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Background: Previous safety issues involving medical devices have stressed the need for better safety signal detection. Various European Union (EU) national competent authorities have started to focus on strengthening the analysis of vigilance data. Consequently, article 90 of the new EU regulation states that the European Commission shall put in place systems and processes to actively monitor medical device safety signals., Methods: A systematic literature review was conducted to synthesize the current state of knowledge and investigate the present tools used for medical device safety signal detection. An electronic literature search was performed in Embase, Medline, Cochrane, Web of science, and Google scholar from inception until January 2017. Articles that included terms related to medical devices and terms associated with safety were selected. A further selection was based on the abstract review. A full review of the remaining articles was conducted to decide on which articles finally to consider relevant for this review. Completeness was assessed based on the content of the articles., Results: Our search resulted in a total of 20,819 articles, of which 24 met the inclusion criteria and were subject to data extraction and completeness scoring. A wide range of data sources, especially spontaneous reporting systems and registries, used for the detection and assessment of product problems and patient harms associated with the use of medical devices, were studied. Coding is remarkably heterogeneous, no agreement on the preferred methods for signal detection exists, and no gold standard for signal detection has been established thus far., Conclusion: Data source harmonization, the development of gold standard signal detection methodologies and the standardization of coding dictionaries are amongst the recommendations to support the implementation of a new proactive approach to signal detection. The new safety surveillance system will be able to use real-world evidence to support regulatory decision-making across all jurisdictions., Competing Interests: Josep Pane and Dorian Villegas are employees of Alcon. Laura Gamez and Irene Rebollo are employees of Novartis. Katia M.C. Verhamme reports working for a research group that received/receives unconditional research grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis, GSK, and Chiesi, none of which are related to the content of this manuscript. Miriam C.J.M. Sturkenboom reports being a principal investigator on post-authorization safety studies for Novartis, non-related to this study. The authors report no other potential conflicts of interest for this work., (© 2021 Pane et al.)

Introduction: The amount of mandatory data that needs to be analyzed as part of a medical device postmarket surveillance (PMS) system has grown exponentially in recent times. This is a consequence of increasingly demanding and complex regulatory requirements from Health Authorities, aimed at a better understanding of the medical device safety evaluation. Proactive approaches to PMS processes are becoming more necessary as regulators increase the scrutiny of device safety. New technologies have been explored to address some of the challenges associated with this changing regulatory environment., Areas Covered: This paper focuses on the different technical aspects of blockchain and how this new technology has the potential to support the ongoing efforts to improve the PMS system for medical devices., Expert Opinion: To address these challenges, we suggest to generate a private PMS data permissioned blockchain with a proof-of-authority consensus mechanism, to which only a restricted number of designated and audited participants have authorization to validate transactions and add them to the PMS data blockchain ledger. Blockchain has the potential to support a more efficient approach, which could offer many advantages to the different stakeholders involved in the PMS process, such as supporting with new regulatory initiatives.

Chronic cough is a common complaint in the general population but there are no precise data on the incidence of, and prospectively examined risk factors for chronic cough in a population-based setting. Therefore, we investigated the period prevalence, incidence and risk factors for chronic cough in adult subjects. In a prospective population-based cohort study among subjects aged ≥45 years, data on chronic cough were collected on two separate occasions using a standardised questionnaire. Chronic cough was defined as daily coughing for at least 3 months duration during the preceding 2 years. Potential risk factors were gathered by interview, physical examination and several investigations. Of the 9824 participants in this study, 1073 (10.9%) subjects had chronic cough at baseline. The prevalence of chronic cough increased with age and peaked in the eighth decade. In subjects aged <70 years, chronic cough was more common in women. During an average follow-up of 6 years, 439 incident cases of chronic cough occurred with an overall incidence rate of 11.6 per 1000 person-years (95% CI 10.6-12.8). In current smokers, the incidence of chronic cough was higher in men. In the multivariable analysis, current smoking, gastro-oesophageal reflux disease (GORD), asthma and COPD were identified as risk factors for chronic cough. Chronic cough is common among adults and highly prevalent in the older population. Current smoking, GORD, asthma and COPD are independent risk factors for chronic cough. Individuals at risk of developing chronic cough may benefit from smoking cessation and control of the underlying disease., Competing Interests: Conflict of interest: J.T. Arinze has nothing to disclose. Conflict of interest: E.W. de Roos has nothing to disclose. Conflict of interest: L. Karimi has nothing to disclose. Conflict of interest: K.M.C. Verhamme works for a research group that, in the past, received unconditional grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis and GSK, none of which relate to the content of this work. Conflict of interest: B.H. Stricker has nothing to disclose. Conflict of interest: G.G. Brusselle reports advisory boards and speaker's fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva; and advisory board fees from Sanofi, outside the submitted work., (Copyright ©ERS 2020.)

