209 results on '"Westendorf, A."'
Search Results
2. Permissive HLA-DPB1 mismatches in HCT depend on immunopeptidome divergence and editing by HLA-DM
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Meurer, Thuja, Crivello, Pietro, Metzing, Maximilian, Kester, Michel, Megger, Dominik A., Chen, Weiqiang, van Veelen, Peter A., van Balen, Peter, Westendorf, Astrid M., Homa, Georg, Layer, Sophia E., Turki, Amin T., Griffioen, Marieke, Horn, Peter A., Sitek, Barbara, Beelen, Dietrich W., Falkenburg, J. H. Frederik, Arrieta-Bolaños, Esteban, and Fleischhauer, Katharina
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- 2021
- Full Text
- View/download PDF
3. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use
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Martinelli, Ida, Lensing, Anthonie W.A., Middeldorp, Saskia, Levi, Marcel, Beyer-Westendorf, Jan, van Bellen, Bonno, Bounameaux, Henri, Brighton, Timothy A., Cohen, Alexander T., Trajanovic, Mila, Gebel, Martin, Lam, Phuong, Wells, Philip S., and Prins, Martin H.
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- 2016
- Full Text
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4. Treatment of Portal, Mesenteric, and Splenic Vein Thrombosis with Rivaroxaban: A Pilot, Prospective Cohort Study
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Riva, Nicoletta, primary, Beyer-Westendorf, Jan, additional, Contino, Laura, additional, Bucherini, Eugenio, additional, Sartori, Maria Teresa, additional, Grandone, Elvira, additional, Santoro, Rita Carlotta, additional, Carrier, Marc, additional, Delluc, Aurelien, additional, De Stefano, Valerio, additional, Pomero, Fulvio, additional, Tosetto, Alberto, additional, Becattini, Cecilia, additional, Martinelli, Ida, additional, Nardo, Barbara, additional, Bertoletti, Laurent, additional, Di Nisio, Marcello, additional, Lazo-Langner, Alejandro, additional, Schenone, Alessandro, additional, and Ageno, Walter, additional
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- 2021
- Full Text
- View/download PDF
5. Checkpoint inhibitors and thrombosis: what’s up?
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Beyer-Westendorf, Jan, primary
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- 2021
- Full Text
- View/download PDF
6. Permissive HLA-DPB1 mismatches in HCT depend on immunopeptidome divergence and editing by HLA-DM
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Dominik A. Megger, J.H. Frederik Falkenburg, Amin T. Turki, Georg Homa, M. Metzing, Thuja Meurer, Sophia E. Layer, Astrid M. Westendorf, Marieke Griffioen, Pietro Crivello, Katharina Fleischhauer, Dietrich W. Beelen, Peter A. van Veelen, Weiqiang Chen, Peter van Balen, Peter A. Horn, Michel G.D. Kester, Barbara Sitek, and Esteban Arrieta-Bolaños
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Permissiveness ,CD4-Positive T-Lymphocytes ,T cell ,Receptors, Antigen, T-Cell, alpha-beta ,Immunology ,Medizin ,HLA-DM ,Human leukocyte antigen ,Endosomes ,Biology ,Biochemistry ,Mass Spectrometry ,Epitopes ,medicine ,Humans ,Permissive ,Gene Rearrangement, beta-Chain T-Cell Antigen Receptor ,Cells, Cultured ,HLA-DP beta-Chains ,HLA-D Antigens ,HLA-DPB1 ,Hematopoietic Stem Cell Transplantation ,Histocompatibility Antigens Class II ,High-Throughput Nucleotide Sequencing ,Cell Biology ,Hematology ,Gene rearrangement ,Allografts ,Transplantation ,Antigens, Differentiation, B-Lymphocyte ,medicine.anatomical_structure ,Histocompatibility ,Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor ,Peptides ,Unrelated Donors ,Biologie ,HeLa Cells ,Molecular Chaperones - Abstract
In hematopoietic cell transplantation (HCT), permissive HLA-DPB1 mismatches between patients and their unrelated donors are associated with improved outcomes compared with nonpermissive mismatches, but the underlying mechanism is incompletely understood. Here, we used mass spectrometry, T-cell receptor-β (TCRβ) deep sequencing, and cellular in vitro models of alloreactivity to interrogate the HLA-DP immunopeptidome and its role in alloreactive T-cell responses. We find that permissive HLA-DPB1 mismatches display significantly higher peptide repertoire overlaps compared with their nonpermissive counterparts, resulting in lower frequency and diversity of alloreactive TCRβ clonotypes in healthy individuals and transplanted patients. Permissiveness can be reversed by the absence of the peptide editor HLA-DM or the presence of its antagonist, HLA-DO, through significant broadening of the peptide repertoire. Our data establish the degree of immunopeptidome divergence between donor and recipient as the mechanistic basis for the clinically relevant permissive HLA-DPB1 mismatches in HCT and show that permissiveness is dependent on HLA-DM–mediated peptide editing. Its key role for harnessing T-cell alloreactivity to HLA-DP highlights HLA-DM as a potential novel target for cellular and immunotherapy of leukemia.
- Published
- 2020
7. Treatment of Portal, Mesenteric, and Splenic Vein Thrombosis with Rivaroxaban: A Pilot, Prospective Cohort Study
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Laura Contino, Marcello Di Nisio, Barbara Nardo, Marc Carrier, Walter Ageno, Ida Martinelli, Cecilia Becattini, Valerio De Stefano, Fulvio Pomero, Aurélien Delluc, Laurent Bertoletti, Elvira Grandone, Alberto Tosetto, Maria Teresa Sartori, Eugenio Bucherini, Alessandro Schenone, Nicoletta Riva, Rita Santoro, Jan Beyer-Westendorf, and Alejandro Lazo-Langner
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medicine.medical_specialty ,Rivaroxaban ,business.industry ,Immunology ,medicine ,Cell Biology ,Hematology ,Splenic vein thrombosis ,Prospective cohort study ,business ,Biochemistry ,Surgery ,medicine.drug - Abstract
Introduction: Anticoagulation plays a crucial role in the treatment of splanchnic vein thrombosis (SVT), including thrombosis of the portal (PVT), mesenteric (MVT) and splenic (SpVT) veins. Rivaroxaban is a potential alternative to heparins and vitamin K antagonists (VKA) in these patients, but data to support its use are scant. Several recent guidelines highlighted the limited evidence available for the use of the direct oral anticoagulants in these patients. In addition, despite anticoagulation, SVT patients carry high risk of recurrent venous thromboembolic events. The aim of this study was to evaluate the safety and efficacy of rivaroxaban for the acute-phase treatment of SVT (first 3 months of treatment). Methods: RIVASVT-100 (NCT02627053) was a prospective cohort study of adult patients with a first episode of symptomatic, objectively diagnosed PVT, MVT or SpVT. Exclusion criteria were known liver cirrhosis, Budd-Chiari syndrome, previous or ongoing variceal bleeding, portal cavernoma, thrombocytopenia, severe renal failure, life expectancy 7 days, ongoing VKA treatment. Patients received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily for a total of 3 months. Afterwards, the decision to continue any available anticoagulant drug was left to the discretion of the attending physicians. Follow-up was performed at 3 weeks, 2 months, 3 months and 6 months. Primary outcome was the occurrence of ISTH-defined major bleeding events during the 3 months of active treatment and up to 2 days after the end of study treatment. Secondary outcomes included death, clinically relevant non-major bleeding (CRNMB), recurrent SVT or symptomatic venous thromboembolism in other sites. We here report the results of the 3-month follow-up. Results: Between June 2015 and March 2021, 103 patients were enrolled from 18 participating centres. After excluding 3 patients who did not meet the criteria for eligibility, 100 patients were included in the analysis. Mean (SD) age was 54.4 (± 15.5) years; 64% were males. Overall, 74% of patients had PVT, 61% MVT and 48% SpVT; 53% of SVT occurred in multiple sites. The most common risk factors were abdominal inflammation/infection (26%), followed by solid cancer (9%), overt myeloproliferative neoplasms (9%) and oestrogen hormonal therapy (9%), while 43% of cases were unprovoked. The JAK2 V617F mutation was detected in 13 out of 50 tested patients (26%). Rivaroxaban was the sole anticoagulant agent used in 21% of patients, whereas the remaining received a combination of anticoagulants, which included low molecular weight heparin, unfractionated heparin or fondaparinux for a median of 5.0 days before transitioning to rivaroxaban. Three patients were lost to follow-up but known to be alive at the end of the study. At 3-month follow-up, 1 (1.0%) patient died due to a non-SVT related cause. Two patients (2.06%; 95% CI, 0.57-7.21) had major bleeding events (both gastrointestinal), while 3 patients (3.09%) had CRNMB. There were 2 recurrent SVT (2.06%) during rivaroxaban treatment, one of these occurred in a patient with metastatic solid cancer. The 6-month follow-up for the last enrolled patient is ongoing. Conclusions: Rivaroxaban appears to be safe and effective for the acute-phase treatment of SVT in non-cirrhotic patients. Disclosures Beyer-Westendorf: Bayer: Other: Personal fees; Daiichi Sankyo: Other: Personal fees; Pfizer: Other: Personal fees; Portola-Alexion: Other: Personal fees. Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; Servier: Honoraria; Sanofi: Honoraria. Bertoletti: BMS: Honoraria, Other: Personal Fees; Pfizer: Honoraria, Other: Personal fees; Aspen: Other: Personal Fees; Bayer: Other: Personal Fees; Leo Pharma: Other: Personal Fee. Di Nisio: Bayer, Daiichi Sankyo, BMS-Pfizer, Leo Pharma, and Sanofi: Other: Personal fees. Ageno: Bayer: Research Funding; Bayer, Portola, Janssen, Aspen, Norgine, Sanofi.: Other: Advisory Board. OffLabel Disclosure: The use of rivaroxaban in splanchnic vein thrombosis is off label in most countries.
