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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.)

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.)