Background: Guidelines recommend omalizumab in patients with uncontrolled severe allergic asthma. We investigated real-life use of omalizumab, the proportion of patients fulfilling eligibility criteria, its costs and its effectiveness., Method: In a cohort of asthma patients initiating treatment with omalizumab in Belgium between 2010 and 2016, we investigated fulfilment of eligibility criteria (chronic use of high-dose inhaled corticosteroids (ICSs) plus long-acting β 2 -agonists (LABAs) and ≥2 severe asthma exacerbations in previous year), and compared hospitalisations and systemic corticosteroid consumption in the year before and after omalizumab initiation. We computed healthcare costs in the respective time periods and compared the cost per prevented hospitalisation in patients fulfilling eligibility criteria versus those who did not., Results: Between 2010 and 2016, omalizumab treatment was initiated in 2068 patients with asthma; only 24% fulfilled the eligibility criteria, mainly due to nonadherence to high-dose ICSs + LABAs. The proportion of patients hospitalised for asthma decreased from 41% to 21% in eligible patients (absolute risk reduction, 20%), whereas the absolute risk reduction was 5% (from 19% to 14%) in noneligible patients. The cost per prevented hospitalisation was €44 238 versus €139 495, respectively. Chronic use of systemic corticosteroids was discontinued in 35% of eligible patients versus 15% of noneligible patients., Conclusion: In Belgium, omalizumab is mostly initiated in uncontrolled asthma patients who are nonadherent to ICSs + LABAs. Omalizumab decreases hospitalisations and the use of systemic corticosteroids, but at a high cost. Careful management of patients with difficult-to-treat asthma should be a priority before prescribing omalizumab., Competing Interests: Conflict of interest: K.M.C. Verhamme works for a research group that, in the past, received unconditional research grants from Pfizer/Boehringer Ingelheim, Yamanouchi, Novartis and GSK. None of these are related to the content of this manuscript. Conflict of interest: C. Lucet has nothing to disclose. Conflict of interest: A. Van Meerhaeghe has nothing to disclose. Conflict of interest: G.G.O. Brusselle reports personal fees for advisory boards and lectures from Astra Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, and for advisory boards from Sanofi, outside the submitted work. Conflict of interest: M-L. Lambert has nothing to disclose., (Copyright ©ERS 2019.)

The role of the β 2 -adrenergic receptor ( ADRB2 ) gene in patients with chronic obstructive pulmonary disease (COPD) is unclear. We investigated the association between ADRB2 variants and the risk of exacerbations in COPD patients treated with inhaled β 2 -agonists. Within the Rotterdam Study, a population-based cohort study, we followed 1,053 COPD patients until the first COPD exacerbation or end of follow-up and extracted rs1042713 (16Arg > Gly) and rs1042714 (27Gln > Glu) in ADRB2 . Exposure to inhaled β 2 -agonists was categorised into current, past or non-use on the index date (date of COPD exacerbation for cases and on the same day of follow-up for controls). COPD exacerbations were defined as acute episodes of worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate exacerbations), or hospitalization (severe exacerbations). The associations between ADRB2 variants and COPD exacerbations were assessed using Cox proportional hazards models, adjusting for age, sex, use of inhaled corticosteroids, daily dose of β 2 -agonists, and smoking. In current users of β 2 -agonists, the risk of COPD exacerbation decreased by 30% (hazard ratio (HR); 0.70, 95% CI: 0.59-0.84) for each copy of the Arg allele of rs1042713 and by 20% (HR; 0.80, 95% CI: 0.69-0.94) for each copy of the Gln allele of rs1042714. Furthermore, current users carrying the Arg16/Gln27 haplotype had a significantly lower risk (HR; 0.70, 95% CI: 0.59-0.85) of COPD exacerbation compared to the Gly16/Glu27 haplotype. In conclusion, we observed that the Arg16/Gln27 haplotype in ADRB2 was associated with a reduced risk of COPD exacerbation in current users of inhaled β 2 -agonists., Competing Interests: The authors declare no conflict of interest related to this manuscript.

