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Job Harenberg - One of the best experts on this subject based on the ideXlab platform.
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Idraparinux and idrabiotaparinux.
Expert review of clinical pharmacology, 2010Co-Authors: Job HarenbergAbstract:Idraparinux is a polymethylated synthetic pentasaccharide that binds to antithrombin with high affinity. Idrabiotaparinux is a derivative of Idraparinux with biotin synthesized to the end-standing hexose. This article reports on data carried out with both compounds until April 2009. Idraparinux once weekly 2.5 mg subcutaneous was almost as effective for treatment of deep vein thrombosis but less effective for pulmonary embolism as initial bodyweight-adjusted subcutaneous enoxaparin followed by international normalized ratio-adjusted warfarin over 6 months for prophylaxis of recurrent venous thromboembolism (VTE). Prolonged prophylaxis of recurrent VTE with Idraparinux was more effective but induced severe bleedings compared with placebo over an additional 6 months of prophylaxis of recurrent VTE. Prophylaxis of embolic events with Idraparinux over an 18-month period in patients with atrial fibrillation was as effective as international normalized ratio-adjusted warfarin but induced more major bleeding com...
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Idraparinux and idrabiotaparinux
Expert Review of Clinical Pharmacology, 2010Co-Authors: Job HarenbergAbstract:Idraparinux is a polymethylated synthetic pentasaccharide that binds to antithrombin with high affinity. Idrabiotaparinux is a derivative of Idraparinux with biotin synthesized to the end-standing hexose. This article reports on data carried out with both compounds until April 2009. Idraparinux once weekly 2.5 mg subcutaneous was almost as effective for treatment of deep vein thrombosis but less effective for pulmonary embolism as initial bodyweight-adjusted subcutaneous enoxaparin followed by international normalized ratio-adjusted warfarin over 6 months for prophylaxis of recurrent venous thromboembolism (VTE). Prolonged prophylaxis of recurrent VTE with Idraparinux was more effective but induced severe bleedings compared with placebo over an additional 6 months of prophylaxis of recurrent VTE. Prophylaxis of embolic events with Idraparinux over an 18-month period in patients with atrial fibrillation was as effective as international normalized ratio-adjusted warfarin but induced more major bleeding complications. The elimination half-life of Idraparinux increased to 60 days in these studies, which may explain the bleeding complications. As such the development of Idraparinux was stopped. Idrabiotaparinux is eliminated after intravenous administration of avidin. Currently idrabiotaparinux once weekly 3.5 mg subcutaneous is being investigated in clinical trials for the prevention of recurrent events in patients with acute VTE and atrial fibrillation. The future of idrabiotaparinux depends on the demonstration of its safety and efficacy. Avidin also has to demonstrate its efficacy and safety after single and repeated injections.
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Development of Idraparinux and idrabiotaparinux for anticoagulant therapy
Thrombosis and Haemostasis, 2009Co-Authors: Job HarenbergAbstract:SummaryIdraparinux 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 sideeffects or overdose. The efficacy of Idraparinux was was proven in clincial 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.
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Anticoagulant effects of Idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials
European Journal of Clinical Pharmacology, 2008Co-Authors: Job Harenberg, Ingrid Jörg, Yvonne Vukojevic, Gerd Mikus, Christel WeissAbstract:Aim To gather information on anticoagulant effects after the termination of long-term therapy with Idraparinux. Methods The anticoagulant effects of Idraparinux, a synthetic polymethylated analogue of its pentasaccharide, were analysed in 23 patients after termination of a 6- or 12-month therapy period for the prevention of recurrent venous thromboembolism (VTE). Plasma samples of patients initially randomized to 2.5 mg Idraparinux (normal creatinine clearance) or 1.5 mg Idraparinux (creatinine clearance
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Anticoagulant effects of Idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials
European journal of clinical pharmacology, 2008Co-Authors: Job Harenberg, Ingrid Jörg, Yvonne Vukojevic, Gerd Mikus, Christel WeissAbstract:To gather information on anticoagulant effects after the termination of long-term therapy with Idraparinux. The anticoagulant effects of Idraparinux, a synthetic polymethylated analogue of its pentasaccharide, were analysed in 23 patients after termination of a 6- or 12-month therapy period for the prevention of recurrent venous thromboembolism (VTE). Plasma samples of patients initially randomized to 2.5 mg Idraparinux (normal creatinine clearance) or 1.5 mg Idraparinux (creatinine clearance
Harry R. Büller - One of the best experts on this subject based on the ideXlab platform.
