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The multicentre non-interventional AVANTI study assessed safety, effectiveness and patient-reported outcomes with approved first-line bevacizumab-containing regimens for HER2-negative locally recurrent/metastatic breast cancer (LR/MBC) in German routine oncology practice. Eligible patients had HER2-negative LR/MBC, no bevacizumab contraindications and no prior chemotherapy for LR/MBC. Chemotherapy schedule, diagnostics and follow-up were at physicians' discretion. Data were collected for 1 year after starting bevacizumab, then every 6 months for 1.5 years (maximum follow-up: 2.5 years). Patients and physicians rated treatment satisfaction. Subgroup analyses were prespecified in clinically relevant populations, including triple-negative breast cancer (TNBC). Between November 1, 2009 and April 30, 2016, 2065 eligible patients at 346 centres received bevacizumab with paclitaxel or capecitabine. Patients receiving bevacizumab–capecitabine were less likely to have de novo disease and more likely to have TNBC, age ≥60 years and prior anthracycline/taxane and/or endocrine therapy. Median PFS was 12.6 (95% CI 11.9–13.2) months (12.8 with bevacizumab–paclitaxel, 10.5 with bevacizumab–capecitabine); median OS was 23.9 (95% CI 22.2–25.1) months. Outcomes were worse in patients with TNBC, prior anthracycline/taxane or prior endocrine therapy. Grade ≥3 adverse events occurred in 27% of patients. Treatment was discontinued for adverse events in 15%. Treatment satisfaction was rated as good or better by 304/394 responding patients (77%) at week 54 and in 1393/2065 patients (67%) by physicians overall. In routine clinical practice, effectiveness and safety of first-line bevacizumab-containing therapy for LR/MBC were consistent with experience from phase III trials. Patient and physician treatment satisfaction showed high concordance. • AVANTI assessed 1st-line bevacizumab-based therapy for LR/MBC in routine practice. • Median progression-free and overall survival were 12.6 and 23.9 months respectively. • Treatment satisfaction was rated as good or better by 77% of patients at week 54. • Physician- and patient-rated treatment satisfaction showed high concordance. • Effectiveness and safety were consistent with experience from phase III trials. [ABSTRACT FROM AUTHOR]

STEPAUT, an Austrian non-interventional study, evaluated the safety and efficacy of everolimus plus exemestane in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) recurring/progressing on/after nonsteroidal aromatase inhibitors (NSAIs) in routine clinical practice. Postmenopausal women with HR+, HER2− ABC progressing on/after NSAIs receiving everolimus plus exemestane in accordance with routine practice and the current version of Summary of Product Characteristics were eligible. Planned individual observation period corresponded to the duration of treatment until formal study end. Overall, 236 patients (median age: 65 years) were enrolled at 17 sites across Austria. The median progression-free survival (mPFS) in the overall population was 9.5 months (95% confidence interval [CI]: 8.6–10.7 months). The mPFS (95% CI) in patients who received everolimus 10 and 5 mg was 9.9 months (7.3–11.5 months) and 8 months (4.7–10.7 months), respectively. The median time to progression was numerically longer in patients who had a therapy break (11.9 months, 95% CI: 10.0–14.6 months) versus those who did not have any therapy break (10.7 months, 95% CI: 8.9–12.6 months). Patients experienced grade 1 (53.7%), grade 2 (35.9%), grade 3 (9.9%), grade 4 (0.2%) adverse events (AEs). The most common AEs of any grade were stomatitis, mucositis (53.8%), rash, exanthema (29.7%), loss of appetite, nausea (28.4%). Real-world safety and efficacy data from STEPAUT were consistent with results from BOLERO-2, supporting everolimus plus exemestane as a suitable treatment option for HR+, HER2− ABC recurring/progressing on/after NSAIs. • STEPAUT, an Austrian non-interventional study, evaluated everolimus plus exemestane. • The median progression-free survival in the overall population was 9.5 months. • Majority of the patients had grade 1 (53.7%) to grade 2 (35.9%) adverse events. • Real-world data from STEPAUT were consistent with results from the BOLERO-2. Trial registration: BASG, AGES, NIS002843 [ABSTRACT FROM AUTHOR]