Background: The FCER2 gene, via encoding of the CD23 receptor, plays an important role in the regulation of IgE responses. A genetic variant of the FCER2 gene (T2206C) was previously shown to be associated with IgE levels in asthmatic children. IgE sensitization has also been linked to increased levels of fractional exhaled nitric oxide (FENO)., Objective: To investigate whether the FCER2 T2206C variant influences FENO levels in asthmatic children with a reported use of inhaled corticosteroids (ICS)., Methods: This cross-sectional study involved 593 asthmatic children with a reported use of ICS, availability of FENO measurements and genotyping data on the FCER2 T2206C variant (rs28364072). An additive genetic model was assumed, and the association between the FCER2 T2206C variant and the log-transformed (ln) FENO levels was evaluated using linear regression analysis, adjusted for age, sex, adapted British Thoracic Society (BTS) treatment steps and atopy., Results: The mean age of the population was 9.1 ± 2.2 years, and the median of FENO levels was 13.0 ppb with an interquartile range (IQR) of (8.0-27.5 ppb). The minor allele (G) frequency of rs28364072 was 29.6%, and each extra copy of the G allele was significantly associated with a lower level of the geometric mean of FENO (log scale, β = -0.12, 95% CI: -0.23, -0.02)., Conclusion and Clinical Relevance: Our results showed that the FCER2 T2206C variant was significantly associated with lower FENO levels in carriers of the G allele. Nevertheless, this SNP contributed little to the variability in FENO levels in this patient population. Our findings contribute to the present knowledge on FENO in asthmatic children; however, future replication studies are required to establish the role of this gene in relation to FENO., (© 2019 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Purpose: Recent public health safety issues involving medical devices have led to a growing demand to improve the current passive-reactive postmarket surveillance (PMS) system. Various European Union (EU) national competent authorities have started to focus on strengthening the postmarket risk evaluation. As a consequence, the new EU medical device regulation was published; it includes the concept of a PMS Plan., Methods: This publication reviewed Annex III Technical Documentation on PMS and Annex XIV Part B: Postmarket clinical follow-up from the new Regulation (EU) 2017/745 of the European Parliament and of the Council on medical devices., Results: The results of the PMS activities will be described in the PMS plan and will be used to update other related documents. A modular approach to structure the contents of the PMS plan will help to consistently update other PMS information. It is our suggestion that the PMS plan should consist of a PMS plan Core and a PMS plan Supplement. The PMS plan Core document will describe the PMS system, and the PMS plan Supplement will outline the specific activities performed by the manufacturer for a particular medical device., Conclusions: The PMS plan may serve as a thorough tool for the benefit-risk evaluation of medical devices. If properly developed and implemented, it will function as a key player in the establishment of a new framework for proactive safety evaluation of medical devices., (© 2019 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.)

Objectives: To estimate the number of patients who started methylphenidate during childhood and continued treatment beyond the age of 18 years and to study the determinants that may be associated with continuing treatment. Methods: Patients 17 years of age and younger who have received at least one prescription of methylphenidate were identified in the Integrated Primary Care Information database (1996-2017). Logistic regression analyses were performed to assess the association between potential determinants and continuation with methylphenidate treatment at the age of 18 years. Results: Fifty-three percent of all methylphenidate users ( n  = 1020) continued their treatment after the age of 18 years. Patients were more likely to continue treatment with methylphenidate if they started treatment at the age of 15-17 years compared with patients of 11 years and younger (adjusted odds ratio [OR]: 5.74, 95% confidence interval [CI]: 1.48-22.31), if they had a medication possession ratio (MPR) between 0.80 and 1.00 compared with a low MPR (adjusted OR: 2.18, 95% CI: 1.23-3.85) and if they lived in an area with a medium level of urbanization (adjusted OR: 1.98, 95% CI: 1.06-3.69). Furthermore, a relatively high number of patients had a MPR >1.0 (24.8%), of whom 91.3% started their treatment when they were between 15 and 17 years of age. Conclusions: Methylphenidate treatment initiated during childhood was continued in half of the study population when reaching the age of 18, where adolescents were more likely to continue treatment than young children. We also found that ∼25% of our study population had a MPR >1, mainly patients 15-17 years of age, which may suggest misuse or abuse of methylphenidate.

Background: The lack of centralized data on severe asthma has resulted in a scarcity of information about the disease and its management. The development of a common data collection tool for the International Severe Asthma Registry (ISAR) will enable standardized data collection, subsequently enabling data interoperability., Objectives: To create a standardized list of variables for the first international registry for severe asthma via expert consensus., Methods: A modified Delphi process was used to reach consensus on a minimum set of variables to capture in ISAR: the core variables. The Delphi panel brought together 27 international experts in the field of severe asthma research. The process consisted of 3 iterative rounds. In each round, all Delphi panel members were issued an electronic ISAR Delphi workbook to complete and return to the ISAR Delphi administrator. Workbooks and result summaries were anonymously distributed by the Delphi administrator to all panel members at subsequent rounds. Finalization of the core variable list was facilitated by 2 face-to-face meetings., Results: Of the initial 747 selected variables, the Delphi panel reached a consensus on 95. The chosen variables will allow severe asthma to be assessed against patient demographics and medical history, patient-reported outcomes, diagnostic information, and clinical characteristics. Physician-reported outcomes such as nonadherence and information about treatment and management strategies will also be recorded., Conclusions: This is the first global attempt to generate an ISAR using a common set of core variables to ensure that data collected across all participating countries are standardized., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Patients with chronic obstructive pulmonary disease (COPD) commonly present with multimorbidity. We aimed to investigate the association between COPD and the development of peripheral arterial disease (PAD) in the general population, and how this might affect mortality among individuals with COPD. We included 3123 participants of the population-based Rotterdam Study without PAD at baseline (mean age 65 years; 57.4% female). The association between COPD at baseline and PAD during follow-up was studied using logistic regression (PAD being indicated by an ankle-brachial index (ABI) of 0.9 or less). Cox regression was used for mortality analysis and interaction terms were used to investigate mortality risk modification by PAD. The presence of COPD was associated with incident PAD (adjusted odds ratio 1.9, 95% CI 1.1-3.2). Mortality rates per 100 000 person-years were as follows: 10.0 in individuals without COPD or PAD, 18.4 in those with COPD only, 16.1 in those with PAD only and 30.1 in individuals with both COPD and PAD. No statistical interaction was found between PAD and COPD on risk of dying. Individuals with COPD have an almost doubled risk of developing PAD. Although PAD does not modify the association between COPD and mortality, people suffering from both diseases have substantially higher mortality rates., Competing Interests: Conflict of interest: N. Terzikhan has nothing to disclose. L. Lahousse reports personal fees (for expert consultation) from Boehringer Ingelheim GmbH and Novartis, and grants (for unrestricted research) from AstraZeneca and Chiesi, outside the submitted work. Conflict of interest: K.M.M. Verhamme has received grants from GSK and Novartis, and works for a research group which has received unconditional research grants from Pfizer/Boehringer Ingelheim, Novartis, GSK and Yamanouchi. None of which are related to the content of this work. Conflict of interest: O.H. Franco reports grants from Nestle (for child nutrition) and Metagenics (for womens health), outside the submitted work. A. Ikram has nothing to disclose. B.H. Stricker has nothing to disclose. G.G. Brusselle has nothing to disclose.