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- 2021
8. Checkpoint inhibitors and thrombosis: what’s up?
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Jan Beyer-Westendorf
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business.industry ,Immune checkpoint inhibitors ,Immunology ,MEDLINE ,Medicine ,Cell Biology ,Hematology ,Bioinformatics ,business ,medicine.disease ,Biochemistry ,Thrombosis - Published
- 2021
9. Patterns of VTE Treatment with Noac in Cancer Patients - Results of the Prospective Dresden Noac Registry (NCT01588119)
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Marten, Sandra, primary, Tittl, Luise, additional, Naue, Christiane, additional, and Beyer-Westendorf, Jan, additional
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- 2019
- Full Text
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10. Patient Preferences Regarding Anticoagulation Therapy in Patients with Cancer Having a VTE Event - a Discrete Choice Experiment in the Cosimo Study
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Picker, Nils, primary, Cohen, Alexander T, additional, Maraveyas, Anthony, additional, Beyer-Westendorf, Jan, additional, Lee, Agnes Yuet Ying, additional, Mantovani, Lorenzo G, additional, De Sanctis, Yoriko, additional, Abdelgawwad, Khaled, additional, Fatoba, Samuel, additional, Bach, Miriam, additional, and Wilke, Thomas, additional
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- 2019
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11. Baseline Characteristics and Clinical Outcomes from the Cancer Associated Thrombosis - Patient Reported Outcomes with Rivaroxaban (COSIMO) Trial
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Maraveyas, Anthony, primary, Beyer-Westendorf, Jan, additional, Lee, Agnes Yuet Ying, additional, Mantovani, Lorenzo G, additional, De Sanctis, Yoriko, additional, Abdelgawwad, Khaled, additional, Fatoba, Samuel, additional, Bach, Miriam, additional, and Cohen, Alexander T, additional
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- 2019
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12. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use
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A.T. Cohen, Phuong Lam, Jan Beyer-Westendorf, Martin Gebel, Mila Trajanovic, Ida Martinelli, Saskia Middeldorp, Henri Bounameaux, Timothy A. Brighton, Bonno van Bellen, Martin H. Prins, Philip S. Wells, Anthonie W. A. Lensing, Marcel Levi, RS: CAPHRI - R5 - Optimising Patient Care, Epidemiologie, MUMC+: KIO Kemta (9), ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Other departments
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Adult ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,030204 cardiovascular system & hematology ,Biochemistry ,Contraceptives, Oral, Hormonal ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Rivaroxaban ,Recurrence ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Enoxaparin ,Proportional Hazards Models ,Randomized Controlled Trials as Topic ,Retrospective Studies ,ddc:616 ,Uterine Hemorrhage ,business.industry ,Anticoagulant ,Hazard ratio ,Bleeding ,Estrogen Replacement Therapy ,Anticoagulants ,Hormone replacement therapy (menopause) ,Retrospective cohort study ,Drug Synergism ,Estrogens ,Cell Biology ,Hematology ,Venous Thromboembolism ,Middle Aged ,Surgery ,Uterine ,Hormonal therapy ,Female ,Hormone therapy ,Progestins ,business ,medicine.drug ,Venous thromboembolism - Abstract
Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown if the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged
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- 2016
13. Baseline Characteristics and Clinical Outcomes from the Cancer Associated Thrombosis - Patient Reported Outcomes with Rivaroxaban (COSIMO) Trial
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Khaled Abdelgawwad, Miriam Bach, Jan Beyer-Westendorf, Yoriko De Sanctis, Anthony Maraveyas, Agnes Yuet Ying Lee, Samuel Fatoba, Alexander T. Cohen, and Lorenzo G. Mantovani
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medicine.medical_specialty ,Rivaroxaban ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Quality of life ,Informed consent ,Baseline characteristics ,Family medicine ,Health care ,medicine ,Cancer associated thrombosis ,business ,Venous thromboembolism ,Cohort study ,medicine.drug - Abstract
Background: Patients living with cancer who develop venous thromboembolism (VTE) have a high risk of VTE recurrence, and traditional anticoagulants (low molecular weight heparin [LMWH] or vitamin K antagonists [VKAs]) are associated with significant treatment burdens. Rivaroxaban is a direct oral anticoagulant (DOAC) that may provide a more convenient treatment option for these patients. Methods: The COSIMO study was a multinational, prospective, non-interventional, single-arm cohort study designed to collect real-world data on patient treatment satisfaction and outcomes associated with rivaroxaban treatment following ≥4 weeks of LMWH/VKA therapy for the treatment of acute VTE in patients with active cancer. Here, we report on the secondary objectives, which were to provide descriptive analyses of clinical characteristics and patterns of use of anticoagulant treatment, and to assess the safety and effectiveness of rivaroxaban in this patient population. Results: Overall, 505 patients were enrolled, and the qualifying venous thromboembolic event was deep vein thrombosis (DVT) only in 45.3% of patients, pulmonary embolism (PE) only in 37.2% of patients, DVT with PE in 9.7% of patients, and catheter-associated DVT in 7.5% of patients (Table). The majority of patients had solid tumors (n=449, 88.9%); 56 patients had hematological malignancies. The most common reasons to switch to rivaroxaban were patient preference/quality of life (n=310, 61.4%) and physician decision (n=174, 34.5%). A total of 150 (29.7%) patients were treated with concomitant chemotherapy and 79 (15.6%) received concomitant radiotherapy. Overall, 117 (23.2%) patients discontinued the study: 59 (11.7%) died, 21 (4.2%) withdrew consent, and 17 (3.4%) were lost to follow-up. 80.2% of patients were treated with rivaroxaban for at least 3 months, and most patients (78.6%) received rivaroxaban 20 mg once daily on study entry. Treatment-emergent adverse events (AEs) were reported: 312 (61.8%) patients had an AE (148 [29.3%] serious AEs), and 95 (18.8%) patients had a bleeding event reported, of which 18 (3.6%) patients had an adjudicated major bleeding event. Adjudicated symptomatic and incidental VTE recurrence occurred in 15 (3.0%) and 3 (0.6%) patients, respectively. Adjudicated other site thromboembolic events such as splanchnic or cerebral vein thromboses were symptomatic in 1 (0.2%) patient and incidental in 1 (0.2%) patient. Conclusions: Observed incidence rates of VTE and bleeding events in COSIMO were similar to previous studies of DOACs for VTE treatment in patients with active cancer (Young AM et al. J Clin Oncol 2018;36:2017; Raskob GE et al. N Engl J Med 2018;378:615). Study governance Bayer AG Funding The COSIMO study is funded by Bayer AG and Janssen Pharmaceuticals. Trial protocol number NCT02742623. Registered 19 April 2016. Documented approval from appropriate independent ethics committees/institutional review boards will be obtained for all participating centers prior to study start. Patients were asked to provide signed informed consent forms before joining the study. Few patients have yet completed the study, and so no data are available to share. Acknowledgements Editorial assistance was provided by Kate Weatherall of Chameleon Communications Int. Ltd. with funding from Bayer AG and Janssen Scientific Affairs, LLC. Disclosures Maraveyas: Bristol-Myers Squibb: Honoraria; Bayer AG: Honoraria, Research Funding; Pfizer: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding. Lee:Pfizer: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Mantovani:Daiichi Sankyo: Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer AG: Honoraria; Fondazione Charta: Consultancy; Pfizer: Honoraria. De Sanctis:Bayer US LLC: Employment, Equity Ownership. Abdelgawwad:Bayer AG: Employment. Fatoba:Bayer AG: Employment. Bach:Bayer AG: Employment. Cohen:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ACI Clinical: Consultancy; CSL Behring: Consultancy; Aspen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Speakers Bureau; TRN: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Temasek Capital: Consultancy; Boston Scientific: Consultancy; Guidepoint Global: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Leo Pharma: Consultancy; GLG: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
- Published
- 2019
14. Patterns of VTE Treatment with Noac in Cancer Patients - Results of the Prospective Dresden Noac Registry (NCT01588119)
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Jan Beyer-Westendorf, Luise Tittl, Christiane Naue, and Sandra Marten
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Rivaroxaban ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Immunology ,Low molecular weight heparin ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Thrombosis ,Gastroenterology ,chemistry.chemical_compound ,chemistry ,Edoxaban ,Internal medicine ,medicine ,Apixaban ,Gastrointestinal cancer ,Upper gastrointestinal bleeding ,business ,medicine.drug - Abstract
Background: Until recently, patients with cancer associated thrombosis (CAT) were predominantly treated with low-molecular weight heparin (LMWH) but trial data and updated guidelines suggest that direct oral anticoagulants (DOAC) may represent feasible and convenient oral alternatives. However, most data supporting this relate to 6-12 months outcomes only and long-term data in this setting are scarce Aims: To evaluate the effectiveness and safety of CAT treatment with DOAC in daily care. Patients and methods: From the multicentric Dresden NOAC Registry, long-term outcomes of a subgroup of CAT patients (active or recent cancer, defined as cancer therapy within 5 years prior to thrombosis) receiving CAT therapy with DOAC were evaluated, based on prospectively collected data and centrally adjudicated outcome events. Results: Of the 1667 VTE patients enrolled in the registry until 30th June 2019, 186 patients (11.2%) were identified to have CAT (mean age 67.3 years; 61.3% male). At enrolment, cancer was reported as active in 97 (52.2) cases and recent in 89 (47.8) cases. Solid malignancies were diagnosed in 163 (87.6%) cases were, the remaining 23 (12.4%) cases were hematologic malignancies; table 1; figure 1). Of the 97 cases with active malignancies, 43.3% had metastatic disease. CAT treatment consisted of rivaroxaban in 80 (43.0%) patients, 66 (35.5%) received edoxaban and 40 (21.5%) apixaban. During follow-up (mean 27.8 months, range 0.5 - 88.6), 14 patients experienced recurrent VTE events (7.5 %; incidence rate 3.5/100 pt. years) of which 4 occurred during DOAC treatment and 10 after discontinuation or during prolonged (>3d) DOAC interruption (figure 2a). During DOAC exposure (within 3 days of last intake), major bleeding occurred in 15 patients (8.1%; incidence rate 5.9/100 pt. years; figure 2b) and presented as gastrointestinal (GI) bleeding in 7, intracranial bleeding in 3 and in other bleeding manifestations in 5 cases. For 34 patients with GI cancer, the incidence rate for major bleeding was 13.3/100 pt. years and all four major bleedings in this group presented as upper GI bleed. 40 patients died during FU (21.5%; incidence rate 9.4/100 pt. years). Causes of death included terminal malignant disease (n=22), infection (n=6), fatal bleeding (n=4), age related death (n=3), fatal cardiovascular event (n=3), and other reasons (n=2). Conclusions: Our results now contribute long-term data of DOAC treatment for CAT. Incidence rates of recurrent VTE and major bleeding were consistent with the results from recent randomized trials in CAT. Most VTE recurrences occurred after interruption or discontinuation of DOAC, which indicates the importance of continued therapy especially for patients with active cancer. On-treatment rates of major bleeding were comparable for patients with recent or active cancer, indicating a need for an individualized risk-benefit assessment, especially since patients with recent cancer were at lower risk for VTE recurrence. Our findings of higher major bleeding rates in patients with GI cancer (both active and recent) is in line with the observations in randomized trials and supports guidelines recommendations, cautioning against DOAC use in CAT patients at high risk for bleeding, such as GI cancer patients. Disclosures Marten: Daiichi Sankyo: Honoraria; Bayer HealthCare: Honoraria. Tittl:Daiichi Sankyo: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding.
