idrabiotaparinux and Venous-Thrombosis

Standard treatment of deep vein thrombosis (DVT) is based on antithrombotic therapy, initially with parenteral administration of unfractionated heparin or low molecular weight heparins (LMWH) for five to seven days, then subsequent long-term therapy with oral vitamin K antagonists (e.g. warfarin). Pentasaccharides are novel anticoagulants that may be favourable over standard therapy due to their predictable effect, no need for frequent monitoring or re-dosing, and few known drug interactions. Heparin-induced thrombocytopenia, a harmful effect of heparins, appears to be rare during treatment with pentasaccharides.. To assess the efficacy and harms of pentasaccharides for the treatment of deep vein thrombosis.. The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (22 March 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2) (searched 22 March 2017). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles for additional citations.. We included randomised controlled trials in which people 18 years of age or older with a DVT confirmed by standard imaging techniques were allocated to receive a pentasaccharide (fondaparinux, idraparinux, or idrabiotaparinux) for the treatment of DVT in comparison with standard therapy or other treatments.. We extracted data characterising the included trials according to the methods, participants, interventions, and outcomes. We assessed risk of bias using Cochrane's 'Risk of bias' tool and employed the GRADE methodology to evaluate the quality of the evidence.The main primary outcome for efficacy was recurrent venous thromboembolism (VTE), and the main primary outcome for harm was major and clinically relevant bleeding. Since our outcomes were dichotomous, we calculated the risk ratio (RR) with a 95% confidence interval (CI). We combined the effects of different comparisons through a meta-analysis using a fixed-effect model.. We included five randomised controlled trials of 6981 participants comparing pentasaccharides with standard therapy or other pentasaccharides. The quality of the evidence varied depending on the outcome and was judged as of moderate to very low quality. We downgraded the quality of the evidence due to risk of bias or imprecision, or both.Two studies evaluated fondaparinux, at doses of 5.0 mg, 7.5 mg, and 10.0 mg, plus vitamin K antagonist in comparison with standard therapy. A meta-analysis of these two studies showed no clear difference in the risk of recurrent VTE (RR 0.80, 95% CI 0.43 to 1.47; 2658 participants); moderate-quality evidence. The frequencies of major bleeding were similar between interventions in the initial period of treatment (approximately five days) (RR 1.15, 95% CI 0.39 to 3.44; 2645 participants) and at three months' follow-up (RR 1.05, 95% CI 0.64 to 1.71; 2645 participants). We judged the quality of the evidence as moderate.One study (757 participants) compared idrabiotaparinux (3.0 mg) with idraparinux (2.5 mg) and demonstrated no clear difference in the risk of recurrent VTE at six months' follow-up (RR 0.72, 95% CI 0.31 to 1.69); low-quality evidence. Major bleeding during the initial treatment period was not reported. Major bleeding at six-month follow-up was less frequent in participants receiving idrabiotaparinux versus participants treated with idraparinux (RR 0.21, 95% CI 0.06 to 0.71); low-quality evidence.The effect of an initial treatment with LMWH followed by three months of idraparinux (10 mg) showed no clear difference from standard therapy for risk of recurrent VTE (RR 1.51, 95% CI 0.26 to 8.90; 263 participants); very low-quality evidence; one study. Major bleeding during the initial treatment period was not reported. The frequency of major and other clinically relevant bleeding at three months' follow-up ranged from 2% to 15% in participants receiving LMWH and increasing doses of idraparinux of 2.5 mg, 5 mg, 7.5 mg, or 10 mg. When dosage groups were combined, there was no clear difference in major plus other clinically relevant bleeding or in major bleeding alone between the idraparinux treatment group and the standard therapy group (RR 1.30, 95% CI 0.70 to 2.40; 659 participants; RR 3.76, 95% CI 0.50 to 28.19; 659 participants, respectively); very low-quality evidence.One study (2904 participants) compared idraparinux (2.5 mg) to standard therapy. There was no clear difference in the risk of recurrent VTE at thre. We found moderate-quality evidence that the effects of fondaparinux at doses of 5.0 mg, 7.5 mg, and 10.0 mg plus vitamin K antagonist are similar in terms of recurrent VTE and risk of major bleeding compared with standard treatment for DVT.Low-quality evidence suggests equal efficacy of idraparinux at 2.5 mg and the equimolar dose of 3.0 mg of idrabiotaparinux with regard to recurrent VTE, but a higher frequency of major bleeding was observed in participants treated with idraparinux.We judged evidence on the effectiveness of idraparinux compared with standard therapy, with or without initial treatment with LMWH, and on associated bleeding risk to be low to very low quality, therefore we have very limited confidence in the estimated effects.The observed similar effectiveness in terms of recurrent DVT and harmful effects in terms of bleeding risk with fondaparinux plus vitamin K antagonist compared to standard treatment for DVT suggest that it may be an alternative to conventional anticoagulants for the treatment of DVT in certain circumstances.

