Impact of changes to reimbursement of fixed combinations of inhaled corticosteroids and long-acting β₂ -agonists in obstructive lung diseases: a population-based, observational study.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.In 2010, the Icelandic government introduced a new cost-saving policy that limited reimbursement of fixed inhaled corticosteroid/long-acting β₂ -agonist (ICS/LABA) combinations.This population-based, retrospective, observational study assessed the effects of this policy change by linking specialist/primary care medical records with data from the Icelandic Pharmaceutical Database. The policy change took effect on 1 January 2010 (index date); data for the year preceding and following this date were analysed in 8241 patients with controlled/partly controlled asthma and/or chronic obstructive pulmonary disease (COPD) who had been dispensed an ICS/LABA during 2009. Oral corticosteroid (OCS) and short-acting β₂ -agonist (SABA) use, and healthcare visits, were assessed pre- and post-index.The ICS/LABA reimbursement policy change led to 47.8% fewer fixed ICS/LABA combinations being dispensed during the post-index period among patients whose asthma and/or COPD was controlled/partly controlled during the pre-index period. Fewer ICS monocomponents were also dispensed. A total of 48.6% of patients were no longer receiving any respiratory medications after the policy change. This was associated with reduced disease control, as demonstrated by more healthcare visits (44.0%), and more OCS (76.3%) and SABA (51.2%) dispensations.Overall, these findings demonstrate that changes in healthcare policy and medication reimbursement can directly impact medication use and, consequently, clinical outcomes and should, therefore, be made cautiously.AstraZenec

Chemotherapy following radium-223 dichloride treatment in ALSYMPCA

BACKGROUND Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following radium-223 treatment is of clinical importance. An exploratory analysis of prospectively collected data, from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) patient subgroup who received chemotherapy after radium-223 or placebo treatment, was conducted to evaluate the safety and efficacy of chemotherapy following radium-223. METHODS In ALSYMPCA, CRPC patients with symptomatic bone metastases and no visceral metastases were randomized 2:1 to receive six injections of radium-223 (50 kBq/kg IV) or placebo plus best standard of care, stratified by prior docetaxel, baseline alkaline phosphatase, and current bisphosphonate use. In this exploratory analysis, chemotherapy agents administered following study treatment were identified; timing and duration were calculated. Hematologic safety was reviewed, and overall survival analyzed. RESULTS Overall, 142 radium-223 and 64 placebo patients received subsequent chemotherapy; most common were docetaxel (70% radium-223, 72% placebo) and mitoxantrone (16% radium-223, 20% placebo). The majority of patients (61% radium-223, 58% placebo) had received prior docetaxel. Radium-223 patients started subsequent chemotherapy later than placebo patients; chemotherapy duration was similar between groups. In radium-223 and placebo patients receiving subsequent chemotherapy, median hematologic values (hemoglobin, neutrophils, and platelets) remained nearly constant up to 18 months following start of chemotherapy, regardless of prior docetaxel treatment. A low percentage of patients in both groups had grades 3–4 hematologic values (<10%). Platelet count decline, from last measurement before chemotherapy, was numerically greater in radium-223 versus placebo patients. Median overall survivals from start of chemotherapy were 16.0 and 15.8 months following radium-223 and placebo, respectively. CONCLUSIONS Chemotherapy following radium-223, regardless of prior docetaxel, is feasible and appears to be well tolerated in patients with CRPC and symptomatic bone metastases

Apparent Half-Lives of Hepta- to Decabrominated Diphenyl Ethers in Human Serum as Determined in Occupationally Exposed Workers

The aim of the present study was to model apparent serum half-lives of polybrominated diphenyl ethers (PBDEs) with 7–10 bromine substituents. Workers with occupational exposure to PBDEs have elevated serum levels of PBDEs, but these substances are also found in the general population and are ubiquitous environmental contaminants. The calculations were based on exposure assessments of rubber workers (manufactured flame-retarded rubber compound) and electronics dismantlers who donated blood during a period with no work-related exposures to PBDEs, and referents without any known occupational exposure (clerks, cleaners, and abattoir workers). The workers had previously been found to have elevated levels of high- and medium-brominated diphenyl ethers compared with the referent populations. We performed nonlinear mixed-effects modeling of kinetics, using data from previous and present chemical analyses. The calculated apparent half-life for decabromodiphenyl ether (BDE-209) was 15 days (95% confidence interval, 11–18 days). The three nona-BDEs and four octa-BDE congeners were found to have half-lives of 18–39 and 37–91 days, respectively. BDE-209 has a short half-life in human blood. Because BDE-209 is commonly present in humans in general, the results of this study imply that humans must be more or less continuously exposed to BDE-209 to sustain the serum concentrations observed. BDE-209 is more readily transformed and/or eliminated than are lower brominated diphenyl ether congeners, and human health risk must be assessed accordingly

Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade $ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease

SLC35A2-related congenital disorder of glycosylation : Defining the phenotype

We aim to further delineate the phenotype associated with pathogenic variants in the SLC35A2 gene, and review all published literature to-date. This gene is located on the X chromosome and encodes a UDP-galactose transporter. Pathogenic variants in SLC35A2 cause a congenital disorder of glycosylation. The condition is rare, and less than twenty patients have been reported to-date. The phenotype is complex and has not been fully defined. Here, we present a series of five patients with de novo pathogenic variants in SLC35A2. The patients' phenotype includes developmental and epileptic encephalopathy with hypsarrhythmia, facial dysmorphism, severe intellectual disability, skeletal abnormalities, congenital cardiac disease and cortical visual impairment. Developmental and epileptic encephalopathy with hypsarrhythmia is present in most patients with SLC35A2 variants, and is drug-resistant in the majority of cases. Adrenocorticotropic hormone therapy may achieve partial or complete remission of seizures, but the effect is usually temporary. Isoelectric focusing of transferrins may be normal after infancy, therefore a congenital disorder of glycosylation should still be considered as a diagnosis in the presence of a suggestive phenotype. We also provide evidence that cortical visual impairment is part of the phenotypic spectrum. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma

Clinical trial information: NCT02963493Altres ajuts: Oncopeptides A

Lower Cardiorenal Risk with Sodium-Glucose Cotransporter-2 Inhibitors versus Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Patients without Cardiovascular and Renal Diseases: A large multinational observational study

BACKGROUND: We compared new use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) vs. dipeptidyl peptidase-4 inhibitor (DPP4i) and the risk of cardiorenal disease, heart failure (HF) or chronic kidney disease (CKD), in type 2 diabetes patients without history of prevalent cardiovascular and renal disease, defined as cardiovascular- and renal disease (CVRD) free, managed in routine clinical practice. METHODS: In this observational cohort study, patients were identified in electronic health records in England, Germany, Japan, Norway, South Korea and Sweden, from 2012 to 2018. A total of 1 006 577 CVRD-free new users of SGLT2i or DPP4i were propensity score matched 1:1. Unadjusted Cox regression was used to estimate hazard ratios (HRs) for outcomes; cardiorenal disease, HF, CKD, stroke, myocardial infarction (MI) cardiovascular- and all-cause death. RESULTS: Baseline characteristics were well-balanced between the treatment groups (n = 105 130 in each group) with total follow up of 187 955 patient years. Patients were mean 56 years, 43% women and indexed between 2013 and 2018. The most commonly used agents were dapagliflozin (91.7% of exposure time) and sitagliptin/linagliptin (55.0%), in the SGLT2i and DPP4i groups respectively. SGLT2i was associated with lower risk of cardiorenal disease, HF, CKD, all-cause- and cardiovascular death; HR (95% CI) 0.56 (0.42-0.74), 0.71 (0.59-0.86), 0.44 (0.28-0.69), 0.67 (0.59-0.77) and 0.61 (0.44-0.85) respectively. No differences were observed for stroke (0.87 [0.69-1.09]) and MI (0.94 [0.80-1.11]). CONCLUSION: In this multinational observational study, SGLT2i was associated with lower risk of heart failure and chronic kidney disease versus DPP4i in T2D patients otherwise free from both cardiovascular and renal disease

Using big data from health records from four countries to evaluate chronic disease outcomes: a study in 114 364 survivors of myocardial infarction

Aims: to assess the international validity of using hospital record data to compare long-term outcomes in heart attack survivors. Methods and results: we used samples of national, ongoing, unselected record sources to assess three outcomes: cause death; a composite of myocardial infarction (MI), stroke, and all-cause death; and hospitalized bleeding. Patients aged 65 years and older entered the study 1 year following the most recent discharge for acute MI in 2002–11 [n = 54 841 (Sweden), 53 909 (USA), 4653 (England), and 961 (France)]. Across each of the four countries, we found consistent associations with 12 baseline prognostic factors and each of the three outcomes. In each country, we observed high 3-year crude cumulative risks of all-cause death (from 19.6% [England] to 30.2% [USA]); the composite of MI, stroke, or death [from 26.0% (France) to 36.2% (USA)]; and hospitalized bleeding [from 3.1% (France) to 5.3% (USA)]. After adjustments for baseline risk factors, risks were similar across all countries [relative risks (RRs) compared with Sweden not statistically significant], but higher in the USA for all-cause death [RR USA vs. Sweden, 1.14 (95% confidence interval 1.04–1.26)] and hospitalized bleeding [RR USA vs. Sweden, 1.54 (1.21–1.96)]. Conclusion: the validity of using hospital record data is supported by the consistency of estimates across four countries of a high adjusted risk of death, further MI, and stroke in the chronic phase after MI. The possibility that adjusted risks of mortality and bleeding are higher in the USA warrants further study

Risk of cardiovascular events and death associated with initiation of SGLT2 inhibitors compared with DPP-4 inhibitors:an analysis from the CVD-REAL 2 multinational cohort study

Background Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. Methods In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. Findings Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12.2), 170 335 (44.1%) of 386 248 were women, and 111933 (30.1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0.69, 95% CI 0. 61-0. 77; p Interpretation In this large, international, observational study, initiation of SGLT2 inhibitors versus DPP-4 inhibitors was associated with lower risks of heart failure, death, myocardial infarction, and stroke, providing further support for the cardiovascular benefits associated with use of SGLT2 inhibitors in patients with type 2 diabetes. Copyright (C) 2020 Elsevier Ltd. All rights reserved