- Published
- 2019
15. Patient Preferences Regarding Anticoagulation Therapy in Patients with Cancer Having a VTE Event - a Discrete Choice Experiment in the Cosimo Study
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Khaled Abdelgawwad, Alexander T. Cohen, Miriam Bach, Agnes Yuet Ying Lee, Jan Beyer-Westendorf, Lorenzo G. Mantovani, Thomas Wilke, Anthony Maraveyas, Nils Picker, Samuel Fatoba, and Yoriko De Sanctis
- Subjects
Rivaroxaban ,medicine.medical_specialty ,medicine.drug_class ,business.industry ,Immunology ,Low molecular weight heparin ,Cancer ,Discrete choice experiment ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Patient preference ,Regimen ,medicine ,In patient ,Intensive care medicine ,business ,Event (probability theory) ,medicine.drug - Abstract
Introduction: Current guidelines recommend low-molecular-weight heparins (LMWH) over Vitamin K Antagonists (VKA) or Non-Vitamin K Antagonist Oral Anticoagulants (NOAC) for the treatment of cancer-associated venous thromboembolism (CAT), but also highlight that ultimately the choice of anticoagulant depends on patient-specific factors such as patient preferences, which is important for the acceptance of the treatment and, thus, for adherence and persistence. So far, little is known about the specific preferences of patients with CAT with respect to anticoagulation therapy. More specifically, the impact of dosing regimen, convenience and costs on patient preferences in CAT is poorly understood. Therefore, the objective of this discrete choice experiment (DCE) was to elucidate patient preferences regarding anticoagulation convenience attributes. Methods: Adult patients with active cancer who experienced a CAT event and for whom the decision was made to start a treatment with rivaroxaban after being treated with the standard of care anticoagulation (LMWH/VKA) for at least four weeks were included in a multinational, observational, single-arm study (COSIMO). As part of this study, a DCE was presented to the participants, who were asked to decide between complete hypothetical treatment options based on a combination of different attributes, regardless of efficacy or safety. The following attributes were preselected in a face-to-face discussion with three focus patients and in-depth interviews with four additional patients: route of administration (injection / tablet),frequency of intake (once / twice daily),need of regular controls of the International Normalized Ratio (INR) at least every 3-4 weeks (yes/no),interactions with food/alcohol (yes/no). Additionally, distance to treating physician (1 km vs. 20 km) was included as neutral comparator to express patients' overall utility in terms of a comprehensible unit. The relative importance of treatment attributes in terms of distances were calculated based on ratios between the utility estimates for each attribute. A fractional factorial design was generated resulting in nine hypothetical choice sets, supplemented by a test choice set to assess the consistency of a patient's responses. DCE data was collected by semi-structured telephone interviews, performed between week 4 and week 12 after enrollment of patients in the study and start of rivaroxaban. For each patient participating in the DCE interview, a written informed consent was obtained. Patient preferences were analyzed based on a conditional logit regression model. Results: Overall, 163 patients were included (Europe: 119; Canada: 41; Australia: 3), mean age 63.7 years, 49.1% were females and diagnosed with cancer for on average 22.4 months. Most patients in the COSIMO study changed to rivaroxaban from LMWH (> 95.0 %). The median time from diagnosis of index CAT event to conduct of DCE was 150 days (IQR 88-229). Patients strongly preferred oral administration compared to self-injections and drugs that can be taken irrespective of type of food or alcohol consumption (Figure 1). Furthermore, patients indicated slight preference for a shorter distance to the treating physician and a once daily dosing regimen compared to a twice-daily intake. The attribute "INR controls" showed no significant impact on the treatment decision. In order of patients' preference for their choice of treatment, the route of administration was by far the most important attribute for a patient's choice (73.8% of the overall decision), followed by food interactions (11.8%), the distance to treating physician (7.2%) and the intake frequency (6.5%). Accordingly, the expected utility of patients receiving an oral anticoagulation can be expressed as willingness to travel an additional distance of 192 km to the treating physician in order to avoid an injection. Conclusions Treatment related decision-making of patients with CAT, assuming equal effectiveness and safety of treatments, is predominantly driven by "route of administration", indicating a strong preference for oral intake. Disclosures Picker: Ingress-Health: Employment. Cohen:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ACI Clinical: Consultancy; GLG: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy; Boston Scientific: Consultancy; AbbVie: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Aspen: Consultancy, Speakers Bureau; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Maraveyas:Bayer AG: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding. Lee:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mantovani:Fondazione Charta: Consultancy; Bayer AG: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria; Daiichi Sankyo: Research Funding. De Sanctis:Bayer US LLC: Employment, Equity Ownership. Abdelgawwad:Bayer AG: Employment. Fatoba:Bayer AG: Employment. Bach:Bayer AG: Employment. Wilke:Astra Zeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Pharmerit: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria.
- Published
- 2019
16. Impact of Prolonged Anticoagulation with Rivaroxaban on Provoked Venous Thromboembolism Recurrence: The Improve-VTE Study
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Coleman, Craig I., primary, Turpie, Alexander G., additional, Bunz, Thomas J., additional, Beyer-Westendorf, Jan, additional, and Baker, William L, additional
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- 2018
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17. NOAC Therapy Is Also Effective and Safe in Patients Older Than 80 Years — Results of the Prospective Dresden NOAC Registry (NCT01588119)
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Beyer-Westendorf, Jan, primary, Tittl, Luise, additional, Naue, Christiane, additional, and Marten, Sandra, additional
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- 2018
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18. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry
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Sven Pannach, Jan Beyer-Westendorf, Luise Tittl, Franziska Ebertz, Christoph Thieme, Vera Gelbricht, Christina Köhler, Kurtulus Sahin, Ulrike Hänsel, Kati Förster, Norbert Weiss, Franziska Michalski, and Sebastian Werth
- Subjects
Male ,medicine.medical_specialty ,Vitamin K ,medicine.drug_class ,Morpholines ,Immunology ,Hemorrhage ,Thiophenes ,Biochemistry ,Thrombosis and Hemostasis ,Cohort Studies ,Rivaroxaban ,Inside BLOOD Commentary ,Germany ,Internal medicine ,Case fatality rate ,medicine ,Humans ,Prospective Studies ,Registries ,Prospective cohort study ,Aged ,Aged, 80 and over ,business.industry ,Anticoagulants ,Atrial fibrillation ,Cell Biology ,Hematology ,Middle Aged ,Vitamin K antagonist ,medicine.disease ,Thrombosis ,Prothrombin complex concentrate ,Confidence interval ,Surgery ,Treatment Outcome ,Female ,business ,Factor Xa Inhibitors ,medicine.drug - Abstract
Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, but little is known about rivaroxaban-related bleeding complications in daily care. Using data from a prospective, noninterventional oral anticoagulation registry of daily care patients (Dresden NOAC registry), we analyzed rates, management, and outcome of rivaroxaban-related bleeding. Between October 1, 2011, and December 31, 2013, 1776 rivaroxaban patients were enrolled. So far, 762 patients (42.9%) reported 1082 bleeding events during/within 3 days after last intake of rivaroxaban (58.9% minor, 35.0% of nonmajor clinically relevant, and 6.1% major bleeding according to International Society on Thrombosis and Haemostasis definition). In case of major bleeding, surgical or interventional treatment was needed in 37.8% and prothrombin complex concentrate in 9.1%. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1 (95% confidence interval 2.2-4.3) for stroke prevention in atrial fibrillation and 4.1 (95% confidence interval 2.5-6.4) for venous thromboembolism patients, respectively. In the as-treated analysis, case fatality rates of bleeding leading to hospitalizations were 5.1% and 6.3% at days 30 and 90 after bleeding, respectively. Our data indicate that, in real life, rates of rivaroxaban-related major bleeding may be lower and that the outcome may at least not be worse than that of major vitamin K antagonist bleeding, and probably better. This trial was registered at www.clinicaltrials.gov as identifier #NCT01588119.
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- 2014
19. Impact of Prolonged Anticoagulation with Rivaroxaban on Provoked Venous Thromboembolism Recurrence: The Improve-VTE Study
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Thomas J. Bunz, Alexander G.G. Turpie, William L. Baker, Craig I Coleman, and Jan Beyer-Westendorf
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Rivaroxaban ,Aspirin ,Surrogate endpoint ,business.industry ,Immunology ,Cell Biology ,Hematology ,Thrombophilia ,medicine.disease ,Biochemistry ,Thrombosis ,Pulmonary embolism ,Heart failure ,Anesthesia ,medicine ,business ,Venous thromboembolism ,medicine.drug - Abstract
Background: The optimal duration of anticoagulation following an incident provoked venous thromboembolism (VTE) remains unclear. Two randomized trials have shown extended duration rivaroxaban use in patients experiencing an unprovoked or provoked VTE can reduce patients' risk of recurrent thrombosis without a significant increased risk of major bleeding compared to placebo or aspirin. Objectives: We sought to evaluate the real-world effectiveness and safety of prolonged anticoagulation with rivaroxaban following an incident provoked VTE. Methods: Using claims data from the US Truven MarketScan databases from November 1, 2012 through March 31, 2017, we identified adult patients with a primary discharge diagnosis of VTE (deep vein thrombosis and/or pulmonary embolism) during a hospitalization or emergency department visit, who had a provoking (major or minor, persistent or transient) risk factor, at least 3-months of continuous rivaroxaban treatment and ≥12-months of continuous medical and prescription insurance benefits prior to their incident VTE. Patients were categorized as either continuing rivaroxaban or discontinuing anticoagulation (no anticoagulation or antiplatelet agents, with or without aspirin) after the initial 3-months of rivaroxaban treatment (index date). Differences in baseline covariates between cohorts were adjusted for using inverse probability-of-treatment weights (IPTW) based on propensity-scores (residual standardized differences Results: Among patients experiencing an incident provoked VTE and treated with rivaroxaban for the first 3-months (N=4,990), continued rivaroxaban use beyond 3-months [median (25%, 75% range) duration of additional rivaroxaban use = 3 (2, 5) months] was associated with a 44% lower hazard of recurrent VTE without significantly altering major bleeding risk when compared to anticoagulation discontinuation with or without aspirin use (Table). The highest risk of recurrent thrombosis following provoked VTE (3.1% in the discontinued anticoagulation cohort) appeared to occur in patients with a minor persisting risk factor; with continued rivaroxaban use associated with a significant 73% reduction in recurrent VTE. Conclusions: Although the absolute incidence of recurrence was low, our study suggests continuing rivaroxaban after the initial 3-month period was associated with a decreased risk of recurrent VTE, particularly in those with a minor persisting risk factor. The observed reduction in recurrent VTE with prolonged rivaroxaban use was not associated with a significantly increased risk of major bleeding. Disclosures Coleman: Bayer AG: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs LLC: Consultancy, Honoraria, Research Funding. Turpie:Bayer AG: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs LLC: Consultancy, Speakers Bureau. Beyer-Westendorf:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding.
