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1. Scoring and psychometric validation of the Perception of Anticoagulant Treatment Questionnaire (PACT-Q©)

Author

Essers B, Gilet H, Gabriel S, Guillemin I, Prins MH, Raskob G, and Kahn SR

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Abstract Background The 'Perception of Anti-Coagulant Treatment Questionnaire' (PACT-Q) was developed to assess patients' expectations of, and satisfaction with their anticoagulant treatment. This questionnaire needs to be finalised and psychometrically validated. Methods The PACT-Q was included in the United States, the Netherlands and France into three phase III multinational clinical trials conducted to evaluate efficacy and safety of a new long-acting anticoagulant drug (idraparinux) compared to vitamin K antagonist (VKA). PACT-Q was administered to patients with deep venous thrombosis (DVT), atrial fibrillation (AF) or pulmonary embolism (PE) at Day 1, to assess patients' expectations, and at 3 and 6 months to assess patients' satisfaction and treatment convenience and burden. The final structure of the PACT-Q (Principal Component Analysis – PCA – with Varimax Rotation) was first determined and its psychometric properties were then measured with validity of the structure (Multitrait analysis), internal consistency reliability (Cronbach's alpha coefficients) and known-group validity. Results PCA and multitrait analyses showed the multidimensionality of the "Treatment Expectations" dimension, comprising 7 items that had to be scored independently. The "Convenience" and "Burden of Disease and Treatment" dimensions of the hypothesised original structure of the questionnaire were combined, thus resulting in 13 items grouped into the single dimension "Convenience". The "Anticoagulant Treatment Satisfaction" dimension remained unchanged and included 7 items. All items of the "Convenience" and "Anticoagulant Treatment Satisfaction" dimensions displayed good convergent and discriminant validity. The internal consistency reliability was good, with a Cronbach's alpha of 0.84 for the "Convenience" dimension, and 0.76 for the "Anticoagulant Treatment Satisfaction" dimension. Known-group validity was good, especially with regard to occurrence of thromboembolic events within 3 months from randomisation. Conclusion The PACT-Q is a valid and reliable instrument that allows the assessment of patients' expectations and satisfaction regarding anticoagulant treatment, as well as their opinion about treatment convenience of use. Its two-part structure – assessment of expectations at baseline in the first part, and of convenience, burden and treatment satisfaction in the second – was validated and displays good and stable psychometric properties. These results are not sufficient to recommend the use of satisfaction as primary endpoint in clinical trials; further validation work is needed to support the interpretation of PACT-Q dimension scores. However, this first validation makes the PACT-Q an appropriate measure for use in clinical and pharmacoepidemiological research, as well as in real-life studies. Trial Registration (ClinicalTrials.gov numbers, NCT00067093, NCT00062803 and NCT00070655).

Published
2009
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2. The development and implementation of a regional network of physiotherapists for exercise therapy in patients with peripheral arterial disease, a preliminary report

Author

Prins MH, Welten RJThJ, van der Berg C, Bendermacher BLW, Willigendael EM, Bie de RA, and Teijink JAW

Subjects
Public aspects of medicine, RA1-1270
Abstract

Abstract Background Exercise therapy (ET) is the main conservative and proven effective treatment of patients with intermittent claudication. Currently, the most frequent exercise prescription is a single 'go home and walk' advise, without supervision or follow-up. There is no evidence to support the efficacy of this advise and compliance is known to be low. Therefore, a systematic approach was used to guarantee quality and standardisation of treatment, optimal guideline adherence and improved of inter-professional communication between vascular surgeons and physiotherapists. In this preliminary report we would like to outline the steps taken for the development and implementation of the Network Exercise Therapy Parkstad Methods In October 2003 all 59 regional physiotherapy practices were invited to attend a symposium regarding ET in a physiotherapeutic setting. Attending physiotherapists interested in providing ET and willing to follow a certified course on ET, were asked to register. Three tastkgroups were formed to accomplish the set targets: Exercise therapy education, Exercise therapy implementation and continuity, and Inter-professional communication in the Parkstad region. Results In total 27 physiotherapists, from 22 different practices followed the educational program and are now trained and accredited to provide ET according to the guideline of the Royal Dutch Society for Physiotherapy. A web-based database wasdesigned to contain information on disease specific items provided by the vascular surgery department, and aspects with respect to ET registered by the physiotherapist. The information is regularly updated and available online. Access tothe database is restricted to vascular surgeons and physiotherapists in the network. The secondary purpose of the database is to register essential benchmark data for future analysis of ET in a physiotherapeutic setting in the Netherlands and to enable physiotherapists continuous feedback on patient performance. A triage system was developed to detect patients with a compromised cardiac history. This group receives ET at the in-hospital department of revalidation with the possibility of immediate consultation of a cardiologist in case of cardiac complications or even CPR. Conclusion The Network Exercise Therapy Parkstad of supervised ET is the first initiative in the Netherlands to provide ET close to the patient's home environment. With the implementation of supervised ET in an outpatient physiotherapeutic setting for all eligible patients with symptomatic PAD, the access to care has been improved. A web-based communication system provides physiotherapists and vascular surgeons with all the necessary and continues updated patient information. Future research, currently in progress, will investigate the therapeutic benefits and cost-effectiveness of exercise therapy in a physiotherapeutic setting.

Published
2005
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3. Anticoagulation in pediatric cancer-associated venous thromboembolism: a subgroup analysis of EINSTEIN-Jr

Author

Palumbo, JS, Lensing, AWA, Brandao, LR, Hooimeijer, HL, Kenet, G, van Ommen, H, Pap, AF, Majumder, M, Kubitza, D, Thelen, K, Willmann, S, Prins, MH, Monagle, P, Male, C, Palumbo, JS, Lensing, AWA, Brandao, LR, Hooimeijer, HL, Kenet, G, van Ommen, H, Pap, AF, Majumder, M, Kubitza, D, Thelen, K, Willmann, S, Prins, MH, Monagle, P, and Male, C

Abstract

Anticoagulant treatment of pediatric cancer-associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 of the 500 children (11.2%) with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy, 64.3%, solid malignant tumor, 35.7%). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins, with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, pharmacokinetic (PK) parameters of rivaroxaban were derived using population PK modeling. During the 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0%-6.4%), and 3-month repeat imaging showed complete or partial vein recanalization in 20 and 24 of 52 evaluable children (38.5% and 46.2%, respectively). Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures, or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Rivaroxaban and standard anticoagulants appeared safe and efficacious and were associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. This trial was registered at www.clinicaltrials.gov as #NCT02234843.

Published
2022

4. Aspirin versus vitamin K antagonist treatment guided by transoesophageal echocardiography in patients with atrial fibrillation: a pilot study

Author

Dinh, Trang, Baur, Leo H B, Pisters, Ron, Kamp, Otto, Verheugt, Freek W A, Smeets, Joep L R M, Cheriex, Emile C, Lindeboom, Jan-Eize, Heesen, Wilfred F, Tieleman, Robert G, Prins, Martin H, Crijns, Harry J G M, Dinh, T, Pisters, R, Tieleman, RG, Prins, MH, Crijns, HJGM, Crijns, HJGM, Dinh, T, Baur, LHB, Kamp, O, Prins, MH, Verheugt, FWA, Pisters, R, Limburg, M, de Zwaan, C, ten Cate, H, and Lip, GY

Published
2014
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5. Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation

Author

Young, G, Lensing, AWA, Monagle, P, Male, C, Thelen, K, Willmann, S, Palumbo, JS, Kumar, R, Nurmeev, I, Hege, K, Bajolle, F, Connor, P, Hooimeijer, HL, Torres, M, Chan, AKC, Kenet, G, Holzhauer, S, Santamaria, A, Amedro, P, Beyer-Westendorf, J, Martinelli, I, Massicotte, MP, Smith, WT, Berkowitz, SD, Schmidt, S, Price, V, Prins, MH, Kubitza, D, Young, G, Lensing, AWA, Monagle, P, Male, C, Thelen, K, Willmann, S, Palumbo, JS, Kumar, R, Nurmeev, I, Hege, K, Bajolle, F, Connor, P, Hooimeijer, HL, Torres, M, Chan, AKC, Kenet, G, Holzhauer, S, Santamaria, A, Amedro, P, Beyer-Westendorf, J, Martinelli, I, Massicotte, MP, Smith, WT, Berkowitz, SD, Schmidt, S, Price, V, Prins, MH, and Kubitza, D

Abstract

BACKGROUND: Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. METHODS: Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to <30, and <12 kg, respectively. Previously, these regimens were confirmed for children weighing ≥20 kg but only predicted in those <20 kg. Based on sparse blood sampling, the daily area under the plasma concentration-time curve [AUC(0-24)ss ] and trough [Ctrough,ss ] and maximum [Cmax,ss ] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients. RESULTS: Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. DISCUSSION: Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.

