Impact of vascular remodeling on the development and regression of tissue fibrosis

Fibrosis is a pathological process with limited therapeutic options that can occur in almost every tissue or organ of the body. Among others, pulmonary fibrosis and liver fibrosis are two increasingly important fibrotic diseases worldwide. Both are characterized by an increased accumulation of myofibroblasts and an excessive deposition of matrix proteins, mostly collagen. These processes lead to scar formation and the destruction of the organ. Furthermore lung and liver fibrosis are associated with an extensive remodeling of the blood and the lymphatic vasculature, though the impact of vascular remodeling on the development and regression of tissue fibrosis is still a matter of debate. Numerous Papers deal with the role of hemangiogenesis in pulmonary fibrosis, yet the role of the lymphatic vasculature in the pathogenesis of pulmonary fibrosis remains to be elucidated. In a murine model of pulmonary fibrosis we show that lymphatics exhibit ectopic mural cell coverage. Lymphatic endothelial cells in fibrotic lungs showed an increased expression of platelet-derived growth factor B (PDGF-B), which led to the recruitment of platelet-derived growth factor receptor-β (PDGFR-β)-expressing mural cells. This abnormal lymphatic vascular pattern in fibrotic lungs caused impaired lymphatic drainage and led to a perilymphatic accumulation of fibrogenic molecules. The pharmacological inhibition of the PDGF-B/PDGFR-β-signaling at the onset of mural cell recruitment prevented mural cell recruitment to lymphatics and restored the transport capacity of the lymphatic vessels. The second part of this thesis investigates the impact of vascular remodeling on liver fibrosis. To date there is no clear evidence whether angiogenesis is a pro- or antifibrotic mediator in liver fibrosis. Furthermore, although liver fibrosis is known to be reversible, the role of hemangiogenesis in the regression of liver fibrosis has not been studied yet. Macrophages are a major source of VEGF-A (VEGF), the most important angiogenic transcription factor. To address the question how hemangiogenesis is affected by macrophage-derived VEGF in liver fibrosis and to determine its impact on the regression of liver fibrosis, we used a murine knockout model for myeloid cell-derived VEGF. We were able to show that myeloid cell-derived VEGF is a major VEGF-source during the resolution of liver fibrosis. Mice that lack myeloid cell-derived VEGF were not able to resolve liver fibrosis. VEGF-deficient mice showed lower expression and activity of matrix metalloproteinases (MMP) and liver sinusoids failed to migrate into fibrotic areas. The reintroduction of myeloid cell-derived VEGF prior to the recovery phase by means of bone marrow transplantation led to an increase in MMP-expression and -activity and resulted in increased collagen degradation. Hence liver sinusoids entered perisinusoidal and pericentral fibrotic areas and supported the regression of the liver fibrosis

Estimation of the costs attributable to vitamin K antagonist treatment in patients with non-valvular atrial fibrillation from a French societal perspective

Background: Little is known about the costs associated with vitamin K antagonist (VKA) treatment in patients with non-valvular atrial fibrillation (NVAF) in France. Objectives: To evaluate monthly per-patient costs attributable to VKA treatment in NVAF patients from a French societal perspective. Study design: Retrospective data were obtained from 7 international normalised ratio (INR) monitoring centres in France. Patients older than 18 years of age with NVAF treated with VKA were recruited. Additional patient-level data assessing resource use corresponding with VKA treatment were collected via self-completed questionnaires. Unit costs applicable to 2015 were multiplied by resource use and summed to generate VKA treatment costs. Results: 363 patients were included; 53% were men. The majority of patients received fluindione (72%). The number of INR tests per patient per month was 1.69 (95% CI, 1.59–1.80). The monthly patient cost was €39.72 (€36.23–43.21) from the French societal perspective. Direct medical costs comprised 76% of overall costs, with drug costs representing 7.4% (€2.4); direct non-medical and indirect costs comprised 10% and 14% respectively. Conclusions: Costs associated with VKA treatment in NVAF cannot be estimated only with drug costs. When direct and indirect attributable costs associated with VKA treatment are considered, the VKA treatment costs are more substantial

Series: Pragmatic trials and real world evidence : Paper 8 Data collection and management Data collection in Pragmatic Trials

Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials. A more pragmatic data collection needs to balance the delivery of highly accurate and complete data with minimizing the level of interference that data entry and verification induce with clinical practice. Further it should allow for the involvement of a representative sample of practices, physicians and patients who prescribe/receive treatment in routine care. This paper discusses challenges that are related to the different methods of data collection and presents potential solutions where possible. No one-size-fits-all recommendation can be given for the collection of data in pragmatic trials, although in general the application of existing routinely used data collection systems and processes seem to best suit the pragmatic approach. However, data access and privacy, the time points of data collection, the level of detail in the data and the lack of a clear understanding of the data collection process were identified as main challenges for the usage of routinely collected data in pragmatic trials. A first step should be to determine to what extend existing healthcare databases provide the necessary study data and can accommodate data collection and management. When more elaborate or detailed data collection or more structured follow-up is required, data collection in a pragmatic trial will have to be tailor-made, often using a hybrid approach utilizing a dedicated electronic case report form (eCRF). In this case the eCRF should be kept as simple as possible to reduce the burden for practitioners and minimize influence on routine clinical practice

Additional file 2: of Stakeholders’ views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs

Consolidated criteria for reporting qualitative research (COREQ) checklist. (DOCX 23 kb

Additional file 1: of Stakeholders’ views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs

Characteristics of the Salford Lung Study (GSK, UK) [24]. (DOC 25 kb

Stakeholders' views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs

Background: We explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders' attitudes towards the implementation of pragmatic trials in the drug development process. Methods: We conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients' organizations) through telephone or face-to-face sessions. Interviews were structured around the question "what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials." Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets. Results: We interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with "real-world" practice reducing the knowledge value of trial results. Conclusions: We identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization

Series: Pragmatic trials and real world evidence : Paper 8 Data collection and management Data collection in Pragmatic Trials

Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials. A more pragmatic data collection needs to balance the delivery of highly accurate and complete data with minimizing the level of interference that data entry and verification induce with clinical practice. Further it should allow for the involvement of a representative sample of practices, physicians and patients who prescribe/receive treatment in routine care. This paper discusses challenges that are related to the different methods of data collection and presents potential solutions where possible. No one-size-fits-all recommendation can be given for the collection of data in pragmatic trials, although in general the application of existing routinely used data collection systems and processes seem to best suit the pragmatic approach. However, data access and privacy, the time points of data collection, the level of detail in the data and the lack of a clear understanding of the data collection process were identified as main challenges for the usage of routinely collected data in pragmatic trials. A first step should be to determine to what extend existing healthcare databases provide the necessary study data and can accommodate data collection and management. When more elaborate or detailed data collection or more structured follow-up is required, data collection in a pragmatic trial will have to be tailor-made, often using a hybrid approach utilizing a dedicated electronic case report form (eCRF). In this case the eCRF should be kept as simple as possible to reduce the burden for practitioners and minimize influence on routine clinical practice