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- 2018
20. SGN-CD48A: a Novel Humanized Anti-CD48 Antibody-Drug Conjugate for the Treatment of Multiple Myeloma
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Lewis, Tim S., primary, Olson, Devra, additional, Gordon, Kristine, additional, Sandall, Sharsti, additional, Quick, Marsha, additional, Finn, Margo, additional, Westendorf, Lori, additional, Linares, Germein, additional, Leiske, Chris, additional, Nesterova, Albina, additional, Huang, Lanshan, additional, Goswami, Maitrayee, additional, Wang, Sa, additional, and Law, Che-Leung, additional
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- 2016
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21. Localization, Management, Resource Consumption and Outcome of Major Gastrointestinal Bleeding in Patients with Direct Oral Anticoagulants, Vka and Antiplatelet Therapy
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Pannach, Sven, primary, Goetze, Julia, additional, Tittl, Luise, additional, Schreier, Thomas, additional, Marten, Sandra, additional, Hampe, Jochen, additional, and Beyer-Westendorf, Jan, additional
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- 2016
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22. Treatment of Acute VTE with Rivaroxaban - Results of the Prospective Dresden Noac Registry (NCT01588119)
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Keller, Loretta, primary, Marten, Sandra, additional, Hecker, Judith, additional, Werth, Sebastian, additional, Tittl, Luise, additional, and Beyer-Westendorf, Jan, additional
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- 2016
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23. Rivaroxaban Versus Fondaparinux in the Treatment of Superficial Vein Thrombosis - the Surprise Trial
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Beyer-Westendorf, Jan, primary, Schellong, Sebastian, additional, Gerlach, Horst, additional, Jersemann, Katja, additional, Rabe, Eberhard, additional, Sahin, Kurtulus, additional, and Bauersachs, Rupert, additional
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- 2016
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24. Rivaroxaban Versus Fondaparinux in the Treatment of Superficial Vein Thrombosis - the Surprise Trial
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Sebastian Schellong, Jan Beyer-Westendorf, Horst E. Gerlach, Eberhard Rabe, Rupert Bauersachs, Katja Jersemann, and Kurtulus Sahin
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medicine.medical_specialty ,Rivaroxaban ,Intention-to-treat analysis ,Superficial vein thrombosis ,business.industry ,Deep vein ,Immunology ,Cell Biology ,Hematology ,Fondaparinux ,medicine.disease ,Placebo ,Biochemistry ,Pulmonary embolism ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Superficial thrombophlebitis ,business ,030215 immunology ,medicine.drug - Abstract
Background The current standard of therapy in superficial vein thrombosis (SVT) comprises subcutaneous injections of the indirect factorXainhibitorfondaparinuxfor up to 45 days, which was highlyeffectivecompared to placebo in the CALISTO trial. However,fondaparinuxis expensive, requires daily injections and cost-effectiveness in SVT therapy has been questioned. Rivaroxaban is a direct oral factorXainhibitor which has been shown to be effective in the prevention and treatment of venous thromboembolism (VTE). We hypothesizedthat SVT patientsat high risk for VTE complications may be treated as efficacious and safe with rivaroxaban as withfondaparinux. Methods The SURPRISE trial, a randomized, open-label blinded outcome event adjudication trial, compared rivaroxaban 10 mg once daily withfondaparinux2.5 mg once daily in patients with SVT at high risk of VTE complications (defined assupragenualSVT + age > 65 years, male sex, previous VTE, cancer, autoimmune disease or SVT of non-varicose veins). Treatment duration for both treatments was 45+5 days with an observational period until day 90+10. The primary efficacy outcome was a composite endpoint of deep vein thrombosis, pulmonary embolism, SVT progression towards thesaphenofemoraljunction, SVT recurrence or all cause death in the per-protocol analysis at day 45. A predefined sensitivity analysis was performed in all randomized patients (full analysis set). The primary safety outcome was the rate of ISTH major bleeding during treatment. Further outcome measures included the composite efficacy outcome up to day 90, each component of the primary efficacy outcome, rates of surgical treatment of SVT and rates of major VTE (composite of symptomatic PE or symptomatic proximal DVT or VTE-related death) at days 45 and 90. The trial was designed to test for non-inferiority of rivaroxaban compared tofondaparinuxwith respect to the primary efficacy outcome and to the rates of ISTH major bleeding. Results A total of 472 patients were randomized (mean age 60.3 years; 60.4% female) and treated with rivaroxaban (n=236) orfondaparinux(n=236). Mean treatment duration was 44.0 days for rivaroxaban and 44.8 days forfondaparinux. Until day 45+5, the primary efficacy outcome (n=435 in per-protocol analysis set) occurred in 3.3% (95%-CI 0.90; 5.73) of patients treated with rivaroxaban and 1.8% (95%-CI 0.05; 3.52) of patients receivingfondaparinux(absolute difference between rivaroxaban andfondaparinuxwas 1.53%; one-sided upper CI limit 4.03%; p-value for non-inferiority 0.025; table 1 and figure 1). Until day 90+10, the respective rates were 7.1% for rivaroxaban and 6.7% forfondaparinux(absolute difference 0.41;one-sided upper CI limit 4.41%;p-value for non-inferiority 0.047). Non-inferiority of rivaroxaban vs.fondaparinuxwas preserved in the full analysis set. No major bleeding occurred and rates of non-major, clinically relevant bleeding were 2.5 vs. 0.4% for day 45+5 and 2.5 vs. 0.9% for day 90+10 in safety set for rivaroxaban andfondaparinux, respectively (table 1).Mean±SDadherence (pill/syringe count at day 45) was 98.9±13.4% for rivaroxaban and 99.3±6.2% forfondaparinux(full analysis set). Conclusions In high-risk SVT patients, rivaroxaban was non-inferior tofondaparinuxin preventing thromboembolic complications with comparable safety. VTE events were predominantly SVT recurrence. Few cases of DVT and PE occurred, which indicates that a 45 days course of rivaroxaban 10 mg orfondaparinux2.5 mg is sufficient to prevent serious complications in this specific subset of SVT patients. As to whether oral rivaroxaban offers a better quality of life compared to 45 days of injections, this has to be investigated in future studies. We found higher SVT complications rates in both treatment arms compared to thefondaparinuxarm in the CALISTO trial. Therefore, patients at higher VTE risk can be identified by use of a simple risk factor assessment, which may help to improve cost-effectiveness of SVT therapy. However, the concept of SVT risk stratification needs to be further investigated, since patients without additional risk factors may not need anticoagulant therapy at all. (Funded by Bayer Vital GmbH, Germany, ClinicalTrials.gov NCT01499953) In response to a pre-submission enquiry, the New England Journal of Medicine indicated potential interest in the study results and a simultaneous publication/presentation is targeted. Disclosures Beyer-Westendorf: Daichii Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding. Schellong:Bayer: Honoraria; Pfizer: Honoraria; Boehringer-Ingelheim: Honoraria; Daichii Sankyo: Honoraria; LeoPharma: Honoraria. Gerlach:ASPEN: Honoraria; Bayer: Honoraria; Boehringer-Ingelheim: Honoraria; LeoPharma.: Honoraria. Rabe:Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daichii-Sankyo: Honoraria; LeoPharma: Honoraria; Pfizer: Honoraria. Bauersachs:Bayer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; BristolMyers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; ASPEN: Honoraria, Research Funding.
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- 2016
25. Localization, Management, Resource Consumption and Outcome of Major Gastrointestinal Bleeding in Patients with Direct Oral Anticoagulants, Vka and Antiplatelet Therapy
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Julia Goetze, Luise Tittl, Jochen Hampe, Thomas Schreier, Sven Pannach, Sandra Marten, and Jan Beyer-Westendorf
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Rivaroxaban ,medicine.medical_specialty ,Gastrointestinal bleeding ,Antiplatelet drug ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Dabigatran ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,Antithrombotic ,medicine ,Apixaban ,Upper gastrointestinal bleeding ,business ,medicine.drug - Abstract
Background Gastrointestinal bleeding (GI-B) is the most common major bleeding complication in oral anticoagulation. While direct oral anticoagulants (DOACs) have been shown to significantly decrease major bleeding, intracranial hemorrhage and fatal bleeding compared to vitamin k antagonists (VKA), there is conflicting evidence regarding the relative risk of GI-B. However, while bleeding rates are important, the exact localization of GI-B, the management, resource consumption and outcome of DOAC-associated GI-B could be even more important from a clinical perspective, but such data are currently lacking. Methods We analyzed all major GI-B events (defined as any GI-B that resulted in or occurred during hospitalization) documented in the prospective Dresden NOAC registry. Only patients with overt bleeding undergoing GI endoscopy were included in our analysis. Bleeding localization, lesion type, endoscopic treatment, consumption of blood and coagulation factor transfusion, length of stay and in-hospital mortality were compared with historic data from consecutive GI-B patients treated at our academic hospital between 2005 and 2010, before the market entry of DOACs to reduce the risk for selection bias. All patients underwent manual chart review to assure optimal data quality. Due to the nature of the datasets, only descriptive comparisons were performed. Results A total of 143 major GI-B episodes fulfilled our inclusion criteria (112 exposures to rivaroxaban, 18 to apixaban and 13 to dabigatran) and were compared against data from 1911 consecutive cases of GI-B in our historic cohort, of which 185 were exposed to VKA and 711 were exposed to antiplatelet drugs at the time of bleeding. Patient characteristics according to type of antithrombotic therapy are presented in table 1. GI-B locations could be identified in the upper GI tract in 63/143 DOAC cases (44.1%), in the lower GI tract in 60 (42.0%) and were in the middle GI-tract or not identified in the remaining 20 DOAC cases (14.0%). This pattern was different from bleeding patterns in patients with VKA or antiplatelet therapy (table 1), where most cases presented as upper GI-B and where, within lower GI-B, hemorrhoid bleeding was considerably less common compared to DOAC recipients. Within upper GI-B, 17/63 cases in DOAC recipients were due to an ulcer (27.0%), which is much lower than the ulcer rate in upper GI-B seen with VKA or antiplatelet drugs (table 1). Transfusion requirements were lower in DOAC recipients compared to GI-B cases with VKA or antiplatelet drugs (table 2). Similarly, length of hospital stay was shorter in cases with DOAC therapy compared to VKA or antiplatelet drug recipients. Finally, patients with GI-B during DOAC therapy demonstrated an in-hospital mortality of only 1.4%, which compared favorably against the in-hospital mortality of GI-B cases exposed to VKA (4.9%) or antiplatelet therapy (10.7%; table 2). Of the 17 DOAC patients with upper GI bleeding due to an ulcer, none died in hospital, whereas ulcer-associated upper GI bleeding was associated with an in-hospital mortality of 11.3% in VKA and 13.5% in antiplatelet drug recipients. In contrast, in-hospital mortality was 0% for hemorrhoid bleeding with DOAC, VKA and antiplatelet therapy. The two fatal GI-bleedings in the DOAC cohort occurred in 84 and 95 year old female patients and manifested as diffuse mucosal bleeding in the upper GI tract. Conclusions Our data indicate that, within GI-B, different bleeding localizations have different outcomes. Patients with GI-B during DOAC therapy have more often lower GI bleed compared to bleeding patients with VKA or antiplatelet drugs, which is driven by a large proportion of hemorrhoid bleeding. In contrast, upper GI-B is much less frequent and less common related to ulcers. DOAC-associated GI-B resulted in comparatively low resource consumption, shorter hospitalization and a low in-hospital mortality compared to GI-B historically seen with VKA or antiplatelet agents. The difference in resource consumption and mortality is likely due to a shift in bleeding patterns, together with the short half- life of DOACs. A focus on GI-B rates with different antithrombotic therapies alone may be misleading, since bleeding localization, resource consumption and outcome may vary considerably. These findings need to be confirmed in larger cohorts, ideally from randomized controlled trials, to allow for statistical comparisons. Disclosures Pannach: Bayer: Honoraria; Pfizer: Honoraria. Marten:Daichii Sankyo: Honoraria; Bayer: Honoraria. Beyer-Westendorf:Daichii Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding.
