Impact of the early COVID-19 pandemic on adult mental health-related dispensed medications, hospitalizations and specialist outpatient visits in Norway and Sweden: Interrupted time series analysis.

AIMS: Norway and Sweden had different early pandemic responses that may have impacted mental health management. The aim was to assess the impact of the early COVID-19 pandemic on mental health-related care. METHODS: We used national registries in Norway and Sweden (1 January 2018-31 December 2020) to define 2 cohorts: (i) general adult population; and (ii) mental health adult population. Interrupted times series regression analyses evaluated step and slope changes compared to prepandemic levels for monthly rates of medications (antidepressants, antipsychotics, anxiolytics, hypnotics/sedatives, lithium, opioid analgesics, psychostimulants), hospitalizations (for anxiety, bipolar, depressive/mood, eating and schizophrenia/delusional disorders) and specialist outpatient visits. RESULTS: In Norway, immediate reductions occurred in the general population for medications (-12% antidepressants to -7% hypnotics/sedatives) except for antipsychotics; and hospitalizations (-33% anxiety disorders to -17% bipolar disorders). Increasing slope change occurred for all medications except psychostimulants (+1.1%/month hypnotics/sedatives to +1.7%/month antidepressants); and hospitalization for anxiety disorders (+5.5%/month), depressive/mood disorders (+1.7%/month) and schizophrenia/delusional disorders (+2%/month). In Sweden, immediate reductions occurred for antidepressants (-7%) and opioids (-10%) and depressive/mood disorder hospitalizations (-11%) only with increasing slope change in psychostimulant prescribing of (0.9%/month). In contrast to Norway, increasing slope changes occurred in specialist outpatient visits for depressive/mood disorders, eating disorders and schizophrenia/delusional disorders (+1.5, +1.9 and +2.3%/month, respectively). Similar changes occurred in the pre-existing mental health cohorts. CONCLUSION: Differences in early COVID-19 policy response may have contributed to differences in adult mental healthcare provision in Norway and Sweden.

Drug utilisation in children and adolescents before and after the start of the COVID-19 pandemic: Interrupted time-series analyses in three European countries.

BACKGROUND: The COVID-19 pandemic has affected children and adolescents in several ways, including worsened mental health, improvement of asthma, and increases in diabetes ketoacidosis. Less is known about how medication use in children and adolescents has been affected by the pandemic. OBJECTIVES: To explore how the COVID-19 pandemic affected drug utilisation in children and adolescents in Norway, Sweden, and Italy, by child age. METHODS: We conducted a longitudinal drug utilisation study among all children and adolescents (<18 years old) in Norway and Sweden and a nationwide paediatric database covering 3% of the paediatric population in Italy. We conducted an interrupted time-series analysis from January 2018 to December 2021, with March 2020 as the interruption point. Dispensing or prescription rates of antidepressants, anxiolytics, sleep medications, attention-deficit/hyperactivity disorder (ADHD) medications, insulin, and asthma medications were examined. RESULTS: The study population in January 2018 consisted of 3,455,521 children and adolescents (136,188 from Italy, 1,160,431 from Norway, and 2,158,902 from Sweden). For sleep medications and insulin, there were only minor changes in level or trend in some age groups after March 2020. For asthma medications, the pandemic was associated with an immediate decrease in dispensing in Norway and Sweden (range of change in level: -19.2 to -3.7 dispensings per 1000 person-months), and an increasing trend in all countries afterward (range of change in trend: 0.3-6.4 dispensings per 1000 person-months), especially for the youngest age groups. Among adolescents, the pandemic was associated with an increased trend for ADHD medications, antidepressants, and anxiolytics in Norway and Sweden, but not in Italy. CONCLUSIONS: The increasing trend of psychotropic medication dispensing, especially among adolescents after the start of the pandemic, is concerning and should be investigated further. Aside from a temporary effect on asthma medication dispensing, the pandemic did not greatly affect the dispensing of the medications investigated.

Incidence of hospital contacts with acute kidney injury after initiation of second-generation antipsychotics in older adults: a Danish population-based cohort study.