Published
2020

6. Safety and efficacy of anticoagulant therapy in pediatric catheter-related venous thrombosis (EINSTEIN-Jr CVC-VTE)

Author

Thom, K, Lensing, AWA, Nurmeev, I, Bajolle, F, Bonnet, D, Kenet, G, Massicotte, MP, Karakas, Z, Palumbo, JS, Saracco, P, Amedro, P, Chain, J, Chan, AK, Ikeyama, T, Lam, JCM, Gauger, C, Pap, AF, Majumder, M, Kubitza, D, Smith, WT, Berkowitz, SD, Prins, MH, Monagle, P, Young, G, Male, C, Thom, K, Lensing, AWA, Nurmeev, I, Bajolle, F, Bonnet, D, Kenet, G, Massicotte, MP, Karakas, Z, Palumbo, JS, Saracco, P, Amedro, P, Chain, J, Chan, AK, Ikeyama, T, Lam, JCM, Gauger, C, Pap, AF, Majumder, M, Kubitza, D, Smith, WT, Berkowitz, SD, Prins, MH, Monagle, P, Young, G, and Male, C

Abstract

Anticoagulant treatment of pediatric central venous catheter-related venous thromboembolism (CVC-VTE) has not been specifically evaluated. In EINSTEIN-Jr, 500 children with any VTE received rivaroxaban or standard anticoagulants. A predefined analysis of the CVC-VTE cohort was performed. Children with CVC-VTE (age, birth to 17 years) were administered rivaroxaban or standard anticoagulants during the 1-month (children <2 years) or 3-month (all other children) study period. Predefined outcomes were recurrent VTE, change in thrombotic burden on repeat imaging, and bleeding. Predictors for continuation of anticoagulant therapy beyond the study period were evaluated. One hundred twenty-six children with symptomatic (n = 76, 60%) or asymptomatic (n = 50, 40%) CVC-VTE received either rivaroxaban (n = 90) or standard anticoagulants (n = 36). There was no recurrent VTE (0%; 95% confidence interval [CI], 0.0%-2.8%). Three children had the principal safety outcome: none had major bleeding and 3 children had clinically relevant nonmajor bleeding (2.4%; 95% CI, 0.7%-6.5%), all in the rivaroxaban arm. Complete or partial vein recanalization occurred in 57 (55%) and 38 (37%) of 103 evaluable children, respectively. Results were similar for symptomatic and asymptomatic CVC-VTE. Continuation of anticoagulant therapy beyond the study period occurred in 61 (48%) of children and was associated with residual VTE but only in children <2 years (odds ratio [OR], 20.9; P = .003) and continued CVC use (OR, 6.7; P = .002). Anticoagulant therapy appeared safe and efficacious and was associated with reduced clot burden in most children with symptomatic or asymptomatic CVC-VTE. Residual VTE and continued CVC use were associated with extended anticoagulation. This trial was registered at www.clinicaltrials.gov as #NCT02234843.

Published
2020

7. Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT)

Author

Connor, P, van Kammen, MS, Lensing, AWA, Chalmers, E, Kallay, K, Hege, K, Simioni, P, Biss, T, Bajolle, F, Bonnet, D, Grunt, S, Kumar, R, Lvova, O, Bhat, R, Van Damme, A, Palumbo, J, Santamaria, A, Saracco, P, Payne, J, Baird, S, Godder, K, Labarque, V, Male, C, Martinelli, I, Soto, MM, Motwani, J, Shah, S, Hooimeijer, HL, Prins, MH, Kubitza, D, Smith, WT, Berkowitz, SD, Pap, AF, Majumder, M, Monagle, P, Coutinho, JM, Connor, P, van Kammen, MS, Lensing, AWA, Chalmers, E, Kallay, K, Hege, K, Simioni, P, Biss, T, Bajolle, F, Bonnet, D, Grunt, S, Kumar, R, Lvova, O, Bhat, R, Van Damme, A, Palumbo, J, Santamaria, A, Saracco, P, Payne, J, Baird, S, Godder, K, Labarque, V, Male, C, Martinelli, I, Soto, MM, Motwani, J, Shah, S, Hooimeijer, HL, Prins, MH, Kubitza, D, Smith, WT, Berkowitz, SD, Pap, AF, Majumder, M, Monagle, P, and Coutinho, JM

Abstract

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.

Published
2020

8. Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

Author

Lensing, AWA, Male, C, Young, G, Kubitza, D, Kenet, G, Massicotte, MP, Chan, A, Molinari, AC, Nowak-Goettl, U, Pap, AF, Adalbo, I, Smith, WT, Mason, A, Thelen, K, Berkowitz, SD, Crowther, M, Schmidt, S, Price, V, Prins, MH, Monagle, P, Lensing, AWA, Male, C, Young, G, Kubitza, D, Kenet, G, Massicotte, MP, Chan, A, Molinari, AC, Nowak-Goettl, U, Pap, AF, Adalbo, I, Smith, WT, Mason, A, Thelen, K, Berkowitz, SD, Crowther, M, Schmidt, S, Price, V, Prins, MH, and Monagle, P

Abstract

BACKGROUND: Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily. METHODS: EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0-18 years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months. CONCLUSIONS: EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT02234843, registered on 9 September 2014.

Published
2018

9. Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial

Author

Prandoni P, Noventa F, Quintavalla R, Bova C, Siragusa S, Bucherini E, Astorri F, Cuppini S, Dalla Valle F, Lensing AW, Prins MH, Villalta S, Canano Investigators Collaborators […, Vedovetto V, Barbar S, Campello E, Milan M, Filippi L, Rocci A, Chiappetta P, Pellegrini R, Fiaschi E, Vallone G, D'Amico E, Noto A, Pili C, Costantini E, Gasperon M, Palareti G, Malato A, Saccullo G, Brini C, Bitti G, Marzolo M, Ramazzina E, Zamboni S., COSMI, BENILDE, Epidemiologie, MUMC+: KIO Kemta (9), RS: CAPHRI School for Public Health and Primary Care, Prandoni P, Noventa F, Quintavalla R, Bova C, Cosmi B, Siragusa S, Bucherini E, Astorri F, Cuppini S, Dalla Valle F, Lensing AW, Prins MH, Villalta S, Canano Investigators Collaborators […, Vedovetto V, Barbar S, Campello E, Milan M, Filippi L, Rocci A, Chiappetta P, Pellegrini R, Fiaschi E, Vallone G, D'Amico E, Noto A, Pili C, Costantini E, Gasperon M, Palareti G, Malato A, Saccullo G, Brini C, Bitti G, Marzolo M, Ramazzina E, Zamboni S., …], Prandoni, P, Noventa, F, Quintavalla, R, Bova, C, Cosmi, B, Siragusa, S, Bucherini, E, Astorri, F, Cuppini, S, Dalla Valle, F, Lensing, A, Prins, M, and Villalta, S

Subjects
Adult, Male, musculoskeletal diseases, medicine.medical_specialty, Time Factors, Immunology, Thigh, behavioral disciplines and activities, Biochemistry, Postthrombotic Syndrome, Settore MED/15 - Malattie Del Sangue, law.invention, POST-THROMBOTIC SYNDROME, Young Adult, Randomized controlled trial, law, medicine, Humans, Knee, Aged, Aged, 80 and over, Venous Thrombosis, First episode, VENOUS THROMBOEMBOLISM, business.industry, Pruritus, Hazard ratio, Cell Biology, Hematology, Middle Aged, musculoskeletal system, medicine.disease, Thrombosis, humanities, Confidence interval, Discontinuation, Surgery, Venous thrombosis, Treatment Outcome, medicine.anatomical_structure, Erythema, Patient Compliance, Female, venous thrombosis, business, Stockings, Compression, Follow-Up Studies
Abstract

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated. This study is registered as Clinical Trial number NCT00426075.

