome.

We conducted a study to identify the factors affecting inpatient thromboprophylaxis use and to assess the impact of pharmacologic prophylaxis on the incidence of postsurgical venous thromboembolism (VTE). Our ultimate goal was to close the gap in knowledge about the need for thromboprophylaxis, including aspirin use. Although prophylaxis was effective in reducing VTE risk in orthopedic patients, it seemed to be underused at some hospitals, and use of aspirin alone in these patients con-thenumber of hand kneereplacements tinues despite guidelines recommending otherwise.

A cost-effectiveness analysis of fondaparinux sodium compared with enoxaparin sodium as prophylaxis against venous thromboembolism: use in patients undergoing major orthopaedic surgery.

OBJECTIVE: To determine the cost effectiveness of fondaparinux sodium compared with enoxaparin sodium for prophylaxis against venous thromboembolism in patients undergoing major orthopaedic surgery. METHODS: Using a cohort simulation model, two primary analyses were conducted from the perspective of the US healthcare payer. Probabilities for a trial-based analysis were obtained from patients participating in the fondaparinux clinical trial programme supplemented with data from published literature. Probabilities for a label-based analysis were estimated for a hypothetical cohort of US patients receiving either fondaparinux or enoxaparin as recommended by US FDA-approved labelling. Resource use and costs were obtained from large US healthcare databases. Outcome measures were rates of symptomatic thromboembolic events and healthcare costs. Costs were in 2003 values. RESULTS: In the trial-based analysis, fondaparinux was estimated to prevent 15.1 symptomatic venous thromboembolic events (per 1,000 patients) at 3 months for patients undergoing major orthopaedic surgery compared with enoxaparin. The cost savings (per patient) of using fondaparinux over enoxaparin are US 61 dollars at 30 days, US 89 dollars at 3 months, and US 155 dollars at 5 years. In the label-based analysis, fondaparinux was estimated to prevent 17.8 venous thromboembolic events (per 1,000 patients) at 3 months compared with enoxaparin, producing savings per patient of US 25 dollars at discharge, US 112 dollars over 1 month, US 141 dollars over 3 months and US 234 dollars over 5 years. Results remain robust to clinically plausible variation in input parameters and assumptions. CONCLUSION: Our model suggests that fondaparinux, when compared with the current standard regimen of enoxaparin for prophylaxis of venous thromboembolism in major orthopaedic surgery, improves outcomes and is cost saving from a US healthcare-payer perspective over the broad range of assumptions evaluated.

Safety syringes can reduce the risk of needlestick injury in venous thromboembolism prophylaxis.

Patients undergoing major orthopaedic surgery of the lower extremities are at high risk of developing venous thromboembolism (VTE). Pharmacologic thromboprophylaxis has greatly reduced the likelihood of VTE. The most effective medications are administered once or twice daily by subcutaneous injection, a drug delivery route associated with an increased risk of needlestick injury. Awareness of the potential lethality of needlestick injuries has increased during the past decade, resulting in the development of national safety guidelines from the Occupational Safety and Health Administration on the handling and management of needles and other sharps. This article reviews the potential risks and costs associated with needlestick injury during the administration of VTE prophylaxis in patients undergoing major orthopaedic surgery. The development of novel anticoagulants and accompanying devices to prevent needlestick injury is also discussed.

The risk of venous thromboembolism in non-large-joint surgeries.

The risk of venous thromboembolism, particularly deep venous thrombosis, after knee arthroscopy, surgically assisted arthroscopy, or treatment of lower extremity fracture may be substantial in patients with factors known to increase the risk of postoperative thromboembolism. Few prospective studies have examined the effect of prophylaxis in these patient populations. However, results suggest that routine administration of a low-molecular-weight heparin reduces the rate of deep venous thrombosis in such patients. Additional clinical studies are necessary to determine whether the benefits of prophylaxis outweigh its risks and whether it is cost-effective. Until such data are available, risk for deep venous thrombosis must be assessed in all patients undergoing an orthopedic procedure. Thromboprophylaxis with pharmacologic agents may be considered in those at high risk.

Thromboprophylaxis dosing: the relationship between timing of first administration, efficacy, and safety.

A unique antithrombotic agent, fondaparinux, selectively inhibits factor Xa and, therefore, thrombin generation, without affecting activity of the thrombin molecule. Its efficacy and safety in preventing venous thromboembolism following major orthopedic surgery, that is, hip and knee replacement and hip fracture, were demonstrated in 4 phase III clinical trials involving 7433 patients. Fondaparinux produced an overall 55% reduction in the risk of venous thromboembolism relative to the low-molecular-weight heparin enoxaparin without increasing the incidence of clinically relevant bleeding, which was similarly low for both agents. However, the incidence of overt bleeding with a bleeding index > or = 2 was higher for fondaparinux. First-dose timing according to the protocol for the 4 phase III trials was fondaparinux, 6 +/- 2 hours postoperatively, and enoxaparin, following the manufacturers' recommendations--either 12 hours preoperatively or 12 to 24 hours postoperatively. Whether the first-dose timing may explain the observed differences in efficacy and safety between the drugs was addressed in post-hoc analyses. Post-hoc analyses of the phase III trial data indicate that the superior efficacy of fondaparinux is maintained independent of the timing of the first dose. These analyses also indicate that administration of fondaparinux earlier than 6 hours postoperatively is associated with an increased incidence of a bleeding index > or = 2. Thus, when fondaparinux is administered according to the manufacturers recommended regimen, that is, not earlier than 6 hours postoperatively, the incidence of a bleeding index > or = 2 decreases to a rate similar to that found in the enoxaparin group. The superior efficacy of fondaparinux relative to enoxaparin is the result of its unique mechanism of action, clinical pharmacology, and dose selection rather than early timing of first administration.