Detection and management of clinically relevant drug-drug interactions with direct oral anticoagulants: an intervention study in community pharmacies.

INTRODUCTION: Direct oral anticoagulants (DOACs) are increasingly used and can be involved in clinically relevant drug-drug interactions (DDIs) that increase the risk of major bleeding or thromboembolism. Skilled drug interaction management is essential to ensure safe and effective use of DOACs. In this study, we aimed to investigate the impact of the detection and management of DDIs with DOACs in a real-life community pharmacy setting on the pharmacotherapy of DOAC users. METHODS: We conducted an intervention study in 201 community pharmacies in Belgium. On random days, patients purchasing DOACs or drugs known to interact with them were screened. When a DDI with the DOAC was detected, the pharmacist contacted the prescribing physician to discuss the management of the interaction. A previously developed practice-oriented DDI list accompanied by management plans for ambulatory care was used for both screening and management of the DDIs. RESULTS: In total, 751 patients were included, among whom 875 DDIs were identified, primarily pharmacodynamic DDIs (95.7 %). Predominant interacting drug classes included selective serotonin or serotonin and norepinephrine reuptake inhibitors (32.9 %), antiplatelets (30.9 %), and non-steroidal anti-inflammatory drugs (28.9 %). In 43.0 % of DDIs, an intervention was decided upon. At three-month follow-up, proposed pharmacotherapy changes had been implemented in 79.1 % of these DDIs. CONCLUSIONS: This study demonstrates that active screening and management of DDIs with DOACs in community pharmacies, in close collaboration with prescribing physicians, resulted in changes in pharmacotherapy in a substantial number of patients. This may contribute significantly to the safer utilisation of DOACs in high-risk populations.

Rhinitis control and medication use in a real-world sample of patients with persistent rhinitis or rhinosinusitis: a community pharmacy study.

BACKGROUND: Little is known about rhinitis control in real-life, nor about the contribution of treatment-related and patient-related factors. OBJECTIVE: This study aimed to examine the level of rhinitis control and rhinitis medication utilization in patients with persistent rhinitis, and to identify predictors of rhinitis control. METHODS: A cross-sectional observational study was conducted in patients with persistent rhinitis recruited in community pharmacies. Participants completed the Rhinitis Control Assessment Test (RCAT), and a questionnaire on patient/rhinitis characteristics, and rhinitis medication use. A visual analogue scale (VAS) for nasal symptoms was also completed. Pharmacy dispensing data was used to calculate adherence to intranasal glucocorticoids. Nasal spray technique was evaluated using a standardized checklist. Predictors of rhinitis control were explored using a linear regression model. RESULTS: A total of 1514 patients, recruited in 215 pharmacies, participated in the study (mean age 48.7 years, 62% female). Almost 60% exhibited suboptimal rhinitis control (RCAT ≤ 21/30). A 50mm cut-off on the VAS yielded 78.1% sensitivity to identify suboptimal rhinitis control. Participants most frequently used intranasal glucocorticoids (55.6%) and intranasal decongestants (47.4%). Only 10.3% of current nasal spray users demonstrated perfect technique. More than half (54.8%) of glucocorticoid users were identified as underadherent. Female sex, self-reported nasal hyperreactivity, active asthma, and use of oral/intranasal decongestants or nasal saline were identified as predictors of worse rhinitis control. CONCLUSION: Suboptimal rhinitis control was common in this real-life sample of persistent rhinitis patients. Improving use of rhinitis medication may be key to increase disease control.

Lung-function trajectories: relevance and implementation in clinical practice.

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.

