Search

Kjell Larsson,1 Karin Lisspers,2 Björn Ställberg,2 Gunnar Johansson,2 Florian S Gutzwiller,3 Karen Mezzi,3 Bine Kjoeller Bjerregaard,4 Leif Jorgensen,4 Hyewon Koo,5 Christer Janson6 1Integrative Toxicology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 3Novartis Pharma AG, Basel, Switzerland; 4IQVIA Solutions, Copenhagen, Denmark; 5IQVIA Solutions, Solna, Sweden; 6Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, SwedenCorrespondence: Kjell Larsson, Integrative Toxicology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-171 77, Sweden, Tel +467 0582 0763, Email kjell.larsson@ki.seBackground: Patients with mild chronic obstructive pulmonary disease (COPD) account for more than half of the total COPD population but are often undiagnosed and sparsely studied. This real-world, longitudinal study compared the socioeconomic burden, clinical characteristics and treatment patterns in patients with mild COPD and age- and gender-matched controls.Patients and methods: Our population included mild COPD patients (forced expiratory volume in one second ≥ 80% of predicted value) and reference controls from 52 Swedish primary care centres over 15 years (2000– 2014). We linked electronic medical record (EMR) data to Sweden’s National Health Registries. The outcomes analyzed were socioeconomic status including annual income from work, presence of comorbidities and the use of medications.Results: 844 patients with mild COPD were included in this study and matched with 844 reference controls. Compared with the reference controls, mild COPD patients had a significantly lower annual income from work (mean difference, men: 12,559€ and women: 7143€) and were significantly less likely to be married or employed. The presence of comorbidities, including cardiovascular disease, anxiety and depression (only women) was significantly higher in mild COPD patients. The use of medications, such as proton pump inhibitors, antidepressants, central painkillers and sleep medications, was significantly higher in the mild COPD group.Conclusion: Mild COPD presents a considerable socioeconomic and clinical burden compared with reference controls The findings suggest that COPD constitutes a condition that influences health status even in mild disease clearly demanding an increased need for early detection and treatment.Keywords: chronic obstructive pulmonary disease, socioeconomic status, comorbidities, co-medications, annual income, exacerbation, Sweden

Kjell Larsson,1 Christer Janson,2 Karin Lisspers,3 Björn Ställberg,3 Gunnar Johansson,3 Florian S Gutzwiller,4 Karen Mezzi,4 Bine Kjoeller Bjerregaard,5 Leif Jorgensen5 1Integrative Toxicology, The National Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; 2Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 3Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 4Novartis Pharma AG, Global Patient Access, Basel, Switzerland; 5IQVIA Solutions, Real World Evidence Solutions, Copenhagen, DenmarkCorrespondence: Kjell LarssonIntegrative Toxicology, The National Institute of Environmental Medicine, Karolinska Institute, Stockholm, SE-171 77, SwedenTel +467 0582 0763Email kjell.larsson@ki.sePurpose: The aim of this study was to assess the association between exacerbation frequency and clinical and economic outcomes in patients with COPD.Patients and Methods: Electronic medical record data linked to National Health Registries were collected from COPD patients at 52 Swedish primary care centers (2000– 2014). The outcomes analyzed were exacerbation rate, mortality, COPD treatments, lung function and healthcare costs during the follow-up period. Based on the exacerbation rate two years before index date, the patients were initially classified into three groups, either 0, 1 or ≥ 2 exacerbations per year. After the index date, the classification into exacerbation groups was updated each year based on the exacerbation rate during the last year of follow-up. A sensitivity analysis was conducted excluding patients with asthma diagnosis from the analysis.Results: In total 18,586 COPD patients were analyzed. A majority of the patients (60– 70%) who either have had no exacerbation or frequent exacerbations (≥ 2/year) during the pre-index period remained in their group (ie, with 0 or ≥ 2 annual exacerbations) during up to 11 years of follow-up. Compared with having no exacerbation, mortality was higher in patients having 1 (HR; 2.06 [1.93– 2.20]) and ≥ 2 (4.58 [4.33– 4.84]) exacerbations at any time during the follow-up. Lung function decline was more rapid in patients with frequent exacerbations and there was an almost linear relationship between exacerbations frequency and mortality. Total healthcare costs were higher in the frequent exacerbation group (≥ 2/year) than in patients with no or one exacerbation annually (p< 0.0001 for both). The results did not differ from the main analysis after exclusion of patients with a concurrent asthma diagnosis.Conclusion: In addition to faster lung function decline and increased mortality, frequent exacerbations in COPD patients imply a significant economic burden.Keywords: chronic obstructive pulmonary disease, exacerbations, mortality, lung function, healthcare cost, Sweden