Background: Little is known on the prevalence and characteristics of asthma in middle-aged and older adults, since previous studies mainly focused on children and young adults. Therefore, the aim was to investigate the prevalence of physician-diagnosed asthma and its comorbidities, in a population-based cohort of adults 45 years of age and over., Methods: We identified participants with physician-diagnosed asthma in the Rotterdam Study; a prospective population-based cohort in the Netherlands. Pulmonary function measurements and comorbidities of the asthma cases were assessed at baseline and compared to those of the general population., Results: Out of 14,621 participants (mean age 65.5 years; 59% women), 524 subjects (31.5%males) had physician-diagnosed asthma at study entry, implicating an asthma prevalence of 3.6% [95% Confidence Interval (CI) 3.3%-3.9%] (2.8% in males and 4.2% in females). Asthmatic subjects had a significantly higher prevalence of obesity and depressive symptoms (Odds Ratio [OR]: 2,02 [95% CI 1,66-2,47] and [OR]: 2,01 [95% CI 1,52-2,66] respectively). Longer duration of asthma and current smoking were associated with lower lung function in asthmatic subjects., Conclusion: Four percent of middle-aged and older adults have physician-diagnosed asthma. These adult asthmatics suffer more frequently from obesity and depression than subjects without obstructive lung disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A pulmonary artery to aorta ratio (PA:A) >1 is a proxy of pulmonary hypertension. It is not known whether this measure carries prognostic information in the general population and in individuals with chronic obstructive pulmonary disease (COPD).Between 2003 and 2006, 2197 participants from the population-based Rotterdam Study (mean±sd age 69.7±6.7 years; 51.3% female), underwent cardiac computed tomography (CT) scanning with PA:A quantification, defined as the ratio between the diameters of the pulmonary artery and the aorta. COPD was diagnosed based on spirometry or clinical presentation and obstructive lung function measured by a treating physician. Cox regression was used to investigate the risk of mortality.We observed no association between 1-sd increase of PA:A and mortality in the general population. Larger PA:A was associated with an increased risk of mortality in individuals with COPD, particularly in moderate-to-severe COPD (hazard ratio 1.36, 95% CI 1.03-1.79). We demonstrated that the risk of mortality in COPD was driven by severe COPD, and that this risk increased with decreasing diffusing capacity.Larger PA:A is not associated with mortality in an older general population, but is an independent determinant of mortality in moderate-to-severe COPD. Measuring PA:A in CT scans obtained for other indications may yield important prognostic information in individuals with COPD., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Purpose: We report on a needs assessment conducted by the International Society of Pharmacoepidemiology (ISPE) Pediatric Special Interest Group (SIG) to identify critical needs in pediatric pharmacoepidemiology and directions for future activities., Methods: A mixed methods survey using a structured interview was conducted in the SIG and ISPE membership to elicit information about current activities in pediatric pharmacoepidemiology and identify critical methodologic issues. The interviews were conducted in two phases over 2013 and 2014, beginning with interviews of SIG members and expanding to the wider ISPE membership. Members of the SIG conducted the interviews and summarized the responses., Results: Twenty-nine ISPE members participated in the needs assessment The respondents reported working with a total of 59 distinct databases, with only eight databases used by more than one respondent. Seventeen respondents (57%) reported issues of limited sample sizes, noting that the problem intensifies when studying age sub-groups or specific genetic populations. Missing data elements were a problem in three main areas: lack of detailed medication information, inability to link to parental data, and lack of detailed information about age. Respondents reported the need for data elements not typically required in studies of adults, such as birthweight and current height and weight, as well as school performance and mental health status., Conclusions: Our needs assessment describes a preliminary picture of the emerging sub-specialty of pediatric pharmacoepidemiology encompassing a range of age sub-groups, disease areas, and medical specialties. The assessment also documents a body of methodologic challenges unique to pharmacoepidemiologic research in children. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Unlabelled: Adherence to treatment remains important for successful asthma management. Knowledge about asthma medication use and adherence in real-life offers opportunities to improve asthma treatment in children., Objective: To describe prescription patterns, adherence and factors of adherence to drugs in children with asthma., Methods: Population-based cohort study in a Dutch primary care database (IPCI), containing medical records of 176,516 children, aged 5-18 years, between 2000 and 2012. From asthma medication prescriptions, age, gender, seasonal and calendar year rates were calculated. Adherence was calculated using medication possession ratio (MPR) and ratio of controller to total asthma drug (CTT). Characteristics of children with high-vs.-low adherence were compared., Results: The total asthma cohort (n = 14,303; 35,181 person-years (PY) of follow-up) was mainly treated with short-acting β2-agonists (SABA; 40 users/100 PY) and inhaled corticosteroids (ICS; 32/100 PY). Median MPR for ICS was 56%. Children with good adherence (Q4 = MPR > 87%) were younger at start of ICS, more often visited specialists and had more exacerbations during follow-up compared to children with low adherence (Q1 = MPR < 37%)., Conclusion: In Dutch primary care children with asthma were mainly prescribed SABA, and ICS. Adherence to ICS was relatively low. Characteristics of children with good adherence were compatible with more severe asthma, suggesting that adherence is driven by treatment need or intensity of medical follow-up., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Individual case safety reports (ICSRs) are a cornerstone in drug safety surveillance. The knowledge on using these data specifically for children is limited. We studied characteristics of pediatric ICSRs reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Public available ICSRs reported in children (0-18 years) to FAERS were downloaded from the FDA-website for the period Jan 2004-Dec 2011. Characteristics of these ICSRs, including the reported drugs and events, were described and stratified by age-groups. We included 106,122 pediatric ICSRs (55% boys and 58% from United States) with a median of 1 drug [range 1-3] and 1 event [1-2] per ICSR. Mean age was 9.1 years. 90% was submitted through expedited (15-days) (65%) or periodic reporting (25%) and 10% by non-manufacturers. The proportion and type of pediatric ICSRs reported were relatively stable over time. Most commonly reported drug classes by decreasing frequency were 'nervous system drugs' (58%), 'antineoplastics' (32%) and 'anti-infectives' (25%). Most commonly reported system organ classes were 'general' (13%), 'nervous system' (12%) and 'psychiatric' (11%) disorders. Duration of use could be calculated for 19.7% of the reported drugs, of which 14.5% concerned drugs being used long-term (>6 months). Knowledge on the distribution of the drug classes and events within FAERS is a key first step in developing pediatric specific methods for drug safety surveillance. Because of several differences in terms of drugs and events among age-categories, drug safety signal detection analysis in children needs to be stratified by each age group.