The AGE-RAGE axis associates with chronic pulmonary diseases and smoking in the Rotterdam study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma associate with high morbidity and mortality. High levels of advanced glycation end products (AGEs) were found in tissue and plasma of COPD patients but their role in COPD and asthma is unclear. METHODS: In the Rotterdam Study (n = 2577), AGEs (by skin autofluorescence (SAF)), FEV1 and lung diffusing capacity (DLCOc and DLCOc /alveolar volume [VA]) were measured. Associations of SAF with asthma, COPD, GOLD stage, and lung function were analyzed using logistic and linear regression adjusted for covariates, followed by interaction and stratification analyses. sRAGE and EN-RAGE associations with COPD prevalence were analyzed by logistic regression. RESULTS: SAF associated with COPD prevalence (OR = 1.299 [1.060, 1.591]) but not when adjusted for smoking (OR = 1.106 [0.89, 1.363]). SAF associated with FEV1% predicted (ß=-3.384 [-4.877, -1.892]), DLCOc (ß=-0.212 [-0.327, -0.097]) and GOLD stage (OR = 4.073, p = 0.001, stage 3&4 versus 1). Stratified, the association between SAF and FEV1%predicted was stronger in COPD (ß=-6.362 [-9.055, -3.670]) than non-COPD (ß=-1.712 [-3.306, -0.118]). Association of SAF with DLCOc and DLCOc/VA were confined to COPD (ß=-0.550 [-0.909, -0.191]; ß=-0.065 [-0.117, -0.014] respectively). SAF interacted with former smoking and COPD prevalence for associations with lung function. Lower sRAGE and higher EN-RAGE associated with COPD prevalence (OR = 0.575[0.354, 0.931]; OR = 1.778[1.142, 2.768], respectively). CONCLUSIONS: Associations between SAF, lung function and COPD prevalence were strongly influenced by smoking. SAF associated with COPD severity and its association with lung function was more prominent within COPD. These results fuel further research into interrelations and causality between SAF, smoking and COPD. TAKE-HOME MESSAGE: Skin AGEs associated with prevalence and severity of COPD and lung function in the general population with a stronger effect in COPD, calling for further research into interrelations and causality between SAF, smoking and COPD.

Clinical relevance of lung function trajectory clusters in middle-aged and older adults.

Background: The determinants and health outcomes of lung function trajectories in adults among the general population are poorly understood. We aimed to identify and characterise clusters of lung function trajectories in adults aged ≥45 years. Methods: Gaussian finite-mixture modelling was applied to baseline and annualised change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio z-scores in participants of the Rotterdam Study, a prospective population-based cohort study, with repeated spirometry (n=3884; mean±sd age 64.7±8.9 years). Longitudinal outcomes were all-cause mortality, respiratory outcomes (symptoms, COPD (FEV1/FVC <0.7 in absence of asthma), preserved ratio impaired spirometry (PRISm; FEV1/FVC ≥0.7 and FEV1 or FVC <80%)), smoking cessation and weight changes. Independent risk factors, including genetics, were identified by multiple logistic regression. Results: We identified eight trajectory clusters, with the reference group having persistently normal spirometry (prevalence 42.8%). Three clusters showed higher mortality, adjusted for confounders: 1) the persistently low FEV1 cluster (prevalence 6.8%, hazard ratio (HR) 1.71, 95% CI 1.37-2.13); 2) rapid FEV1 decliners (prevalence 4.6%, HR 1.48, 95% CI 1.10-1.99); and 3) FVC decliners (prevalence 3.7%, HR 1.49, 95% CI 1.09-2.03). In contrast, FVC improvers (prevalence 6.7%, HR 0.61, 95% CI 0.41-0.90) and persistently high FEV1 (prevalence 29.2%, HR 0.82, 95% CI 0.69-0.98) were protective trajectory clusters. Clusters were characterised by differences in genetic predisposition (polygenic scores of FEV1 and FEV1/FVC), demographics, cigarette smoking, respiratory symptoms (chronic cough, wheezing and dyspnoea), cardiovascular factors (body mass index, hypertension and heart failure) and serum C-reactive protein levels. Frailty, weight changes and the development of respiratory symptoms, COPD and PRISm were significantly associated with trajectory clusters. Conclusions: This study reveals clinically relevant lung function trajectory clusters in older adults of the general population.

Asthma exacerbations and eosinophilia in the UK Biobank: a genome-wide association study.

Background: Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g. T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk. Methods: UK Biobank data were used to perform a genome-wide association study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalisation data and general practitioner records. Exacerbations were identified as either asthma-related hospitalisation, general practitioner record of asthma exacerbation or an oral corticosteroid burst prescription. A logistic regression model adjusted for age, sex, smoking status and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (p<5×10-6) in the GERA cohort. Results: In the UK Biobank, we identified 11 604 cases and 37 890 controls. While no variants reached genome-wide significance (p<5×10-8) in the primary analysis, 116 signals were suggestively significant (p<5×10-6). In GERA, two single nucleotide polymorphisms (rs34643691 and rs149721630) replicated (p<0.05), representing signals near the NTRK3 and ABCA13 genes. Conclusions: Our study has identified reproducible associations with asthma exacerbations in the UK Biobank and GERA cohorts. Confirmation of these findings in different asthma subphenotypes in diverse ancestries and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.