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Net clinical benefit of combination anticoagulant and antiplatelet therapy versus anticoagulation alone in atrial fibrillation patients: Results from the amadeus trial
Journal of the American College of Cardiology, 2010Co-Authors: Deirdre A. Lane, Harry R. Büller, Pieter Willem Kamphuisen, Pascal Minini, Olaf R. De Peuter, Gregory Y.h. LipAbstract:Background: To compare the effect of combination anticoagulant and antiplatelet (AP) therapy with anticoagulation alone on stroke and bleeding risk in atrial fibrillation (AF) patients and examine predictors of clinically relevant bleeding. Methods: Post-hoc analysis of 4576 AF patients [mean (SD) age 70.1 (9.1) years, 66.5% men] enrolled in the AMADEUS trial, randomised to receive either subcutaneous Idraparinux (2.5mg weekly, n=2283) or dose-adjusted vitamin K antagonists (VKAs) (INR 2.0-3.0, n=2293). 1031 (22.5%) patients used concomitant AP therapy [Idraparinux n=521 & VKAs n=510]. Results: 43 strokes [17 (0.6%) vs. 26 (2.7%)] and 553 clinically relevant bleeds [322 (11.2%) vs. 231 (27.6%)] occurred during follow-up on anticoagulation alone versus combination antithrombotic therapy, respectively. Clinically relevant bleeding was significantly associated with poor renal function, age ≥65, baseline VKA naivety, and concomitant AP therapy. Multivariate analyses [HR, 95% CI] revealed that age >65 years [1.45 (1.15-1.84) & 1.62 (1.28-2.04) for 65-74 & >75 years, respectively] and concomitant aspirin therapy [1.76 (1.47-2.10)] or aspirin plus clopidogrel/ticlopidine [1.57 (1.08-2.26)] predicted clinically relevant bleeding. Conclusions: Combination antithrombotic therapy increases the risk of clinically relevant bleeding in AF patients and does not reduce the risk of stroke. Such treatment should be avoided unless there is a clear indication for concomitant AP therapy(Table present).
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Idrabiotaparinux, a Biotinylated Long-Acting Anticoagulant, in the Treatment of Deep Venous Thrombosis (EQUINOX Study): Safety, Efficacy, and Reversibility by Avidin
Blood, 2008Co-Authors: Harry R. Büller, Alexander Gallus, Martin H. Prins, Jean-michel Destors, Gary E. RaskobAbstract:Idrabiotaparinux is a novel synthetic anticoagulant that links Idraparinux, a specific, indirect factor Xa inhibitor, to biotin. The long half-life of Idraparinux allows once-weekly (o.w.) subcutaneous (s.c.) injection. Avidin, a hen egg protein, specifically and tightly binds with biotin. When given by intravenous (i.v.) infusion, avidin (half life: 15-minutes) reverses the anti-factor Xa (a-Xa) activity of idrabiotaparinux by forming a complex that is rapidly cleared from the circulation. Idraparinux 2.5 mg s.c. o.w. was effective and safe in the van Gogh DVT trial of 2904 patients with deep vein thrombosis (DVT), when compared with standard anticoagulant therapy 1. Methods: In EQUINOX, patients with symptomatic and confirmed DVT were randomised to receive weekly s.c. injection of equimolar amounts of idrabiotaparinux (3 mg) or Idraparinux (2.5 mg) for 6 months. The aims of this multicentre, double-blind, study were to demonstrate, at the end of the 6 months of therapy, bioequipotency of idrabiotaparinux with Idraparinux, to measure the effect of i.v. avidin on peak circulating a-Xa activity, and to document efficacy and safety. The main outcome events were clinically relevant bleeding (major or not), death, or symptomatic recurrent venous thromboembolism (VTE) within 6 months of randomisation, assessed by a blinded independent adjudication committee. Reversal of anticoagulant effect by 100 mg i.v. avidin infused over 30 minutes, and its safety, were assessed in a subset of patients re-randomised at 6 months and blindly allocated to receive avidin (idrabiotaparinux arm) or placebo (idrabiotaparinux and Idraparinux arms, to preserve blinding). Avidin or placebo was infused 2–5 hours (around tmax) after the last injection of the 6 month treatment period; plasma a-Xa activity was measured just before avidin/placebo infusion, just after, and then for 5 days. Results: Of 757 patients randomised, 385 received idrabiotaparinux and 370 Idraparinux. Overall, 22.7% had previous venous thromboembolism (VTE), 5.2% had cancer within the past 6 months, 53.8% had apparently unprovoked thrombosis, and 36.2% were aged >65. There was less clinically relevant bleeding (20 v. 27; 5.2% v. 7.3%) and less major bleeding (3 v. 14; 0.8% v. 3.8%) with idrabiotaparinux than with Idraparinux. Rates of recurrent VTE and of fatal or non-fatal pulmonary embolism PE were similar with idrabiotaparinux and Idraparinux (VTE: 9 v. 12; 2.3% v. 3.2%. PE: 6 v. 7; 1.6% v. 1.8%). Trough levels of a-Xa activity were identical in the treatment groups throughout 6 months. Of 52 idrabiotaparinux patients re-randomised at 6 months to receive i.v. avidin or placebo, 41 were analysable for reversal of a-Xa activity (23 avidin and 18 placebo). At the end of the 30 minute avidin infusion, mean anti-Xa activity was reduced by 77.8%, sustained for at least 5 days, compared with 2.4% after placebo (p = 3.45 × 10−15). No allergic reactions were observed to avidin. Conclusion: A 6-month treatment period with idrabiotaparinux, compared to Idraparinux in patients with DVT, showed a comparable efficacy with a trend to less bleeding. Trough a-Xa activity was identical in the two groups. Avidin infusion at around tmax after the last idrabiotaparinux injection led to rapid and substantial reversal of a-Xa activity, sustained for at least 5 days. Avidin infusion was well-tolerated.