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- 2016
26. Treatment of Acute VTE with Rivaroxaban - Results of the Prospective Dresden Noac Registry (NCT01588119)
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Judith Hecker, Sandra Marten, Luise Tittl, Sebastian Werth, Jan Beyer-Westendorf, and Loretta Keller
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Pediatrics ,medicine.medical_specialty ,Rivaroxaban ,030504 nursing ,business.industry ,Deep vein ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Thrombosis ,Pulmonary embolism ,Discontinuation ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,030212 general & internal medicine ,Dosing ,0305 other medical science ,business ,Venous thromboembolism ,medicine.drug - Abstract
Background: The effectiveness and safety of acute venous thromboembolism (VTE) treatment with rivaroxaban, demonstrated in phase-III trials, needs to be evaluated in unselected patients treated under daily care conditions. Patients and methods: The Dresden NOAC registry is a prospective regional registry in which patients with oral anticoagulation undergo prospective follow- up (FU). So far, more than 3200 patients have been enrolled, including 772 VTE patients with rivaroxaban treatment. For this analysis, only patients with acute VTE who started rivaroxaban within 14 days after diagnosis of VTE and who were enrolled within these 14 days were evaluated with regard to patient characteristics, treatment persistence and clinical outcomes. All reported outcome events were centrally adjudicated based on source documentation and standard definitions. Results: Between December 1st 2011 and March 31st 2016, 407 patients received rivaroxaban for acute VTE treatment (51.6% female, 80.8% DVT; 19.2% PE±DVT, mean age 61.4 years). Mean time between VTE diagnosis and initiation of rivaroxaban was 1.7±3.3 days (median 0d; 25th/75th percentile 0; 1d). At baseline, rivaroxaban doses consisted of 15 mg BID in 93.1%, 20 mg OD in 3.4%, 15 mg OD in 3.2% and 10 mg OD in 0.2% of patients. Reasons for not using 2x15 mg rivaroxaban BID were pre-treatment with therapeutic parenteral anticoagulants for ≥7 d in 14 cases, comorbidities (e.g. bleeding history, renal impairment) in 4 cases and unknown in 10 cases. During FU (mean 762.4±462.7d), the mean rivaroxaban exposure was 357.7±385.9 days. During treatment with rivaroxaban, 4/407 patients (1.0%) experienced a recurrent VTE, which translated into a recurrence rate of 1.0/ 100 pt. years. During treatment, 172/407 (42.3%) patients reported bleeding complications, which in 13 cases (3.2%; 3.3/100 pt. years) were major bleeding according to ISTH definition, including one fatal intracranial bleeding. Patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) had similar rates of recurrent VTE during rivaroxaban treatment (1.01 and 1.01/100 pt. years) but PE patients had numerically higher rates of major bleeding (3.99/100 pt. years compared to 3.09/100 pt.years in the DVT group). Effectiveness and safety profiles were consistent across relevant subgroups (table 1). 18 patients died during FU (2.12/100 pt.years), of which 8 deaths occurred during or within 3 days after last intake of rivaroxaban. Most common causes of death were fatal cardiovascular event (n=7) and terminal malignant disease (n=4), followed by sepsis/infection (n=3), age related death (n=1), fatal bleeding (n=1) and other reasons (n=2). At 6 months (FU completed in 365 pts.), 61.4% of patients were still taking rivaroxaban. The remaining patients had a scheduled end of treatment (28.8%) or were switched to other anticoagulants (7.1%). Therefore, the rate of unplanned complete discontinuation at 6 months was 2.7%. At 12 months (FU completed in 289 pts.), 41.5% of patients were still taking rivaroxaban. The remaining patients had a scheduled end of treatment (45.0%) or were switched to other anticoagulants (8.3%). Therefore, the rate of unplanned complete discontinuation at 12 months was 5.2%. After rivaroxaban interruption for more than 3 days or permanent discontinuation, 21 patients experienced a recurrent VTE (9 PE±DVT, 12 DVT) with a mean time between last intake of rivaroxaban and VTE recurrence of 351.2±282.6 days (range 7-926d). PE was a common manifestation of VTE recurrence and, despite numerically lower bleeding rates after discontinuation, 2 cases of intracranial haemorrhage occurred (table 2). Conclusions: In unselected patients in daily care, rivaroxaban treatment for acute VTE has high effectiveness and acceptable rates major bleeding. Initial dosing was according to label in over 90% of patients and, at 6 and 12 months, persistence to rivaroxaban therapy was excellent with low rates of unplanned complete discontinuation. Fatal VTE and fatal bleeding are rare events during rivaroxaban therapy and all-cause mortality is mostly related to underlying diseases, age or acute co-morbidities. Treatment discontinuation resulted in a relevant increase in VTE recurrence, of which more than 40% manifested as PE. In contrast, major bleeding rates declined after discontinuation but with 1%/year remained at a clinically relevant level, probably due to co-morbidities. Disclosures Marten: Bayer: Honoraria; Daichii Sankyo: Honoraria. Werth:Pfizer: Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; OmniaMed: Honoraria; LEO-Pharma: Honoraria. Beyer-Westendorf:Pfizer: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding.
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- 2016
27. SGN-CD48A: a Novel Humanized Anti-CD48 Antibody-Drug Conjugate for the Treatment of Multiple Myeloma
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Chris Leiske, Che-Leung Law, Marsha Quick, Sa Wang, Maitrayee Goswami, Lori Westendorf, Devra Olson, Kristine A. Gordon, Margo Finn, Albina Nesterova, Sharsti Sandall, Germein Linares, Lanshan Huang, and Timothy S. Lewis
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0301 basic medicine ,Antibody-drug conjugate ,medicine.drug_class ,Immunology ,Monoclonal antibody ,Biochemistry ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Cytotoxic T cell ,Multiple myeloma ,medicine.diagnostic_test ,biology ,business.industry ,Cell Biology ,Hematology ,CD48 ,medicine.disease ,Tumor antigen ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Antibody ,business - Abstract
Multiple myeloma (MM) is an incurable hematologic malignancy of transformed plasma cells. New targeted biological therapeutics are needed to increase the stringency and durability of remissions. In this study we describe SGN-CD48A, a potent CD48-targeting antibody-drug conjugate (ADC) utilizing a novel glucuronide-monomethylauristatin E (MMAE) linker, under development for the treatment of MM. CD48, or SLAMF2 (Signaling Lymphocyte Activation Molecule family member 2), is a GPI-anchored membrane protein in the SLAM family of immunoreceptors. CD48 is expressed on B and T lymphocytes, natural killer (NK) cells, and other immune cell types where it functions to modulate immune cell activation, proliferation, and differentiation. CD48 is also a tumor antigen broadly expressed in MM. We observed CD48 expression on the surface of malignant plasma cells in 90% (90/100) of human multiple myeloma patient samples examined by flow cytometry. Monoclonal antibodies (mAbs) specific for human CD48 were evaluated and a lead antibody was selected based on binding characteristics and cytotoxic activity against myeloma cells as an auristatin ADC. SGN-CD48A is a humanized anti-CD48 mAb to which eight molecules of MMAE, a potent microtubule disrupting cytotoxic drug, have been conjugated via a β-glucuronidase-cleavable linker. This novel glucuronide-MMAE drug-linker incorporates a PEG side chain and self-stabilizing maleimide to achieve homogenous drug-to-antibody ratio (DAR) 8 conjugates with decreased plasma clearance and increased preclinical antitumor activity. Following binding of CD48 at the myeloma cell surface, SGN-CD48A internalizes and traffics to lysosomal vesicles. Intracellular MMAE drug released from SGN-CD48A in myeloma cells induced cell cycle arrest at G2/M phase, phospho-histone H3 (Ser-10) phosphorylation, and caspase 3/7 dependent apoptotic cell death. SGN-CD48A demonstrated potent cytotoxic activity (EC50 values 1.0 - 11 ng/mL) against a panel of human MM cell lines, with CD48 expression levels of 135,000 - 480,000 receptors per cell. In contrast, SGN-CD48A had negligible cytotoxic activity against normal resting human B, NK, and T lymphocytes. We evaluated the in vivo antitumor activity of SGN-CD48A in disseminated MM cell line mouse xenograft models. In the NCI-H929 and EJM xenograft models, a single intraperitoneal dose of 0.3 mg/kg SGN-CD48A produced durable complete remissions in 8/8 and 6/8 mice, respectively. Similarly, in the U-266 xenograft model, a single dose of 1.0 mg/kg SGN-CD48A produced durable complete remissions in 7/8 mice. Neither unconjugated mAb nor a non-binding control MMAE ADC were active in these MM xenograft models, demonstrating that targeted delivery of MMAE drug through CD48 binding is required for activity. In summary, CD48 is a highly expressed new multiple myeloma target and the novel glucuronide-MMAE ADC SGN-CD48A shows potent antitumor activity against cell line models of MM. Disclosures Lewis: Seattle Genetics, Inc.: Employment, Equity Ownership. Olson:Seattle Genetics, Inc.: Employment, Equity Ownership. Gordon:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandall:Seattle Genetics, Inc.: Employment, Equity Ownership. Quick:Seattle Genetics, Inc.: Employment, Equity Ownership. Finn:Seattle Genetics, Inc.: Employment, Equity Ownership. Westendorf:Seattle Genetics, Inc.: Employment, Equity Ownership. Linares:Seattle Genetics, Inc.: Employment, Equity Ownership. Leiske:Seattle Genetics, Inc.: Employment, Equity Ownership. Nesterova:Seattle Genetics, Inc.: Employment, Equity Ownership. Law:Seattle Genetics, Inc.: Employment, Equity Ownership.
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- 2016
28. Small clots with large impact
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Walter Ageno and Jan Beyer-Westendorf
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Male ,Pathology ,medicine.medical_specialty ,Immunology ,Biochemistry ,Malignant disease ,medicine ,Humans ,Splanchnic Circulation ,Venous Thrombosis ,business.industry ,Medicine (all) ,Liver Neoplasms ,Cell Biology ,Hematology ,medicine.disease ,Occult ,Pancreatic Neoplasms ,Venous thrombosis ,Splanchnic vein thrombosis ,Female ,cardiovascular system ,Radiology ,business ,Venous thromboembolism - Abstract
In this issue of Blood, Kirstine Søgaard and colleagues report on the relevance of splanchnic vein thrombosis (SVT) as a marker of occult malignant disease.
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- 2015
29. Pattern and Management of Vaginal Bleeding Complications, Especially Hypermenorrhea, with Direct Oral Anticoagulants - Results of the Prospective Dresden Noac Registry (NCT01588119)
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Marten, Sandra, primary, Tittl, Luise, additional, Daschkow, Katharina, additional, and Beyer-Westendorf, Jan, additional
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- 2015
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30. Pattern and Management of ISTH Major Bleeding Complications with Direct Oral Anticoagulants - Results of the Prospective Dresden Noac Registry (NCT01588119)
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Marten, Sandra, primary, Tittl, Luise, additional, Daschkow, Katharina, additional, and Beyer-Westendorf, Jan, additional
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- 2015
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31. Pattern and Management of Intracranial Haemorrhage with Rivaroxaban or Dabigatran Compared to Vitamin K Antagonists - Results of the Prospective Dresden Noac Registry
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Marten, Sandra, primary, Tittl, Luise, additional, Daschkow, Katharina, additional, and Beyer-Westendorf, Jan, additional
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- 2015
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32. Outcome of Noac Exposure during Pregnancy (...and the problem of event reporting...)