Published
2012

10. Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2)

Author

Eriksson, Bi, Turpie, Ag, Lassen, Mr, Prins, Mh, Agnelli, G, Kälebo, P, Wetherill, G, Wilpshaar, Jw, Meems, L, Paireddy, A, Wall, M, Hermus, G, Willems, M, Zachrisson, B, Wallin, J, Eriksson, H, Sandgren, G, Angerås, U, Falk, A, Bergqvist, D, Gallus, A, Tijssen, Jg, Pessayre, D, Grohs, Jg, Nogler, M, Wurnig, C, Gavrankapetanovic, I, Maric, V, Pavic, V, Deniger, J, Kofránek, I, Pink, M, Pink, T, Hölmich, P, Mejdahl, S, Mikkelsen, S, Leppilahti, J, Pesola, M, Fink, B, Göbel, F, Graichen, H, Halder, Am, Kienapfel, H, Kurth, A, Ferrousis, I, Macheras, G, D'Angelo, A, Baudo, F, Borghi, B, Della Rocca, G, Fanelli, G, Grappiolo, G, Grossi, P, Piovella, F, Silingardi, M, Spotorno, L, Baurovskis, A, Keselis, J, Peredistijs, A, Kocius, M, Smailys, A, Buciuto, R, Hedlund, T, Talsnes, O, Bednarek, A, Blacha, J, Kwiatkowski, K, Niedzwiedzki, T, Skowronski, Jc, Wojciechowski, P, Dryagin, V, Ivanov, P, Kopenkin, S, Kuropatkin, G, Lapshinov, E, Levin, G, Linnik, S, Medvedev, A, Nikolaev, V, Safronov, A, Sergeev, S, Harhaji, V, Kecojevic, V, Mitkovic, M, Nedeljkovic, R, Ristic, B, Stosic, P, Todorovic, P, Hlavác, M, Oslanec, D, Alonso Aguirre MA, Casa Pantoja, V, Cruz Pardos, A, Díaz Almodovar JL, Gomar Sancho, F, Otero Fernández, R, Valle Ortiz MJ, Vilanova Vázquez JL, Ahnfelt, L, Andersson, C, Petersson, Lg, Ponzer, S., Eriksson BI., Turpie AG., Lassen MR., Prins MH., Agnelli G., Kalebo P., Wetherill G., Wilpshaar JW., Meems L., ONYX-2 study group, Borghi B., ACS - Amsterdam Cardiovascular Sciences, Cardiology, Epidemiologie, MUMC+: KIO Kemta (9), and RS: CAPHRI School for Public Health and Primary Care

Subjects
Time Factors, total hip arthroplasty, Arthroplasty, Replacement, Hip, Deep vein, medicine.medical_treatment, Administration, Oral, direct factor Xa inhibitor, law.invention, chemistry.chemical_compound, Randomized controlled trial, oral anticoagulant, law, Stroke, Aged, 80 and over, medicine.diagnostic_test, Incidence, Darexaban, Hematology, Middle Aged, Thrombosis, Treatment Outcome, medicine.anatomical_structure, Elective Surgical Procedures, Anesthesia, prophylaxis, Adult, medicine.medical_specialty, Acute coronary syndrome, venous thromboembolism, Venography, Postoperative Hemorrhage, Risk Assessment, Young Adult, direct factor Xa inibhitor, YN150, oral thromboprophylaxis, flebography, arthroplasty, Double-Blind Method, Fibrinolytic Agents, medicine, Humans, cardiovascular diseases, Enoxaparin, Aged, Dose-Response Relationship, Drug, business.industry, Phlebography, medicine.disease, Arthroplasty, Surgery, Logistic Models, chemistry, YM150, business, Factor Xa Inhibitors
Abstract

Summary. Background: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively. Objectives: To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty. Patients/methods: Patients were randomized to postoperative, once-daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double-blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery. Results: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose-related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin. Conclusions: The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.

Published
2010

11. Efficacy and safety of once weekly subcutaneous idrabiotaparinux in the treatment of patients with symptomatic deep venous thrombosis

Author

Büller, Hr, Destors, Jm, Gallus, A, Prins, Mh, Raskob, G, Charbonnier, B, Decousus, H, Leizorovicz, A, Laporte, S, Brandjes, Dp, Middeldorp, S, Pillion, G, Ceresetto, Jm, Hendler, H, Xavier, Dl, Santini, F, del Carmen Gallo, M, Coughlin, P, Chong, B, Leahy, M, Ward, C, Leyden, M, Prosser, I, Carroll, P, Gan, E, Mcrae, S, Salem, H, Pilger, E, Koppensteiner, R, Jurecka, W, Forstner, K, Hainaut, P, Motte, S, Vermassen, F, Araujo, Gr, Timi, Jr, Costa, Ja, Manenti, F, Yoshida, Wb, Kovacs, M, Delle Siega, A, Rodger, M, Miron, Mj, Anderson, D, Yeo, E, Kassis, J, Spacek, R, Klimsa, Z, Patek, F, Matoska, P, Maly, J, Srnsky, V, Cepelak, C, Nielsen, H, Noelsen, Hk, Avstrom, S, Husted, S, Tuxen, C, Stender, S, Azarian, R, Leftheriotis, G, Jego, P, Achkar, A, Zeltser, D, Keidar, S, Inbal, A, Piovella, F, Barone, M, Prandoni, Paolo, Imberti, D, Palaretti, G, Jerjes, C, Calvo, C, Van Marwijk Kooij, M, Timmerman, R, Mol, J, Ten Cate, H, Kamphuisen, P, Dullemond, A, Kroon, C, Veth, D, Biesma, D, Van Leendert, R, Ockelford, P, Chunilal, S, Szyber, P, Strzelczyk, J, Checinsli, P, Nizankowki, R, Cianciara, J, Kloczko, J, Tomkowski, W, Gutowski, P, Stupin, V, Sokurenko, G, Kirienko, A, Baesukov, A, Sokora, V, Katelnitsky, I, Didenko, Y, Lukianov, Y, Zatevakhin, I, Gavrilenko, A, Van Zyl LJ, Basson, Mm, Becker, Lh, Siebert, S, Engelbrecht, Jm, Otero, Dr, Paloma, Mj, del Toro, H, Kürşat Bozkurt, A, Joseph, S, Nadar, V, Baird, I, Han, D, Jacobson, A, Martin, J, Smith, D, Comerota, A, Guza, E, Wright, P., Epidemiologie, MUMC+: KIO Kemta (9), Interne Geneeskunde, Biochemie, RS: CARIM School for Cardiovascular Diseases, RS: CAPHRI School for Public Health and Primary Care, Amsterdam Cardiovascular Sciences, and Vascular Medicine

Subjects
Adult, Male, medicine.medical_specialty, Time Factors, medicine.drug_mechanism_of_action, Injections, Subcutaneous, Idraparinux, Factor Xa Inhibitor, Biotin, Oligosaccharides, Once weekly, Hemorrhage, Risk Assessment, Gastroenterology, bioequipotency, Drug Administration Schedule, treatment randomized trial, law.invention, auticoagulants, Double-Blind Method, Randomized controlled trial, Recurrence, law, Internal medicine, medicine, Humans, Blood Coagulation, deep venous thrombosis, Aged, Venous Thrombosis, Idrabiotaparinux, business.industry, Incidence (epidemiology), Anticoagulants, Hematology, Middle Aged, medicine.disease, United States, Confidence interval, Europe, Venous thrombosis, Treatment Outcome, Factor Xa, Female, business, Factor Xa Inhibitors
Abstract

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.? 2010 International Society on Thrombosis and Haemostasis.

Published
2011

12. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein–DVT Dose-Ranging Study

Author

Buller, Hr, Lensing, Aw, Prins, Mh, Agnelli, Giancarlo, Cohen, A, Gallus, As, Misselwitz, F, Raskob, G, Schellong, S, Segers, A, Einstein DVT Dose Ranging Study investigators, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine

Subjects
Adult, Male, Drug-Related Side Effects and Adverse Reactions, Morpholines, Deep vein, Antithrombin III, Immunology, Population, Hemorrhage, Thiophenes, Biochemistry, Asymptomatic, law.invention, Double-Blind Method, Rivaroxaban, Randomized controlled trial, law, medicine, Humans, education, Aged, Ultrasonography, Aged, 80 and over, Venous Thrombosis, education.field_of_study, Dose-Response Relationship, Drug, business.industry, Cell Biology, Hematology, Middle Aged, Dose-ranging study, medicine.disease, Thrombosis, Venous thrombosis, Treatment Outcome, medicine.anatomical_structure, Anesthesia, Acute Disease, Female, medicine.symptom, business, medicine.drug
Abstract

We performed a randomized dose-ranging study, double-blind for rivaroxaban doses and open-label for the comparator (low-molecular-weight heparin followed by vitamin K antagonists) to assess the optimal dose of rivaroxaban for the treatment of deep vein thrombosis. A total of 543 patients with acute deep-venous thrombosis received rivaroxaban 20, 30, or 40 mg once daily or comparator. Treatment lasted for 84 days. The primary efficacy outcome was the 3-month incidence of the composite of symptomatic venous thromboembolic complications and asymptomatic deterioration in thrombotic burden as assessed by comparison of ultrasound and perfusion lung scanning at day 84 with baseline. The main safety outcome was the composite of major bleeding and clinically relevant nonmajor bleeding. A total of 449 (83%) of the 543 patients could be included in the per-protocol population. The primary efficacy outcome occurred in 6.1%, 5.4%, and 6.6% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 9.9% of those receiving standard therapy. The main safety outcome occurred in 5.9%, 6.0%, and 2.2% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 8.8% of those receiving standard therapy. These results with simple fixed-dose oral regimens justify phase 3 evaluations (www.ClinicalTrials.gov no.NCT00395772).