Objective: The ability to predict impending asthma exacerbations may allow better utilization of healthcare resources, prevention of hospitalization and improve patient outcomes. We aimed to develop models using machine learning to predict risk of exacerbations., Methods: Data from 29,396 asthma patients was collected from electronic medical records and national registers covering clinical and epidemiological factors (e.g. comorbidities, health care contacts), between 2000 and 2013. Machine-learning classifiers were used to create models to predict exacerbations within the next 15 days. Model selection was done using the mean cross validation score of area under precision-recall curve (AUPRC)., Results: The most important predictors of exacerbation were comorbidity burden and previous exacerbations. Model validation on test data yielded an AUPRC = 0.007 (95% CI: ± 0.0002), indicating that historic clinical information alone may not be sufficient to predict a near future risk of asthma exacerbation., Conclusions: Supplementation with additional data on environmental triggers, (e.g. weather, pollen count, air quality) and from wearables, might be necessary to improve performance of the short-term predictive model to develop a more clinically useful tool., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The effect of inhaled corticosteroids (ICS) on the risk of osteoporosis and fracture in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to assess this risk in patients with COPD.Electronic medical record data linked to National Health Registries were collected from COPD patients and matched reference controls at 52 Swedish primary care centres from 2000 to 2014. The outcomes analysed were the effect of ICS on all fractures, fractures typically related to osteoporosis, recorded osteoporosis diagnosis, prescriptions of drugs for osteoporosis and a combined measure of any osteoporosis-related event. The COPD patients were stratified by the level of ICS exposure.A total of 9651 patients with COPD and 59 454 matched reference controls were analysed. During the follow-up, 19.9% of COPD patients had at least one osteoporosis-related event compared with 12.9% of reference controls (p<0.0001). Multivariate analysis in the COPD population demonstrated a dose-effect relationship, with high-dose ICS being significantly associated with any osteoporosis-related event (risk ratio 1.52 (95% CI 1.24-1.62)), while the corresponding estimate for low-dose ICS was 1.27 (95% CI 1.13-1.56) compared with COPD patients not using ICS. A similar dose-related adverse effect was found for all four of the specific osteoporosis-related events: all fractures, fractures typically related to osteoporosis, prescriptions of drugs for osteoporosis and diagnosis of osteoporosis.We conclude that patients with COPD have a greater risk of bone fractures and osteoporosis, and high-dose ICS use increased this risk further., Competing Interests: Conflict of interest: C. Janson reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, outside the submitted work. Conflict of interest: K. Lisspers reports personal fees from AstraZeneca, Novartis, Boehringer Ingelheim, GlaxoSmithKline and Chiesi, outside the submitted work. Conflict of interest: B. Ställberg reports personal fees from AstraZeneca, Novartis, Boehringer Ingelheim, GlaxoSmithKline, Meda, Teva and Chiesi, outside the submitted work. Conflict of interest: G. Johansson has nothing to disclose. Conflict of interest: F.S. Gutzwiller is an employee of Novartis Pharma AG. Conflict of interest: K. Mezzi is an employee of Novartis Pharma AG. Conflict of interest: L. Mindeholm is a consultant to Novartis, and shareholder of Novartis, Alcon and Novo-Nordisk. Conflict of interest: B.K. Bjerregaard is an employee of IQVIA and received remuneration in relation to statistical analyses. Conflict of interest: L. Jörgensen is an employee of IQVIA. Conflict of interest: K. Larsson has, during the last 5 years, on one or more occasion served in an advisory board, served as a speaker and/or participated in education activities arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, Novartis, Chiesi, Orion and Teva., (Copyright ©ERS 2021.)

This study reports the association of ICS use and the risk of type 2 diabetes mellitus (T2DM) in Swedish patients with COPD using data from real-world, primary care settings. A total of 7078 patients with COPD were included in this analysis and the 5-year cumulative incidence rate per 100,000 person years was 1506.9. The yearly incidence rate per 100,000 person years ranged from 850 to 1919. Use of ICS especially at a high dose in patients with COPD was related to an increased risk of T2DM.