The benefits of drug therapy for asthma have been well established, but adherence to treatment is poor, and this might be associated with an increased risk of asthma exacerbations. The aim of this study was to review the literature on the association between adherence to asthma controller treatment and risk of severe asthma exacerbations in children and adults. A systematic literature search was performed in PubMed, Embase and Web of Science, from inception until January 2014. Studies were included if data on the association between medication adherence and severe asthma exacerbations were presented. Quality was assessed using a modified version of the Newcastle-Ottawa Scale. The search yielded 2319 unique publications, of which 23 met the inclusion criteria and underwent data extraction and quality scoring. High levels of heterogeneity across studies with regard to adherence and exacerbation measurements, designs and analysis precluded a formal meta-analysis. Although effect measures varied widely, good adherence was associated with fewer severe asthma exacerbations in high-quality studies. Good adherence tended to be associated with lower risk of severe asthma exacerbations. Future studies should use standardised methodology to assess adherence and exacerbations, and should consider inhaler competence., (Copyright ©ERS 2015.)

Tiotropium, a long-acting anticholinergic, is delivered via HandiHaler or via Respimat. Randomised controlled trials suggest that use of tiotropium Respimat increases the risk of dying. We compared the risk of mortality between tiotropium Respimat versus HandiHaler. Within the Integrated Primary Care Information database, we defined a source population of patients, aged ≥ 40 years, with ≥ 1 year of follow-up. Based on prescription data, we defined episodes of tiotropium use (Respimat or HandiHaler). The risk of mortality, within these episodes, was calculated using a Cox proportional hazard regression analysis. From the source population, 11 287 patients provided 24 522 episodes of tiotropium use. 496 patients died while being exposed to HandiHaler or Respimat. Use of Respimat was associated with almost 30% increased risk of dying (adjusted HR 1.27, 95% CI 1.03-1.57) with the highest risk for cardiovascular/cerebrovascular death (adjusted HR 1.56, 95% CI 1.08-2.25). The risk was higher in patients with co-existing cardiovascular disease (adjusted HR 1.36, 95% CI 1.07-1.73) than in patients without (adjusted HR 1.02, 95% CI 0.61-1.71). Use of tiotropium Respimat was associated with an almost 30% increase of mortality compared with HandiHaler and the association was the strongest for cardiovascular/cerebrovascular death. It is unclear whether this association is causal or due to residual confounding by chronic obstructive pulmonary disease severity.