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Idraparinux versus standard therapy for venous thromboembolic disease.
The New England journal of medicine, 2007Co-Authors: Harry R. Büller, A T Cohen, Bruce L Davidson, Alexander Gallus, Gerard Pillion, Martin H. Prins, Gary E. RaskobAbstract:A b s t r ac t Background Venous thromboembolism is treated with unfractionated heparin or low-molecularweight heparin, followed by a vitamin K antagonist. We investigated the potential use of Idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. Methods We conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of Idraparinux versus standard therapy. Patients received either subcutaneous Idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). Results In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the Idraparinux group as compared with 3.0% in the standardtherapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for Idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the Idraparinux group and 7.0% in the standard-therapy group (P = 0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the Idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement. Conclusions In patients with deep venous thrombosis, once-weekly subcutaneous Idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, Idraparinux was less efficacious than standard therapy. (ClinicalTrials.gov numbers, NCT00067093 and NCT00062803.)
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extended prophylaxis of venous thromboembolism with Idraparinux
The New England Journal of Medicine, 2007Co-Authors: Harry R. Büller, A T Cohen, Bruce L Davidson, Gerard Pillion, Martin H. Prins, Herve Decousus, A S Gallus, Michael Gent, Franco Piovella, Gary E. RaskobAbstract:A b s t r ac t Background The extended use of vitamin K antagonists for prophylaxis against venous thromboembolism is often constrained by risk–benefit limitations and inconvenience. We evaluated the efficacy and safety of a 6-month extension of prophylaxis against recurrent venous thromboembolism with Idraparinux in patients who had initially received 6 months of prophylaxis with an anticoagulant. Methods We randomly assigned patients who had completed 6 months of prophylaxis with Idraparinux or a vitamin K antagonist and in whom extended anticoagulation was warranted to receive once-weekly injections of 2.5 mg of Idraparinux or placebo for 6 months without monitoring. The primary efficacy and safety outcomes were recurrent venous thromboembolism and major bleeding. Results Of 1215 patients, 6 of 594 (1.0%) in the Idraparinux group and 23 of 621 (3.7%) in the placebo group had recurrent venous thromboembolism (P = 0.002). Major bleeding occurred in 11 patients (1.9%) in the Idraparinux group and in none in the placebo group (P<0.001). Of these 11 episodes, 3 were fatal intracranial hemorrhages. As compared with patients whose initial treatment was a vitamin K antagonist, patients whose initial treatment was Idraparinux who were assigned to 6 months in the placebo group had a lower incidence of recurrent thromboembolism (0.7% vs. 5.9%); patients who received 6 additional months of Idraparinux therapy had a higher incidence of major bleeding (3.1% vs. 0.9%). Conclusions During a 6-month extension of thromboprophylaxis, Idraparinux was effective in preventing recurrent thromboembolism but was associated with an increased risk of a major hemorrhage. (ClinicalTrials.gov number, NCT00071279.)
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Extended prophylaxis of venous thromboembolism with Idraparinux.