PURPOSE: To investigate the association between acute kidney injury (AKI) and use of second-generation antipsychotics (SGA) in older adults. METHODS: In a population-based cohort study using Danish national registries, new users of SGAs (aged ≥ 65) were identified during 2005-2015. Each SGA user was matched to 10 population controls on age, sex, and the SGA initiation date. The outcome was incident AKI within 90 days after the index date. Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: In the study, 36,581 new SGA users and 365,810 controls were included. The 90-day incidence rate of AKI was 4.38 and 1.70 per 1000 person-years among SGA users and controls, respectively, corresponding to a crude HR of 2.57 (1.79-3.68). The fully adjusted HR (aHR) was 1.43 (0.89-2.27) for all SGAs. The risk differed among individual drugs with aHRs for olanzapine 3.50 (1.20-10.23), quetiapine 1.62 (0.81-3.26), and risperidone 0.68 (0.28-1.64). In sensitivity analyses, the aHR declined to 1.24 (0.95-1.61) at 1-year follow-up. CONCLUSIONS: Olanzapine use was associated with a significantly increased 90-day AKI risk. For quetiapine, the risk was elevated but not significant, and risperidone had no association. CIs were wide and confounder adjustment largely impacted the estimates. Main limitations included residual confounding and incomplete recording of AKI diagnoses.

Comparing risk of major bleeding between users of different oral anticoagulants in patients with nonvalvular atrial fibrillation.

AIMS: The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for nonvalvular atrial fibrillation, but observational studies on the benefit-risk balance of DOACs compared to vitamin K antagonists (VKAs) are needed. The aim of this study was to characterize the risk of major bleeding in DOAC users using longitudinal data collected from electronic health care databases from 4 different EU-countries analysed with a common study protocol. METHODS: A cohort study was conducted among new users (≥18 years) of DOACs or VKAs with nonvalvular atrial fibrillation using data from the UK, Spain, Germany and Denmark. The incidence of major bleeding events (overall and by bleeding site) was compared between current use of DOACs and VKAs. Cox regression analysis was used to calculate hazard ratios and 95% confidence intervals (CI) and adjust for confounders. RESULTS/CONCLUSION: Overall, 251 719 patients were included across the 4 study cohorts (mean age ~75 years, % females between 41.3 and 54.3%), with overall hazard ratios of major bleeding risk for DOACs vs VKAs ranging between 0.84 (95% CI: 0.79-0.90) in Denmark and 1.13 (95% CI 1.02-1.25) in the UK. When stratifying according to the bleeding site, risk of gastrointestinal bleeding was increased by 48-67% in dabigatran users and 30-50% for rivaroxaban users compared to VKA users in all data sources except Denmark. Compared to VKAs, apixaban was not associated with an increased risk of gastrointestinal bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban.

Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies.

OBJECTIVE: To establish the risk of major bleeding in direct oral anticoagulant (DOAC) users (overall and by class) versus vitamin K antagonist (VKA) users, using health care databases from four European countries and six provinces in Canada. METHODS: A retrospective cohort study was performed according to a similar protocol. First-users of VKAs or DOACs with a diagnosis of non-valvular atrial fibrillation (NVAF) were included. The main outcome of interest was major bleeding and secondary outcomes included gastrointestinal (GI) bleeding and intracranial haemorrhage (ICH). Incidence rates of events per 1000 person years were calculated. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox proportional hazard regression model. Exposure and confounders were measured and analysed in a time-dependant way. Risk estimates were pooled using a random effect model. RESULTS: 421 523 patients were included. The risk of major bleeding for the group of DOACs compared to VKAs showed a pooled HR of 0.94 (95% CI: 0.87-1.02). Rivaroxaban showed a modestly increased risk (HR 1.11, 95% CI: 1.06-1.16). Apixaban and dabigatran showed a decreased risk of respectively HR 0.76 (95% CI: 0.69-0.84) and HR 0.85 (95% CI: 0.75-0.96). CONCLUSIONS: This study confirms that the risk of major bleeding of DOACs compared to VKAs is not increased when combining all DOACs. However, we observed a modest higher risk of major bleeding for rivaroxaban, whereas for apixaban and dabigatran lower risks of major bleeding were observed compared to VKAs.