Aims: A number of insulin regimens are used in type 2 diabetes. This analysis aims to better understand the evolution of insulin therapy in different regions of Europe.Methods: Data from people starting any insulin were collected in eastern Europe (EEur: Croatia, Russia, Ukraine), northern Europe (NEur: Finland, Germany, UK) and southern Europe (SEur: France, Italy, Portugal, Spain). Retrospective data on starting insulin and prospective follow-up data were extracted from clinical records.Results: At 4years, 1699 (76.0%) of 2236 eligible people had data. EEur participants were mostly female, younger and had shorter diabetes duration on starting insulin, yet had highest baseline HbA1c and more micro-/macrovascular disease. A majority (60%-64%) in all regions started on basal insulin alone, declining to 30%-38% at 4years, with most switching to basal+mealtime insulin regimen (24%-40%). Higher baseline (28%) and 4-year use (34%) of premix insulin was observed in NEur. Change in HbA1c (SD) ranged from -1.2 (2.1)% (-13 [23]mmol/mol) in NEur to -2.4 (2.0)% (-26 [22]mmol/mol) in EEur. Weight change ranged from +1.9 (8.3) kg in NEur to +3.2 (7.0) kg in SEur. Overall documented hypoglycemia ranged from 0.3 (1.3) to 1.3 (4.4) events/person/6-months (NEur vs. EEur, respectively) and was stable with time. Severe hypoglycemia rates remained low.Conclusion: When starting insulin, HbA1c and prevalence of complications were higher in EEur. Regional differences exist in choice of insulin regimens in Europe. However, people starting insulin improved and sustained their glycemic control regardless of regional differences or insulin regimens used. [ABSTRACT FROM AUTHOR]

Introduction XALIA assessed the safety and effectiveness of rivaroxaban for deep vein thrombosis (DVT) treatment in routine clinical practice. This substudy describes the clinical characteristics and outcomes of ‘early switchers’ – patients who received heparin or fondaparinux for > 2–14 days and/or a vitamin K antagonist (VKA) for 1–14 days before switching to rivaroxaban. Materials and methods Patients with DVT (latterly with concomitant pulmonary embolism) received rivaroxaban or standard anticoagulation (initial treatment with heparin or fondaparinux, usually overlapping with and followed by a VKA). Patients administered rivaroxaban alone, or heparin or fondaparinux for ≤ 48 h pre-enrollment were included in the rivaroxaban cohort. Therapy type, dose, and duration were at the physician's discretion. Primary outcomes were major bleeding, recurrent venous thromboembolism (VTE), and all-cause mortality. Results In 368 early switchers, recurrence or bleeding risk factors were more prevalent versus the rivaroxaban cohort, including creatinine clearance < 50 mL/min (6.5% vs. 3.9%), previous major bleeding (4.6% vs. 1.4%), active cancer (8.2% vs. 5.6%), and concomitant pulmonary embolism (20.9% vs. 8.4%). Crude incidence rates were numerically higher versus the rivaroxaban cohort for major bleeding (1.4% vs. 0.7%), recurrent VTE (2.2% vs. 1.4%), and all-cause mortality (0.8% vs. 0.5%). Conclusions Patients who switched to rivaroxaban early in the treatment process had a higher frequency of risk factors for bleeding and recurrent VTE than patients treated with rivaroxaban; reflected by the higher risk of adverse events in that group during follow-up. [ABSTRACT FROM AUTHOR]