Published
2008

14. Oral Contraceptives and Inherited Thrombophilia: A Gene-Environment Interaction with a Risk of Venous Thrombosis?

Author

Mac Gillavry Mr and Prins Mh

Subjects
medicine.medical_specialty, Pediatrics, Population, Thrombophilia, Risk Factors, medicine, Coagulopathy, Humans, Mass Screening, Risk factor, education, Family Health, Venous Thrombosis, Gynecology, education.field_of_study, business.industry, Hematology, medicine.disease, Thrombosis, Venous thrombosis, Embolism, Family planning, Female, Cardiology and Cardiovascular Medicine, business, Contraceptives, Oral
Abstract

There are indications in the literature that asymptomatic women with an inherited thrombophilic defect who use oral contraceptive have an increased risk of venous thrombosis. There are no consistent data regarding the thrombotic risk in users of oral contraceptives with an inherited thrombophilic defect and personal history of venous thrombosis. Selective genetic screening on the basis of clinical judgment, and family and personal history, instead of universal screening, may be useful before oral contraceptives are prescribed. Nonetheless, the actual risks and benefits of such practice remain to be examined.

Published
2003

15. Oral rivaroxaban for symptomatic venous thromboembolism

Author

Bauersachs, R, Berkowitz, SD, Brenner, B, Buller, HR, Decousus, H, Gallus, AS, Lensing, AW, Misselwitz, F, Prins, MH, Raskob, GE, Segers, A, Verhamme, P, Wells, P, Agnelli, G, Bounameaux, H, Cohen, A, Davidson, BL, Piovella, F, Schellong, S, Berkowitz, S, Büller, H, Gallus, A, Lensing, A, Peters, G, Prins, M, Raskob, G, et, al, DI MINNO, GIOVANNI, Department of Vascular Medicine (DVM - AMC), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Department of Epidemiology (MHP), Maastricht University [Maastricht], Service d'angiologie et d'hémostase (MR), Hôpital Universitaire de Genève, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tewes, Mitra (Beitragende*r), Bauersachs, R, Berkowitz, Sd, Brenner, B, Buller, Hr, Decousus, H, Gallus, A, Lensing, Aw, Misselwitz, F, Prins, Mh, Raskob, Ge, Segers, A, Verhamme, P, Wells, P, Agnelli, G, Bounameaux, H, Cohen, A, Davidson, Bl, Piovella, F, Schellong, S, Berkowitz, S, Büller, H, Lensing, A, Peters, G, Prins, M, Raskob, G, DI MINNO, Giovanni, Et, Al, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Epidemiologie, MUMC+: KIO Kemta (9), and RS: CAPHRI School for Public Health and Primary Care

Subjects
MESH: Pulmonary Embolism, MESH: Enoxaparin, medicine.drug_class, MESH: Factor Xa, Medizin, MESH: Morpholines, 030204 cardiovascular system & hematology, MESH: Anticoagulants, MESH: Intention to Treat Analysis, MESH: Venous Thromboembolism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Edoxaban, medicine, MESH: Double-Blind Method, 030212 general & internal medicine, MESH: Warfarin, MESH: Kaplan-Meier Estimate, MESH: Aged, Rivaroxaban, Acenocoumarol, MESH: Humans, MESH: Middle Aged, business.industry, Warfarin, MESH: Injections, Subcutaneous, MESH: Vitamin K, General Medicine, Vitamin K antagonist, MESH: Thiophenes, medicine.disease, MESH: Male, 3. Good health, Venous thrombosis, chemistry, Anesthesia, MESH: Administration, Oral, MESH: Venous Thrombosis, MESH: Acute Disease, Apixaban, MESH: Acenocoumarol, business, MESH: Female, MESH: Hemorrhage, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, Andexanet alfa
Abstract

Background: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. Methods: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. Results: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P

Published
2010

16. Duration of Oral Anticoagulant Treatment in Patients with Venous Thromboembolism and a Deficiency of Antithrombin, Protein C or Protein S - A Decision Analysis

Author

Prins Mh, Hutten Ba, van den Belt Ag, and Bossuy Pm

Subjects
medicine.medical_specialty, biology, business.industry, Antithrombin, Hematology, medicine.disease, Gastroenterology, Thrombosis, Protein S, Pulmonary embolism, Surgery, Venous thrombosis, Protein C deficiency, Internal medicine, Coagulopathy, biology.protein, Medicine, Protein S deficiency, business, medicine.drug
Abstract

SummaryPatients with a first venous thromboembolic event and a deficiency of the coagulation inhibitors antithrombin, protein C or protein S have an increased risk of recurrent venous thromboembolism compared to patients without such a deficiency. A decision analysis was performed to assess the effect of continuing treatment with vitamin K antagonists on mortality by a reduction in fatal recurrent pulmonary embolism and an induction of fatal haemorrhages associated with their use. The treatment decision involves continuation or discontinuation of vitamin K antagonists in patients with a first spontaneous or secondary venous thromboembolism and an antithrombin, protein C or S deficiency. Although the efficiency of oral anticoagulation is high in all age groups early after the first thromboembolic event, it decreases over time. Our analysis indicates that the optimal treatment duration will vary, depending on the type of the initial event (spontaneous or secondary; deep venous thrombosis or pulmonary embolism), age, and time passed since the initial thromboembolic episode. Moreover, life-long duration of the prophylaxis seems not warranted in all patients.