Topics: Anticoagulants; Biotin; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Oligosaccharides; Polysaccharides; Randomized Controlled Trials as Topic; Recurrence; Time Factors; Venous Thrombosis

In the last few years, several phase III clinical trials of new drug treatments for deep vein thrombosis (DVT) have been carried out or are about to finish. These drugs have a predictable and reliable pharmacokinetic and pharmacodynamic response and do not require monitoring and are consequently an attractive alternative for the treatment of a high proportion of patients with DVT. Dabigatran, edoxaban and idrabiotaparinux have been developed as an alternative to warfarin, and apixaban and rivaroxaban as one-drug only treatment for this disease, with a 1- or 3-week intensified phase of initial treatment, respectively. So far, the reported results show non-inferior efficacy and safety to warfarin or to conventional treatment. Therefore, the new anticoagulants will be particularly useful in patients with unstable INRs, warfarin incompatible pharmacologic interactions, and in those without access to regular coagulation monitoring.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Biotin; Clinical Trials, Phase III as Topic; Dabigatran; Drug Administration Schedule; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thrombosis

To assess the bioequipotency of equimolar doses of idraparinux (2.5 mg) and idrabiotaparinux (3.0 mg).. In a phase I study, 48 healthy male volunteers were randomized to a single subcutaneous injection of idrabiotaparinux or idraparinux, followed by plasma sampling over 27 days. In a prospective substudy of the phase III EQUINOX trial, 228 patients treated for acute symptomatic deep vein thrombosis received idrabiotaparinux or idraparinux once weekly for 6 months. Plasma sampling was performed within 5 days following the last injection. The primary pharmacodynamic endpoint was the inhibition of activated factor X (FXa) activity. Maximal anti-FXa activity (Amax) and area under anti-FXa activity vs. time curve (AAUC) were calculated. Safety and tolerability were also assessed.. In both studies, pharmacodynamic anti-FXa vs. time profiles of idrabiotaparinux and idraparinux were superimposable. Ratio estimates (90% confidence intervals [CIs]) for idrabiotaparinux : idraparinux were 0.96 (0.89, 1.04) for Amax and 0.95 (0.87, 1.04) for AAUC in the phase I study, and 1.11 (1.00, 1.22) for Amax and 1.06 (0.96, 1.16) for AAUC at month 6 in the EQUINOX substudy. Idrabiotaparinux and idraparinux were considered bioequipotent because 90% CIs were within the pre-specified interval (0.80, 1.25). Study treatments were well tolerated.. Pharmacodynamic parameters reported after single dose in healthy volunteers and after repeated once weekly dosing in patients demonstrated the bioequipotency of idrabiotaparinux and idraparinux based on FXa inhibition. These outcomes support the use of an idrabiotaparinux dose bioequipotent to an idraparinux dose in large clinical trials, and the possibility to substitute idrabiotaparinux to idraparinux for the treatment of venous thromboembolism.