The present study aimed to generate real-world evidence regarding gender differences among chronic obstructive pulmonary disease (COPD) patients, especially as regards the diagnosis and outcomes in order to identify areas for improvement and management and optimize the associated healthcare resource allocation. ARCTIC is a large, real-world, retrospective cohort study conducted in Swedish COPD patients and a matched reference population from 52 primary care centers in 2000-2014. The incidence of COPD, prevalence of asthma and other comorbidities, risk of exacerbations, mortality rate, COPD drug prescriptions, and healthcare resource utilization were analyzed. In total, 17,479 patients with COPD were included in the study. During the study period, COPD was more frequent among women (53.8%) and women with COPD experienced more exacerbations vs. men (6.66 vs. 4.66). However, the overall mortality rate was higher in men compared with women (45% vs. 38%), but no difference for mortality due to COPD was seen between genders over the study period. Women seemed to have a greater susceptibility to asthma, fractures, osteoporosis, rheumatoid arthritis, rhinitis, depression, and anxiety, but appeared less likely to have diabetes, kidney diseases, and cardiovascular diseases. Furthermore, women had a greater risk of COPD-related hospitalization and were likely to receive a significantly higher number of COPD drug prescriptions compared with men. These results support the need to reduce disease burden among women with COPD and highlight the role of healthcare professionals in primary care who should consider all these parameters in order to properly diagnose and treat women with COPD.

Knowledge of patterns of treatment discontinuation in attention-deficit/hyperactivity disorder (ADHD) drug treatment is of importance, for both the clinical practice and the study of long-term treatment outcomes. The purpose of this study was to describe early discontinuation of ADHD drug treatment. Using the Danish National Prescription Registry, all first-time users of the ADHD drugs methylphenidate and atomoxetine were identified between 2000 and 2012. Early discontinuation was defined as failing to fill a second prescription for any ADHD drug within 6 months. Analyses were conducted stratified by calendar year, drug formulation, patient sex, age and region of residence. 59,116 first-time users of methylphenidate and atomoxetine with at least 6 months of eligible follow-up were identified. Overall, 12.6% (n = 7441) failed to fill a second prescription within 6 months. This proportion changed over time, dropping from 20.8% in 2000 to 12.5% in 2012. The proportion of early discontinuation was considerably lower among children than among adults. Proportions were comparable when stratifying by index drug. Proportions of early discontinuation were similar between regions of Denmark, except in the capital region, where it remained at around 20% among 18- to 49-year-olds throughout the study period (22.6% in 2012). In conclusion, we found that the proportion of early discontinuation among ADHD drug users in Denmark dropped markedly during the past decade for both sexes, all age groups and all regions, except for adults in the capital region. Overall, early discontinuation was somewhat lower than expected, considering rates of side effects or non-response to ADHD drug treatment., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose: The purpose of this study was to characterise the utilization of the glucagon-like peptide-1 (GLP-1) analogues exenatide and liraglutide in Denmark., Methods: From the Danish National Prescription Registry, we extracted all prescriptions for either liraglutide or exenatide twice-daily in the period 1 April 2007 to 31 December 2012. Using descriptive statistics, we calculated incidence rates, prevalence proportions, daily consumption, and concomitant drug use. For a subset of users we included data from other registries and characterised the baseline characteristics of incident users of GLP-1 analogues., Results: We identified 21,561 and 2,354 users of liraglutide and exenatide respectively. From market entry in 2009 liraglutide showed an increasing prevalence reaching 2.4 per thousand inhabitants in 2012. Exenatide ranged between 0.01 and 0.25 per thousand inhabitants from 2007 to 2012. Treatment intensity showed geographical variation ranging from 1.84per thousand inhabitants to 3.22 per thousand inhabitants for liraglutide. Average doses were 1.34 mg/day (liraglutide) and 16.4 μg/day (exenatide). Treatment initiation was most often performed by a hospital physician and was not associated with any changes in concomitant treatment with antihypertensives, cholesterol-lowering drugs or anticoagulants. Of liraglutide and exenatide users, 38 % and 43 % also used insulin. Low kidney function (eGFR < 30 ml/min) was found in 10.1 % and 9.0 % of users of liraglutide and exenatide respectively., Conclusions: The preferred GLP-1 analogue in Denmark is liraglutide. Certain aspects of the utilization of GLP-1 analogues, such as large regional differences and concomitant use of GLP-1 analogues and insulin, warrant further investigation.