Background: Functional gastrointestinal disorders (FGIDs) of the upper and lower digestive system in children and adolescents present with heterogeneous gastrointestinal symptoms and are a common reason for specialist consultations. The herbal medicinal preparation STW-5 has already shown efficacy and safety in clinical studies with more than 7000 adult participants suffering from functional dyspepsia (FD) or irritable bowel syndrome (IBS). Here, we evaluate with a prospective observational study the effectivity and safety of STW-5 in children with FGID under real-life conditions and interpret these data versus the background of controlled clinical studies in a predominantly adult population.Methods: This prospective observational study included 980 children (age 3-14 years) with FGID. For inclusion, Rome III criteria were recommended to apply. The inclusion of the patients for treatment with STW-5 followed routine clinical practice. Patients were treated for approximately 1 week. The presence and severity of symptoms was documented at the study start and at the end of treatment period utilizing the adapted gastrointestinal symptom score (GIS). Other target parameters included global effectivity and tolerability assessments as well as adverse events.Results: The average patient age was 7.6 ± 2.9 years. Most of the patients were treated for IBS (n = 418; 43 %) or FD (n = 259; 26 %), with a mean baseline GIS of 16.1 ± 8.9. During the treatment period, the GIS decreased 76 % to 3.8 ± 4.2. The decrease in symptoms was similar for different age groups, gender, and indications. Patients with a shorter duration of complaints had a lower GIS at study end (p < 0.0001. The global treatment effect was assessed as good or very good by 87-89 % of patients/parents and physicians. Physicians rated the global tolerability as good or very good for 95 % of the patients. Seven patients (0.7 %) reported adverse events.Conclusions: The treatment effect of STW-5 in this study was in its range comparable to according data from controlled clinical trials with predominantly adult participants.Thus, supporting robustness of these data generated in an uncontrolled observational setting. The results of this observational study indicate that STW-5 may be an effective and well tolerated treatment option also for children with FGIDs. [ABSTRACT FROM AUTHOR]

Background In elderly patients with HER2-positive breast cancer, few data on efficacy and toxicity of adjuvant trastuzumab treatment exists since older patients were in general excluded from large randomized studies. This prospective observational study aimed to confirm the beneficial findings from pivotal trials in age cohorts ≥ 65 years. Materials and Methods There were no restrictions for recruitment with respect to age or concomitant/sequential adjuvant medication. Long-term relapse/survival status of the patients was assessed once a year. Results Among the 3940 evaluable patients enrolled between 2006 and 2012 at 339 institutions, 507 were aged between 65 and 69 years, with another 507 patients ≥ 70 years. Elderly patients suffered from significantly more advanced primary tumors. Preceding or concomitant chemotherapy showed decreasing aggressiveness with patient's age. Trastuzumab treatment was stopped prematurely in only 11% of the elderly, but more often than in younger patients ( p = 0.0008). With 453 events hitherto reported, elderly patients did not exhibit an inferior relapse-free survival when adjusted for other relevant prognostic factors (hazard ratio: 1.01 per year; p = 0.24). Three-year overall survival was significantly lower in the population older than 64 years than in younger patients (94.2% vs. 96.8%, p = 0.0011). Conclusions To our knowledge, our population of elderly patients treated with adjuvant trastuzumab is the largest analyzed so far. The beneficial long-term results were comparable to those in the younger cohorts. Although the risk of cardiotoxicity increased significantly with age, it also remained manageable in older patients. Thus, chronological age alone should not preclude HER2 antibody treatment. [ABSTRACT FROM AUTHOR]

Aims It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. Methods People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. Results Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22] mmol/mol) and BMI 29.3 (6.3) kg/m 2 . Initial insulin therapy was basal 52%, premix 23%, mealtime + basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2 U/day at the start and 45.8 U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was −2.0 (2.2)% (−22 [24] mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1–4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5) kg at year 4. Conclusion Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen. [ABSTRACT FROM AUTHOR]

Abstract: Aims: The aim of this A1chieve sub-group analysis was to examine populations beginning insulin aspart together with any basal insulin, all ± oral glucose lowering drugs: insulin aspart added to existing basal insulin (n =519); switched from biphasic insulin (n=947); switched from NPH plus human meal-time insulins (n =586); and insulin-naïve begun with basal plus insulin aspart (n =1594). Methods: A1chieve was a 24-week non-interventional study evaluating insulin analogues in 66,726 people with type 2 diabetes in routine clinical care in 28 non-Western countries. Major endpoints were analysed as change from baseline using Student's paired t-test. Results: Baseline glycaemic control was poor (mean HbA1c: 9.4–10.1% [79–87 mmol/mol]). HbA1c, FPG and PPPG improved significantly from baseline in all groups (mean change from baseline in HbA1c: −2.8 to −1.8% [−31 to −20 mmol/mol]; FPG: −4.9 to −2.9 mmol/L; PPPG: −6.7 to −3.9 mmol/L; p <0.001 for all), resulting in a similar level of blood glucose control for all groups at study end. Unsurprisingly, hypoglycaemia rates increased in those starting insulin, but decreased in the other groups. Clinically significant improvements in serum lipids and quality of life occurred across all groups. Conclusions: These data support the use of basal plus prandial insulin regimens in routine clinical practice in people with type 2 diabetes with inadequate glycaemic control. [Copyright &y& Elsevier]

