Original Article
Extended Prophylaxis of Venous Thromboembolism with Idraparinux
N Engl J Med 2007; 357:1105-1112September 13, 2007
- Abstract
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.)
Media in This Article
Figure 1
Enrollment and Outcomes.Figure 2
Kaplan–Meier Cumulative Incidence of First Confirmed Symptomatic Recurrent Venous Thromboembolism, According to Study Group.Article Activity
- Article
Patients who have had venous thromboembolism have a risk of recurrence of approximately 30% during the first 8 years after the initial episode.1-3 Most of these events occur during the first 6 to 12 months after the first event.
Vitamin K antagonists are highly effective in reducing the risk of recurrence,4-6 but their use requires close laboratory monitoring and dose adjustments to reduce the risk of bleeding. For these reasons, vitamin K antagonists are often discontinued before the recommended period of prophylaxis for idiopathic venous thromboembolism (6 to 12 months).7 However, the risks and benefits of extending prophylaxis for 6 to 12 months remain uncertain.
Idraparinux (Sanofi-Aventis) is a long-acting synthetic pentasaccharide that is an antithrombin-dependent inhibitor of activated factor X. Initial clinical experience with idraparinux suggested that a fixed dose, given subcutaneously once weekly and without laboratory monitoring, is effective prophylaxis against recurrent venous thromboembolism and may be associated with a lower risk of bleeding than vitamin K antagonists.8,9 Our double-blind, placebo-controlled study evaluated patients who had completed 6 months of initial treatment for deep venous thrombosis or pulmonary embolism and who were then randomly assigned to receive an additional 6 months of prophylaxis with idraparinux. We evaluated the efficacy and safety of this method of thromboprophylaxis in these patients.
Methods
Study Design
The steering committee (including two representatives of the sponsor, Sanofi-Aventis) was responsible for the design of the study, clinical protocols, statistical analyses, study oversight, verification and analysis of the data, and writing of the manuscript. The data were collected and maintained by the sponsor and were available to all members of the steering committee. The writing committee vouches for the accuracy and completeness of this article. All suspected outcome events were reviewed and classified by a central adjudication committee, whose members were unaware of study-group assignment. An independent data and safety monitoring board periodically reviewed the study and advised the steering committee.
Patients
Consecutive patients (age, ≥18 years) with confirmed, symptomatic deep venous thrombosis or pulmonary embolism who had been treated for 6 months with acenocoumarol or warfarin (either in previous van Gogh studies or outside these studies)10 or idraparinux (in van Gogh studies) were eligible. The diagnostic criteria for deep venous thrombosis were a calf trifurcation or a noncompressible proximal vein on ultrasonography or an intraluminal filling defect on venography. For pulmonary embolism, the criteria were an intraluminal filling defect in subsegmental or more proximal pulmonary arteries on spiral computed tomography (CT) or conventional pulmonary angiography, a high-probability finding on a ventilation–perfusion lung scan, or a nondiagnostic finding on a lung scan with objectively documented deep venous thrombosis.11,12
Patients were ineligible if they met one or more of the following criteria: an indication to continue anticoagulant therapy for the index deep venous thrombosis or pulmonary embolism beyond 6 months, other indications for prophylaxis with a vitamin K antagonist, pregnancy or breast-feeding, a creatinine clearance of less than 10 ml per minute, severe hepatic disease, bacterial endocarditis, active bleeding or a high risk of bleeding, uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg), or a life expectancy of less than 3 months.
After patients gave written informed consent, randomization was performed centrally with the use of a computerized voice-response system. Randomization was stratified according to study center and the anticoagulant treatment received in the 6 months before randomization (idraparinux within the van Gogh studies or vitamin K antagonists within or outside the van Gogh studies).10 Randomization was to be performed not more than 1 hour before the administration of the first dose of the study drug. The institutional review board at each clinical center approved the study protocol.
Treatment
Patients received a once-weekly subcutaneous dose of 2.5 mg of idraparinux or placebo with an identical appearance for 6 months (26 injections). In patients who had received idraparinux before randomization, the first dose of idraparinux or placebo was given 6 to 8 days after the last injection of the drug. In patients who had received a vitamin K antagonist before randomization, the first dose was given when the international normalized ratio (INR) was 3.0 or less. For patients with a creatinine clearance of less than 30 ml per minute, the idraparinux dose was 1.5 mg, with a first dose of 2.5 mg in patients who had received a vitamin K antagonist before randomization.