Impact of frailty on the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a nationwide cohort study.

AIMS: Data on non-vitamin K antagonist oral anticoagulants (NOACs) use in patients with atrial fibrillation (AF) and frailty are scarce. Therefore, the impact of frailty on AF-related outcomes and benefit-risk profiles of NOACs in patients with frailty were investigated. METHODS AND RESULTS: AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Frailty was assessed with the Claims-based Frailty Indicator. Among 254 478 anticoagulated AF patients, 71 638 (28.2%) had frailty. Frailty was associated with higher all-cause mortality risks [adjusted hazard ratio (aHR) 1.48, 95% confidence interval (CI) (1.43-1.54)], but not with thromboembolism or bleeding. Among subjects with frailty (78 080 person-years of follow-up), NOACs were associated with lower risks of stroke or systemic embolism (stroke/SE) [aHR 0.77, 95%CI (0.70-0.86)], all-cause mortality [aHR 0.88, 95%CI (0.84-0.92)], and intracranial bleeding [aHR 0.78, 95%CI (0.66-0.91)], a similar major bleeding risk [aHR 1.01, 95%CI (0.93-1.09)], and higher gastrointestinal bleeding risk [aHR 1.19, 95%CI (1.06-1.33)] compared with VKAs. Major bleeding risks were lower with apixaban [aHR 0.84, 95%CI (0.76-0.93)], similar with edoxaban [aHR 0.91, 95%CI (0.73-1.14)], and higher with dabigatran [aHR 1.16, 95%CI (1.03-1.30)] and rivaroxaban [aHR 1.11, 95%CI (1.02-1.21)] compared with VKAs. Apixaban was associated with lower major bleeding risks compared with dabigatran [aHR 0.72, 95%CI (0.65-0.80)], rivaroxaban [aHR 0.78, 95%CI (0.72-0.84)] and edoxaban [aHR 0.74, 95%CI (0.65-0.84)], but mortality risk was higher compared with dabigatran and edoxaban. CONCLUSION: Frailty was an independent risk factor of death. Non-vitamin K antagonist oral anticoagulants had better benefit-risk profiles than VKAs in patients with frailty, especially apixaban, followed by edoxaban.

Potentially inappropriate prescribing in multimorbid and polymedicated older adults with AF: A Systematic Review and Meta-Analysis.

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 (I2 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.

The Impact of Polypharmacy on the Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation.

BACKGROUND: Polypharmacy may affect outcomes in patients with atrial fibrillation (AF) using non-vitamin K antagonist oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) due to interactions or reduced adherence, but comparative data are lacking. Therefore, the impact of polypharmacy on AF-related outcomes and benefit-risk profiles of NOACs in patients with polypharmacy were investigated. METHODS: AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate outcomes. RESULTS: Among 254,478 AF patients, 167,847 (66.0%) used ≥5 drugs. Polypharmacy was associated with higher stroke or systemic embolism (stroke/SE) (adjusted hazard ratio [aHR]: 1.08, 95% confidence interval [CI]: 1.02-1.15), all-cause mortality (aHR: 1.45, 95% CI: 1.40-1.50), and major bleeding risks (aHR: 1.29, 95% CI: 1.23-1.35). Among patients with polypharmacy, NOACs were associated with lower stroke/SE (aHR: 0.68, 95% CI: 0.63-0.73), all-cause mortality (aHR: 0.80, 95% CI: 0.77-0.84), major bleeding (aHR: 0.92, 95% CI: 0.87-0.97), and intracranial bleeding risks (aHR: 0.77, 95% CI: 0.69-0.85), but higher gastrointestinal bleeding risks (aHR: 1.10, 95% CI: 1.01-1.19) compared to VKAs. Major bleeding risks were lower with apixaban (aHR: 0.79, 95% CI: 0.74-0.85), but nonsignificantly different with other NOACs compared to VKAs. Lower major bleeding risks were observed with dabigatran (aHR: 0.91, 95% CI: 0.85-0.97) and apixaban (aHR: 0.77, 95% CI: 0.73-0.81) compared to rivaroxaban, and with apixaban compared to dabigatran (HR: 0.83, 95% CI: 0.77-0.90) and edoxaban (HR: 0.77, 95% CI: 0.70-0.85). CONCLUSION: Polypharmacy was associated with increased thromboembolic, bleeding, and mortality risks in AF patients. NOACs had better benefit-risk profiles than VKAs in patients with polypharmacy.