Published
2000

17. 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

Author

Büller, Hr, Gallus, As, Prins, Mh, Raskob, G, Decousus, H, Charbonnier, B, Leizorovicz, A, Laporte, S, Quenet, S, Brandjes, Dp, Middeldorp, S, Blüguermann, J, Amuchastegui, L, Ahuad Guerrero, R, Oberti, P, Alvarez, C, Cassettari, A, Santos, D, Macin, S, Santini, F, Ward, C, Coughlin, P, Salem, H, Gan, E, Leyden, M, Prosser, I, Crispin, P, Carroll, P, Gallus, A, Mcrae, S, Waites, J, Pilger, E, Koppensteiner, R, Kyrle, P, Schinko, H, Mrochek, A, Mitkovskaya, N, Prystrom, A, Motte, S, Ninane, V, Delcroix, M, Hainaut, P, Schneider, E, Saraiva, J, Maia, L, Barreto, S, Fernandes Manenti, E, Araujo, G, Dutra, O, Fiss, E, Moreira, R, Yankov, K, Nenkova, S, Ivanov, Y, Kostov, V, Bhargava, R, Chan, Y, Miron, Mj, Cusson, J, Ugarte, S, Morales, A, Andresen, M, Lanas, F, Arriagada, G, Mendoza, Jj, Zuñiga, C, Sepulveda, P, Wang, C, Liu, Z, Yuan, Y, Ma, Z, Fang, B, Liu, J, Bai, C, Wu, H, Yang, L, Ying, K, Kang, J, Li, Q, Cheng, Z, Zhang, J, Wang, H, Xie, C, Xia, G, Du, Y, Wu, Q, Zhou, X, Chen, L, Yi, Q, Wu, C, Hao, Q, Liu, S, Xiong, S, Jiang, S, Zhao, L, Xiao, Q, Qin, Z, Zhou, J, Dennis, R, Miserque, N, Igueredo, M, Londoño, D, Hildebrando, J, Granados, M, Buitrago, R, Solano, Mh, Pacheco Alvis PM, Botero, R, Saenz, O, Bergovec, M, Padovan, M, Vucic, N, Samarzija, M, Chlumsky, J, Spacek, R, Klimsa, Z, Gregor, P, Povolny, J, Podpera, I, Holm, F, Lang, P, Matoska, P, Sabl, P, Spinar, J, Spac, J, Husted, S, Avnstrom, S, Rasmussen, S, Christensen, A, Guindy, R, Hassanein, M, Paumets, M, Meriste, S, Ferrari, E, Achkar, A, Azarian, R, Meneveau, N, Lorut, C, Mouallem, J, Crestani, B, Proton, A, Salmeron, S, Lerousseau, L, Mottier, D, Wahl, D, Siafakas, N, Papadimitriou, D, Katis, K, Katsaris, G, Gaga, A, Damianos, A, Tipparaju, S, Kalkunte, S, Vidhut, J, Kalashetti, S, Mehta, P, Talwar, D, Ramanathan, R, Mishra, R, Zeltzer, D, Lahav, M, Brenner, B, Caraco, Y, Elias, M, Piovella, F, Barone, M, Poggio, R, Palla, A, Ghirarduzzi, A, Pini, M, Lodigiani, C, Prandoni, Paolo, Agnelli, G, Imberti, D, Scannapieco, G, Salvi, A, Bautista, E, Diaz, J, Mercado, R, Ranero, A, Rodriguez, D, Jerjes, C, Villeda Espinoza, E, Van Der Meer, J, Ijfering, W, Van Marwijk Kooy, M, Boersma, W, Van Leendert, R, Kroon, C, Dullemond Westland, A, Viergever, P, Kuipers, A, Grootenboers, M, Creemers, J, Pieters, W, De Munck, D, Timmer, H, Jackson, S, Sandset, P, Meyer, P, Kristiansen, T, Portugal, J, Paz, E, Salazar, D, Chavez, W, Castillo, L, De Guia, T, Lenora, F, Tomkowski, W, Kloczko, J, Rybak, Z, Gaciong, Z, Sobkowicz, B, Pruszczyk, P, Nizankowski, R, Mirek Bryniarska, E, Kukla, P, Reis, A, França, A, Cortez, M, Sa, J, Santos, F, Marques, Ma, Gordeev, I, Gendlin, G, Yablonsky, P, Sokurenko, G, Soroka, V, Lusov, V, Markov, V, Shvats, Y, Katerlnitskiy, I, Lapin, O, Lyamina, N, Subbotin, Y, Kim, I, Zilber, E, Kchaisheva, L, Poliacik, P, Macek, V, Pretorius, Jp, Abdullah, I, Basson, M, Bollinger, C, Breedt, J, Gani, M, Jansen, J, Le Roux, G, Nortje, H, Van Der Linder, M, Van Zyl, L, Viljoen, J, Bruning, A, Pujol Farriols, R, Raguer, E, Nuffal, D, Sanchez Rodriguez, A, Eriksson, H, Almgren, T, Carlsson, A, Elf, J, Olsson, Cg, Aagesen, J, Savas, I, Sahin, A, Erdogan, Y, Ozhan, M, Ongen, G, Celikel, T, Turker, H, Arseven, O, Tuncay, E, Ozacar, R, Gudz, I, Nykonenko, O, Skupyy, O, Kovalskyy, I, Prasol, V, Cohen, A, Rodriguez Cintron, W, Gurka, D, Bradley, J, Oliver, G, Spyropoulos, A, Lerner, R, Fulmer, J, Lu, Np, Wright, P, Han, D, Servi, R, Nadar, V, Quaranta, A, Gehring, J, Ginsberg, R, Jacobson, A, Colan, D, Vanway, C, Gurza, E, Braslow, B, Shorr, A, Rehm, J, Martin, J, Sellers, M, Concha, M, Gordon, I, Pullman, J, Moran, J, Welker, J, Panzarella, P, Mullins, M, Willms, D, Mcgrew, F, Turki, M, Menajovsky, L., Epidemiologie, MUMC+: KIO Kemta (9), RS: CAPHRI School for Public Health and Primary Care, Amsterdam Cardiovascular Sciences, Vascular Medicine, Department of Vascular Medicine (DVM - AMC), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), SA Pathology at Flinders Medical Center (ASG), Flinders University, Department of Epidemiology (MHP), Maastricht University [Maastricht], College of Public Health (CPH), University of Oklahoma (OU), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)

Subjects
Male, MESH: Pulmonary Embolism, Oligosaccharides, MESH: Factor X, 030204 cardiovascular system & hematology, MESH: Intention to Treat Analysis, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: Double-Blind Method, 030212 general & internal medicine, MESH: Warfarin, Aged, 80 and over, MESH: Aged, education.field_of_study, Idrabiotaparinux, MESH: Middle Aged, General Medicine, Heparin, Middle Aged, Intention to Treat Analysis, 3. Good health, Pulmonary embolism, Acute Disease, MESH: Acute Disease, Drug Therapy, Combination, Female, medicine.drug, Adult, medicine.medical_specialty, MESH: Enoxaparin, Adolescent, Population, Biotin, MESH: Anticoagulants, Double blind, 03 medical and health sciences, Double-Blind Method, Internal medicine, MESH: Biotin, medicine, Humans, Enoxaparin, education, Aged, MESH: Adolescent, MESH: Humans, Intention-to-treat analysis, business.industry, Warfarin, Anticoagulants, MESH: Adult, Odds ratio, medicine.disease, MESH: Male, Surgery, MESH: Drug Therapy, Combination, Factor X, Pulmonary Embolism, business, MESH: Female, MESH: Oligosaccharides, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; BACKGROUND: Treatment of pulmonary embolism with low-molecular-weight heparin and vitamin K antagonists, such as warfarin, is not ideal. We aimed to assess non-inferiority of idrabiotaparinux, a reversible longlasting indirect inhibitor of activated factor X, to warfarin in patients with acute symptomatic pulmonary embolism. METHODS: In our randomised, double-blind, double-dummy, non-inferiority trial, we enrolled adults with objectively documented acute symptomatic pulmonary embolism attending 291 centres in 37 countries. We excluded patients who were pregnant, had active bleeding, kidney failure, or malignant hypertension, or were at high risk of death, bleeding, or adverse reactions to study drugs. We randomly allocated patients to receive 5-10 days' enoxaparin 1*0 mg/kg twice daily followed by subcutaneous idrabiotaparinux (starting dose 3*0 mg) or adjusted-dose warfarin (target international normalised ratio 2*0-3*0); regimens lasted 3 months or 6 months dependent on clinical presentation. Block randomisation was done with a central interactive computerised system, stratified by study centre and intended treatment duration. The primary efficacy outcome was recurrent venous thromboembolism at 99 days after randomisation. We estimated the odds ratio and 95% CI with a Mantel-Haenzsel χ(2) analysis (non-inferiority margin 2*0) in the intention-to-treat population. The main safety outcome was clinically relevant bleeding (major or non-major) in all patients at day 99. This study is registered with ClinicalTrials.gov, number NCT00345618. FINDINGS: Between Aug 1, 2006, and Jan 31, 2010, we enrolled 3202 patients aged 18-96 years. 34 (2%) of 1599 patients randomly allocated to receive enoxaparin-idrabiotaparinux and 43 (3%) of 1603 patients randomly allocated to receive enoxaparin-warfarin had recurrent venous thromboembolism (odds ratio 0*79, 95% CI 0*50-1*25; p(non-inferiority)=0*0001). 72 (5%) of 1599 patients in the enoxaparin-idrabiotaparinux group and 106 (7%) of 1603 patients in the enoxaparin-warfarin group had clinically relevant bleeding (0*67, 0*49-0*91; p(superiority)=0*0098). We noted similar differences in outcomes in those patients treated to 6 months. INTERPRETATION: Idrabiotaparinux could provide an attractive alternative to warfarin for the long-term treatment of pulmonary embolism, and seems to be associated with reduced bleeding. FUNDING: Sanofi-Aventis (Paris, France).