Incidence of direct oral anticoagulant use in patients with nonvalvular atrial fibrillation and characteristics of users in 6 European countries (2008-2015): A cross-national drug utilization study.

AIMS: To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European healthcare databases representing 6 European countries. METHODS: Longitudinal drug utilization study from January 2008 to December 2015. A common protocol approach was applied. Annual period incidences and direct standardisation by age and sex were performed. Dose adjustment related to change in age and by renal function as well as concomitant use of potentially interacting drugs were assessed. RESULTS: A total of 186 405 new DOAC users (age ≥18 years) were identified. Standardized incidences varied from 1.93-2.60 and 0.11-8.71 users/10 000 (2011-2015) for dabigatran and rivaroxaban, respectively, and from 0.01-8.12 users/10 000 (2012-2015) for apixaban. In 2015, the DOAC incidence ranged from 9 to 28/10 000 inhabitants in SIDIAP (Spain) and DNR (Denmark) respectively. There were differences in population coverage among the databases. Only 1 database includes the total reference population (DNR) while others are considered a population representative sample (CPRD, BIFAP, SIDIAP, EGB, Mondriaan). They also varied in the type of drug data source (administrative, clinical). Dose adjustment ranged from 4.6% in BIFAP (Spain) to 15.6% in EGB (France). Concomitant use of interacting drugs varied between 16.4% (SIDIAP) and 70.5% (EGB). Cardiovascular comorbidities ranged from 25.4% in Mondriaan (The Netherlands) to 82.9% in AOK Nordwest (Germany). CONCLUSION: Overall, apixaban and rivaroxaban increased its use during the study period while dabigatran decreased. There was variability in patient characteristics such as comorbidities, potentially interacting drugs and dose adjustment. (EMA/2015/27/PH).

Epidemiological surveillance of drug safety using cumulative sequential analysis in electronic healthcare data.

BACKGROUND: Methods for safety signal detection in electronic healthcare data analysing data sequentially are being developed to meet the limitations of spontaneous reporting systems. OBJECTIVES: This study aims to provide an overview of the literature on sequential analysis of electronic healthcare data and describe the development and testing of a novel epidemiological surveillance system. METHODS: We searched Medline, Embase, PubMed, Scopus, Web of Science, and the Cochrane Library applying similar in- and exclusion criteria as those of a previous systematic review. The proposed system consisted of repeated cohort studies and was tested in an emulated prospective setting. Two signal evaluations were performed with several sensitivity analyses and a target trial emulation. FINDINGS: In the literature, 11 studies analysed the data sequentially of which two applied traditional epidemiological methods. Epidemiological surveillance of several exposures and outcomes can be successfully conducted with the newly proposed sequential analysis of electronic healthcare data. Signal evaluation studies confirmed the results of the system. CONCLUSIONS: Very few studies in the literature analysed data at multiple time points, although this seems to be a prerequisite for testing the methods in a realistic setting. We demonstrated the feasibility of a sequential surveillance system using electronic healthcare data.

Comparative effectiveness of heterologous third dose vaccine schedules against severe covid-19 during omicron predominance in Nordic countries: population based cohort analyses.