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Beyer-Westendorf, Jan, primary, Marten, Sandra, additional, and Michalski, Franziska, additional
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- 2015
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33. SGN-CD123A, a Pyrrolobenzodiazepine Dimer Linked Anti-CD123 Antibody Drug Conjugate, Demonstrates Effective Anti-Leukemic Activity in Multiple Preclinical Models of AML
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Sutherland, May S.K., primary, Yu, Changpu, additional, Walter, Roland B., additional, Westendorf, Lori, additional, Valliere-Douglass, John, additional, Pan, Lucy, additional, Sussman, Django, additional, Anderson, Martha, additional, Zeng, Weiping, additional, Stone, Ivan, additional, Klussman, Kerry, additional, Ulrich, Michelle, additional, Jonas, Mechthild, additional, Senter, Peter, additional, Drachman, Jonathan G., additional, and Benjamin, Dennis, additional
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- 2015
- Full Text
- View/download PDF
34. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML
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Scott C. Jeffrey, Irwin D. Bernstein, David W. Meyer, Julie A. McEarchern, Changpu Yu, Jonathan G. Drachman, Ivan Stone, Lori Westendorf, Kimberly H. Harrington, Django Sussman, Dennis Benjamin, Maureen Ryan, Heather Kostner, Roland B. Walter, Robert P. Lyon, May Kung Sutherland, Kerry Klussman, Patrick J. Burke, Peter D. Senter, and Weiping Zeng
- Subjects
Antibody-drug conjugate ,Immunoconjugates ,Gemtuzumab ozogamicin ,DNA damage ,Immunology ,CD33 ,Sialic Acid Binding Ig-like Lectin 3 ,Pyrrolobenzodiazepine ,Apoptosis ,HL-60 Cells ,Drug resistance ,Pharmacology ,Antibodies, Monoclonal, Humanized ,Biochemistry ,chemistry.chemical_compound ,Benzodiazepines ,Mice ,medicine ,Animals ,Humans ,Cysteine ,business.industry ,Cell Cycle ,Myeloid leukemia ,Cell Biology ,Hematology ,Cell cycle ,Leukemia, Myeloid, Acute ,Cross-Linking Reagents ,HEK293 Cells ,chemistry ,Drug Resistance, Neoplasm ,Drug Design ,business ,Dimerization ,medicine.drug - Abstract
Outcomes in acute myeloid leukemia (AML) remain unsatisfactory, and novel treatments are urgently needed. One strategy explores antibodies and their drug conjugates, particularly those targeting CD33. Emerging data with gemtuzumab ozogamicin (GO) demonstrate target validity and activity in some patients with AML, but efficacy is limited by heterogeneous drug conjugation, linker instability, and a high incidence of multidrug resistance. We describe here the development of SGN-CD33A, a humanized anti-CD33 antibody with engineered cysteines conjugated to a highly potent, synthetic DNA cross-linking pyrrolobenzodiazepine dimer via a protease-cleavable linker. The use of engineered cysteine residues at the sites of drug linker attachment results in a drug loading of approximately 2 pyrrolobenzodiazepine dimers per antibody. In preclinical testing, SGN-CD33A is more potent than GO against a panel of AML cell lines and primary AML cells in vitro and in xenotransplantation studies in mice. Unlike GO, antileukemic activity is observed with SGN-CD33A in AML models with the multidrug-resistant phenotype. Mechanistic studies indicate that the cytotoxic effects of SGN-CD33A involve DNA damage with ensuing cell cycle arrest and apoptotic cell death. Together, these data suggest that SGN-CD33A has CD33-directed antitumor activity and support clinical testing of this novel therapeutic in patients with AML.
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- 2013
35. Expression and function of Fas (APO-1/CD95) in patient myeloma cells and myeloma cell lines
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Diane F. Jelinek, Jennifer J. Westendorf, and John M. Lammert
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medicine.drug_class ,Immunology ,Cell Biology ,Hematology ,Plasma cell ,Biology ,Fas receptor ,Monoclonal antibody ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Cell culture ,Apoptosis ,hemic and lymphatic diseases ,Cancer research ,medicine ,Bone marrow ,Monoclonal gammopathy of undetermined significance ,Multiple myeloma - Abstract
Cross-linkage of the Fas antigen induces programmed cell death in many normal and malignant lymphoid cells by a process known as apoptosis. In this study, we examined the sensitivity of myeloma cell lines and patient plasma cells to a cytolytic anti-Fas monoclonal antibody (MoAb). Eight of 10 myeloma cell lines were induced to undergo programmed cell death by anti-Fas MoAb as determined by DNA fragmentation and morphologic changes. Of the two myeloma cell lines that were resistant to anti-Fas treatment, one did not express the Fas antigen. Only the U266 cell line expressed Fas, but was not killed by the anti0Fas MoAb. To extend these studies, we have examined the expression and function of Fas in freshly isolated CD38hiCD45neg-int plasma cells from patients with multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and primary amyloidosis (AL). By three-color flow cytometry, we found Fas expression in CD38hiCD45neg-int plasma cells from all patient groups to be variable, as Fas was expressed in 15 of 28 MM, 3 of 6 MGUS, and 2 of 7 AL patients. In morphologic studies of apoptosis, Fas-positive myeloma cells in patient bone marrow mononuclear cell (MNC) cultures appeared to be resistant to anti-Fas-mediated apoptosis. By contrast, purified myeloma cells from the same patient were sensitive to anti-Fas treatment, suggesting the presence of a protective factor(s) in unseparated MNC cultures that may inhibit Fas-induced apoptosis of plasma cells. Of interest, serum from normal individuals and myeloma patients also protected myeloma cell lines from undergoing Fas-mediated apoptosis. These studies show that Fas expression in myeloma cell lines and CD38hiCD45neg-int patient plasma cells is variable and may reflect a variance in the maturation status of the various plasma cell populations. Moreover, Fas-mediated killing of patient cells and myeloma cell lines was also variable, which may be influenced, in part, by the presence of a soluble protective factor.
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- 1995
36. Pattern and Management of ISTH Major Bleeding Complications with Direct Oral Anticoagulants - Results of the Prospective Dresden Noac Registry (NCT01588119)
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Jan Beyer-Westendorf, Luise Tittl, Sandra Marten, and Katharina Daschkow
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Gastrointestinal bleeding ,medicine.medical_specialty ,Rivaroxaban ,business.industry ,Immunology ,Warfarin ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Dabigatran ,Embolism ,medicine ,Apixaban ,Fresh frozen plasma ,business ,Stroke ,medicine.drug - Abstract
Background: The most common side effects of oral anticoagulants are bleeding complications. In large trials, direct oral anticoagulants (DOAC) have been shown to reduce the risk of major bleeding compared to warfarin. However, little is known about the management and outcome of survivors of major DOAC bleeding. Patients and methods: Using data from the prospective, non-interventional Dresden NOAC registry, we evaluated the management and outcome of survivors of major DOAC bleeding. All DOAC bleeding complications were centrally adjudicated and classified according to ISTH definition. For this analysis, every ISTH major bleeding was identified in the database and for each case, the first major bleeding was evaluated. Restart of oral anticoagulation (OAC) 30 days after major DOAC bleeding was assessed and the impact of restart on the composite endpoint of (recurrent major bleeding, stroke, TIA, systemic embolism, venous thromboembolism) or survival was evaluated using Kaplan-Meier time-to-first event estimation. Results: Until January 31th 2015, 2771 patients were enrolled into the registry (1898 treated with rivaroxaban, 525 apixaban and 348 dabigatran). During follow-up (mean follow-up duration 23.6 months) 127 patients developed 170 ISTH major bleeding events during DOAC exposure (drop of hemoglobin ≥2g/l in 106 (62.4%) cases, transfusion of ≥2 units of red blood cells in 105 (61.8%) cases, critical site bleeding in 43 (25.3%) cases and/or fatal outcome in 9 cases (5.3%)). Of the 127 patients with major bleeding (mean age 77±11 years; range 37-94), 53.5% were male the median HAS-BLED score was 2 (25th/75th percentile 1/2, range 0-5). The majority major bleeding events occurred spontaneously (64.6%). In contrast, 14.2% major bleeding events occurred after trauma and 21.3% occurred after surgical or interventional procedures that were performed during treatment or within 3 days after last DOAC intake. Most common sites of bleeding were gastrointestinal tract (37%), diffuse bleeding during or after surgery (15.7%), intracranial (11%), skin/mucosal (9.4%), intraocular (8.7%), genitourinary (7.9%), intraarticular bleeding (6.3%) and bleeding in other sites (4%). 85 cases lead on to a hospitalization (mean duration 9±7d) and 11 cases were managed as outpatient. The remaining 31 bleeding events occurred during a hospital stay. The majority of cases were managed with surgical or interventional treatment (55.9%; mainly endoscopic treatment for gastrointestinal bleeding. In 75 (57.1%) cases red blood cell transfusion was given and 11 (8.7%) of cases received fresh frozen plasma. Furthermore, 15 (11.8%) of cases received PCC and 4 (3.1%) fibrinogen. The restart of OAC (DOAC or vitamin K antagonists; VKA) was assessed at day 30 after major bleeding. While OAC was restarted in 80 patients (63%) it was not restarted 30 days after bleeding in the remaining 47 (37%). Patients who restarted OAC had a similar mean age (76 vs. 78y, p=0.309) and a similar mean HAS-BLED score (1.8 vs. 2.1, p=0.115) compared to patients who did not restart OAC. During follow up after bleeding (mean follow-up duration 15.2 months), the rate of combined endpoint of recurrent major bleed and thromboembolism was significantly lower in patients that restarted OAC compared to those who did not restart (14.7/100 patient years; 95%-CI 8.0-24.7 vs. 38.6/100 patient years; 21.1-64.7; p=0.0342). All-cause mortality was found to be 23.9/100 patient years (95% CI 16.9-32.8). Mortality was significantly lower in patients that restarted OAC compared to those who did not restart (16.4/100 patient years [9.7-25.9] vs. 40.6/100 patient years [24.8-62.7]; p=0.0099). Most common cause of death was fatal cardiovascular event (12/38, 31.6%) and fatal bleeding (9/38, 23.7%) followed by terminal malignant disease (6/38, 15.8%), infection/sepsis (6/38, 15.8%) and age related death (5/38, 13.2%). Conclusion: Even in cases with major DOAC bleeding, acute mortality is low with a case-fatality rate of 5.3%. Furthermore, OAC is restarted within 30 days after major bleeding in only 63%. Patients who restarted OAC had significantly lower rates of the combined endpoint of thromboembolism or recurrent major bleeding and had a significantly better survival. Therefore, benefits of OAC continuation may outweigh the risks even in patients with major DOAC-related bleeding. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Marten: Bayer HealthCare: Honoraria. Beyer-Westendorf:Bayer HealthCare: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bristol- Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.