Published
2012

18. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism

Author

Agnelli, G, Berkowitz, S, Bounameaux, H, Büller, Hr, Cohen, A, Gallus, A, Lensing, Aw, Misselwitz, F, Haskell, L, Prins, Mh, Raskob, G, Schellong, S, Bauersachs, R, van Bellen, B, Boda, Z, Borris, L, Brenner, B, Brighton, T, Chlumsky, J, Davidson, B, Decousus, H, Eriksson, H, Jacobson, B, Kakkar, A, Kwong, Yl, Lee, Lh, Meijer, K, van der Meer, J, Minar, E, Monreal, M, Piovella, F, Sandset, Pm, Smith, M, Tomkowski, W, Verhamme, P, Wang, Y, Wells, P, Brandjes, D, Mac Gillavry, M, Otten, Hm, Carlsson, A, Laporte, S, Schulman, S, Gent, M, Turpie, A, Martinelli, I, Segers, A, Muhlhofer, E, Tewes, M, Trajanovic, M, Muller, K, Kim, C, Gebel, M, Benson, A, Pap, Af, Godrie, J, Horvat Broecker, A, Spadari, G, Peters Wulf, C, Roig, J, Baker, R, Bianchi, A, Blombery, P, Campbell, P, Carroll, P, Geraghty, R, Chong, B, Ramanathan, S, Archis, C, Coughlin, P, Salem, H, Crispin, P, Dean, M, Soni, R, Denaro, C, Kubler, P, Coghlan, D, Gan, Te, Tran, H, Coleman, C, Jackson, D, Khalafallah, A, Leahy, M, Leyden, M, Leyden, D, Sturtz, C, Mccann, A, Gibbs, H, Mcrae, S, Richards, B, Ward, C, Curnow, J, Baghestanian, M, Erdogmus, B, Samaha, E, Nikoupayan Mofrad, M, Hirschl, M, Sturm, W, Kirchmair, R, Marschang, P, Drexel, H, Mathies, R, Pilger, E, Brodmann, M, Weltermann, A, Buche, M, Demelenne, J, Gustin, M, Hainaut, P, Pothen, L, de Leersnyder, J, Motte, S, Schroë, H, Sprynger, M, Peerlinck, K, Delcroix, M, Vermassen, F, Verstraeten, P, Smet, V, Vossaert, R, Panico, M, Costa, C, Blondal, J, Kovacs, M, Rodger, M, Carrier, M, Wong, T, Bi, J, Chen, Z, Chen, R, Jing, Zc, He, J, Liu, C, Liu, S, Long, S, Ma, Y, Shao, Y, Wang, C, Yang, Yh, Xie, C, Xu, J, Ying, K, Zhihong, L, Hola, D, Jirat, S, Vitovec, M, Kovářová, K, Gilík, J, Dosál, J, Mandakova, E, Matoška, P, Podpera, I, Podperova, M, Spacek, R, Urbanova, R, Tuxen, C, Sukles, K, Pietila, K, Vesanen, M, Achkar, A, Agraou, B, Aquilanti, S, Rifaï, A, Berremili, T, Brisot, D, Brousse, C, Tarodo, P, Bura, A, Amid Lacombe, C, Malloizel, J, Boulon, C, Alavoine, L, Crestani, B, Mismetti, P, Buchmuller, A, Accassat, S, Elias, A, Elias, M, Emmerich, J, Ferrari, E, Guérin, T, Beaka, P, Lacroix, P, Szwebel, Ta, Benhamou, Y, de Maistre, E, Falvo, N, Mahe, I, Meneveau, N, Schiele, F, Meyer, G, Sanchez, O, Planquette, B, Mottier, D, Le Moigne, E, Couturaud, F, Parent, F, Pernod, G, Imbert, B, Elkouri, D, Dary, M, Queguiner, A, Quere, I, Galanaud, Jp, Roy, Pm, de Boisjolly Bonnefoi JM, Schmidt, J, Breuil, N, Heuser, S, Sevestre, Ma, Simoneau, G, Bergmann, Jf, Stephan, D, Trinh Duc, A, Gaillardou, A, Grange, C, Fassier, T, Wahl, D, Baron Von Bilderling, P, Kuhlencordt, P, Beyer Westendorf, J, Halbritter, K, Werth, S, Diehm, C, Lawall, H, Eifrig, B, Espinola Klein, C, Weisser, G, Giannitsis, E, Haering, Hu, Hasslacher, C, Herrmann, T, Hoffmann, U, Czihal, M, Horacek, T, Ibe, M, Bauer, A, Kieback, A, Landgraf, H, Lindhoff Last, E, Malyar, N, Petermann, W, Potratz, J, Ranft, J, Röcken, M, Pomper, L, Frommhold, R, Schwaiblmair, M, Berghaus, T, Taute, B, Lau, Yk, Tse, E, Olah, Z, Farkas, K, Kolossváry, E, Gurzó, M, Kis, E, Kovács, A, Landi, A, Lupkovics, G, Pecsvarady, Z, Riba, M, Sipos, G, Parakh, R, Sembiring, R, Barton, J, Goldstein, L, Gavish, D, Hoffman, R, Hussein, O, Inbal, A, Lishner, M, Elis, A, Lugassy, G, Varon, D, Zeltser, D, Rogowski, O, Steinvil, A, Zisman, D, Ageno, W, Ambrosio, G, Cattaneo, M, D'Angelo, A, Ghirarduzzi, A, Lotti, M, Pierfranceschi, Mg, Lodigiani, C, Palareti, G, Barone, M, Beltrametti, C, Porreca, E, Prandoni, Paolo, Spiezia, L, Quintavalla, R, Cho, Wh, Ha, Jw, Kim, Hs, Park, K, Sime, I, Miliauskas, S, Petrauskiene, R, Sathar, J, Beeker, A, Ten Cate, H, De Groot, M, Kamphuisen, P, Douma, R, Kooy, Mv, Coenen, J, Mäkelburg, A, Knol, M, Tichelaar, V, Harper, P, Knottenbelt, E, Ockelford, P, Young, L, Royle, G, Simpson, D, Chunilal, S, Ghanima, W, Foyn, S, Tveit, A, Abola, Mt, Adamiec, R, Gorski, P, Kloczko, J, Lewczuk, J, Nowak, M, Musial, J, Wronski, J, Ng, Hj, Adler, D, Becker, Jh, Ellis, G, Isaacs, R, Bloy, B, Allie, R, Eckstein, F, van Rensburg JH, Schmidt, S, Siebert, H, Zyl, L, Carrera, M, Del Campo, F, Diego, I, Garcia Bragado, F, Jiménez, D, Sánchez Álvarez, J, Redondo, M, Roman Sanchez, P, Villalta, J, Villegas Scivetti, M, Jonson, T, Tygesen, H, Lapidus, L, Ottosson, E, Själander, A, Asmis, L, Banyai, M, Heidemann, M, Baumgartner, I, Righini, M, Frank, U, Hayoz, D, Periard, D, Chang, Wt, Chiu, K, Wang, Ky, Weng, Zc, Angchaisuksiri, P, Pothirat, C, Rojnuckarin, P, Solis, J, Hunt, B, Luckit, J, Albrecht, C, Banish, D, Feinbloom, D, Botnick, W, Chen, D, Dexter, J, Ettinger, N, Gleeson, J, Jaffer, A, Joseph, S, Kennedy, M, Krell, K, Lavender, R, Lyons, R, Moll, S, Nadar, V, Darrow, K, Hardman, V, Rathbun, S, Rehm, J, Rodriguez Cintron, W, Stevens, K, Wright, P, Ramaswamy, M., ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Epidemiologie, MUMC+: KIO Kemta (9), RS: CAPHRI School for Public Health and Primary Care, Department of Vascular Medicine (DVM - AMC), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Department of Epidemiology (MHP), Maastricht University [Maastricht], Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Service d'angiologie et d'hémostase (MR), Hôpital Universitaire de Genève, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Centre d'Investigation Clinique (CIC - Brest), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Pulmonary Embolism, Male, Vitamin K, Administration, Oral, Pulmonary Embolism/drug therapy/mortality, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Rivaroxaban, Edoxaban, Recurrence, Hemorrhage/chemically induced, 030212 general & internal medicine, Vitamin K/antagonists & inhibitors, Enoxaparin/adverse effects/therapeutic use, MESH: Treatment Outcome, MESH: Aged, ddc:616, MESH: Middle Aged, Hazard ratio, General Medicine, MESH: Follow-Up Studies, Vitamin K antagonist, MESH: Thiophenes, Middle Aged, Thrombosis, Morpholines/adverse effects/therapeutic use, 3. Good health, Pulmonary embolism, MESH: International Normalized Ratio, Treatment Outcome, Anesthesia, MESH: Administration, Oral, Administration, Combination, Apixaban, Drug Therapy, Combination, Female, MESH: Hemorrhage, medicine.drug, Oral, MESH: Enoxaparin, medicine.drug_class, Morpholines, Anticoagulants/adverse effects/therapeutic use, MESH: Morpholines, Hemorrhage, Thiophenes, MESH: Anticoagulants, 03 medical and health sciences, Drug Therapy, medicine, Humans, International Normalized Ratio, Enoxaparin, MESH: Kaplan-Meier Estimate, Aged, MESH: Humans, business.industry, MESH: Vitamin K, Anticoagulants, medicine.disease, MESH: Male, MESH: Recurrence, Regimen, MESH: Drug Therapy, Combination, chemistry, Thiophenes/adverse effects/therapeutic use, business, Pulmonary Embolism, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

International audience; BACKGROUND: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. METHODS: In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).