Surveillance and Follow-up
All patients were contacted after 1 week and at 3 and 6 months. All had an observation period of at least 3 months and up to 6 months after the study drug was stopped (regardless of whether the discontinuation was planned or premature). At each contact, patients were systematically questioned concerning symptoms and signs of recurrent venous thromboembolism and bleeding. All patients were informed of the symptoms and signs of recurrent pulmonary embolism and deep venous thrombosis and the potential for bleeding. They were instructed to report to the study center immediately if any of these conditions occurred. In cases of suspected recurrent pulmonary embolism or deep venous thrombosis, objective testing was required.11,12
Outcome Assessment
The primary efficacy outcome was the incidence of symptomatic recurrence of venous thromboembolism, defined as objectively documented recurrent pulmonary embolism, deep venous thrombosis, or death attributed to pulmonary embolism. A diagnosis of recurrent venous thromboembolism was accepted in the absence of an adequate objective test result if the investigator had treated the patient with therapeutic doses of heparin for more than 2 days or with a vena cava filter, thrombectomy, or thrombolysis, or if recurrent venous thromboembolism could not be ruled out.
The criteria for the objective diagnosis of recurrent pulmonary embolism were a new intraluminal filling defect on spiral CT or pulmonary angiography, a cutoff of a vessel of more than 2.5 mm in diameter on pulmonary angiography, a new perfusion defect of at least 75% of a segment with corresponding normal ventilation (high probability), a new non–high-probability perfusion defect associated with deep venous thrombosis documented on ultrasonography or venography, or a new pulmonary embolism confirmed at autopsy.
The criteria for the objective diagnosis of a new deep venous thrombosis were a new, noncompressible venous segment or a substantial increase (4 mm or more) in the diameter of the thrombus during full compression in a previously abnormal segment on ultrasonography or a new intraluminal filling defect on venography.
The principal safety outcome was major bleeding. Bleeding was defined as major if it was clinically overt and associated with a fall in the hemoglobin level of 2 g per deciliter or more, if it led to the transfusion of two or more units of red cells, or if it was retroperitoneal or intracranial, occurred in a critical organ, or contributed to death. All bleeding episodes that were clinically relevant but did not qualify as major bleeding (e.g., epistaxis that required an intervention or spontaneous macroscopic hematuria) constituted an additional safety outcome.9,11,12
Deaths from all causes were also recorded. Death was classified as due to pulmonary embolism, bleeding, cancer, or another established diagnosis. Pulmonary embolism was considered to be the cause of death if the condition was objectively documented or if the cause of death was unexplained and pulmonary embolism could not be confidently ruled out.
Statistical Analysis
On the basis of an assumed 4% incidence of the primary efficacy outcome in the placebo group at 6 months, we calculated that a sample of 600 patients per group would provide a power of 90% to detect a hypothesized 75% reduction in risk in the idraparinux group (with a two-sided type I error of 0.05).
Analysis of the primary efficacy outcome, the incidence of symptomatic recurrent venous thromboembolism at 6 months, was performed with the use of the Mantel–Haenszel test, stratified according to the previous treatment (idraparinux within the van Gogh studies or a vitamin K antagonist within or outside the van Gogh studies). In addition, reductions in the adjusted risk and two-sided 95% confidence intervals were calculated with the use of the normal approximation of the log relative risk. Secondary planned efficacy analyses included a calculation of the cumulative incidence of recurrent venous thromboembolism with the use of nonparametric Kaplan–Meier estimates.
Analysis of the principal safety outcome, the incidence of major bleeding at 6 months, was performed with the use of the Mantel–Haenszel test, stratified according to the previous treatment. The effect of initial, prerandomization treatment on efficacy and safety was also analyzed. All efficacy analyses were based on the total randomized population, whereas the safety analyses were based on the total randomized population that received at least one dose of a study drug.
