Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin.

Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy caused by antibodies against a complex of platelet factor 4 and heparin. Fondaparinux (Arixtra) is a new synthetic selective factor Xa inhibitor. We performed a serologic study to determine the cross-reactivity of HIT sera with fondaparinux. Using a prospective, blinded study design, 39 clinically and serologically confirmed sera from patients with HIT and 15 control sera were sent to 3 different laboratories, each of which specialized in a particular HIT assay. These include the serotonin release assay, heparin-induced platelet agglutination assay, and platelet aggregation assay. Two of 82 assays (2.4%) performed in the presence of control sera were positive, both with unfractionated heparin. In the presence of HIT sera, 75 of 94 (79.8%) evaluable assays were positive with unfractionated heparin; fondaparinux was significantly (P < .001) less reactive than unfractionated heparin, only 3 of 91 evaluable assays (3.3%) being positive. Using flow cytometry, unlike unfractionated heparin, fondaparinux did not induce the binding of PAC1 and anti-CD62 monoclonal antibodies or of annexin V to platelets with HIT sera. Together, these results suggest that fondaparinux is nonreactive to HIT sera and raise the possibility that the drug may be used for prophylaxis and treatment of thrombosis in patients with a history of HIT.

Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial.

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

The pharmacokinetics of fondaparinux sodium in healthy volunteers.

OBJECTIVE: Fondaparinux sodium is the first in a new class of synthetic factor Xa inhibitors that binds reversibly with high affinity to antithrombin III. It has been investigated for the prevention and treatment of arterial and venous thrombotic disorders and approved for use at a dose of 2.5mg once daily in the prevention of venous thromboembolism in major orthopaedic surgery. The pharmacokinetics of fondaparinux sodium were determined in eight studies in young and elderly healthy volunteers. RESULTS: After a 2.5mg subcutaneous dose to young volunteers, absolute bioavailability was 100% and absorption was rapid and complete [peak plasma concentration (C(max)) 0.34 mg/L occurred at approximately 2 hours]. Within- and total-subject variability estimates were small: 5.5 and 11.6%, respectively, for C(max )and 4.4 and 17.5% for area under the concentration-time curve (AUC). Steady state was obtained after the third or fourth once-daily dose, with a 1.3-fold increase in C(max) and AUC. Distribution volume (7 to 11L) was limited to blood volume. There was no evidence of metabolism. Fondaparinux sodium was almost completely excreted in urine as unchanged compound (64 to 77% of the dose was recovered at 72 hours after administration). Plasma clearance was 5.1 to 7.9 ml/min, renal clearance 4.0 to 7.9 ml/min, and the terminal half-life was 17 hours in young volunteers and 21 hours in elderly volunteers. Pharmacokinetics of fondaparinux sodium were linear in the range 2 to 8mg subcutaneously and 2 to 20mg intravenously. Pharmacokinetics observed in healthy elderly volunteers were consistent with findings in young male volunteers. CONCLUSION: The favourable pharmacokinetic profile of fondaparinux sodium is likely to play an important role in the major advance that the drug represents in the prevention and treatment of thrombotic disorders.

The synthetic pentasaccharide fondaparinux: first in the class of antithrombotic agents that selectively inhibit coagulation factor Xa.

Fondaparinux (Arixtra), a synthetic pentasaccharide, is the first in a new class of antithrombotic agents that selectively inhibit coagulation factor Xa. In vitro experiments demonstrated that it is a selective inhibitor of factor Xa. In plasma, fondaparinux selectively binds to antithrombin, catalyzes factor Xa inhibition, and thereby inhibits thrombin generation. Its antithrombotic efficacy has been demonstrated in various animal models mimicking venous and arterial thrombosis. In humans, its pharmacokinetic profile is favorable, with a rapid onset of antithrombotic activity and an elimination half-life allowing a convenient once-daily dosing regimen. In several clinical trials, fondaparinux was more effective than the reference drug, enoxaparin, in preventing venous thromboembolism after hip fracture, major knee, and elective hip replacement surgeries. The overall reduction in the risk of venous thromboembolism ranged between 26.3 and 56.4%, depending on the trial. This superior efficacy was achieved without increasing the risk of clinically relevant bleeding. Fondaparinux also showed promising results in the treatment of patients with venous thromboembolism and acute coronary syndromes. Thus, it is now established that selective factor Xa inhibition is an efficient way to prevent venous thrombosis. The advent of fondaparinux offers an opportunity to improve substantially the management of venous thromboembolism.