Published
2012

20. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial

Author

Kenemans, P, Bundred, Nj, Foidart, Jm, Kubista, E, von Schoultz, B, Sismondi, Piero, Vassilopoulou Sellin, R, Yip, Ch, Egberts, J, Mol Arts, M, Mulder, R, van Os, S, Beckmann, Mw, Sismondi, P, Beckmann, M, Baum, M, Gray, R, Burger, Cw, van Diest PJ, Harbeck, N, Senn, Hj, Svane, G, Prins, Mh, Davidson, B, Peters, R, Longo, Ml, Kappelle, Lj, Maclennan, Ah, Baber, R, Eden, Ja, Furnival, C, Stuckey, B, Farrell, E, Singer, Cf, Marth, C, Reitsamer, R, Sevelda, P, Salzer, H, Thiel, I, Winter, R, Putyrski, L, Beliakouski, V, Gedrevich, Z, Tjalma, W, Desreux, J, Dhont, M, Depypere, H, van den Broecke, R, L'Hermite, M, Nolens, Jp, Rozenberg, S, Simon, P, Vergote, I, Gaspard, U, Janssens, D, De Gezelle, H, Merchiers, E, Aldrighi, Jm, Badalotti, M, Bagnoli, Vr, Fernandes, Ce, Ferriani, R, Pinto Neto AM, Menke, Ch, Petti, Da, Urbanetz, A, Del Giglio, A, Cunill, E, Sepúlveda, H, Soto, L, Uribe, A, Valdivia, I, Baptista, J, Loaciga, K, Bendova, M, Buchta, K, Pecha, V, Reslova, T, Hlavackova, O, Mikulik, M, Kütner, R, Padrik, P, Puistola, U, Ylikorkala, O, Mäenpää Liukko, K, Brémond, A, Faure, C, Seffert, P, Delozier, T, Espie, M, Dupaigne, D, Hoffet, M, Laffargue, F, Tunon de Lara, C, Largillier, L, Namer, M, Dognon, L, Routiot, T, This, P, Touraine, P, Kimmig, R, Kümmel, S, Weiss, J, Engel, U, Brucker, C, de Waal JC, Mallmann, P, Rühl, I, Untch, M, Neumann, C, Kulp, A, Krause Bergmann, B, Schmidt Rhode, P, Seifert Klauss, V, Wallwiener, D, Nestle Krämling, C, Starfl inger, F, Sohn, C, Bastert, G, Thomas, A, Lichtenegger, W, Höss, C, Chatsiproios, D, Jonat, W, de Wilde, R, Dewitz, T, Kühn, T, Kiesel, L, Blümel, B, Schindler, C, Splitt, G, Leitsmann, H, Köhler, U, Langanke, D, Landthaler, R, Hindenburg, Hj, Schoenegg, W, Conrad, B, Ortmann, O, Boér, K, Boros, J, Cseh, J, Kövér, E, Landherr, L, Ruzsa, A, Erfán, J, Fábián, F, Páli, K, Biglia, Nicoletta, Genazzani, Ar, Mariani, R, Martoni, A, Scambia, G, Santoro, A, Burlizzi, S, Amunni, G, Amadori, D, Noh, Dy, Kim, Jg, Ahn, Sh, Kang, Bm, Noh, Wc, Kim, Mh, Lee, Mh, Lee, Jj, Keire, G, Baltina, D, Nik Nasri, N, Gomez, P, Sivalingam, Muniandy, S, Cardenas, J, Mainero, F, Uscanga, S, Fuentes, A, Lugo, R, Heijmans, H, The, Hs, Franke, H, van Riel, J, van der Vegt, S, Boven, E, Houben, P, Kok, A, van Weering, H, van de Walle, A, Burggraaff, Jm, Alcedo, J, Kornafel, J, Litwiniuk, M, Karnicka, H, Bablok, L, Marianowski, Basta, A, Jakimiuk, A, Curescu, S, Draganescu, Me, Eniu, Ae, Zbranca, E, Peltecu, G, Ancar, V, Smetnik, V, Kullikov, Ep, Petrossian, A, Stekolschikova, O, Popov, A, Zoziouk, N, Krikunova, Li, Semiglazov, V, Konstantinova, M, Bezhenar, Vf, Diatchouk, A, Manikhas, G, Korytova, Ly, Vinogradov, V, Sokurenko, V, Baranov, An, Arkhipovsky, Vl, Bogatova, Ik, Akhmadulina, Li, Kuts, Tn, Susloparova, Sa, Mitashok, I, Kanzalie, Al, Bryuzgin, Vv, Malygin, En, Sergeev, Ie, Pasman, Nm, Akishina, Zv, Tuev, Av, Kopp, M, Soloviev, Vi, Evtushenko, Id, Ershov, Gv, Devyatchenko, Nf, Potapov, Yn, Cheporov, Sv, Ogurtsov, Av, Chrustalev, On, Lazareva, Dg, Bryukhina, E, Matrosova, M, Yu, Sl, Wong, Pc, Masak, L, Sadovsky, O, Petrovicova, Z, Suska, P, De Pablo JL, García, E, Iglesias, J, Mattsson, L, Granberg, G, Berglund, L, Friberg, B, Chen, St, Chow, Sn, Lee, Jn, Wang, Kl, Limpaphayom, Kk, Boonjong, S, Jirapinyo, M, Sakondhavat, C, Taechakraichana, N, Techatraisak, K, Wilawan, K, Tatarchuk, T, Dudar, L, Koshukova, G, Gyryachyy, V, Hotko, Ys, Kostynskyy, Y, Paramonov, V, Pertseva, T, Shparyk, Y, Tarasova, O, Kosey, N, Solskiy, Y, Smolanka, I, Kvashenko, V, Grishyna, O, Dzyak, G, Drew, Jp, Mansel, R, Williamson, J, Kingsland, Cr, Vishwanath, L, Bliss, R, Crawford, D, Winters, Z, Browell, D, Paterson, M, Ind, T, Rostom, A, and Pitkin, J.

Subjects
recurrence, treatment, Breast Cancer, menopause, hot flushes
Published
2009

22. A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery

Author

Eriksson, Bi, Turpie, Ag, Lassen, Mr, Prins, Mh, Agnelli, Giancarlo, Kälebo, P, Gaillard, Ml, Meems, L, and ONYX study group

Subjects
Adult, Male, medicine.medical_specialty, medicine.drug_mechanism_of_action, Arthroplasty, Replacement, Hip, Factor Xa Inhibitor, Antithrombin III, Venography, Administration, Oral, Hip replacement (animal), Drug Administration Schedule, chemistry.chemical_compound, Clinical endpoint, Medicine, Humans, Enoxaparin, Aged, Aged, 80 and over, Venous Thrombosis, medicine.diagnostic_test, Dose-Response Relationship, Drug, business.industry, Darexaban, Incidence (epidemiology), Hematology, Middle Aged, Surgery, Treatment Outcome, chemistry, Cohort, Orthopedic surgery, Female, business
Abstract

Summary. Background: YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. Objectives: To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. Patients/methods: Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7–10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study. Results: No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1–15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0–18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9–71.4), 38.7% (95% CI, 22.6–57.0), 22.6% (95% CI, 9.7–39.4), and 18.5% (95% CI, 7.5–36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6–57.0). Conclusions: YM150, 10–60 mg daily, starting 6–10 h after primary hip replacement, was shown to be safe, well tolerated and effective.