Aims: This subgroup analysis of the A1chieve study examined data from 15,545 people who started treatment with insulin detemir±oral glucose-lowering drugs in routine clinical care. Methods: A1chieve was a 24-week, international, prospective, non-interventional study of people with type 2 diabetes from non-Western nations starting treatment with basal insulin detemir, bolus insulin aspart or biphasic insulin aspart 30, alone or in combination, to evaluate their safety and effectiveness in routine clinical practice. Results: HbA1c for the global cohort improved after 24 weeks from 9.5±1.6% by −2.0±1.6% [80±17 by −22±17 mmol/mol] (−2.1±1.6% [−23±17 mmol/mol] for insulin-naïve participants; −1.6±1.7% [−17±19 mmol/mol] for prior insulin users). Fasting plasma glucose and postprandial plasma glucose were also significantly reduced (p <0.001), irrespective of prior therapy or geographical region. The incidence of major hypoglycaemia decreased significantly over 24 weeks in both the insulin-naïve and insulin-experienced groups (p <0.0001). Mean body weight decreased overall by −0.4±4.0kg and blood pressure, lipid profiles, and self-reported quality of life improved over 24 weeks for all people starting treatment with insulin detemir. Conclusion: People with type 2 diabetes in poor glycaemic control starting treatment with insulin detemir reported significant improvements in glycaemic control with improved treatment tolerability, irrespective of prior treatment and geographical region, after 24 weeks. [ABSTRACT FROM AUTHOR]

Abstract: Aims: This A1chieve® study subgroup analysis examined clinical safety and effectiveness of biphasic insulin aspart 30 (BIAsp30) ±OGLDs in 6323 individuals with T2D, switching from biphasic human insulin 30 (BHI30) ±OGLDs. Methods: A1chieve was a 24-week, international, prospective, observational, multi-centre, open-label study in individuals with T2D starting treatment with BIAsp30, insulin detemir or insulin aspart as part of routine clinical care. Results: Mean baseline (SD) dose BHI was 0.56 (0.25) IU/kg. BIAsp30 was initiated at 0.57 (0.25) U/kg; the daily dose was 0.62 (0.28)U/kg by Week 24. Switching from BHI30 to BIAsp30 was associated with significant mean reduction in HbA1c of 1.7% [−18 mmol/mol] (1.6) from a baseline of 9.1% [76 mmol/mol] (p<0.001); FPG and PPG were also significantly reduced (p<0.001). Major hypoglycaemic episodes decreased from 0.69 events/patient/year at baseline to 0.03 events/patient/year at Week 24. Minor hypoglycaemia decreased from 5.31 to 2.04 events/patient/year from baseline to study-end. Five serious adverse drug reactions (hypoglycaemia) were reported by five individuals (0.1%). Mean bodyweight increased by 0.1 (3.3)kg from baseline to 24 weeks. Improved self-reported quality of life was observed. Conclusion: Switching from BHI30 to BIAsp30 in individuals with T2D is associated with improvement in glycaemic control and reduced rates of hypoglycaemia, without tolerability or safety issues. Clinical trial registration: Clinicaltrials.gov, NCT00869908. [Copyright &y& Elsevier]

