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Rationale: Research suggests that respiratory and cardiovascular drugs can ameliorate the rate of lung function decline. Objectives: To investigate the impact of respiratory and cardiovascular pharmacotherapy on lung function trajectories in the general population. Methods: Repeated spirometry was performed in the Rotterdam Study, a population-based cohort of adults aged ≥45 years. Exposure to long-acting beta2-agonists (LABA), long-acting muscarinic antagonists (LAMA), inhaled corticosteroids (ICS), cardioselective beta-blockers, calcium channel blockers, ACE-inhibitors, angiotensin-II receptor blockers, and statins was quantified from pharmacy records to account for therapy adherence. Propensity-score matching and multinomial logistic regression were performed to model medication effects on lung function trajectories, which were previously identified based on FEV 1 and FVC patterns. Models were additionally stratified by genetic variation in each drug target. Measurement and Main Results: Among 3,783 individuals, 2,974 (78.6%) were classified as normal lung function decliners, 432 (11.4%) as rapid decliners, and 377 (10.0%) as improvers. Exposure to LABA (odds ratio (OR) =1.09 [95%-CI: 1.03-1.16] per 10% increase in exposure), ICS (OR=1.08 [95%-CI: 1.02-1.14]), and statins (OR=1.04 [95%-CI: 1.02-1.06]) significantly increased the odds of being an improver compared to a normal decliner. Beta 1 -blocker use was associated with higher odds of being a rapid decliner (OR=1.04 [95%-CI: 1.00-1.09]), which was driven by incident users. Pharmacogenetic analysis suggests that the effects of LABA, ICS, and beta 1 -blockers are dependent on genetic variation in their drug targets. Conclusions: Our study suggests that LABA, ICS, and statins may favorably modulate lung function trajectories in adults, while initiation of beta 1 -blockers was associated with rapid lung function decline.

Background: Assessing medication adherence is crucial in chronic obstructive pulmonary disease (COPD) management to prevent exacerbations. However, it is unclear whether this association between adherence and exacerbations is influenced by the adherence assessment methods or thresholds used. Electronic healthcare databases are valuable to study exacerbations and adherence in real life. We aimed to systematically review the literature to identify adherence assessment methods and thresholds used in healthcare databases when investigating the association between medication adherence and COPD exacerbations and to meta-analyse the associated effect sizes., Method: MEDLINE, Web of Science and Embase were searched for peer-reviewed articles, written in English, published up to 10 October 2022 (PROSPERO: CRD42022363449). Two reviewers independently conducted screening for inclusion and performed data extraction. A qualitative approach described the adherence assessment methods and thresholds used. A quantitative approach (meta-analysis using random effects model) estimated the association between adherence and the risk of COPD exacerbations., Results: Eight studies were included in the systematic review of which five studies were included in the meta-analysis. The medication possession ratio (MPR) and the proportion of days covered (PDC) were the adherence assessment methods used and 0.80 was always used as threshold to differentiate good from poor adherence. Adherence and exacerbations were mostly measured over the same time period. Poor adherence (MPR or PDC<0.80) was significantly associated with a higher COPD exacerbation risk (OR 1.40, 95% CI 1.21 to 1.62, I 2 =85%), regardless of the adherence assessment method used. Results were consistent when stratified by exacerbation severity. Poor adherence was also associated with a time-dependent risk of COPD exacerbations (incidence rate ratio 1.31, 95% CI 1.17 to 1.46)., Conclusion: Our systematic review with meta-analysis demonstrated a 40% increased risk of COPD exacerbations in case of poor adherence to inhaler medication., Prospero Registration Number: CRD42022363449., Competing Interests: Competing interests: Outside this manuscript, LL received a consulting fee paid to her institution from AstraZeneca, GSK and Sanofi and has given a lecture sponsored by Chiesi. Outside this manuscript, LL and MG have given lectures sponsored by IPSA vzw, a non-profit organisation facilitating lifelong learning for healthcare providers. Neither author has received any fees personally. LL is an unpaid member of European Respiratory Society and Belgian Respiratory Society, member of Faculty Board of Ghent University–Faculty of Pharmaceutical Sciences and faculty committees., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Polypharmacy in multimorbid older patients with atrial fibrillation (AF) is a risk factor for potentially inappropriate prescribing (PIP). We aimed to systematically assess the evidence on the prevalence of PIP and its impact on adverse health outcomes in this patient group., Methods: A systematic search of the published peer-reviewed literature describing the prevalence of PIP and/or its association with adverse health outcomes in multimorbid (AF plus one comorbidity) and polymedicated (≥ 2 drugs) adults ≥ 65 years was done up to March 2023. A meta-analysis of the prevalence of PIP of (direct) oral anticoagulants ((D)OACs) was conducted using a random-effects model. Leave-one-out analysis was performed with R (version 4.2.2) and RStudio (version 2022.12.0+353)., Results: Of the 12 studies included, only one reported on the prevalence of overall PIP (65%). The meta-analysis of 10 studies assessing PIP of (D)OACs produced a pooled prevalence [95% confidence interval (CI)] of 35% [30-40%], with significant heterogeneity between the included studies (I 2 95%). No statistically significant association was reported in three studies between PIP of (D)OACs, cardiovascular (CV) and all-cause mortality, hospital readmission, CV hospitalisation and stroke. Reported associations between PIP and major bleeding differed, with one study demonstrating a significant association (odds ratio 2.17; 95% CI 1.14-4.12) and the other study not showing such association., Conclusion: This systematic review highlights the scarce evidence regarding the prevalence of PIP and its association with adverse health outcomes in multimorbid older adults with AF. Large, prospective and better-designed studies are needed., (© 2023. The Author(s).)