Descriptive analysis on disproportionate medication errors and associated patient characteristics in the Food and Drug Administration's Adverse Event Reporting System.

BACKGROUND: Medication errors (MEs) are a major public health concern which can cause harm and financial burden within the healthcare system. Characterizing MEs is crucial to develop strategies to mitigate MEs in the future. OBJECTIVES: To characterize ME-associated reports, and investigate signals of disproportionate reporting (SDRs) on MEs in the Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: FAERS data from 2004 to 2020 was used. ME reports were identified with the narrow Standardised Medical Dictionary for Regulatory Activities® (MedDRA®) Query (SMQ) for MEs. Drug names were converted to the Anatomical Therapeutic Chemical (ATC) classification. SDRs were investigated using the reporting odds ratio (ROR). RESULTS: In total 488 470 ME reports were identified, mostly (59%) submitted by consumers and mainly (55%) associated with females. Median age at time of ME was 57 years (interquartile range: 37-70 years). Approximately 1 out of 3 reports stated a serious health outcome. The most prevalent reported drug class was "antineoplastic and immunomodulating agents" (25%). The most common ME type was "incorrect dose administered" (9%). Of the 1659 SDRs obtained, adalimumab was the most common drug associated with MEs, noting a ROR of 1.22 (95% confidence interval: 1.21-1.24). CONCLUSION: This study offers a first of its kind characterization of MEs as reported to FAERS. Reported MEs are frequent and may be associated with serious health outcomes. This FAERS data provides insights on ME prevention and offers possibilities for additional in-depth analyses.

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities. METHODS: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed. RESULTS: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits. CONCLUSION: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.

The role of community pharmacists in primary and secondary prevention of skin cancer: an evaluation of a Flemish skin cancer prevention campaign.

BACKGROUND: Skin cancer is a leading form of cancer in Belgium. Prevention of skin cancer by community pharmacists can play a role in increasing awareness and promoting sun protection. However, which persons could be reached by community pharmacists for skin cancer awareness in Belgium and whether this increased awareness is associated with increased sun protection and early detection remains unclear. METHODS: Demographics of approached persons in Flemish community pharmacies during the months of May-June 2022 and the content of the skin cancer counseling were retrieved from the pharmacy database. Sunscreen purchases and dermatologist visits were evaluated up to 180 days after the skin cancer counseling. RESULTS: Community pharmacists provided skin cancer counseling to a broad population of visitors (n = 822, 69% females, median age of 59 years Q1-Q3: 44-71 years). During the campaign, 822 visitors received a leaflet with skin cancer prevalence and sunscreen importance. On top of that, 335 visitors (41%) received additional counseling: skin type sensitivity was checked for 198 visitors (24%), typical characteristics of melanoma were discussed with 100 visitors (12%) and 37 visitors (5%) were referred to a physician for further information or concerns regarding a skin spot. Overall, one out of three visitors purchased sunscreen on the day of the counseling (33%, increasing up to 38% after 180 days). Among people under 20 years, this was even higher (51%). Additional counseling increased the likelihood of a dermatologist visit within 180 days (OR = 1.80; 95%CI: 1.12-2.88). CONCLUSIONS: By providing skin cancer counseling in Belgian community pharmacies, a broad range of citizens was reached and triggered to purchase sunscreen, often on the same day as the counseling. Notably, young people were likely to purchase sunscreen. Citizens receiving additional counseling were more likely to visit a dermatologist within 180 days.

Pharmacodynamic Drug-Drug Interactions and Bleeding Outcomes in Patients with Atrial Fibrillation Using Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study.