Results
Patients
Between November 2003 and February 2005, 1882 patients were screened in 145 centers; of these patients, 1215 underwent randomization (Figure 1Figure 1
Enrollment and Outcomes.). There were no significant differences in the baseline characteristics of the patients between the two study groups (Table 1Table 1
Demographic and Clinical Characteristics of the Patients.).Table 2Table 2
Details of the Study Groups. shows data on the administration of idraparinux or placebo and the reasons for premature discontinuation of treatment. Information on efficacy 6 months after randomization was complete in 99.8% of patients in the idraparinux group and in 99.7% of patients in the placebo group.Recurrent Venous Thromboembolism
During the 6 months of randomly assigned treatment, 6 of 594 patients in the idraparinux group (1.0%) and 23 of 621 patients in the placebo group (3.7%) had symptomatic, objectively confirmed venous thromboembolism. The reduction in the relative risk with idraparinux was 72.7% (95% confidence interval [CI], 33.5 to 88.8; P=0.002). Figure 2Figure 2
Kaplan–Meier Cumulative Incidence of First Confirmed Symptomatic Recurrent Venous Thromboembolism, According to Study Group. shows the occurrence of events over time, and Table 3Table 3
Clinical Outcomes. lists the types of recurrent episodes.In patients who had an initial pulmonary embolism, a recurrent event occurred in 3 of 283 (1.1%) in the idraparinux group and in 13 of 304 in the placebo group (4.3%, P=0.02). Among patients who had deep venous thrombosis only, 3 of 311 patients (1.0%) in the idraparinux group had a recurrent event, as compared with 10 of 317 patients (3.2%) in the placebo group (P=0.09) (data not shown). The incidence of recurrent venous thromboembolism in the placebo group appeared to be related to the anticoagulant treatment (vitamin K antagonist or idraparinux) that was received in the 6 months before randomization (P=0.004) (Table 3), whereas the incidence seemed to be unrelated to previous treatment in the idraparinux group.
Hemorrhagic Complications
Major bleeding occurred in 11 of 594 patients in the idraparinux group (1.9%) and in none of the 621 patients in the placebo group (P<0.001). A higher incidence of major bleeding was observed in patients who had received idraparinux before randomization than in those who had received a vitamin K antagonist (3.1% vs. 0.9%, P=0.06) (Table 3). Three bleeding episodes in the idraparinux group were fatal intracranial hemorrhages and occurred in patients who had received idraparinux before entry into the trial. Table 3 also lists clinically relevant episodes of nonmajor bleeding.
Additional Observations
During the observation period after the end of the additional 6 months of thromboprophylaxis, 7 patients in the idraparinux group (1.2%) and 13 patients in the placebo group (2.1%) had recurrent venous thromboembolism (P=0.21). The cumulative incidence of recurrent venous thromboembolism 1 year after randomization, as estimated with the Kaplan–Meier method, was 1.7% in the idraparinux group and 5.9% in the placebo group (P=0.002). In the placebo group, the cumulative incidence of recurrent thromboembolism during the entire year after randomization was lowest in the group of 268 patients who had received idraparinux in the 6 months before randomization (Figure 3Figure 3
Kaplan–Meier Cumulative Incidence of First Confirmed Symptomatic Recurrent Venous Thromboembolism in the Placebo Group, According to Treatment Received before Randomization.).Major bleeding after discontinuation of the study drug occurred in five patients in the idraparinux group (0.8%) and in none in the placebo group (P=0.02). The episodes of bleeding, none of which were fatal, occurred from 1 to 20 weeks after the discontinuation of a study drug. During the entire period of observation, a major hemorrhagic episode occurred in 16 patients in the idraparinux group and in none of the patients in the placebo group (P<0.001).
Discussion
We found that in patients with venous thromboembolism who had completed 6 months of anticoagulant therapy, a further 6 months of thromboprophylaxis with idraparinux reduced the frequency of recurrent thromboembolism to 1.0%, as compared with 3.7% in the placebo group. However, there was an excess of major bleeding episodes, including fatal bleeding, in the idraparinux group (in 1.9% of patients, vs. none in the placebo group). During the entire duration of observation, including the period after discontinuation of thromboprophylaxis, 2.7% of patients in the idraparinux group had a major hemorrhagic episode, whereas there were no such episodes in the placebo group. A risk of major bleeding during an 18-month period of 1.2 to 2.5% has been reported with extended thromboprophylaxis with vitamin K antagonists.3-7,13
The overall frequency of recurrences in the placebo group was lower than expected (3.7%), but among patients in the placebo group who had received vitamin K antagonists for 6 months before randomization, the frequency of recurrence was 5.9%, which is consistent with other studies.13,14 By contrast, in patients who first received idraparinux, the 6-month recurrence rate in the placebo group was less than 1%. The reason for this difference is unknown, but the observation suggests a prolonged antithrombotic effect of idraparinux.