OBJECTIVE: To investigate the comparative vaccine effectiveness of heterologous booster schedules (ie, three vaccine doses) compared with primary schedules (two vaccine doses) and with homologous mRNA vaccine booster schedules (three vaccine doses) during a period of omicron predominance. DESIGN: Population based cohort analyses. SETTING: Denmark, Finland, Norway, and Sweden, 27 December 2020 to 31 December 2022. PARTICIPANTS: All adults aged ≥18 years who had received at least a primary vaccination schedule of AZD1222 (Oxford-AstraZeneca) or monovalent SARS-CoV-2 wild type (ancestral) strain based mRNA vaccines BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), in any combination. MAIN OUTCOME MEASURES: The main outcome measure was country combined risks of covid-19 related hospital admission and death with covid-19 and additional outcomes of covid-19 related admission to an intensive care unit and SARS-CoV-2 infection. During a period of omicron predominance, these outcomes were compared in those who received a heterologous booster versus primary schedule (matched analyses) and versus those who received a homologous mRNA vaccine booster (weighted analyses). Follow-up was for 75 days from day 14 after the booster dose; comparative vaccine effectiveness was calculated as 1-risk ratio. RESULTS: Across the four Nordic countries, 1 086 418 participants had received a heterologous booster schedule of AZD1222+BNT162b2 or mRNA-1273 and 2 505 093 had received a heterologous booster schedule of BNT162b2+mRNA-1273. Compared with the primary schedule only (two doses), the vaccine effectiveness of heterologous booster schedules comprising AZD1222+BNT162b2 or mRNA-1273 and BNT162b2+mRNA-1273 was 82.7% (95% confidence interval 77.1% to 88.2%) and 81.5% (78.9% to 84.2%) for covid-19 related hospital admission and 95.9% (91.6% to 100.0%) and 87.5% (82.5% to 92.6%) for death with covid-19, respectively. Homologous mRNA booster schedules were similarly associated with increased protection against covid-19 related hospital admission (≥76.5%) and death with covid-19 (≥84.1%) compared with previous primary course vaccination only. When a heterologous booster schedule was compared with the homologous booster schedule, vaccine effectiveness was 27.2% (3.7% to 50.6%) for AZD1222+BNT162b2 or mRNA-1273 and 23.3% (15.8% to 30.8%) for BNT162b2+mRNA-1273 schedules against covid-19 related hospital admission and 21.7% (-8.3% to 51.7%) and 18.4% (-15.7% to 52.5%) against death with covid-19, respectively. CONCLUSION: Heterologous booster schedules are associated with increased protection against severe, omicron related covid-19 outcomes compared with primary course schedules and homologous booster schedules.

Serious arrhythmia in initiators of citalopram, escitalopram, and other selective serotonin reuptake inhibitors: A population-based cohort study in older adults.

The selective serotonin reuptake inhibitors (SSRIs) citalopram and escitalopram are associated with QT prolongation, which increases the risk of serious arrhythmia. Consequently, regulatory agencies issued safety warnings in 2011. This study aimed to investigate the risk of serious arrhythmia following initiation of citalopram or escitalopram compared to other SSRIs and the risk in the periods before and after the warnings were issued. We conducted a series of nationwide cohort studies emulating a target trial using Danish healthcare register data from January 1, 2002, to December 31, 2016. We included patients (aged ≥65 years) who filled an SSRI prescription with a 1-year washout period before the index date. The outcome was an event of serious arrhythmia. Individuals were followed for a maximum of 6 months using an intention-to-treat approach. Log-binomial regression analyses were performed, estimating risk ratios (RRs) and 95% confidence intervals (CIs) adjusting for age and sex, comorbidities, and comedications with propensity scores. Dose-response effects were not investigated because dosage instructions were not available. We included 167,366 (146,014 individuals), 40,113 (37,069 individuals), and 50,281 (44,754 individuals) person-trials of citalopram, escitalopram, and other SSRIs, respectively. In total, there were 228 events of serious arrhythmia. No difference in risk was observed in the entire study period for either citalopram (0.87 [0.62-1.22]) or escitalopram (0.85 [0.53-1.40]). We identified lower point estimates after the safety warning, RR 0.54 (95% CI 0.31-0.93) for citalopram and 0.58 (0.20-1.63) for escitalopram. Initiation of citalopram and escitalopram was not associated with an increased risk of serious arrhythmia. However, lower point estimates were observed after the safety warning.

Investigation of the potential association between the use of fluoxetine and occurrence of acute pancreatitis: a Danish register-based cohort study.

