idrabiotaparinux and Atrial-Fibrillation

Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have predictable pharmacokinetics that allow fixed dosing without laboratory monitoring, and are being compared with vitamin K antagonists or aspirin in phase III clinical trials [corrected]. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.

Topics: Anticoagulants; Atrial Fibrillation; Benzamides; Benzimidazoles; Biotin; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Vitamin K

Idraparinux is an analogue of fondaparinux binding with high affinity to antithrombin. It was designed for weekly, rather than daily, administration, with an exceptionally long half-life. One potential problem with small heparin-like fragments of this type is the difficulty of neutralising excessive activity in the case of side-effects or overdose. The efficacy of idraparinux was was proven in clinical studies with patients suffering from venous thromboembolism (VTE) or atrial fibrillation. Due to major bleeding events during treatment for more than six months the development of idraparinux was stopped. Idrabiotaparinux has an attached biotin moiety at the non-reducing end unit, which allows its neutralisation with avidin, an egg-derived protein with low antigenicity. This compound is currently investigated in clinical trials for prevention of recurrent VTE in patients with acute pulmonary embolism. The future of idrabiotaparinux depends also on the safety and efficacy of avidin.

Topics: Animals; Anticoagulants; Antithrombin III; Atrial Fibrillation; Avidin; Biotin; Carbohydrate Conformation; Carbohydrate Sequence; Drug Design; Drug Evaluation, Preclinical; Fondaparinux; Hemorrhage; Heparin Antagonists; Humans; Molecular Sequence Data; Molecular Structure; Oligosaccharides; Polysaccharides; Randomized Controlled Trials as Topic; Structure-Activity Relationship; Thrombosis; Treatment Outcome

Idrabiotaparinux, a long-acting inhibitor of factor Xa, was shown to be effective in the treatment of patients with venous thromboembolism.. To assess non-inferiority for the efficacy of idrabiotaparinux versus warfarin in patients with atrial fibrillation (AF) at risk of stroke and systemic embolism. Bleeding was also assessed.. This randomized, double-blind trial enrolled patients with electrocardiogram-documented AF. Idrabiotaparinux was administered weekly via subcutaneous injection, and warfarin was administered daily with dose adjustment to maintain the international normalized ratio between 2.0 and 3.0. Each idrabiotaparinux injection was 3 mg for the first 7 weeks, followed by 2 mg thereafter, except in patients with a creatinine clearance of 30-50 mL min(-1) or aged ≥ 75 years. The patients received 1.5 mg after the first 7 weeks. The efficacy outcome was the composite of all fatal or non-fatal strokes and systemic embolism. The safety outcome was clinically relevant bleeding (major and clinically relevant non-major bleeding).. The study was terminated prematurely by the sponsor for strategic/commercial, not scientific, reasons, with 39% of the planned number of patients included and an average duration of treatment of 240 days. Of the 1886 idrabiotaparinux recipients, 20 developed stroke or systemic embolism (1.5% per year), whereas this occurred in 22 of the 1887 warfarin patients (1.6% per year, hazard ratio 0.98, 95% confidence interval 0.49-1.66). The annual incidence of bleeding was 6.1% in the idrabiotaparinux and 10.0% in the warfarin group (hazard ratio 0.61, 95% confidence interval 0.46-0.81).. If anything, despite its early termination, the idrabiotaparinux regimen studied suggested a comparable efficacy to dose-adjusted warfarin, with a lower bleeding risk.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Biotin; Double-Blind Method; Drug Administration Schedule; Early Termination of Clinical Trials; Electrocardiography; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Oligosaccharides; Predictive Value of Tests; Risk Factors; Stroke; Thromboembolism; Time Factors; Treatment Outcome; Vitamin K; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Biotin; Factor Xa Inhibitors; Female; Humans; Male; Oligosaccharides; Stroke; Thromboembolism; Vitamin K; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Biotin; Factor Xa Inhibitors; Female; Humans; Male; Oligosaccharides; Stroke; Thromboembolism; Vitamin K; Warfarin