PURPOSE: Pharmacodynamic drug-drug interactions (PD DDIs) may influence the safety of non-vitamin K antagonist oral anticoagulants (NOACs), but the extent to which PD DDIs increase bleeding risks, remains unclear. Therefore, the impact of PD DDIs on bleeding outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated. METHODS: Using Belgian nationwide data, NOAC-treated AF patients were included between 2013-2019. Concomitant use of PD interacting drugs when initiating NOAC treatment was identified. RESULTS: Among 193,072 patients, PD DDIs were identified in 114,122 (59.1%) subjects. After multivariable adjustment, concomitant use of PD interacting drugs was associated with significantly higher risks of major or clinically-relevant non-major bleeding (adjusted hazard ratio (aHR) 1.19, 95% confidence interval (CI) (1.13-1.24)), gastrointestinal (aHR 1.12, 95%CI (1.03-1.22)), urogenital (aHR 1.21, 95%CI (1.09-1.35)) and other bleeding (aHR 1.28, 95%CI (1.20-1.36)), compared to NOAC-treated AF patients without PD interacting drug use. Increased bleeding risks were most pronounced with P2Y12 inhibitors (aHR 1.62, 95%CI (1.48-1.77)) and corticosteroids (aHR 1.53, 95%CI (1.42-1.66)), followed by selective serotonin or serotonin and norepinephrine reuptake inhibitors (SSRI/SNRI, aHR 1.26, 95%CI (1.17-1.35)), low-dose aspirin (aHR 1.14, 95%CI (1.08-1.20)) and non-steroidal anti-inflammatory drugs (NSAID, aHR 1.10, 95%CI (1.01-1.21)). Significantly higher intracranial bleeding risks in NOAC users were observed with SSRI/SNRIs (aHR 1.50, 95%CI (1.25-1.81)) and corticosteroids (aHR 1.49, 95%CI (1.21-1.84)). CONCLUSION: Concomitant use of PD interacting drugs, especially P2Y12 inhibitors and corticosteroids, was associated with higher major, gastrointestinal, urogenital, and other bleeding risks in NOAC-treated AF patients. Remarkably, higher intracranial bleeding risks were observed with SSRI/SNRIs and corticosteroids.

Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants: a nationwide cohort study.

AIMS: The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated. METHODS AND RESULTS: AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality. CONCLUSION: Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks.

Methods to assess COPD medications adherence in healthcare databases: a systematic review.

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.

Oral corticosteroid use and sarcopenia-related traits in older people with chronic airway disease: a population-based study.

Background: Sarcopenia is characterised by two major phenotypic components: low handgrip strength (HGS) and appendicular skeletal muscle index (ASMI). Oral corticosteroid (OCS) use is an important medication for acute respiratory exacerbations in patients with COPD and asthma. However, the association of OCS and sarcopenia components in older people is largely unexplored. The aim of this study was to examine the association between OCS use and HGS or ASMI in the general population and explore interactions with chronic airway diseases. Methods: From the population-based Rotterdam Study, 5054 participants (age 69.0±8.8 years; 56% females) were included in the cross-sectional analysis and 1324 in the longitudinal analysis. Associations between OCS and muscle strength and mass were analysed using linear regression models adjusted for age, sex, fat %, height, kidney function, smoking and comorbidities. Results: At baseline, ever-OCS users had lower handgrip strength (ß= -0.48, 95% CI -0.84- -0.12) than never-OCS users, with cumulative frequency (≥10 OCS prescriptions)-dependent effects (ß= -1.25, 95% CI -2.16- -0.33). COPD ever-OCS users, but not asthma, had lower handgrip strength (ß= -0.98, 95% CI -1.91- -0.06) and lower lean mass (ß= -0.14, 95% CI -0.27- -0.01) than never-OCS users. After 5.6 years of follow-up in those free of sarcopenia traits at baseline, COPD ever-OCS users developed lower handgrip strength (ß= -1.64, 95% CI -2.87- -0.40) with frequency (ß= -3.64, 95% CI -6.57- -0.72) and duration (ß= -1.51, 95% CI -2.87- -0.15) association compared to never-OCS users. Conclusions: OCS use is associated with a decline in handgrip strength in people with COPD in a cumulative frequency and duration-dependent manner. Routine muscle examination may be necessary for patients with COPD.

Minimal Adherence Threshold to Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation to Reduce the Risk of Thromboembolism and Death: A Nationwide Cohort Study.

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%.