BACKGROUND: There is currently conflicting evidence of the association between the use of selective serotonin reuptake inhibitors (SSRIs) and acute pancreatitis. The SSRI fluoxetine has been suspected to be the driver of this serious outcome. Therefore, this study aims to investigate the potential association between fluoxetine use and the occurrence of acute pancreatitis. METHODS: We conducted a nationwide cohort study using Danish register-based data from 1996 to 2016. The exposed group were new users of fluoxetine (1-year washout). The control subjects were new users of citalopram or SSRIs, excluding fluoxetine. The outcome was an incident diagnosis of acute pancreatitis with a 5-year washout. We used an intention-to-treat approach following patients for a maximum of 6 months. Cox regression analyses were performed, estimating hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age/sex, comorbidities and co-medications, using propensity score adjustment and matching. RESULTS: In the propensity score-matched analyses, 61 783 fluoxetine users were included. The incidence rates among users of fluoxetine and other SSRIs were 5.33 (3.05-8.66) and 5.36 (3.06-8.70) per 10 000 person-years, respectively. No increased risk of acute pancreatitis was identified following fluoxetine exposure compared with either citalopram [HR 1.00, 95% CI 0.50-2.00) or other SSRIs (0.76, 0.40-1.46). CONCLUSIONS: Fluoxetine use was not associated with an increased risk of acute pancreatitis compared with citalopram or other SSRIs. The absolute risk of acute pancreatitis was low and did not vary between different SSRIs. Further research is needed to determine whether there is a class effect on the risk of acute pancreatitis.

Surveillance of Antidepressant Safety (SADS): Active Signal Detection of Serious Medical Events Following SSRI and SNRI Initiation Using Big Healthcare Data.

INTRODUCTION: The current process for generating evidence in pharmacovigilance has several limitations, which often lead to delays in the evaluation of drug-associated risks. OBJECTIVES: In this study, we proposed and tested a near real-time epidemiological surveillance system using sequential, cumulative analyses focusing on the detection and preliminary risk quantification of potential safety signals following initiation of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: We emulated an active surveillance system in an historical setting by conducting repeated annual cohort studies using nationwide Danish healthcare data (1996-2016). Outcomes were selected from the European Medicines Agency's Designated Medical Event list, summaries of product characteristics, and the literature. We followed patients for a maximum of 6 months from treatment initiation to the event of interest or censoring. We performed Cox regression analyses adjusted for standard sets of covariates. Potential safety signals were visualized using heat maps and cumulative hazard ratio (HR) plots over time. RESULTS: In the total study population, 969,667 new users were included and followed for 461,506 person-years. We detected potential safety signals with incidence rates as low as 0.9 per 10,000 person-years. Having eight different exposure drugs and 51 medical events, we identified 31 unique combinations of potential safety signals with a positive association to the event of interest in the exposed group. We proposed that these signals were designated for further evaluation once they appeared in a prospective setting. In total, 21 (67.7%) of these were not present in the current summaries of product characteristics. CONCLUSION: The study demonstrated the feasibility of performing epidemiological surveillance using sequential, cumulative analyses. Larger populations are needed to evaluate rare events and infrequently used antidepressants.

Prescribers' compliance with summary of product characteristics of dabigatran, rivaroxaban and apixaban-A European comparative drug utilization study.