With regard to safety, no major bleeding was observed in the placebo group, including patients who initially had received idraparinux, whereas in the idraparinux group, the incidence was 1.9%. Of the 11 patients in the idraparinux group who had a major hemorrhage, 8 had previously received idraparinux, and 3 had received a vitamin K antagonist. After completion of the extended idraparinux treatment, there were another five episodes of major bleeding in the idraparinux group. These observations suggest a prolonged risk of hemorrhage in patients treated with idraparinux for more than 6 months.
The strengths of our study were its double-blind, randomized design, which minimized the risk of bias in the reporting and assessment of recurrences and bleeding complications. Moreover, all initial thrombotic events and suspected outcomes were adjudicated by a blinded and independent adjudication committee.
In summary, our placebo-controlled trial showed the efficacy of idraparinux during a 6-month extended treatment period, at the expense of an increased risk of bleeding. We conclude that the net clinical benefit of such treatment is marginal.
Supported by Sanofi-Aventis.
Drs. Buller, Cohen, and Piovella report receiving consulting and lecture fees and grant support from Sanofi-Aventis; Dr. Davidson, consulting fees from Sanofi-Aventis, Portola, Bayer, Boehringer Ingelheim, and GlaxoSmithKline; Dr. Decousus, consulting fees and grant support from Sanofi-Aventis; Dr. Gallus, consulting fees and grant support from Sanofi-Aventis; Dr. Gent, consulting fees from Sanofi-Aventis, Bayer, and Portola; Dr. Pillion, being an employee of Sanofi-Aventis and having equity interest in the company; Dr. Prins, consulting and lecture fees from Sanofi-Aventis; and Dr. Raskob, consulting fees from Sanofi-Aventis, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, and Daiichi Sankyo and lecture fees from Sanofi-Aventis, Bayer, and Boehringer Ingelheim. No other potential conflict of interest relevant to this article was reported.
Source Information
The members of the writing committee (Harry R. Buller, M.D., Ander T. Cohen, M.D., Bruce Davidson, M.D., Hervé Decousus, M.D., Alex S. Gallus, M.D., Michael Gent, M.Sc., Gerard Pillion, M.D., Franco Piovella, M.D., Martin H. Prins, M.D., and Gary E. Raskob, Ph.D.) assume responsibility for the overall content and integrity of the article.
Address reprint requests to Dr. Buller at the Academic Medical Center, Department of Vascular Medicine, F4-211, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands, or at h.r.buller@amc.uva.nl.
The institutions and investigators participating in the van Gogh study and the affiliations of the members of the writing committee are listed in the Appendix.
Appendix
The writing committee's affiliations are as follows: the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (H.R.B.); King's College Hospital, London (A.T.C.); the Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle (B.D.); INSERM CIE3, Université Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne, Hôpital Bellevue, Service de Médecine Interne et Thérapeutique, Saint-Etienne, France (H.D.); Flinders Medical Centre, Bedford Park, SA, Australia (A.S.G.); Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (M.G.); Sanofi-Aventis, Antony, France (G.P.); U.O. Angiologia I, Malattie Thromboemboliche, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy (F.P.); Department of Epidemiology, Care and Public Health Research Institute, University of Maastricht, and Department of Clinical Epidemiology and Medical Technology Assessment, Academic Hospital, Maastricht, the Netherlands (M.H.P.); and College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City (G.A.R.).