New England Journal of Medicine, 2007Co-Authors: Non Renseigné, Harry R. Büller, Gerard Pillion, Herve Decousus, A S Gallus, Michael Gent, Franco Piovella, Ander T Cohen, Bruce Davidson, Martin H. PrinsAbstract:BACKGROUND: The extended use of vitamin K antagonists for prophylaxis against venous thromboembolism is often constrained by risk-benefit limitations and inconvenience. We evaluated the efficacy and safety of a 6-month extension of prophylaxis against recurrent venous thromboembolism with Idraparinux in patients who had initially received 6 months of prophylaxis with an anticoagulant. METHODS: We randomly assigned patients who had completed 6 months of prophylaxis with Idraparinux or a vitamin K antagonist and in whom extended anticoagulation was warranted to receive once-weekly injections of 2.5 mg of Idraparinux or placebo for 6 months without monitoring. The primary efficacy and safety outcomes were recurrent venous thromboembolism and major bleeding. RESULTS: Of 1215 patients, 6 of 594 (1.0%) in the Idraparinux group and 23 of 621 (3.7%) in the placebo group had recurrent venous thromboembolism (P=0.002). Major bleeding occurred in 11 patients (1.9%) in the Idraparinux group and in none in the placebo group (P
Settipalli Pavithra - One of the best experts on this subject based on the ideXlab platform.
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Idraparinux or Idrabiotaparinux for Long-Term Venous Thromboembolism Treatment: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
2016Co-Authors: Yanzhi Song, Settipalli PavithraAbstract:Background: Venous thromboembolism (VTE) is a prevalent disease with potential serious consequences. Idraparinux and idrabiotaparinux are two kinds of long-acting pentasaccharides. Evidence has shown that Idraparinux and idrabiotaparinux are effective anticoagulants. However, up to now, there is no consensus on whether they are better than other anticoagulation methods for long-term VTE treatment. Objective: To evaluate the effect of Idraparinux or idrabiotaparinux versus other anticoagulation methods for long-term VTE treatment. Methods:We searched Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of science, clinical trial registry web sites (clinical trials,WHO clinical trial registry), Googlescholar, PubMed related articles and companies ’ web sites electronically up to Dec 30th, 2012 and manually searched the reference lists and conference proceedings. Only randomized controlled trial (RCT) involving adult patients comparing Idraparinux and/or idrabiotaparinux versus other anticoagulation methods for long-term VTE treatment was included. Two reviewers evaluated the studies and extracted data independently. Pooled risk ratios (RRs) were calculated as outcome measures and Revman 5.2 software was used to analyze data. Our primary efficacy and safety outcomes were the recurrent VTE and major bleeding rates. Results: We included four RCTs and involved 8584 participants on Idraparinux or idrabiotaparinux versus standard warfari
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Idraparinux or idrabiotaparinux for long-term venous thromboembolism treatment: a systematic review and meta-analysis of randomized controlled trials.
PloS one, 2013Co-Authors: Yanzhi Song, Settipalli PavithraAbstract:Background Venous thromboembolism (VTE) is a prevalent disease with potential serious consequences. Idraparinux and idrabiotaparinux are two kinds of long-acting pentasaccharides. Evidence has shown that Idraparinux and idrabiotaparinux are effective anticoagulants. However, up to now, there is no consensus on whether they are better than other anticoagulation methods for long-term VTE treatment. Objective To evaluate the effect of Idraparinux or idrabiotaparinux versus other anticoagulation methods for long-term VTE treatment. Methods We searched Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of science, clinical trial registry web sites (clinical trials,WHO clinical trial registry), Googlescholar, PubMed related articles and companies' web sites electronically up to Dec 30th, 2012 and manually searched the reference lists and conference proceedings. Only randomized controlled trial (RCT) involving adult patients comparing Idraparinux and/or idrabiotaparinux versus other anticoagulation methods for long-term VTE treatment was included. Two reviewers evaluated the studies and extracted data independently. Pooled risk ratios (RRs) were calculated as outcome measures and Revman 5.2 software was used to analyze data. Our primary efficacy and safety outcomes were the recurrent VTE and major bleeding rates. Results We included four RCTs and involved 8584 participants on Idraparinux or idrabiotaparinux versus standard warfarin for VTE treatment from 9364 references. We did not perform meta-analysis on the VTE rate because of the significant heterogeneity. We used the fixed effect model to analyze the safety outcomes and demonstrated that Idraparinux or idrabiotaparinux decreased major bleeding rate significantly (RR 0.73, 95% CI 0.54 to 0.98, P = 0.04) but had a trend to increase the all cause mortality (RR 1.26, 95% CI 1.00 to 1.57, P = 0.05) compared with warfarin. Conclusions Until now there is not sufficient evidence to clarify whether Idraparinux or idrabiotaparinux is as effective and safe as the standard warfarin treatment for VTE treatment.
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Characteristics of included studies.