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- 2015
37. Pattern and Management of Vaginal Bleeding Complications, Especially Hypermenorrhea, with Direct Oral Anticoagulants - Results of the Prospective Dresden Noac Registry (NCT01588119)
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Sandra Marten, Luise Tittl, Jan Beyer-Westendorf, and Katharina Daschkow
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medicine.medical_specialty ,Rivaroxaban ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Surgery ,Discontinuation ,Dabigatran ,medicine.anatomical_structure ,Vagina ,Medicine ,Vaginal bleeding ,Apixaban ,medicine.symptom ,business ,Complication ,Tranexamic acid ,medicine.drug - Abstract
Background : Bleeding is a common complication of oral anticoagulation (OAC). In anticoagulated women of child-bearing potential (WOCBP), increase of menstrual bleeding may be discomforting and severe cases of menorrhagia may require dedicated treatment or even discontinuation of OAC. Since hypermenorrhea seems to be more frequent in patients receiving direct oral anticoagulants (DOAC) compared to classic OAC with vitamin-K antagonists, patterns of menorrhagia need to be studied in daily care cohorts. Patients and methods: Using data from the prospective, non-interventional Dresden NOAC registry and phase-III DOAC trial patients at our site, we evaluated rates, severity and management of vaginal bleeding complications in WOCBP (defined as age ≤55 years and without sterilizing procedures or age >55 years with documented menstrual bleeding). All bleeding complications were centrally adjudicated and classified according to ISTH definition. Annualized rates of vaginal bleeding and hypermenorrhea were calculated as number of bleeding events divided by cumulative days of DOAC exposure divided by 365 days. OAC treatment satisfaction was assessed in all registry patients at every follow-up visit by a simple six-graded scale (ranging from 1=very satisfied to 6=very unsatisfied). To assess impact of vaginal bleeding on quality of live, the first available score after a vaginal bleeding was compared with the last available score of WOCBPs without vaginal bleeding. Results: Until March 31th 2015, 1343 women were enrolled, of which 154 were WOCBPs (mean age 39±12 years; range 14-56). In these patients, OAC consisted of dabigatran (1.3%), rivaroxaban (92.2%), apixaban (5.8%) or edoxaban (0.6%). During follow-up (mean FU duration 24.6 months), 85 female patients reported 107 vaginal bleeding complications, of which 68 occurred in 53 WOCBPs (53 cases of hypermenorrhea and 15 bleedings unrelated to cycle). Table 1 indicates severity of hypermenorrhea and vaginal bleedings unrelated to cycle. According to ISTH definition, 37/68 (54.4%) of the vaginal bleeding in WOCBPs were minor, 25/68 (36.8%) were non-major, clinically relevant (NMCR) and 6/68 (8.8%) major bleeding (classified as "major" due to drop of hemoglobin ≥2g/l in 5 cases and/or transfusion of ≥2 units of red blood cells in 5 cases). In relation to all exposed WOCBPs, the rate of vaginal bleeding events was found to be 0.41 events per exposure year and the rate of hypermenorrhea was found to be 0.32 events per exposure year (median exposure time 243d; 25th/75th percentile 105/674d and median time to first hypermenorrhea 26d; 25th/75th percentile 10/46d). Of the 53 WOCBPs that described vaginal bleeding complications (including hypermenorrhea and cycle-unrelated bleeding), 12/53 (22.6%) experienced a 2nd and 3/53 (5.7%) a 3rd event (figure 1). While bleeding intensity remained stable in most recurrent events, bleeding intensity increased in 6 cases with a 2nd bleeding episode while bleeding intensity remained stable or decreased in all 3 cases with a third episode. In only 16 of the 53 hypermenorrhea events, anatomical causes could be established and 3 of these cases progressed to major bleeding (necessity of at ≥2 units of red blood cells). In contrast, in the 34 hypermenorrhea events without anatomical causes, bleeding intensity was less severe (table 1). Surgical or interventional treatment was necessary in 6/68 (8.8%) vaginal bleeding events. The remaining 62 (91.2%) events were treated conservatively (start or change of hormone therapy, tranexamic acid, OAC dose reduction or temporary interruption). Overall, OAC treatment satisfaction in WOCBP was good (mean score 1.6; 25th/75th percentile 1/2 with data available for 98/154 WOCBPs) and not different in patients with and without vaginal bleeding complications (1.6; 25th/75th percentile 1/2 vs. 1.5; 1/2; p=0.548). Conclusion : Vaginal bleeding and especially hypermenorrhea is a common complication in WOCBPs receiving oral anticoagulation. Only a small proportion of affected patients have underlying anatomical causes for bleeding but these patients often develop more severe bleeding. The majority of cases can be conservatively managed and bleeding intensity rarely increases over time. Overall, the impact of vaginal bleeding complications on treatment satisfaction seems small. Disclosures Marten: Bayer HealthCare: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding.
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- 2015
38. SGN-CD123A, a Pyrrolobenzodiazepine Dimer Linked Anti-CD123 Antibody Drug Conjugate, Demonstrates Effective Anti-Leukemic Activity in Multiple Preclinical Models of AML
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May Kung Sutherland, Changpu Yu, Ivan Stone, Peter D. Senter, Lucy Yan Pan, Mechthild Jonas, Lori Westendorf, Michelle Ulrich, Roland B. Walter, Kerry Klussman, Weiping Zeng, John F. Valliere-Douglass, Jonathan G. Drachman, Dennis Benjamin, Martha Anderson, and Django Sussman
- Subjects
Antibody-drug conjugate ,business.industry ,Immunology ,Myeloid leukemia ,Pyrrolobenzodiazepine ,Cell Biology ,Hematology ,Biochemistry ,Minimal residual disease ,Immunoconjugate ,chemistry.chemical_compound ,chemistry ,Cancer research ,Medicine ,Cytotoxic T cell ,Interleukin-3 receptor ,Stem cell ,business - Abstract
Survival expectations for acute myeloid leukemia (AML) patients remain poor, highlighting the need for further treatment options. The majority of AML blasts express CD123, the alpha subunit of the IL-3 receptor, which regulates the proliferation, survival and differentiation of hematopoietic cells. CD123 is also robustly expressed on leukemic stem cells and is a marker for minimal residual disease (MRD, Roug et al. 2012). Poor prognosis has previously been associated with elevated expression of CD123 on leukemic stem cells and blasts (Vergez et al. 2011, Testa et al. 2002). These findings identify CD123 as a rational therapeutic target in AML. Here we report the preclinical development of a novel CD123-directed immunoconjugate SGN-CD123A, consisting of a humanized anti-CD123 antibody conjugated to a highly potent DNA binding pyrrolobenzodiazepine (PBD) dimer drug via a protease-cleavable dipeptide linker. An engineered cysteine on each heavy chain attaching the PBD dimer to the antibody allows uniform drug loading of approximately two PBD dimers per antibody. Fluorescence microscopy studies show that SGN-CD123A is rapidly internalized and traffics to lysosomes within hours of binding to CD123-positive AML cells. Uptake of the antibody-drug-conjugate (ADC) induced DNA damage as measured by dose-and time-dependent increases in the phosphorylation of histone 2AX (γH2AX) and cell death associated with G2-M cell cycle arrest, caspase-3 activity, formation of cleaved poly ADP-ribose polymerase, and DNA fragmentation in target cells. The anti-leukemic activity of SGN-CD123A was assessed in cytotoxicity assays in 12 AML cell lines and 23 primary AML patient samples with variable cytogenetic abnormalities (favorable, intermediate and adverse) and multi-drug resistance (MDR) status. SGN-CD123A was highly active in 11 of 12 AML cell lines tested (mean IC50, 6 ng/ml; range of 0.02 to 38 ng/ml), including 4 of 5 MDR-positive cell lines, whereas it was inactive in CD123-negative HEL92.1.7 AML cells. SGN-CD123A was also active against 20 of 23 primary samples isolated from AML patients (mean IC50 of responsive samples, 0.8 ng/mL; range of 0.06 to 2.5 ng/ml). In both AML panels, molecular abnormalities, including the presence of a p53 mutation, FLT3-ITD, as well as MDR positivity, did not affect the in vitro cytotoxic activity of SGN-CD123A. In vivo antitumor activity was evaluated in AML xenograft models established with CD123-positive, MDR-negative Molm-13, HNT-34, and THP-1 cell lines and the MDR-positive KG-1 cell line. In all of the in vivo models, a single dose of SGN-CD123A delivered significant antitumor activity. SGN-CD123A dosed once at 10 mcg/kg yielded complete cures and significant survival advantage in the Molm-13 disseminated model of AML (p < 0.0001 compared to untreated or control ADC groups). Durable complete regressions were observed with a single dose of 25 or 75 mcg/kg in the MDR-negative HNT-34 subcutaneous model (p =0.0019 to control ADC group). In the THP-1 model, a single 100 mcg/kg dose of SGN-CD123A yielded durable complete regressions in 2 of 8 mice (p=0.0003 to untreated) whereas a higher dose of 300 mcg/kg gave complete tumor regressions in all mice (p < 0.0001 to untreated group). SGN-CD123A was also effective in a MDR-positive model of AML. A single dose of 100 mcg/kg SGN-CD123A significantly decreased tumor growth (p=0.003 to controls) whereas a single dose of 300 mcg/kg yielded durable complete regressions compared to the control groups in the KG-1 subcutaneous model of MDR-positive AML (p =0.008). Early evidence of the antitumor activity of SGN-CD123A was found in tumors harvested from THP-1 mice. Within 48h of dosing with SGN-CD123A, tumor cells showed elevated levels of the DNA damage marker γH2AX and changes in nuclear morphology. These data demonstrate that SGN-CD123A exhibits significant antitumor activity against a broad panel of primary AML samples and in preclinical models of MDR-positive AML that are characteristically resistant to chemotherapy. CD123-directed delivery of PBD may represent a promising new approach for the treatment of AML. Disclosures Sutherland: Seattle Genetics, Inc.: Employment. Yu:Seattle Genetics, Inc: Employment, Equity Ownership. Walter:Seattle Genetics, Inc: Consultancy, Research Funding. Westendorf:Seattle Genetics, Inc: Employment. Valliere-Douglass:Seattle Genetics, Inc: Employment. Pan:Seattle Genetics, Inc: Employment. Sussman:Seattle Genetics, Inc: Employment. Anderson:Seattle Genetics, Inc: Employment. Zeng:Seattle Genetics, Inc: Employment. Stone:Seattle Genetics, Inc: Employment. Klussman:Seattle Genetics, Inc: Employment. Ulrich:Seattle Genetics, Inc: Employment. Jonas:Seattle Genetics, Inc: Employment. Senter:Seattle Genetics, Inc: Employment. Drachman:Seattle Genetics, Inc: Employment. Benjamin:Seattle Genetics, Inc: Employment.