The investigators who participated in the study were as follows: Steering Committee — H.R. Buller, A.T. Cohen, B. Davidson, H. Decousus, A. Gallus, M. Gent, F. Piovella, M.H. Prins, G. Raskob, J. Bouthier, A.W.A. Lensing. Data and Safety Monitoring Board — S. Schulman, E. Minar, G.J. Weverling. Adjudication Committee — M.H. Prins, D.P.M. Brandjes, S. Middeldorp, E.J.R. van Beek. Study Director — G. Pillion, R. van Amsterdam. Argentina (11 patients, 4 centers) — F. Santini, D. Roubiseck, Buenos Aires (8); H. Hendler, M. Hendler, Buenos Aires (1); J.M. Ceresetto, C. Doti, Buenos Aires (1); L.D. Xavier, M. Gracia Michelini, Buenos Aires (1). Australia (135 patients, 11 centers) — H. Salem, Clayton (41); A. Gallus, Bedford Park (24); T. Brighton, Kogarak (17); E. Gan, Clayton (13); K. Narayan, Ringwood East (12); J. D'Rosario, Garran (8); J. Waites, Coffs Harbour (6); C. Ward, St. Leonards (6); P. Caroll, Redcliff (4); H. Gibbs, Woolloongabba (3); U. Hanh, Woodville (1). Austria (36 patients, 2 centers) — E. Pilger, Graz (29); M. Baghestanian, Vienna (7). Belgium (12 patients, 5 centers) — M. Delcroix, Leuven (3); J. De Leersnyder, Duffel (3); J.C. Wautrecht, S. Motte, Brussels (2); M. Zicot, Liège (2); R. Vossaert, Zottegem (2). Brazil (22 patients, 6 centers) — L.C. Bodanse, Porto Alegre (9); J.P. Esteves, Salvador (5); S. Rassi, J.M.C. Kluthcouski, Goiania (3); J.A. Costa, Sorocaba (3); V. Van Bellen, F.C. Carvalho, Sao Paulo (1); R.C. Rocha Moreira, I.C. Stanischesk, Curitiba (1). Canada (10 patients, 24 centers) — M.J. Mant, L. Larratt, Edmonton (4); L. Desjardins, M. Ruel, Sainte Foy (4); L. Vickars, P. Galbraith, Vancouver (4); J. Douketis, T. Schurr, Hamilton (3); A.G.G. Turpie, C. Bradley, Hamilton (3); P. Wells, M. Rodger, Ottawa (2); S.R. Khan, A. Hirsch, Montreal (1); Y. Pesant, St. Jerome (1); D. Rolf, M. DeLorme, Kelowna (1); T. Wong, G. Robot, Winnipeg (1). Czech Republic (227 patients, 11 centers) — R. Spacek, G.P. Stanka, Prague (89); K. Klimsa, M. Holub, Jihlava (43); J. Chlumsky, V. Srnsky, R. Kratochvilova, Prague (35); P. Matoska, P. Stverak, Ostrava (28); J. Povolny, R. Stepanovova, Kladno (14); J. Vitovec, O. Hlinomaz, Brno (7); V. Cepelak, H. Cepelakova, Plzen (6); Z. Kasalova, Prague (2); J. Maly, J. Horacek, Hradec Kralové (1); F. Patek, F. Kulic, Usti nad Labern (1); J. Zak, B. Podzemska, Karlovy Vary (1). Denmark (42 patients, 7 centers) — H. Nielsen, A. Bank, Brædstrup (11); C. Jespersen, Copenhagen (10); S. Husted, B. Ziegler, Aarhus (8); K. Pedersen, J. Hallas, Odense (5); S. Avnstrøm, J. Rasmussen, Copenhagen (4); C. Tuxen, Frederiksberg (2), H. Ibsen, L. Petersen, Glostrup (2). Finland (3 patients, 1 center) — M. Kottila, T. Keski-Opas, Seinäjoki (3). France (57 patients, 12 centers) — H. Decousus, Saint-Etienne (16); D. Mottier, Brest (8); B. Agraou, Valenciennes (7); G. Simonneau, Clamart (4); B. Charbonnier, Tours (4); J.P. Bassand, Besançon (4); E. Decoulx, Tourcoing (4); B. Crestani, Paris (3); T. Meurice, Armentières (3); R. Deturck, Lens (2); P. Carpentier, Grenoble (1); E. Duhamel, Saint Brieuc (1). Germany (73 patients, 5 centers) — J. Harenberg, Mannheim (43); S. Schellong, W. Oettler, Dresden (21); A. Muegge, T. Brodherr, Bochum (7); M. Ritter, S. Yueksek, Ibbenbueren (1); A. Graf, T. Porst, Dresden (1). Italy (87 patients, 12 centers) — P. Prandoni, D. Tormene, Padua (14); A. Ghirarduzzi, M. Lotti, Reggio Emilia (13); F. Piovella, M. Baronne, C. Piovella, Pavia (12); G. Scannapieco, V. Pagliara, Treviso (11); A. D'Angelo, A. Fattorini, Milan (10); C. Giuntini, A. Palla, Pisa (6); G.B. Ambosio, R. Parisi, Venice (6); M. Cattaneo, S. Caberlon, Milan (5); D. Imberti, E. Croci, Piacenza (4); R. Poggio, A. Schenone, Genoa (4); P.M. Manucci, I. Martinelli, T. Battaglioli, Milan (1); R. Quintavalla, C. Pattaccini, Parma (1). Mexico (9 patients, 2 centers) — O. Reyes, L. Sanchez Escalante, Monterrey (6); E. Anaya Santacruz, Mexico City (3). New Zealand (8 patients, 1 center) — P. Oeckelford, Auckland (8). Norway (10 patients, 1 center) — P. Morten Sandset, A. Haaland, Oslo (10). Poland (183 patients, 10 centers) — J. Lewczuk, P. Piszko, Wroclaw (36); Z. Rybak, A. Milnerowicz, Wroclaw (31); W. Witkiwicz, Z. Chmielecki, Wroclaw (30); W. Tomkowski, J. Kober, Warsaw (26); P. Szyber, A. Ruciński, Wrocław (26); J. Kłoczko, J. Jaromin, Białystok (11); P. Gutowski, B. Trojnacka, Szczecin (7); J. Wasiak, P. Czekalski, Łódź (7); P. Pruszczyk, M. Kostrubiec, Warsaw (5); J. Cianciara, J. Pawełczyk, Wrocław (4). South Africa (15 patients, 3 centers) — D. Adler, D. Grolman, P. Grolman, Bryanston (6); J. Becker, N. Wilcovics, Pretoria (5); B. Warren, D.F. du Toit, Parow (4). Spain (15 patients, 4 centers) — E. Grau, F. Hernandez, Xàtiva (5); M. José Paloma, M. Redondo Izal, Pamplona (5); R. Valle, M. José Delgado, Torrelavega (4); D. Jiménez, A. Sueiro Bendito, Madrid (1). Sweden (74 patients, 6 centers) — H. Eriksson, P.O. Hansson, Göteborg (24); L. Engquist, M. Svensson, Värnamo (11); J. Aagesen, M. Kentson, Jönköping (11); G. Lärfars, E. Ottosson, Stockholm (11); M. Holmström, A. Carlsson, Stockholm (10); T. Wallén, J. Alsenhed, Västervik (7). Switzerland (1 patient, 1 center) — A. Cerny, S. Regazzoni, Lugano (1). The Netherlands (184 patients, 10 centers) — K. Hamulyak, A.J. Ten Cate-Hoek, Maastricht (74); M. Van Marwijk Kooy, J.L.L.M. Coebe, Zwolle (29); S. Middeldorp, M. Coppens, Amsterdam (22); D.H. Biesma, O. de Weerdt, Nieuwegein (12); M.H.H. Kramer, S. Wittebol, Amersfoort (11); J.J. Mol, V. Mattijssen, Arnhem (11); C.A.M. De Swart, J.G. Schrama, Hoofddorp (10); F.L.G. Erdkamp, F.P.J. Peters, Sittard (7); T. Haitjema, W.G. Boersma, Alkmaar (6); C.D.A. Stehouwer, M.T. Nurmohamed, Amsterdam (2). United Kingdom (8 patients, 1 center) — A. Cohen, Y. Yavin, London (8). United States (46 patients, 18 centers) — A. Spyrolous, Albuquerque, NM (12); M. Fusco, Melbourne, FL (4); M. Cipolle, Allentown, PA (3), B. Davidson, Seattle (3); S. Kaatz, Detroit (3); K. Stevens, Troy, NY (3); A. Jacobson, Loma Linda, CA (2); S. Joseph, Spokane, WA (2); J. Muntz, Houston (2); S. Ratbun, Oklahoma City (2); J. Stocks, Tyler, TX (2); D. Garcia, Albuquerque (2); C. Anderson, Bay Pines, FL (1); J. Bradley, Olathe, KS (1); J. Cooper, Alexandria, VA (1); J. Godwin, Maywood, IL (1); J. Gossage, Augusta, GA (1); J. Rehm, Fredricksburg, MD (1).
- References
References
1
Prandoni P ,Lensing AWA ,Cogo A , et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7
Web of Science | Medline2
The PREPIC Study Group
CrossRef | Web of Science | Medline3
Agnelli G ,Prandoni P ,Becattini C , et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003;139:19-25
Web of Science | Medline4
Agnelli G ,Prandoni P ,Santamaria MG , et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001;345:165-169
Full Text | Web of Science | Medline5
Schulman S ,Rhedin A-S ,Lindmarker P , et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661-1665
Full Text | Web of Science | Medline6
Hutten BA ,Prins MH . Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Cochrane Database Syst Rev 2006;1:CD001367-CD001367
Medline7
Buller HR ,Agnelli GA ,Hull RD ,Hyers TM ,Prins MH ,Raskob GE . Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl 3:401S-428S[Erratum, Chest 2005;127:416.]