2013Co-Authors: Yanzhi Song, Settipalli PavithraAbstract:*There were four doses of Idraparinux groups (2.5 mg, 5 mg, 7.5 mg and 10 mg once weekly) and a standard warfarin treatment group in it. We included the 2.5 mg group and the warfarin group as a comparator into our data analysis because it was the routine dose of Idraparinux used to treat VTE [14].SD, standard deviation; VTE, venous thromboembolism; DVT deep venous thrombosis; PE, pulmonary embolism; s.c. subcutaneously.
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Efficacy of Idraparinux or idrabiotaparinux versus standard warfarin treatment.
2013Co-Authors: Yanzhi Song, Settipalli PavithraAbstract:Efficacy of Idraparinux or idrabiotaparinux versus standard warfarin treatment.
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Safety of of Idraparinux or idrabiotaparinux versus standard warfarin treatment.
2013Co-Authors: Yanzhi Song, Settipalli PavithraAbstract:Safety of of Idraparinux or idrabiotaparinux versus standard warfarin treatment.
Gary E. Raskob - One of the best experts on this subject based on the ideXlab platform.
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Idraparinux versus standard therapy in the treatment of deep venous thrombosis in cancer patients: A subgroup analysis of the Van Gogh DVT trial
Thrombosis and haemostasis, 2010Co-Authors: F. F. Van Doormaal, A T Cohen, Bruce L Davidson, Alexander Gallus, Martin H. Prins, Gary E. Raskob, Herve Decousus, Michael Gent, Franco Piovella, H R BüllerAbstract:Standard treatment with heparin followed by vitamin K antagonists is frequently complicated by bleeding and recurrent venous thromboembolism (VTE) in cancer patients with VTE. To compare the efficacy, safety and overall survival of long-term Idraparinux treatment to standard therapy in cancer patients we conducted a post-hoc analysis in the subgroup of non-active and active cancer patients included in the Van Gogh DVT clinical trial. The cancer patients with deep venous thrombosis (DVT) and without pulmonary embolism (PE) were randomised to standard treatment or a once-weekly subcutaneous injection of Idraparinux (2.5 mg), a synthetic pentasaccharide. 421 cancer patients were included. A total of 220 patients received Idraparinux and 201 were allocated to standard therapy for three months (8%) or six months (92%). A recurrent VTE was observed during the first six months in 2.5% (n=5) of the Idraparinux recipients compared to 6.4% (n=12) in the standard therapy group (hazard ratio 0.39, 95% confidence interval [CI]; 0.14–1.11). The rate of bleeding was comparable (odds ratio 0.89, 95% CI; 0.50–1.59). The outcomes were similar at three months after randomisation in all patients. Of the Idraparinux recipients, 22.7% (n=50) died during the study period compared to 48 patients (23.9%) in the standard treatment group (hazard ratio 0.99, 95% CI; 0.66–1.48). In conclusion, no significant safety or survival differences were observed between cancer patients with DVT treated with Idraparinux for six months compared to standard therapy. Fewer recurrent VTEs were observed in the Idraparinux group; however, this was not statistically significant and also because of study limitations this should be interpreted with caution.
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Idrabiotaparinux, a Biotinylated Long-Acting Anticoagulant, in the Treatment of Deep Venous Thrombosis (EQUINOX Study): Safety, Efficacy, and Reversibility by Avidin
Blood, 2008Co-Authors: Harry R. Büller, Alexander Gallus, Martin H. Prins, Jean-michel Destors, Gary E. RaskobAbstract:Idrabiotaparinux is a novel synthetic anticoagulant that links Idraparinux, a specific, indirect factor Xa inhibitor, to biotin. The long half-life of Idraparinux allows once-weekly (o.w.) subcutaneous (s.c.) injection. Avidin, a hen egg protein, specifically and tightly binds with biotin. When given by intravenous (i.v.) infusion, avidin (half life: 15-minutes) reverses the anti-factor Xa (a-Xa) activity of idrabiotaparinux by forming a complex that is rapidly cleared from the circulation. Idraparinux 2.5 mg s.c. o.w. was effective and safe in the van Gogh DVT trial of 2904 patients with deep vein thrombosis (DVT), when compared with standard anticoagulant therapy 1. Methods: In EQUINOX, patients with symptomatic and confirmed DVT were randomised to receive weekly s.c. injection of equimolar amounts of idrabiotaparinux (3 mg) or Idraparinux (2.5 mg) for 6 months. The aims of this multicentre, double-blind, study were to demonstrate, at the end of the 6 months of therapy, bioequipotency of idrabiotaparinux with Idraparinux, to measure the effect of i.v. avidin on peak circulating a-Xa activity, and to document efficacy and safety. The main outcome events were clinically relevant bleeding (major or not), death, or symptomatic recurrent venous thromboembolism (VTE) within 6 months of randomisation, assessed by a blinded independent adjudication committee. Reversal of anticoagulant effect by 100 mg i.v. avidin infused over 30 minutes, and its safety, were assessed in a subset of patients re-randomised at 6 months and blindly allocated to receive avidin (idrabiotaparinux arm) or placebo (idrabiotaparinux and