Topics: Adolescent; Adult; Anticoagulants; Area Under Curve; Biotin; Factor Xa; Factor Xa Inhibitors; Humans; Male; Middle Aged; Oligosaccharides; Therapeutic Equivalency; Venous Thrombosis; Young Adult

Idraparinux, a long acting inhibitor of factor (F) Xa, is as effective as standard anticoagulant therapy for patients with symptomatic deep venous thrombosis. We investigated the potential use of the biotinylated molecule, idrabiotaparinux. Biotinylation enables reversal of the anticoagulant effect.. We performed a randomized double-blind trial in 757 patients with symptomatic deep venous thrombosis, comparing equimolar doses of idrabiotaparinux (3 mg) with idraparinux (2.5 mg), both given subcutaneously, once weekly for 6 months. Inhibition of FXa activity was measured at days 15, 36, 57, 92 and 183. The efficacy outcome was recurrent venous thromboembolism. The safety outcomes were clinically relevant bleeding and death.. Inhibition of FXa was similar in the two treatment groups at each time point of measurement. Recurrent venous thromboembolism during the 6-month treatment period occurred in nine of 386 patients (2.3%) in the idrabiotaparinux group and in 12 of 371 patients (3.2%) in the idraparinux group, a difference of - 0.9% (95% confidence interval, -3.2-1.4%). The incidence of clinically relevant bleeding was 5.2% in the idrabiotaparinux group and 7.3% in the idraparinux group (P = 0.29), a difference of - 2.1% (95% confidence interval, -5.6-1.4%). Six patients (1.6%) who received idrabiotaparinux died, compared with 12 patients (3.2%) given idraparinux, a difference of - 1.7% (95% confidence interval, -3.9-0.5%).. Idrabiotaparinux has a similar time course of FXa inhibition, efficacy and safety to idraparinux for the treatment of deep venous thrombosis.

Topics: Adult; Aged; Anticoagulants; Biotin; Blood Coagulation; Double-Blind Method; Drug Administration Schedule; Europe; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Oligosaccharides; Recurrence; Risk Assessment; Time Factors; Treatment Outcome; United States; Venous Thrombosis

Idraparinux is an inhibitor of activated factor X (FXa) with a long half-life allowing once-weekly dosing. Idrabiotaparinux is a biotinylated version of idraparinux; its activity can be reversed with avidin.. To investigate the tolerability, safety and pharmacodynamics of avidin in healthy subjects and patients with deep vein thrombosis (DVT) receiving idrabiotaparinux.. In a placebo-controlled, randomized, double-blind Phase I study, 41 healthy males received subcutaneous idrabiotaparinux before being randomized to a 30-min intravenous avidin infusion or placebo. Idrabiotaparinux plus avidin were re-administered 10-14 months later in eight subjects. In addition, in a prospective substudy of the Phase III EQUINOX trial, 55 patients who received weekly idrabiotaparinux for 6 months were randomized to receive either 100 mg avidin (n = 33) or placebo (n = 22). The primary activity outcome was anti-FXa activity calculated immediately before and after avidin infusion. Adverse events were recorded to assess safety and tolerability.. Avidin rapidly reversed the anti-FXa activity of idrabiotaparinux, ranging from 66.1 to 90.3% in healthy subjects and from 67 to 97% (mean 78%) in DVT patients. Avidin was well tolerated, with a similar nature and frequency of adverse events to placebo. No venous thromboembolism recurrence occurred in the 3-month post-avidin infusion.. A 30-min intravenous infusion of avidin 100 mg is well tolerated, safe, and offers immediate and specific reversibility both after single and repeated doses of idrabiotaparinux in healthy subjects, and in DVT patients following a 6-month treatment period.

Topics: Adolescent; Adult; Anticoagulants; Avidin; Biotin; Coagulants; Dose-Response Relationship, Drug; Double-Blind Method; Factor Xa Inhibitors; Female; Humans; Infusions, Intravenous; Injections, Subcutaneous; Lower Extremity; Male; Oligosaccharides; Prospective Studies; Secondary Prevention; Time Factors; Treatment Outcome; Venous Thrombosis; Young Adult