Published
2007

24. Elevated levels of FVIII: C within families are associated with an increased risk for venous and arterial thrombosis

Author

Bank, [No Value], Libourel, EJ, Middeldorp, S, Hamulyak, K, van Pampus, ECM, Koopman, MMW, Prins, MH, van der Meer, J, Buller, HR, Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), and Groningen Kidney Center (GKC)

Subjects
FIBRINOGEN, congenital, hereditary, and neonatal diseases and abnormalities, VON-WILLEBRAND-FACTOR, venous thromboembolism, ORAL-CONTRACEPTIVES, arterial thrombosis, DISEASE, premature, THROMBOEMBOLISM, hemic and lymphatic diseases, FVIII : C, FACTOR-V-LEIDEN, family study, THROMBOPHILIA, DEEP-VEIN THROMBOSIS, atherosclerosis, FACTOR-VIII LEVELS, POPULATION
Abstract

Elevated levels of coagulation factor VIII:C (FVIII:C) are associated with an increased risk for venous and arterial thromboembolism. Whether relatives of patients with elevated levels of FVIII:C are also at increased risk for thrombotic disease is unknown. The objective was to determine the annual incidences of both venous and arterial thrombotic events in first-degree relatives of patients with elevated levels of FVIII:C and venous thromboembolism (VTE) or premature atherosclerosis. A retrospective study with 584 first-degree relatives of 177 patients with elevated levels of FVIII:C was performed. The level of FVIII:C was determined and relatives with elevated and normal levels of FVIII:C were compared. Of the participants, 40% had elevated levels of FVIII:C. The annual incidence of a first episode of VTE was 0.34% and 0.13% in relatives with elevated levels of FVIII:C and those with normal levels, respectively [OR 3.7 (95% CI 1.9-7.5)]. The absolute annual incidence in the youngest age group with elevated levels of FVIII:C was 0.16% (0.05-0.37) and gradually increased to 0.99% (0.40-2.04) in those older than 60 years of age, although the odds ratios were not statistically significant. The annual incidences of a first arterial thrombotic event were 0.29% and 0.14% in relatives with and without elevated levels of FVIII:C, respectively [OR 3.1 (1.4-6.6)]. In particular the risks for a first myocardial infarction [OR 4.3 (1.0-18.1); P = 0.046] and a first peripheral arterial thrombosis [OR 8.6 (1.6-47.6)] were increased. Within families of patients with elevated levels of FVIII:C and VTE or premature atherosclerosis, 40% of their first-degree relatives has elevated levels of FVIII:C as well, and they are at increased risk for both VTE and arterial thrombosis as compared with their relatives with normal levels.

Published
2005

25. Fibrin D-dimer measurement in suspected pulmonary embolism

Author

de Moerloose P and Prins Mh

Subjects
medicine.medical_specialty, Suspected pulmonary embolism, Disease, Pulmonary Artery, Diagnostic tools, Sensitivity and Specificity, Fibrin Fibrinogen Degradation Products, Predictive Value of Tests, D-dimer, medicine, Humans, In patient, Intensive care medicine, Radionuclide Imaging, Lung, Venous Thrombosis, business.industry, Age Factors, medicine.disease, Pulmonary embolism, Hospitalization, Radiography, Cardiology and Cardiovascular Medicine, business, Pulmonary Embolism, Algorithms, Biomarkers
Abstract

Due to increased awareness among physicians, the prevalence of pulmonary embolism (PE) in patients clinically suspected of the disease has steadily decreased during the past 15 years. This has led to the development of simple diagnostic tools in an attempt to reduce the number of invasive or costly exams needed to manage these patients. D-dimer (DD) measurement has proven to be a simple and very useful test to exclude PE and several strategies combining DD with clinical probability and other exams have been validated in large outcome studies. The problem faced by many physicians is the choice of the specific DD test and its more appropriate position in the diagnostic work-up of patients suspected of PE. This article focuses on these questions and also provides some limitations of DD use, such as its poor specificity in hospitalized and elderly patients.

Published
2004

26. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial

Author

Piccioli, A, Lensing, Awa, Prins, Mh, Falanga, A, Scannapieco, Gl, Ieran, M, Cigolini, M, Ambrosio, Gb, Monreal, M, Girolami, A, Prandoni, P, Girolami, B, Bernardi, E, Bagatella, P, Marchiori, A, Marchetti, M, Vignoli, A, Doria, S, Parisi, R, Bortoluzzi, C, Paolicelli, Mi, Filippi, F, Baggio, Elda, and Lipari, Giovanni

Subjects
venous thromboembolism, cancer, Deep venous thrombosis
Published
2004

31. The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders

Author

Meinardi, [No Value], Middeldorp, S, de Kam, PJ, Koopman, MMW, van Pampus, ECM, Hamulyak, K, Prins, MH, Buller, HR, and Faculteit Medische Wetenschappen/UMCG

Subjects
ORAL ANTICOAGULANT-THERAPY, FIRST EPISODE, factor V, RISK FACTOR, PROTHROMBIN GENE, thromboembolism, APC resistance, ACTIVATED PROTEIN-C, COAGULATION-FACTOR-V, blood coagulation disorders, DEEP-VEIN THROMBOSIS, MUTATION, RESISTANCE, HYPERHOMOCYSTEINEMIA
Abstract

The duration of anticoagulant treatment after a first episode of venous thromboembolism primarily depends on the risk of recurrence, Variability of recurrence rates in factor (F) V Leiden carriers may be due to concomitant thrombophilic disorders. A retrospective study was performed in 329 FV Leiden carriers with a history of venous thromboembolism (262 probands, 67 relatives). The annual rate of first recurrence was estimated in relatives. The contribution of concomitant thrombophilic disorders to the recurrence rate was evaluated in probands and relatives by a nested case-control analysis in 10 5 matched pairs of carriers either with or without recurrence, The overall annual recurrence rate was 2.3 per 100 patient-years, The adjusted risk of recurrence for concomitant thrombophilic disorders was: 9.1 (1.3-62.8) for the FII mutation; 1.0 (0.2-4.9) for homozygosity for FV Leiden; 1.5 (0.2-9.5) for inherited deficiencies of protein C or S: 1.8 (0.7-4.9) for FVIII coagulant activity (FVIII:C) levels > 122%.; 5.4 (1.6-18.6) for fasting homocysteine levels > 15.2 mumol/l: and 4.4 (1.0-18.7) for loading homocysteine levels >45.8 mumol/l. Of these disorders, only the FII mutation and hyperhomocysteinaemia significantly increased the risk of recurrence in FV Leiden carriers. The estimated recurrence rate ranged from 0.45 per 100 patient-years after a secondary first event in the absence of concomitant disorders to 4.8 per 100 patient-years when a spontaneous first event was combined with concomitant disorders, Our study provides supportive evidence that the incidence of recurrent venous thromboembolism in heterozygous FV Leiden carriers depends on the concomitance of other thrombophilic disorders. in addition to whether the first thrombotic event occurred spontaneously.

Published
2002

32. Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

Author

Nin, Jwm, Ferreira, I, Schalkwijk, Cg, Prins, Mh, Chaturvedi, N, Fuller, Jh, Stehouwer, Cda, Eurodiab Prospective Complication, Study, Minnella, Angelo Maria, Minnella, Angelo Maria (ORCID:0000-0001-5896-5313), Nin, Jwm, Ferreira, I, Schalkwijk, Cg, Prins, Mh, Chaturvedi, N, Fuller, Jh, Stehouwer, Cda, Eurodiab Prospective Complication, Study, Minnella, Angelo Maria, and Minnella, Angelo Maria (ORCID:0000-0001-5896-5313)

Abstract

High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro- and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein.

Published
2012

34. Probiotics versus antibiotic decontamination of the digestive tract: infection and mortality

Author

Oudhuis, GJ, Bergmans, DC, Dormans, T, Zwaveling, JH, Kessels, A, Prins, MH, Stobberingh, EE, Verbon, Annelies, Oudhuis, GJ, Bergmans, DC, Dormans, T, Zwaveling, JH, Kessels, A, Prins, MH, Stobberingh, EE, and Verbon, Annelies

Abstract

Selective decontamination of the digestive tract (SDD) has been shown to decrease the infection rate and mortality in intensive care units (ICUs); Lactobacillus plantarum 299/299v plus fibre (LAB) has been used for infection prevention and does not harbour the potential disadvantages of antibiotics. The objective was to assess whether LAB is not inferior to SDD in infection prevention. Two hundred fifty-four consecutive ICU patients with expected mechanical ventilation a parts per thousand yen48 h and/or expected ICU stay a parts per thousand yen72 h were assigned to receive SDD: four times daily an oral paste (polymyxin E, gentamicin, amphotericin B), enteral solution (same antibiotics), intravenous cefotaxime (first 4 days) or LAB: two times daily L. plantarum 299/299v with rose-hip. The primary endpoint was infection rate. A difference < 12% between both groups indicated non-inferiority of LAB. The trial was prematurely stopped after a study reporting increased mortality in critically ill pancreatitis patients receiving probiotics. No significant difference in infection rate [31% in the LAB group, 24% in the SDD group (OR 1.68, 95% CI 0.91-3.08; p = 0.10)] was found. ICU mortality was 26% and not significantly different between the LAB and SDD groups. Gram-positive cocci and Pseudomonas aeruginosa were significantly more frequently isolated from surveillance cultures in the SDD group compared to the LAB group (for sputum: 18 vs. 10% and 33 vs. 14%). Significantly more Enterobacteriaceae were found in the LAB group (23 vs. 50%). No increase in antibiotic resistance was found during and after SDD or LAB use. The trial could not demonstrate the non-inferiority of LAB compared with SDD in infection prevention. Results suggest no increased ICU mortality risk in the LAB group.

Published
2011

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