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- 2015
39. Outcome of Noac Exposure during Pregnancy (...and the problem of event reporting...)
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Franziska Michalski, Sandra Marten, and Jan Beyer-Westendorf
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Gynecology ,Rivaroxaban ,medicine.medical_specialty ,Pregnancy ,Pediatrics ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Dabigatran ,Pharmacovigilance ,medicine ,Caesarean section ,Apixaban ,business ,Risk assessment ,Case report form ,medicine.drug - Abstract
Background : Women of child-bearing potential (WOCBP) in need of oral anticoagulation should apply effective contraceptive measures, since exposure to vitamin-K antagonists (VKA) carries a relevant risk for embroypathy. Currently, non-VKA oral anticoagulants (NOACs) are replacing VKA. NOACs are small molecules that have been shown to cross the placenta but the clinical risk of embryopathy with NOACs is unknown. Since exposure in pregnant women can occur, we aimed to evaluate case numbers and pregnancy outcomes using data from various sources. Patients and methods: Cases of NOAC exposure during pregnancy were collected from our institution and by sending out questionnaires to German gynecologists, obstetricians and hematologists. Furthermore, all NOAC manufacturers were asked to provide cases that were registered in the pharmacovigilance system. Finally, German drug authority (BfArM) and the European Medicines Agencies (EMA) were contacted for cases from their databases. All reports were screened by two independent physicians using a standardized case report form. Results: In this ongoing project, a total of 169 NOAC exposures in pregnancy were collected: 5 cases from our institution, 7 cases reported by physician questionnaires, 25 cases extracted from Boehringer Ingelheim pharmacovigilance, 10 cases extracted from BfArM pharmacovigilance and 122 cases were provided by EMA based on the safety reports from Bayer (export of further reports pending). NOAC exposure consisted of rivaroxaban (n=143), dabigatran (25) and apixaban (1) and venous thromboembolism was the indication for NOAC in >95% of cases with available information. Duration of NOAC exposure ranged between single dose to complete 2nd and 3rd trimester. The most complete data were found in cases collected from physicians: All 12 cases presented details on duration of NOAC exposure (median 6 weeks; range 3-19 weeks) and on pregnancy outcome. In contrast, data provided by manufacturers and authorities had significant data gaps (see table). Information of pregnancy outcome was available in 85/169 cases (50.3%) and consisted of 31 live births (36.5%); 21 miscarriages/abortions (24.7%); 27 elective pregnancy interruptions (31.8%), while 6 pregnancies (7.1%) were still ongoing at the time of our assessment. Of the 20 live births, 3 newborns demonstrated abnormalities: renal pelvis dilatation and facial dysmorphismin in 1 case (rivaroxaban exposure in 1st trimester) and low birth weight in 2 cases (girl of 2570g born in week 37 with dabigatran exposure in 1st trimester; girl of 1175 g delivered by caesarean section for preeclampsia in week 30 with rivaroxaban exposure in 1st trimester). Of the 21 miscarriages, details were available for 5 cases (4 miscarriages occurred in 1st trimesterand one case in week 20 with preceding growth restriction). Of the 27 elective pregnancy interruptions, details were available for 7 cases and decision was based on social reasons (3), fear of NOAC embroypathy (3) and medical reasons (maternal thyreotoxicosis with heart failure). Conclusion: Currently available data do not suggest a high risk for NOAC embryopathy but case numbers are limited and demonstrate significant data gaps. Therefore, risk assessment needs to continue and pregnancy has to be further avoided in NOAC patients by effective contraceptive measures and education of WOCBP. However, currently available data do not justify pregnancy termination just because of NOAC exposure and non-directive counselling as well as close pregnancy surveillance is recommended. Due to the strict anonymization of data provided from NOAC manufacturers and authorities, cases of double-reporting cannot be completely ruled out but, so far, NOAC exposure during pregnancy seems not uncommon. Further initiatives are needed to collect more data on the risk of NOAC embryopathy. However, the quality of data provided by manufacturers and drug authorities on request is inferior to the data quality obtained from direct physicians contact, which indicates the need to improve exposure and outcome assessment in this important medical scenario. Further data exports from EMA are pending and updated results will be presented at ASH. Disclosures Beyer-Westendorf: Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding. Marten:Bayer HealthCare: Honoraria. Michalski:Bayer HealthCare: Honoraria.
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- 2015
40. Pattern and Management of Intracranial Haemorrhage with Rivaroxaban or Dabigatran Compared to Vitamin K Antagonists - Results of the Prospective Dresden Noac Registry
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Luise Tittl, Katharina Daschkow, Sandra Marten, and Jan Beyer-Westendorf
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Aspirin ,education.field_of_study ,Pediatrics ,medicine.medical_specialty ,Rivaroxaban ,business.industry ,Immunology ,Population ,Atrial fibrillation ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Dabigatran ,Clinical trial ,Antithrombotic ,medicine ,Apixaban ,education ,business ,medicine.drug - Abstract
Background: In recent phase-III trials, the rate of intracranial haemorrhage (ICH) - the most feared complication of anticoagulant therapy - was around 0.8% per year for patients treated with vitamin K antagonists (VKA) and consistently lower (around 0.3-0.5%) for patients treated with the non-VKA oral anticoagulants (NOACs) rivaroxaban and dabigatran However, patients in clinical trials present a selected population treated under a strict protocol in dedicated academic facilities. Consequently, the risk, management and outcome of ICH need to be evaluated in cohorts of patients treated with NOACs or VKA in daily care. Aim: To evaluate the rate of ICH in patients treated with NOAC compared to VKA patients. Patients and methods: The prospective NOAC registry was initiated in November 2011. A network of more than 230 physicians in the district of Saxony, Germany, enrol up to 3000 patients in the registry, which are prospectively followed by the central registry office for up to 60 months with central outcome event adjudication. For this analysis, every intracranial haemorrhage was identified in the database and ICH management and outcome were evaluated. Results: Until January 31th 2015, 2682 patients were registered and treated with dabigatran (348, mostly treated for atrial fibrillation), Rivaroxaban (1907; 1204 treated for atrial fibrillation and 703 for venous thromboembolism) or vitamin K antagonists (427; treated for atrial fibrillation). VKA patients had lower HAS-BLED scores compared to NOAC patients and were excellently managed with a time-in-therapeutic-range of 75%. During follow-up (mean follow-up duration 25.6 months) ICH occurred in 7/427(1.6%) of VKA treated patients and in 14/2255 (0.6%) of patients treated with NOAC, which translated into an annualized rate of 1.3 events/100 pt. years (95%-CI 0.5-2.7) for VKA and 0.4 events/100 pt. years (95%-CI 0.2-0.6) for NOAC (p=0.0039). Treatment of ICH consisted of PCC in 10 cases, plasma in 3 cases and surgical or interventional therapy in 7 cases (table 1, multiple treatments possible). As indicated, use of factor concentrates, plasma or other hemostatic agents or surgery was much more frequent in VKA patients compared to NOAC patients. Table 1. Cause and treatment of ICH ICH/total Spontaneous vs. traumatic ICH (n) treatment with PCC treatment with fresh frozen plasma treatment with other hemostatic agents no hemostatic treatment surgical or interventional therapy dabigatran 2/348 (0.6%) 2 vs. 0 0 0 0 2/2 (100%) 1/2 (50%) rivaroxaban 12/1907 (0.6%) 4 vs. 8 5/12 (41.7%) 2/12 (16.7%) 2/12 (16.7%) 7/12 (58.3%) 3/12 (25%) VKA 7/427 (1.6%) 2 vs. 5 5/7 (71.4%) 1/7 (14.3%) 4/7 (57.1%) 2/7 (28.6%) 3/7 (42.9%) At Day 90 after ICH, 7/21 patients were dead (2/7 or 28.6% of VKA patients and 5/14 or 35.7% of NOAC patients). The surviving 14 patients received the following antithrombotic agents: 5 (35.7%) rivaroxaban, 3 (21.4%) heparin, 1 (7.1%) apixaban, 1 (7.1%) VKA, 3 (21.4%) aspirin, 1 (7.1%) none.Following ICH, oral anticoagulation therapy was either interrupted (n=7; 6 NOAC vs. 1 VKA) or permanently discontinued (n=10; 6 NOAC vs. 4 VKA). Conclusion: Despite low bleeding risk and excellent INR control in our VKA cohort, the rate of ICH was higher than that of VKA patients treated in recent phase-III trials. Furthermore, ICH rates in our VKA cohort were significantly higher than those seen in our NOAC cohorts, which represented more patients with relevant comorbidities and higher bleeding risk. Consequently, the risk of ICH remains high even in "stable" VKA patients with good INR control and a preventive switch from VKA to NOAC may help to reduce ICH risk and should be discussed with the patient. Disclosures Marten: Bayer HealthCare: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding.
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- 2015
41. Effectiveness and Safety of Rivaroxaban Versus Warfarin for Treatment of Venous Thromboembolism in Patients with Known Primary Hypercoagulable States
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Coleman, Craig I., Turpie, Alexander G.G., Bunz, Thomas J., and Beyer-Westendorf, Jan
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- 2017
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42. Splanchnic Vein Thrombosis Treatment with Rivaroxaban - a Case Series from the Prospective Dresden Noac Registry (NCT01588119)
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Pannach, Sven, Tittl, Luise, Marten, Sandra, Endig, Sebastian, and Beyer-Westendorf, Jan
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- 2017
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43. Healthcare Cost Impact of Continued Anticoagulation Therapy with Rivaroxaban Versus Aspirin for Prevention of Recurrent Symptomatic Venous Thromboembolism in the Einstein Choice Trial Population
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Davidson, Bruce L., Wells, Philip S., Prins, Martin H., Beyer-Westendorf, Jan, Lensing, Anthonie WA., Haskell, Lloyd, Levitan, Bennett, Laliberté, François, Ashton, Veronica, Xiao, Yongling, Lejeune, Dominique, Crivera, Concetta, Lefebvre, Patrick, Zhao, Qi, Yuan, Zhong, Schein, Jeff, and Prandoni, Paolo
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- 2017
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44. Small clots with large impact
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Beyer-Westendorf, Jan, primary and Ageno, Walter, additional
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- 2015
- Full Text
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45. Antithrombotic Treatment and Outcomes of Splanchnic Vein Thrombosis in an International Prospective Registry: Results of 2-Year Follow-up
- Author
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Ageno, Walter, primary, Riva, Nicoletta, additional, Schulman, Sam, additional, Beyer-Westendorf, Jan, additional, Bang, Soo-Mee, additional, Senzolo, Marco, additional, Grandone, Elvira, additional, Barillari, Giovanni, additional, Di Minno, Matteo, additional, Duce, Rita, additional, Malato, Alessandra, additional, Santoro, Rita, additional, Poli, Daniela, additional, Verhamme, Peter, additional, Martinelli, Ida, additional, Kamphuisen, Pieter W., additional, and Dentali, Francesco, additional
- Published
- 2014
- Full Text
- View/download PDF
46. Drug Persistence with Rivaroxaban Therapy in Atrial Fibrillation Patients Results from the Dresden NOAC registry
- Author
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Beyer-Westendorf, Jan, primary, Förster, Kati, additional, Ebertz, Franziska, additional, Gelbricht, Vera, additional, Michalski, Franziska, additional, Tittl, Luise, additional, and Weiss, Norbert, additional
- Published
- 2014
- Full Text
- View/download PDF
47. Centrally Adjudicated Cause of Death during Noac Treatment – Results of the Prospective Dresden Noac Registry (NCT01588119)
- Author
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Michalski, Franziska, primary, Werth, Sebastian, additional, Köhler, Christina, additional, Tittl, Luise, additional, Daschkow, Katharina, additional, and Beyer-Westendorf, Jan, additional
- Published
- 2014
- Full Text
- View/download PDF
48. Real Life Efficacy and Safety of Dabigatran for Stroke Prevention in Atrial Fibrillation – Final Results of the Prospective Noac Registry (NCT01588119)
- Author
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Ebertz, Franziska, primary, Werth, Sebastian, additional, Köhler, Christina, additional, Michalski, Franziska, additional, Hänsel, Ulrike, additional, Tittl, Luise, additional, Daschkow, Katharina, additional, Schreier, Thomas, additional, and Beyer-Westendorf, Jan, additional
- Published
- 2014
- Full Text
- View/download PDF
49. Characteristics of Atrial Fibrillation Patients Not Switched from Vka to Noac and Persistence on Vka – a Subgroup Analysis of the Prospective Dresden Noac Registry (NCT01588119)
- Author
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Beyer-Westendorf, Jan, primary, Michalski, Franziska, additional, Werth, Sebastian, additional, Tittl, Luise, additional, Köhler, Christina, additional, and Weiss, Norbert, additional
- Published
- 2014
- Full Text
- View/download PDF
50. Real Life Efficacy and Safety of Rivaroxaban for Stroke Prevention in Atrial Fibrillation – First Results of the Prospective Noac Registry (NCT01588119)
- Author
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Werth, Sebastian, primary, Koehler, Christina, additional, Gelbricht, Vera, additional, Haensel, Ulrike, additional, Tittl, Luise, additional, Beyer-Westendorf, Ines, additional, Schreier, Thomas, additional, and Beyer-Westendorf, Jan, additional
- Published
- 2012
- Full Text
- View/download PDF
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