Idraparinux arms, to preserve blinding). Avidin or placebo was infused 2–5 hours (around tmax) after the last injection of the 6 month treatment period; plasma a-Xa activity was measured just before avidin/placebo infusion, just after, and then for 5 days. Results: Of 757 patients randomised, 385 received idrabiotaparinux and 370 Idraparinux. Overall, 22.7% had previous venous thromboembolism (VTE), 5.2% had cancer within the past 6 months, 53.8% had apparently unprovoked thrombosis, and 36.2% were aged >65. There was less clinically relevant bleeding (20 v. 27; 5.2% v. 7.3%) and less major bleeding (3 v. 14; 0.8% v. 3.8%) with idrabiotaparinux than with Idraparinux. Rates of recurrent VTE and of fatal or non-fatal pulmonary embolism PE were similar with idrabiotaparinux and Idraparinux (VTE: 9 v. 12; 2.3% v. 3.2%. PE: 6 v. 7; 1.6% v. 1.8%). Trough levels of a-Xa activity were identical in the treatment groups throughout 6 months. Of 52 idrabiotaparinux patients re-randomised at 6 months to receive i.v. avidin or placebo, 41 were analysable for reversal of a-Xa activity (23 avidin and 18 placebo). At the end of the 30 minute avidin infusion, mean anti-Xa activity was reduced by 77.8%, sustained for at least 5 days, compared with 2.4% after placebo (p = 3.45 × 10−15). No allergic reactions were observed to avidin. Conclusion: A 6-month treatment period with idrabiotaparinux, compared to Idraparinux in patients with DVT, showed a comparable efficacy with a trend to less bleeding. Trough a-Xa activity was identical in the two groups. Avidin infusion at around tmax after the last idrabiotaparinux injection led to rapid and substantial reversal of a-Xa activity, sustained for at least 5 days. Avidin infusion was well-tolerated.
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Idraparinux versus standard therapy for venous thromboembolic disease.
The New England journal of medicine, 2007Co-Authors: Harry R. Büller, A T Cohen, Bruce L Davidson, Alexander Gallus, Gerard Pillion, Martin H. Prins, Gary E. RaskobAbstract:A b s t r ac t Background Venous thromboembolism is treated with unfractionated heparin or low-molecularweight heparin, followed by a vitamin K antagonist. We investigated the potential use of Idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. Methods We conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of Idraparinux versus standard therapy. Patients received either subcutaneous Idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). Results In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the Idraparinux group as compared with 3.0% in the standardtherapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for Idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the Idraparinux group and 7.0% in the standard-therapy group (P = 0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the Idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement. Conclusions In patients with deep venous thrombosis, once-weekly subcutaneous Idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, Idraparinux was less efficacious than standard therapy. (ClinicalTrials.gov numbers, NCT00067093 and NCT00062803.)
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extended prophylaxis of venous thromboembolism with Idraparinux
The New England Journal of Medicine, 2007Co-Authors: Harry R. Büller, A T Cohen, Bruce L Davidson, Gerard Pillion, Martin H. Prins, Herve Decousus, A S Gallus, Michael Gent, Franco Piovella, Gary E. RaskobAbstract:A b s t r ac t Background The extended use of vitamin K antagonists for prophylaxis against venous thromboembolism is often constrained by risk–benefit limitations and inconvenience. We evaluated the efficacy and safety of a 6-month extension of prophylaxis against recurrent venous thromboembolism with Idraparinux in patients who had initially received 6 months of prophylaxis with an anticoagulant. Methods We randomly assigned patients who had completed 6 months of prophylaxis with Idraparinux or a vitamin K antagonist and in whom extended anticoagulation was warranted to receive once-weekly injections of 2.5 mg of Idraparinux or placebo for 6 months without monitoring. The primary efficacy and safety outcomes were recurrent venous thromboembolism and major bleeding. Results Of 1215 patients, 6 of 594 (1.0%) in the Idraparinux group and 23 of 621 (3.7%) in the placebo group had recurrent venous thromboembolism (P = 0.002). Major bleeding occurred in 11 patients (1.9%) in the Idraparinux group and in none in the placebo group (P<0.001). Of these 11 episodes, 3 were fatal intracranial hemorrhages. As compared with patients whose initial treatment was a vitamin K antagonist, patients whose initial treatment was Idraparinux who were assigned to 6 months in the placebo group had a lower incidence of recurrent thromboembolism (0.7% vs. 5.9%); patients who received 6 additional months of Idraparinux therapy had a higher incidence of major bleeding (3.1% vs. 0.9%). Conclusions During a 6-month extension of thromboprophylaxis, Idraparinux was effective in preventing recurrent thromboembolism but was associated with an increased risk of a major hemorrhage. (ClinicalTrials.gov number, NCT00071279.)