Aim: Our aim was to characterize utilization patterns for drugs used to treat attention deficit/hyperactivity disorder (ADHD) on the level of the individual patient among Danish users, focusing on treatment duration, doses used, and concurrent use of ADHD and non-ADHD drugs., Methods: Using the Danish Registry of Medicinal Product Statistics, we extracted data on 1,085,099 prescriptions for ADHD drugs issued to a total of 54,024 persons in the study period 1 January 1995 to 30 September 2011. For users in the final year of the study period, we further extracted 315,365 prescriptions for non-ADHD drugs. Drug utilization was characterized using descriptive statistics., Results: The mean duration of ADHD treatment was highest (3.6-4.2 years) for patients initiating therapy at a young age (age<13). Dropout rate after receiving only one prescription was highest among off-label users (age<6 and age >17). All age categories showed an increase in the average daily dosage of methylphenidate used from 2003 to 2010. Concomitant treatment with methylphenidate and atomoxetine was rare, as only 2 % of methylphenidate treatment overlapped with atomoxetine treatment. Nineteen percent of methylphenidate instant-release treatment overlapped with methylphenidate controlled-release treatment. Users of ADHD drugs across all age categories had an increased use of drugs related to the nervous system, especially antipsychotics [standardized morbidity rate (SMR), 6.4-19.5] and antiepileptics (SMR, 4.0-5.5)., Conclusion: We found certain traits that warrant further investigation: the apparent increase in average daily doses, the low adherence to treatment among off-label users, and the increased use of other psychotropic medication.

Purpose: The purpose of the study was to characterize the utilization of medication against attention deficit hyperactivity disorder (ADHD) in Denmark between 1995 and 2011 from a national perspective, by using population-based prescription data., Methods: National data on drug use in Denmark between 1 January 1995 and 30 September 2011 were extracted from the Registry of Medicinal Product Statistics (RMPS). Drug utilization was characterized using descriptive statistics., Results: A total of 1,085,090 prescriptions issued to 54,020 persons were identified. The incidence rate was stable in the last 3 years of the study period, and a slightly decreasing incidence rate and a stabilizing prevalence were observed towards the end of this period. The therapeutic intensity was 6.7 defined daily dose/person/day, with large regional differences that ranged from 64 to 145 % of the national average. Methylphenidate accounted for 92.6 % of DDDs used. The general practitioner (GP) rarely initiated treatment, although treatment initiation based on the GP's advice increased with older age of the patient. Maintenance treatment was found to be distributed roughly equally between prescriber types. For methylphenidate, 1 % of users accounted for 6.1 % of the drug volume and 50 % of users accounted for 84.4 %. The data therefore do not suggest a high proportion of heavy users., Conclusion: The findings of this analysis are mostly reassuring, with the data indicating a seemingly stagnant incidence and prevalence rate and lacking evidence of heavy users. However, the prescriber profile for incident users and the large regional variances raise concerns. It is therefore vital that the use of ADHD drugs is closely monitored.

Objective: Most studies on tobacco smoking have focused on daily-smokers. Occasional smokers, who have never smoked daily, have often been included in the reference group of never-smokers. We have investigated the association between occasional smoking and cancer of the bladder, kidney, pancreas, upper aero-digestive tract and lung., Methods: The study population consisted of 158,488 persons, who provided information on occasional smoking, within the European Prospective Investigation into Cancer and Nutrition (EPIC), 780 of whom developed a smoking-related cancer. We used Cox proportional hazard model, stratified by gender and country to estimate incidence rate ratios (IRR) for smoking-related cancers., Results: The results suggest that occasional smokers have a higher risk of bladder cancer (IRR: 1.92, 95% confidence interval (CI) 0.93-3.98) and of the major smoking-related cancers combined (IRR: 1.24, 95% CI 0.80-1.94) than true never-smokers. Including occasional smokers in the reference group resulted in a lower risk estimate for former and current smokers., Conclusions: Occasional smoking should be discouraged.

The purpose of the present study was to investigate the association between smoking and the development of bladder cancer. The study population consisted of 429,906 persons participating in the European Prospective Investigation into Cancer and Nutrition (EPIC), 633 of whom developed bladder cancer during the follow-up period. An increased risk of bladder cancer was found for both current- (incidence rate ratio 3.96, 95% confidence interval: 3.07-5.09) and ex- (2.25, 1.74-2.91) smokers, compared to never-smokers. A positive association with intensity (per 5 cigarettes) was found among current-smokers (1.18, 1.09-1.28). Associations (per 5 years) were observed for duration (1.14, 1.08-1.21), later age at start (0.75, 0.66-0.85) and longer time since quitting (0.92, 0.86-0.98). Exposure to environmental tobacco smoke (ETS) during childhood increased the risk of bladder cancer (1.38, 1.00-1.90), whereas for ETS exposure as adult no effect was detected. The present study confirms the strong association between smoking and bladder cancer. The indication of a higher risk of bladder cancer for those who start smoking at a young age and for those exposed to ETS during childhood adds to the body of evidence suggesting that children are more sensitive to carcinogens than adults.