CrossRef | Web of Science | Medline8
Herbert JM ,Herault JP ,Bernat A , et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting pentasaccharide. Blood 1998;91:4197-4205
Web of Science | Medline9
The PERSIST Investigators
CrossRef | Web of Science | Medline10
The van Gogh Investigators
Full Text | Web of Science | Medline11
Buller HR ,Davidson BL ,Decousus H , et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004;140:867-873
Web of Science | Medline12
The Matisse Investigators
Full Text | Web of Science | Medline13
Ridker PM ,Goldhaber SZ ,Danielson E , et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434
Full Text | Web of Science | Medline14
Schulman S ,Wahlander K ,Lundstrom T ,Clason SB ,Eriksson H . Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-1721
Full Text | Web of Science | Medline
- Citing Articles (37)
Citing Articles
1
Harry R Büller, Alex S Gallus, Gerard Pillion, Martin H Prins, Gary E Raskob. (2012) Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial. The Lancet 379:9811, 123-129
CrossRef2
John W Eikelboom, Jeffrey I Weitz. (2012) Idrabiotaparinux treatment for venous thromboembolism. The Lancet 379:9811, 96-98
CrossRef3
Pamala Kanagasabapathy, Pratima Chowdary, Alex Gatt. (2011) Alternatives to Warfarin-The Next Generation of Anticoagulants. Cardiovascular Therapeutics 29:6, e80-e88
CrossRef4
F. Couturaud. (2011) Durée optimale du traitement anticoagulant au décours d’une embolie pulmonaire. Revue des Maladies Respiratoires 28:10, 1265-1277
CrossRef5
J. Elmer, K. A. Wittels. (2011) Emergency reversal of pentasaccharide anticoagulants: a systematic review of the literature. Transfusion Medicineno-no
CrossRef6
Job Harenberg, Martin Wehling. (2011) Future of Anticoagulant Therapy. Cardiovascular Therapeutics 29:5, 291-300
CrossRef7
Vincenzo Toschi, Maddalena Lettino. (2011) Inhibitors of propagation of coagulation: factors V and X. British Journal of Clinical Pharmacology 72:4, 563-580
CrossRef8
L. Bertoletti, P. Mismetti. (2011) Les nouveaux anticoagulants dans la maladie thrombo-embolique veineuse. Revue des Maladies Respiratoires 28:8, 1008-1016
CrossRef9
Mátyás Keltai, Katalin Keltai. (2011) Új antikoagulánsok a vénás thromboembolia megelőzésében és kezelésében. Orvosi Hetilap 152:25, 983-992
CrossRef10
(2011) Efficacy and safety of once weekly subcutaneous idrabiotaparinux in the treatment of patients with symptomatic deep venous thrombosis. Journal of Thrombosis and Haemostasis 9:1, 92-99
CrossRef11
G. Palareti. (2011) Bleeding with anticoagulant treatments. Hämostaseologie 31:4, 237-242
CrossRef12
The EINSTEIN Investigators. (2010) Oral Rivaroxaban for Symptomatic Venous Thromboembolism. New England Journal of Medicine 363:26, 2499-2510
Full Text13
Timothy A. Morris. (2010) New Synthetic Antithrombotic Agents for Venous Thromboembolism: Pentasaccharides, Direct Thrombin Inhibitors, Direct Xa Inhibitors. Clinics in Chest Medicine 31:4, 707-718
CrossRef14
Hans-Juergen Rupprecht, Ralf Blank. (2010) Clinical Pharmacology of Direct and Indirect Factor Xa Inhibitors. Drugs1
CrossRef15
(2010) Meeting the Unmet Needs in Anticoagulant Therapy. European Journal of Haematology 85, 1-28
CrossRef16
I. PATY, M. TRELLU, J.-M. DESTORS, P. CORTEZ, E. BOËLLE, G. SANDERINK. (2010) Reversibility of the anti-FXa activity of idrabiotaparinux (biotinylated idraparinux) by intravenous avidin infusion. Journal of Thrombosis and Haemostasis 8:4, 722-729
CrossRef17