Bruce L Davidson - One of the best experts on this subject based on the ideXlab platform.
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Idraparinux versus standard therapy in the treatment of deep venous thrombosis in cancer patients: A subgroup analysis of the Van Gogh DVT trial
Thrombosis and haemostasis, 2010Co-Authors: F. F. Van Doormaal, A T Cohen, Bruce L Davidson, Alexander Gallus, Martin H. Prins, Gary E. Raskob, Herve Decousus, Michael Gent, Franco Piovella, H R BüllerAbstract:Standard treatment with heparin followed by vitamin K antagonists is frequently complicated by bleeding and recurrent venous thromboembolism (VTE) in cancer patients with VTE. To compare the efficacy, safety and overall survival of long-term Idraparinux treatment to standard therapy in cancer patients we conducted a post-hoc analysis in the subgroup of non-active and active cancer patients included in the Van Gogh DVT clinical trial. The cancer patients with deep venous thrombosis (DVT) and without pulmonary embolism (PE) were randomised to standard treatment or a once-weekly subcutaneous injection of Idraparinux (2.5 mg), a synthetic pentasaccharide. 421 cancer patients were included. A total of 220 patients received Idraparinux and 201 were allocated to standard therapy for three months (8%) or six months (92%). A recurrent VTE was observed during the first six months in 2.5% (n=5) of the Idraparinux recipients compared to 6.4% (n=12) in the standard therapy group (hazard ratio 0.39, 95% confidence interval [CI]; 0.14–1.11). The rate of bleeding was comparable (odds ratio 0.89, 95% CI; 0.50–1.59). The outcomes were similar at three months after randomisation in all patients. Of the Idraparinux recipients, 22.7% (n=50) died during the study period compared to 48 patients (23.9%) in the standard treatment group (hazard ratio 0.99, 95% CI; 0.66–1.48). In conclusion, no significant safety or survival differences were observed between cancer patients with DVT treated with Idraparinux for six months compared to standard therapy. Fewer recurrent VTEs were observed in the Idraparinux group; however, this was not statistically significant and also because of study limitations this should be interpreted with caution.
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comparison of Idraparinux with vitamin k antagonists for prevention of thromboembolism in patients with atrial fibrillation a randomised open label non inferiority trial
The Lancet, 2008Co-Authors: M G Bousser, H R Büller, J Bouthier, A T Cohen, Harry J G M Crijns, Bruce L Davidson, Jonathan L Halperin, Graeme J Hankey, Shawn E Levy, Vittorio PengoAbstract:BACKGROUND: Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this randomised, open-label non-inferiority trial was to compare the efficacy and safety of Idraparinux with vitamin K antagonists. METHODS: Patients with atrial fibrillation at risk for thromboembolism were randomly assigned to receive either subcutaneous Idraparinux (2.5 mg weekly) or adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2-3). Assessment of outcome was done blinded to treatment. The primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism. The principal safety outcome was clinically relevant bleeding. Analyses were done by intention to treat; the non-inferiority hazard ratio was set at 1.5. This trial is registered with ClinicalTrials.gov, number NCT00070655. FINDINGS: The trial was stopped after randomisation of 4576 patients (2283 to receive Idraparinux, 2293 to receive vitamin K antagonists) and a mean follow-up period of 10.7 (SD 5.4) months because of excess clinically relevant bleeding with Idraparinux (346 cases vs 226 cases; 19.7 vs 11.3 per 100 patient-years; p <0.0001). There were 21 instances of intracranial bleeding with Idraparinux and nine with vitamin K antagonists (1.1 vs 0.4 per 100 patient-years; p=0.014); elderly patients and those with renal impairment were at greater risk of such complications. There were 18 cases of thromboembolism with Idraparinux and 27 cases with vitamin K antagonists (0.9 vs 1.3 per 100 patient-years; hazard ratio 0.71, 95% CI 0.39-1.30; p=0.007), satisfying the non-inferiority criterion. There were 62 deaths with Idraparinux and 61 with vitamin K anatagonists (3.2 vs 2.9 per 100 patient-years; p=0.49). INTERPRETATION: In patients with atrial fibrillation at risk for thromboembolism, long-term treatment with Idraparinux was no worse than vitamin K antagonists in terms of efficacy, but caused significantly more bleeding
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Comparison of Idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation : a randomised, open-label, non-inferiority trial
