Ajay K. Kakkar

The management of atrial fibrillation (AF), the most common sustained arrhythmia, impacts healthcare resource utilization (HCRU). This study aims to estimate global resource use in AF patients, using the GARFIELD-AF registry. A prospective cohort study was conducted to characterize HCRU in AF patients enrolled in sequential cohorts from 2012 to 2016 in 35 countries. Components of HCRU studied were hospital admissions, outpatient care visits, and diagnostic and interventional procedures occurring during follow-up. AF-related HCRU was reported as the percentage of patients demonstrating at least one event and was quantified as rate-per-patient-per-year (PPPY) over time. A total of 49,574 patients was analyzed, having an overall median follow-up of 719 days. Almost all patients (99.5%) had at least one outpatient care visit, while hospital admissions were the second most frequent medical contact, with similar proportions in North America (37.5%) and Europe (37.2%), and slightly higher in the other GARFIELD-AF countries (42.0%; namely Australia, Egypt, and South Africa). Asia and Latin America showed lower percentages of hospitalizations, outpatient care visits, and diagnostic and interventional procedures. Analyses of GARFIELD-AF highlighted the vast AF-related HCRU, underlying significant geographical differences in the type, quantity, and frequency of AF-related HCRU. These differences were likely attributable to health service availability and differing models of care.

Introduction The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) aims to determine real-life treatment patterns and clinical outcomes of patients with newly diagnosed non-valvular atrial fibrillation (AF) and at least one investigator-determined risk factor for stroke. The registry includes a wide array of baseline characteristics and has a particular focus on: (1) bleeding and thromboembolic events; (2) international normalized ratio fluctuations; and (3) therapy compliance and persistence patterns. Methods Evolution in baseline treatment for patients enrolled in sequential cohorts showed an increase in prescribing of novel oral anticoagulants over time. Variability in novel oral anticoagulant prescription is primarily due to differences in availability of treatment and prescribing habits between countries and care settings. The GARFIELD-AF registry also provides insights into clinical management and related outcomes of AF in Middle East populations. Results A total of 1660 patients with non-valvular AF (median age 64.0 years, interquartile range 56.0–72.0), mostly diagnosed in cardiology settings from Egypt, the United Arab Emirates and Turkey, were recruited in cohorts 3–5. Data from patient populations in the Middle East related to the rates of stroke/systemic embolism, major bleeding and all-cause mortality 1 year after diagnosis of AF and treatment strategies, based on the stroke and bleeding risk, have been analysed and compared with the rest of the world. The use of antithrombotic treatment in the Middle East was generally higher than the non-Middle East, with increased prescription of antiplatelet therapy (AP) therapy. Appropriate use of Factor Xa inhibitors/direct thrombin inhibitors (DTIs) were 74.4% and Factor Xa/DTI + APs were 70.4% in the overall population, whereas they were 57.1% and 63.6%, respectively, in the Middle East. Conclusion We have found that rates of stroke and bleeding were lower, although mortality was higher, in the Middle East population. This paper describes the baseline characteristics, patterns of antithrombotic treatment and 1-year outcomes in Middle East AF patients. Trial Registration http://www.clinicaltrials.gov. Identifier, NCT01090362.

Background: Fundamental Research in Oncology and Thrombosis (FRONTLINE) is a global survey of physicians' perceptions and practice in the management of venous thromboembolism (VTE) in patients with cancer. Materials and Methods: The present survey, FRONTLINE 2, follows the original FRONTLINE survey (published in The Oncologist in 2003) and provides insights into how physicians perceive risk of VTE in cancer and approach its prophylaxis and treatment. Results: Between November 2015 and February 2016, 5,233 respondents participated, representing cancer physicians and surgeons. Most believed that less than one in five patients with any cancer might be at risk of VTE, with a slightly higher risk in patients with brain, pancreatic, and lung tumors. The most frequently reported reasons for giving prophylaxis were prior history of VTE (74.6%), abnormal platelet count (62.0%), and obesity (59.5%). In surgical and medical cancer patients, low-molecular-weight heparin (LMWH) was the most popular prophylactic measure, used by 74.2% and 80.6%, respectively. Oral anticoagulants (OACs) were given in less than one fifth of cases. In surgical patients, prophylaxis was usually provided for 1 month postoperatively. Following a diagnosis of VTE, patients initially received treatment with LMWH and were maintained long term on OACs, primarily warfarin, dabigatran, and rivaroxaban. Most surgical and medical cancer patients underwent treatment of VTE for 3–6 months. Conclusion: Compared with the original FRONTLINE survey, FRONTLINE 2 reveals some differences in the management of VTE in patients with cancer. Newer anticoagulants such as fondaparinux, dabigatran, and rivaroxaban are being incorporated into the contemporary management of VTE in patients with cancer. Implications for Practice: This globally conducted survey of more than 5,000 cancer clinicians revealed a number of insights into the perceived risk for venous thromboembolism as well as contemporary approaches to its prevention and treatment. Although guidelines have consistently recommended anticoagulant medications for prevention and treatment of cancer-associated thrombosis, clinicians report substantial variation in their practice.

Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world. Unique identifier: NCT02444221 . Registerd 14 May 2015; Retrospectively Registered.

Limited data are available on the characteristics, clinical management, and outcomes of patients with atrial fibrillation at risk of stroke, from a worldwide perspective. The aim of this study was to describe the baseline characteristics and initial therapeutic management of patients with non-valvular atrial fibrillation across the spectrum of sites at which these patients are treated. The Global Anticoagulant Registry in the FIELD (GARFIELD) is an observational study of patients newly diagnosed with non-valvular atrial fibrillation. Enrollment into Cohort 1 (of 5) took place between December 2009 and October 2011 at 540 sites in 19 countries in Europe, Asia-Pacific, Central/South America, and Canada. Investigator sites are representative of the distribution of atrial fibrillation care settings in each country. Cohort 1 comprised 10,614 adults (≥18 years) diagnosed with non-valvular atrial fibrillation within the previous 6 weeks, with ≥1 investigator-defined stroke risk factor (not limited to those in existing risk-stratification schemes), and regardless of therapy. Data collected at baseline included demographics, medical history, care setting, nature of atrial fibrillation, and treatments initiated at diagnosis. The mean (SD) age of the population was 70.2 (11.2) years; 43.2% were women. Mean±SD CHADS₂ score was 1.9±1.2, and 57.2% had a score ≥2. Mean CHA₂DS₂-VASc score was 3.2±1.6, and 8,957 (84.4%) had a score ≥2. Overall, 38.0% of patients with a CHADS₂ score ≥2 did not receive anticoagulant therapy, whereas 42.5% of those at low risk (score 0) received anticoagulant therapy. These contemporary observational worldwide data on non-valvular atrial fibrillation, collected at the end of the vitamin K antagonist-only era, indicate that these drugs are frequently not being used according to stroke risk scores and guidelines, with overuse in patients at low risk and underuse in those at high risk of stroke. ClinicalTrials.gov TRI08888

Summary: Heparansulfate-proteoglycans (HSPGs) interact via their polyanionic heparansulfate (HS) side chains with a variety of proteins on the cell surface or within the extracellular matrix membrane. The large number of heparin/HS binding proteins form a highly interconnected functional network, which has been termed as the heparin/HS interactome and is functionally linked to physiological and pathological processes. The aim of this study was to investigate the global effect of these protein-HSPG interactions on the tumourigenicity of two breast cancer cell lines (MCF-7 and MDA-MB-231). Cancer cells were cultured in serum-free medium and treated with a concentration of heparin which was capable of modulating HS/ligand interaction. Microarray analysis of MCF-7 cells cultured under these conditions showed that expression of 105 of 1,357 genes potentially related to the pathogenesis of breast neoplasm was significantly altered by heparin treatment. The changes in gene expression correlated with a less tumourigenic phenotype, including reduction of cell adhesive, invasive and migratory properties. These effects were associated with an inhibition of the PI3K/Akt and Raf/MEK/ERK signalling pathways. The modulatory effect of heparin on HS-associated activity was confirmed with one example of heparin/HS interactomes, transforming growth factor β (TGFβ). The innate TGFβ activity of MCF-7 cells was reduced by heparin treatment, with specific interruption of the TGFβ–Smad signalling pathway. The pro-tumourigenic contribution of the heparin/HS interactomes was verified in cells in which HSPG synthesis was blocked using β-xyloside. In conclusion, the interaction between cell surface HPSGs and innate heparin/HS interactomes makes a significant contribution to the tumourigenicity.