The aim of present study was to investigate the risk of heart failure associated with dopamine agonist use in patients with Parkinson's disease. The data sources of this study were four different population-based, healthcare databases in United Kingdom, Italy and Netherlands. A case control study nested within a cohort of Parkinson's disease patients who were new users of either dopamine agonist or levodopa was conducted. Incident cases of heart failure were identified and validated, using Framingham criteria. Controls were matched to cases on age, gender and database. To estimate the risk of newly diagnosed heart failure with ergot and non-ergot derived dopamine agonists, as compared to levodopa, odds ratios and 95% confidence intervals were calculated through conditional logistic regression. In the cohort of 25,459 Parkinson's disease patients (11,151 new users of dopamine agonists, 14,308 new users of levodopa), 518 incident heart failure cases were identified during follow-up. Compared to levodopa, no increased risk of heart failure was found for ergot dopamine agonists (odds ratio: 1.03; 95% confidence interval: 0.69-1.55). Among non-ergot dopamine agonists, only pramipexole was associated with an increased risk of heart failure (odds ratio: 1.61; 95%confidence interval: 1.09-2.38), especially in the first three months of therapy (odds ratio: 3.06; 95% confidence interval: 1.74-5.39) and in patients aged 80 years and older (odds ratio: 3.30; 95% confidence interval: 1.62-7.13). The results of this study indicate that ergot dopamine agonist use in Parkinson's disease patients was not associated with an increased risk of newly diagnosed heart failure. Among non-ergot dopamine agonists, we observed a statistically significant association between pramipexole use and heart failure, especially during the first months of therapy and in very old patients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Worldwide, COPD is a leading cause of chronic morbidity and mortality. Although its prevalence is already well documented, very few studies have measured its incidence. We therefore investigated the prevalence, incidence and lifetime risk of COPD in the general population. In a population-based study including subjects ≥ 40, with 12 months of history available in the Dutch IPCI database, we identified COPD cases by a two-step validation algorithm. Among 185,325 participants with 601,283 years of follow-up, 7308 subjects with COPD were identified, and 1713 had incident COPD. The overall IR of physician-diagnosed COPD was 2.92/1000PY (95%CI 2.78-3.06). The incidence of COPD was higher in men (3.54; 95%CI 3.33-3.77) than in women (2.34; 95%CI 2.17-2.52), and the overall baseline prevalence of COPD was 3.02% (95%CI 2.94-3.10). For people who had entered the study free of COPD at the age of 40, the risk of developing COPD within the next 40 years was 12.7% for men and 8.3% for women. In patients with very severe COPD, 26% died after 1 year of follow-up, whereas 2.8% died among the non-COPD subjects. In the general population in the Netherlands, three on 1000 subjects were diagnosed with COPD per year. The incidence increased rapidly with age and was higher in men than in women. One in eight men and one in 12 women, being COPD free at the age of 40, will develop COPD during their further life. Mortality rates differed substantially between COPD patients and non-COPD subjects of the same age, underlining the burden of this disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: This study sought to evaluate the long-term clinical outcome of patients with an angiographically intermediate left anterior descending coronary artery (LAD) stenosis in whom the revascularization strategy was based on fractional flow reserve (FFR)., Background: When revascularization is based mainly on angiographic guidance, a number of hemodynamically nonsignificant stenoses will be revascularized., Methods: In 730 patients with a 30% to 70% isolated stenosis in the proximal LAD and no significant valvular disease, FFR measurements were obtained to guide treatment strategy. When FFR was ≥ 0.80, the patients (n = 564) were treated medically (medical group); when FFR was <0.80, the patients (n = 166) underwent a revascularization procedure (revascularization group; 13% coronary artery bypass graft surgery and 87% percutaneous coronary intervention). A 100% long-term clinical follow-up (median follow-up: 40 months) was obtained. The 5-year survival of the medical group was compared with that of a reference population. For each patient, 4 controls were selected from an age- and sex-matched control population., Results: The 5-year survival estimate was 92.9% in the medical group versus 89.6% in the controls (p = 0.74). The mean diameter stenosis was significantly smaller in the medical than in the revascularization group (39 ± 14% vs. 54 ± 13%, p < 0.0001), but there was a large overlap between both groups. The 5-year event-free survival estimates (death, myocardial infarction, and target vessel revascularization) were 89.7% and 68.5%, respectively (p < 0.0001)., Conclusions: Medical treatment of patients with a hemodynamically nonsignificant stenosis (FFR ≥ 0.80) in the proximal LAD is associated with an excellent long-term clinical outcome with survival at 5 years similar to an age- and sex-matched control population., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cross-sectional studies have demonstrated that increased levels of interleukin-6 (IL6) are present in the airways and blood samples of patients with chronic obstructive pulmonary disease (COPD)., Objectives: To investigate the association between IL6 and the risk of COPD using a Mendelian randomization approach., Methods: Eight common single-nucleotide polymorphisms (SNPs) in the region of the IL6 gene were genotyped using both TaqMan and Illumina in the Rotterdam Study, a prospective population-based cohort study consisting of 7,983 participants aged 55 years or older, including 928 COPD patients. At baseline, blood was drawn in a random sample of 714 subjects to measure the IL6 plasma level. Analysis of variance, logistic regression, and Cox proportional hazard models--adjusted for age, gender, pack years, and BMI--were used for analyses., Results: High levels of IL6 (>2.4 pg/ml, the highest tertile) were associated with a three-fold increased risk of developing COPD, in comparison to low levels (<1.4 pg/ml, the lowest tertile). The rs2056576 SNP was associated with a 10% increase in the risk of COPD per additional T allele. However, the association was no longer significant after adjustment. No association was found with other common SNPs in the IL6 gene and COPD., Conclusions: Although increased IL6 plasma levels at baseline are associated with the risk of developing COPD during follow-up, there was no strong evidence for an association between common variation in the IL6 gene and the risk of COPD., (Copyright © 2011 S. Karger AG, Basel.)