The Lancet, 2008Co-Authors: M G Bousser, H R Büller, J Bouthier, A T Cohen, Harry J G M Crijns, Bruce L Davidson, Jonathan L Halperin, Graeme J Hankey, Shawn E Levy, Vittorio PengoAbstract:BACKGROUND: Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this randomised, open-label non-inferiority trial was to compare the efficacy and safety of Idraparinux with vitamin K antagonists. METHODS: Patients with atrial fibrillation at risk for thromboembolism were randomly assigned to receive either subcutaneous Idraparinux (2.5 mg weekly) or adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2-3). Assessment of outcome was done blinded to treatment. The primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism. The principal safety outcome was clinically relevant bleeding. Analyses were done by intention to treat; the non-inferiority hazard ratio was set at 1.5. This trial is registered with ClinicalTrials.gov, number NCT00070655. FINDINGS: The trial was stopped after randomisation of 4576 patients (2283 to receive Idraparinux, 2293 to receive vitamin K antagonists) and a mean follow-up period of 10.7 (SD 5.4) months because of excess clinically relevant bleeding with Idraparinux (346 cases vs 226 cases; 19.7 vs 11.3 per 100 patient-years; p
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Idraparinux versus standard therapy for venous thromboembolic disease.
The New England journal of medicine, 2007Co-Authors: Harry R. Büller, A T Cohen, Bruce L Davidson, Alexander Gallus, Gerard Pillion, Martin H. Prins, Gary E. RaskobAbstract:A b s t r ac t Background Venous thromboembolism is treated with unfractionated heparin or low-molecularweight heparin, followed by a vitamin K antagonist. We investigated the potential use of Idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. Methods We conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of Idraparinux versus standard therapy. Patients received either subcutaneous Idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). Results In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the Idraparinux group as compared with 3.0% in the standardtherapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for Idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the Idraparinux group and 7.0% in the standard-therapy group (P = 0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the Idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement. Conclusions In patients with deep venous thrombosis, once-weekly subcutaneous Idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, Idraparinux was less efficacious than standard therapy. (ClinicalTrials.gov numbers, NCT00067093 and NCT00062803.)
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extended prophylaxis of venous thromboembolism with Idraparinux
The New England Journal of Medicine, 2007Co-Authors: Harry R. Büller, A T Cohen, Bruce L Davidson, Gerard Pillion, Martin H. Prins, Herve Decousus, A S Gallus, Michael Gent, Franco Piovella, Gary E. RaskobAbstract:A b s t r ac t Background The extended use of vitamin K antagonists for prophylaxis against venous thromboembolism is often constrained by risk–benefit limitations and inconvenience. We evaluated the efficacy and safety of a 6-month extension of prophylaxis against recurrent venous thromboembolism with Idraparinux in patients who had initially received 6 months of prophylaxis with an anticoagulant. Methods We randomly assigned patients who had completed 6 months of prophylaxis with Idraparinux or a vitamin K antagonist and in whom extended anticoagulation was warranted to receive once-weekly injections of 2.5 mg of Idraparinux or placebo for 6 months without monitoring. The primary efficacy and safety outcomes were recurrent venous thromboembolism and major bleeding. Results Of 1215 patients, 6 of 594 (1.0%) in the Idraparinux group and 23 of 621 (3.7%) in the placebo group had recurrent venous thromboembolism (P = 0.002). Major bleeding occurred in 11 patients (1.9%) in the Idraparinux group and in none in the placebo group (P<0.001). Of these 11 episodes, 3 were fatal intracranial hemorrhages. As compared with patients whose initial treatment was a vitamin K antagonist, patients whose initial treatment was Idraparinux who were assigned to 6 months in the placebo group had a lower incidence of recurrent thromboembolism (0.7% vs. 5.9%); patients who received 6 additional months of Idraparinux therapy had a higher incidence of major bleeding (3.1% vs. 0.9%). Conclusions During a 6-month extension of thromboprophylaxis, Idraparinux was effective in preventing recurrent thromboembolism but was associated with an increased risk of a major hemorrhage. (ClinicalTrials.gov number, NCT00071279.)