Lori-Ann Linkins, Jeffrey I. Weitz. (2010) New and Emerging Anticoagulant Therapies for Venous Thromboembolism. Current Treatment Options in Cardiovascular Medicine 12:2, 142-155
CrossRef18
Daniel S. Weitz, Jeffrey I. Weitz. (2010) Update on heparin: what do we need to know?. Journal of Thrombosis and Thrombolysis 29:2, 199-207
CrossRef19
M. Lancé, B. Stessel, K. Hamulyák, M.A. Marcus. (2010) Alte und neue Gerinnungshemmer. Der Anaesthesist 59:1, 62-68
CrossRef20
Job Harenberg. (2010) Idraparinux and idrabiotaparinux. Expert Review of Clinical Pharmacology 3:1, 9-16
CrossRef21
James E. Muntz, Franklin A. Michota. (2010) Prevention and management of venous thromboembolism in the surgical patient: options by surgery type and individual patient risk factors. The American Journal of Surgery 199:1, S11-S20
CrossRef22
Y. Buyue, J. P. Sheehan. (2009) Fucosylated chondroitin sulfate inhibits plasma thrombin generation via targeting of the factor IXa heparin-binding exosite. Blood 114:14, 3092-3100
CrossRef23
Richard H White, Susan Murin. (2009) Long-term incidence of death due to thromboembolic disease among patients with unprovoked pulmonary embolism. Current Opinion in Pulmonary Medicine 15:5, 418-424
CrossRef24
Jan Steffel, Thomas F Lüscher. (2009) Novel anticoagulants in clinical development: focus on factor Xa and direct thrombin inhibitors. Journal of Cardiovascular Medicine 10:8, 616-623
CrossRef25
Pieter W. Kamphuisen, Harry R. Büller. 2009. New Heparins: Synthetic Pentasaccharides. , 253-268.
CrossRef26
Sam Schulman. 2009. Anticoagulants for the Treatment ofVenous Thromboembolism. , 155-170.
CrossRef27
C. VEYRAT-FOLLET, N. VIVIER, M. TRELLU, C. DUBRUC, G. J. SANDERINK. (2009) The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials. Journal of Thrombosis and Haemostasis 7:4, 559-565
CrossRef28
Agnes Y.Y. Lee. (2009) Treatment of venous thromboembolism in cancer patients. Best Practice & Research Clinical Haematology 22:1, 93-101
CrossRef29
Brian L Henry, Jay N Thakkar, Erika J Martin, Donald F Brophy, Umesh R Desai. (2009) Characterization of the plasma and blood anticoagulant potential of structurally and mechanistically novel oligomers of 4-hydroxycinnamic acids. Blood Coagulation & Fibrinolysis 20:1, 27-34
CrossRef30
Alex C. Spyropoulos. (2008) Brave new world: The current and future use of novel anticoagulants. Thrombosis Research 123, S29-S35
CrossRef31
Guy Meyer, Benjamin Planquette, Olivier Sanchez. (2008) Long-term outcome of pulmonary embolism. Current Opinion in Hematology 15:5, 499-503
CrossRef32
Kenneth A Bauer. (2008) New anticoagulants. Current Opinion in Hematology 15:5, 509-515
CrossRef33
Job Harenberg, Ingrid Jörg, Yvonne Vukojevic, Gerd Mikus, Christel Weiss. (2008) 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 64:6, 555-563
CrossRef34
Paolo Prandoni, Daniela Tormene, Marica Perlati, Barbara Brandolin, Luca Spiezia. (2008) Idraparinux: review of its clinical efficacy and safety for prevention and treatment of thromboembolic disorders. Expert Opinion on Investigational Drugs 17:5, 773-777
CrossRef35
J. HARENBERG, Y. VUKOJEVIC, G. MIKUS, I. JOERG, C. WEISS. (2008) Long elimination half-life of idraparinux may explain major bleeding and recurrent events of patients from the van Gogh trials. Journal of Thrombosis and Haemostasis 6:5, 890-892
CrossRef36
Job Harenberg. (2008) Indirect and direct anticoagulants predominantly inhibiting factor Xa. Therapy 5:2, 177-192
CrossRef37
Guy Meyer, Benjamin Planquette, Olivier Sanchez. (2008) Long-term outcome of pulmonary embolism. Therapy 5:2, 159-167
CrossRef