Purpose: Antiepileptic drug (AED) use in young people is increasing. However, evidence of its use at a multinational level is limited. This study aims to characterize AED prescribing in the young in three European countries and to assess the capacity of drug safety surveillance., Methods: A retrospective cohort study was conducted in 2001-2005 using primary care databases: PEDIANET (Italy, 0-11 years), IPCI (The Netherlands, 0-18 years), and IMS Disease Analyzer (United Kingdom, 0-18 years). Prescribing prevalence was calculated by country, patient age, and drug type., Results: In 2005, AED prevalence in children (0-11 years) was highest in Italy [3.9 subjects/1,000 person-years (PY)] followed by the United Kingdom (3.0 subjects/1,000 PY) and The Netherlands (2.2 subjects/1,000 PY). Over the study period, prescribing prevalence in 0-11 year olds was stable in all countries. In contrast, a steady rise of AED prevalence was observed in adolescents (12-18 years) in the United Kingdom (p = 0.0003) but not in The Netherlands (p = 0.88). All countries showed a slight increase in prevalence for newer AEDs. Simultaneously, the prevalence of conventional AEDs decreased in The Netherlands and Italy, but not in the United Kingdom. In 2005, lamotrigine use was highest in The Netherlands and the United Kingdom, whereas topiramate was favored in Italy., Discussion: In Europe, conventional AEDs are still the main treatment choice for children with epilepsy, and the use of newer AEDs remains low. Our study highlights a lack of research capacity to conduct multinational AED safety studies in children. Further work should explore large databases and other health care settings to meet these research needs.

Childhood eczema is common in infants, but its nature and extent during later childhood remains unclear. In this cross-sectional study we examined the prevalence and characteristics of eczema in an unbiased community population of 2,021 Belgian schoolchildren, aged 3.4 to 14.8 years with skin prick testing and parental questionnaires. Our study identified an eczema prevalence of 23.3% and a considerable allergic comorbidity, mainly in sensitized children. The reported prevalence of eczema in infancy was 18.5% and for current eczema 11.6%. The overall sensitization rate (33.2%) as well as sensitization rates for the individual allergens were significantly higher in children with "eczema ever." Sensitization to Dermatophagoides pteronyssinus (19.6%), mixed grass pollen (15.1%), and cat (9.1%) were most common. Until the age of 6 years, boys with eczema were significantly more sensitized than girls (p = 0.007). Children with both eczema in infancy and current eczema show a tendency to be more sensitized than children with eczema in infancy only or current eczema only, but significance was only noted for a few individual allergens. Analysis of factors associated with eczema revealed a predominantly atopic profile characterized by family or personal history of allergy. Breastfeeding and environmental factors seemed to assume little relevance except for a protective effect of prematurity and having a dog at birth.