Abstract: Aim: To obtain data on efficacy, safety and tolerability of acarbose monotherapy or combination therapy during daily-life treatment. Methods: This prospective, non-controlled, observational study enrolled patients with type 2 diabetes, whose physician decided that acarbose treatment was appropriate, from China, Middle East, Indonesia, Morocco, Pakistan, Philippines, Poland and Taiwan. The observation period included an initial visit and up to three follow-up visits; an extension of 2 years was realized in Pakistan and Poland. Results: Of 14,574 patients enrolled, 14,418 comprised the intent-to-treat population. At the initial visit, 74.1% of patients had been treated with a glucose-lowering agent. Fasting blood glucose was reduced from 175.2mg/dL at the initial visit to 133.7mg/dL at the last visit (mean of 11.3 weeks after initial visit; P <0.0001). Mean 2-h postprandial blood glucose decreased from 244.7mg/dL to 172.4mg/dL (P <0.0001). HbA1c reduced from 8.4% to 7.4% (P <0.0001). Glycemic efficacy was maintained over the 2-year extension period. There were 432 adverse events in 293 patients (2.03%), mainly gastrointestinal. Physicians assessed efficacy as “very good”/“good” in 85.1% of patients, and were “very satisfied”/“satisfied” with acarbose therapy in 94.3% of cases. Conclusion: Acarbose therapy was efficacious and well tolerated in daily life in patients with type 2 diabetes. [Copyright &y& Elsevier]

The effectiveness of intravitreal anti-vascular endothelial growth factor agents is usually lower in real world settings compared with randomized clinical trials (RCTs), often limiting the use of real-world evidence (RWE) in regulatory and healthcare decisions. The current analysis aimed to develop and validate an algorithm to explain the difference in outcomes between RWE studies and RCTs in patients with neovascular age-related macular degeneration. The algorithm was developed using ranibizumab real world data (RWD) from the US and validated on Australian and UK RWD. A decision model was developed using machine learning principles, in which the model learns how to partition the most influential factors (out of 59 variables) so that they maximally relate to the change in visual acuity (VA) over 12 months. The algorithm identified baseline VA <73 Early Treatment Diabetic Retinopathy Study letters, presence of baseline subretinal fluid, and administration of three loading doses by Day 90 from drug initiation as the characteristics with the greatest impact on VA at month 12. When applying the different criteria, RWE outcomes became similar to those obtained in known RCTs. Machine learning techniques can be used to classify real world cohorts and identify subsets of patients who benefit to the same extent as that reported in RCTs. This methodology may support the translation of clinical trial findings to treatment performance in the clinical practice setting. [ABSTRACT FROM AUTHOR]

Aim: To examine the clinical safety and effectiveness of insulin aspart (IAsp) therapy in type 2 diabetes (T2D) patients from the ASEAN cohort of the international, 24-week, non-interventional A1chieve study. Methods: T2D patients from Indonesia, Malaysia, Philippines and Singapore, who started IAsp therapy with or without oral glucose-lowering drugs, were included. The primary endpoint was the incidence of serious adverse drug reactions (SADRs), including major hypoglycaemic events. Secondary endpoints included hypoglycaemia, glycated haemoglobin A1c [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPPG], systolic blood pressure [SBP], body weight and lipids. Quality of life (QoL) was assessed using the EQ-5D questionnaire. Results: Overall, 312 T2D patients (222 insulin-naive and 90 insulin-experienced) with a mean±SD age of 56.6±11.2 years, BMI of 24.2±3.9 kg/m2 and diabetes duration of 7.0±5.7 years were included. The mean daily IAsp dose was 0.51±0.31U/kg at baseline titrated up to 0.60±0.29U/kg at Week 24. No SADRs or major hypoglycaemic events were reported in the entire subgroup. The proportion of patients who reported overall hypoglycaemia decreased from baseline to Week 24 (7.1% vs. 0.3%, p < 0.0001). The mean HbA1c improved from 9.5±1.6% at baseline to 7.6±1.3% after 24 weeks (p < 0.001). The mean FPG, post-breakfast PPPG and SBP also improved (p < 0.001). Health-related QoL scores increased in the entire subgroup (mean increase: 9.8±14.6 points, p < 0.001). Conclusions: Starting IAsp therapy was well-tolerated and was associated with significantly improved overall glycaemic control in the ASEAN cohort. [ABSTRACT FROM AUTHOR]