Background: The Global Initiative for Chronic Obstructive Lung Disease 2023 report recommends medication adherence assessment in COPD as an action item. Healthcare databases provide opportunities for objective assessments; however, multiple methods exist. We aimed to systematically review the literature to describe existing methods to assess adherence in COPD in healthcare databases and to evaluate the reporting of influencing variables., Method: We searched MEDLINE, Web of Science and Embase for peer-reviewed articles evaluating adherence to COPD medication in electronic databases, written in English, published up to 11 October 2022 (PROSPERO identifier CRD42022363449). Two reviewers independently conducted screening for inclusion and performed data extraction. Methods to assess initiation (dispensing of medication after prescribing), implementation (extent of use over a specific time period) and/or persistence (time from initiation to discontinuation) were listed descriptively. Each included study was evaluated for reporting variables with an impact on adherence assessment: inpatient stays, drug substitution, dose switching and early refills., Results: 160 studies were included, of which four assessed initiation, 135 implementation and 45 persistence. Overall, one method was used to measure initiation, 43 methods for implementation and seven methods for persistence. Most of the included implementation studies reported medication possession ratio, proportion of days covered and/or an alteration of these methods. Only 11% of the included studies mentioned the potential impact of the evaluated variables., Conclusion: Variations in adherence assessment methods are common. Attention to transparency, reporting of variables with an impact on adherence assessment and rationale for choosing an adherence cut-off or treatment gap is recommended., Competing Interests: Conflict of interest: Outside this manuscript, J.K. Quint received grants paid to her institution from the Medical Research Council, Health Data Research UK, GlaxoSmithKline, Boehringer Ingelheim, Asthma + Lung UK and AstraZeneca, and consulting fees from GlaxoSmithKline, Evidera, AstraZeneca and Insmed. None of which are related to the content of this work. Outside this manuscript, K. Verhamme received unconditional research grants paid to her institution from Chiesi, Amgen, Union Chimique Belge (UCB), Johnson & Johnson (J&J) and the European Medicines Agency (EMA). None of which are related to the content of this work. Outside this manuscript, L. Lahousse received a consulting fee paid to her institution from AstraZeneca and honoraria for lectures paid to her institution from Chiesi and IPSA vzw, a non-profit organisation facilitating lifelong learning for healthcare providers. L. Lahousse is an unpaid member of European Respiratory Society and Belgian Respiratory Society, member of Faculty board of Ghent University – Faculty of Pharmaceutical Sciences and faculty committees. None of which are related to the content of this work. All other authors declare no competing interests., (Copyright ©The authors 2023.)

Purpose: Poor adherence to non-vitamin K antagonist oral anticoagulants (NOACs) may raise thromboembolic risks in patients with atrial fibrillation (AF). However, the minimal adherence to maintain the protective effect of NOACs is currently unknown. Therefore, we investigated thresholds of NOAC adherence in association with thromboembolic and mortality risks., Methods: Patients with AF initiating NOACs between 2013 and 2019 were identified in Belgian nationwide data. Adherence was measured using the proportion of days covered (PDC) after one year of treatment. Inverse probability of treatment weighted Cox regression was used to investigate outcomes., Results: 92,111 persons were included (250,750 person-years). Compared to NOAC users with a one-year PDC of 100%, significantly higher risks of stroke or systemic embolism were observed among NOAC users with PDCs of 85-89% (adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) (1.19-1.54)), 80-84% (aHR 1.31, 95%CI (1.08-1.58)) and < 80% (aHR 1.64, 95%CI (1.34-2.01)), while no significant differences were observed among NOAC users with one-year PDCs of 95-99% (aHR 1.02, 95%CI (0.94-1.12)) or 90-94% (aHR 1.06, 95%CI (0.95-1.18)). Significantly higher risks of all-cause mortality were observed with decreasing levels of NOAC adherence, which were already higher among NOAC users with a one-year PDC of 90-94% versus 100% (aHR 1.09, 95%CI (1.01-1.17)). Findings were similar with once-daily and twice-daily dosed NOACs., Conclusion: Poor adherence to NOACs is associated with increased risks of thromboembolism and all-cause mortality. The minimal adherence threshold should be ≥ 90%, preferably even ≥ 95%., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly preferred over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management. However, differences in oral anticoagulant (OAC) prescribing according to patient's age, sex and physician's specialty may be present. Therefore, incident and prevalent use of OACs, NOACs and VKAs, stratified by age, sex and prescriber, and factors associated with the choice of OAC were investigated., Methods: Using two Belgian nationwide healthcare databases, AF patients ≥45 years old with ≥1 OAC prescription claim between 2013 and 2019 were identified. OAC use was investigated per half-year. Factors influencing NOAC vs. VKA initiation were identified by multivariable logistic regression., Results: Among 448 661 included OAC-treated AF patients, 297 818 were newly treated. Incident OAC use ranged from 45-49 to 42-44 users/10 000 persons between 2013 and 2019, whereas prevalent OAC use increased from 337 to 435 users/10 000 persons. Incident and prevalent NOAC use exceeded VKA use since 2013 and 2015, respectively, and NOACs represented 92% of incident and 81% of prevalent OAC users in 2019. Apixaban was the most frequently used NOAC since 2016. NOACs were significantly more prescribed by cardiologists and to older patients, whereas VKAs were more initiated in patients with cardiovascular, renal and hepatic comorbidities. Prevalent OAC use increased less in women than men (25.3% vs. 33.0% between 2013 and 2019) and female subjects had 5% significantly lower odds of NOAC vs. VKA initiation than men., Conclusion: Since 2013, prevalent anticoagulant use increased almost one third in Belgium, while incident use was stable. Potential (N)OAC underuse in women requires further exploration., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)