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by substantial chronic inflammation in the pulmonary compartment as well as in the systemic circulation., Objectives: To investigate potentially causal association, we examined whether serum levels of high-sensitivity C-reactive protein (hsCRP) and variations in the CRP gene are associated with the risk of developing COPD., Methods: This study is part of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55 years or older. At baseline, 6,836 subjects without COPD had a blood sample available for assessment of hsCRP serum levels and haplotypes of the CRP gene. We analyzed the association between hsCRP levels, CRP gene haplotypes, and incident COPD with Cox proportional hazard models, adjusted for age, sex, and other confounders., Measurements and Main Results: High levels of hsCRP (>3 mg/L) were associated with a significantly increased risk of incident COPD (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.16-2.49) compared with persons with low levels (<1 mg/L). The risk remained increased after adjusting for potential confounders and introducing a latency period of 3 years. The risk was most pronounced in former smokers (HR, 2.2; 95% CI, 1.12-3.74). hsCRP was not a risk factor in never smokers. No CRP single nucleotide polymorphism or haplotype was associated with a significantly increased or decreased COPD risk., Conclusions: Increased hsCRP levels are predictive for the occurrence of COPD in smokers. However, haplotypes of the CRP gene, which influence hsCRP levels, are not associated with an altered risk of developing COPD.

Purpose: To identify and describe European health care databases that can be used for pediatric pharmacoepidemiological research., Methods: A web-based survey was conducted among all European databases that were listed on the website of the International Society of Pharmacoepidemiology (ISPE) and/or known by an expert group. The survey comprised of questions regarding (a) the nature of the database, (b) database size, (c) demographic, clinical and drug related data provided, (d) cost, and (e) accessibility of the database., Results: A total of 25 data sources from 12 European countries were identified and invited to participate in the survey. Responses were obtained from 21 (84%) databases located in 10 different European countries. Seventeen databases were included in the assessment comprising a total of at least 9 million children aged 0-18 years. The majority of databases are based on outpatient data and all keep either prescription or drug dispensing data. Ten databases are based on electronic patient records from primary care physicians and five databases are predominantly claims oriented. Three databases do not belong to either of the above mentioned categories. Almost all of the databases can be used for pediatric drug utilization studies. For drug safety studies it is more appropriate to use electronic patient record databases because of the available clinical information and the potential to obtain additional information., Conclusions: There are many European healthcare databases providing an enormous potential for pediatric pharmacoepidemiological research. Future research should focus on methods to bring data from different databases together to use the full capacity effectively., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Objective: To provide an overview of drug use in children in three European countries., Design: Retrospective cohort study, 2000-5., Setting: Primary care research databases in the Netherlands (IPCI), United Kingdom (IMS-DA), and Italy (Pedianet)., Participants: 675 868 children aged up to 14 (Italy) or 18 (UK and Netherlands)., Main Outcome Measure: Prevalence of use per year calculated by drug class (anatomical and therapeutic). Prevalence of "recurrent/chronic" use (three or more prescriptions a year) and "non-recurrent" or "acute" use (less than three prescriptions a year) within each therapeutic class. Descriptions of the top five most commonly used drugs evaluated for off label status within each anatomical class., Results: Three levels of drug use could be distinguished in the study population: high (>10/100 children per year), moderate (1-10/100 children per year), and low (<1/100 children per year). For all age categories, anti-infective, dermatological, and respiratory drugs were in the high use group, whereas cardiovascular and antineoplastic drugs were always in the low use group. Emollients, topical steroids, and asthma drugs had the highest prevalence of recurrent use, but relative use of low prevalence drugs was more often recurrent than acute. In the top five highest prevalence drugs topical inhaled and systemic steroids, oral contraceptives, and topical or systemic antifungal drugs were most commonly used off label., Conclusion: This overview of outpatient paediatric prescription patterns in a large European population could provide information to prioritise paediatric therapeutic research needs.

Purpose: To evaluate the extent, characteristics and determinants of adverse drug reaction (ADR)-related hospitalisations on a population-based level in 2003., Methods: We performed a cohort study in the Integrated Primary Care Information (IPCI) database, a general practitioners (GPs) research database with longitudinal data from electronic patient records of a group of 150 GP throughout the Netherlands. Hospital discharge letters and patient records were reviewed to evaluate ADR-related hospitalisations applying WHO causality criteria. The prevalence of ADR-related hospitalisations per total admissions and the incidence per drug group were calculated. Avoidability and seriousness of the ADRs causing admission were assessed applying the algorithm from Hallas., Results: We identified 3515 hospital admissions, 1277 elective and 2238 acute. Of the acute admissions, 115 were caused by an ADR giving a prevalence of 5.1% (95% confidence intervals (CI): 4.3-6.1%). The prevalence of ADR-related acute admissions increased with age up to 9.8% (95%CI: 7.5-12.7) for persons >75 years. The ADRs that most frequently caused hospitalisations were gastro-intestinal bleeding with anti-thrombotics, bradycardia/hypotension with cardiovascular drugs and neutropenic fever with cytostatics. The incidence rate of ADR-related hospitalisations per drug group was highest for anti-thrombotics and anti-infectives and was relatively low for cardiovascular drugs. Fatality as a direct consequence of the ADR-related admission was 0.31%. In elderly patients 40% of the ADRs causing hospitalisation were judged to be avoidable., Conclusions: The extent and potential avoidability of ADR-related hospitalisations is still substantial, especially in elderly patients. Measures need to be put into place to reduce the burden of ADRs.