Despite a tremendous increase of direct oral anticoagulants (DOACs) prescriptions in recent years, only few data is available analysing prescribers' adherence to Summary of Product Characteristics (SmPC). We aimed to assess adherence to registered indications, contraindications, special warnings/precautions, and potential drug-drug interactions for three DOAC compounds (dabigatran, rivaroxaban, and apixaban) in six databases of five European countries (The Netherlands, United Kingdom, Spain, Denmark, and Germany). We included adult patients (≥18 years) initiating DOACs between 2008 and 2015. For several SmPC items, broad definitions were used due to ambiguous SmPC terms or lacking data in some databases. Within the study period, a DOAC was initiated in 407 576 patients (rivaroxaban: 240 985 (59.1%), dabigatran: 95 303 (23.4%), and apixaban: 71 288 (17.5%)). In 2015, non-valvular atrial fibrillation was the most common indication (>60% in most databases). For the whole study period, a substantial variation between the databases was found regarding the proportion of patients with at least one contraindication (inter-database range [IDR]: 8.2%-55.7%), with at least one special warning/precaution (IDR: 35.8%-75.2%) and with at least one potential drug-drug interaction (IDR: 22.4%-54.1%). In 2015, the most frequent contraindication was "malignant neoplasm" (IDR: 0.7%-21.3%) whereas the most frequent special warning/precaution was "prescribing to the elderly" (≥75 years; IDR: 25.0%-66.4%). The most common single compound class interaction was "concomitant use of non-steroidal anti-inflammatory drugs" (IDR: 3.0%-25.3%). Contraindications, special warnings/precautions, and potential drug-drug interactions were present in a relevant number of new DOAC users. Due to broad definitions used for some SmPC terms, overall proportions for contraindications are prone to overestimation. However, for unambiguous SmPC terms documented in the databases sufficiently, the respective estimates can be considered valid. Differences between databases might be related to "true" differences in prescription behaviour, but could also be partially due to differences in database characteristics.

Differences in Kidney Function Estimates Based on Creatinine and/or Cystatin C in Non-Traumatic Amputation Patients and Their Impact on Drug Prescribing.

Accurate kidney function estimates are necessary when prescribing renally-eliminated medications. Our objectives were to investigate how amputation affects estimated glomerular filtration rate (eGFR) and to determine if dosing recommendations differ among different eGFR equations. In a cohort study of non-traumatic amputation patients, eGFR based on creatinine and/or cystatin C were measured before and after amputation. Prescribed, renally-eliminated medications were compared with dosing guidelines in Renbase®. Data from 38 patients with a median age of 75 years were analyzed. The median (range) eGFR was 65 (15⁻103), 38 (13⁻79), and 48 (13⁻86) mL/min/1.73 m² before amputation and 80 (22⁻107), 51 (13⁻95), and 62 (16⁻100) mL/min/1.73 m² after amputation for eGFRCreatinine, eGFRCystatinC, and eGFRCombined, respectively (p < 0.01). From before to after amputation, eGFR increased on average by 8.5, 6.1, and 7.4 mL/min/1.73 m² for eGFRCreatinine, eGFRCystatinC, and eGFRCombined (all p < 0.01), respectively. At least one renally-eliminated medication was prescribed at a higher dose than recommended in 37.8% of patients using eGFRCystatinC, 17.6% using eGFRCombined and 10.8% using eGFRCreatinine. In conclusion, amputation affects eGFR regardless of the eGFR equations. The differences among equations would impact prescribing of renally-eliminated medications, particularly when switching from creatinine to cystatin C.

Creatinine-Based Renal Function Estimates and Dosage of Postoperative Pain Management for Elderly Acute Hip Fracture Patients.

Many analgesics and their metabolites are renally excreted. The widely used Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) equations are not developed for use in the elderly, while the recent Berlin Initiative Study (BIS), Full Age Spectrum (FAS), and Lund-Malmö revised (LMR) equations are. This observational study investigated differences between creatinine-based eGFR equations and how the choice of equation influences dosage of analgesics in elderly (≥70 years) patients admitted with acute hip fracture. eGFR was calculated by the CKD-EPI, BIS, Cockcroft-Gault (CG), FAS, LMR, and Modification of Diet in Renal Disease (MDRD) equations. Standard daily dose for postoperative pain medications ibuprofen, morphine and gabapentin was simulated for each equation according to dosage recommendations in Renbase®. For 118 patients, mean eGFR from the CKD-EPI, BIS, CG, FAS, LMR, and MDRD equations was 67.3 mL/min/1.73 m², 59.1 mL/min/1.73 m², 56.9 mL/min/1.73 m², 60.3 mL/min/1.73 m², 58.9 mL/min/1.73 m², and 79.1 mL/min/1.73 m², respectively (p < 0.0001). Mean difference to CKD-EPI was -10.4 mL/min/1.73 m² to 11.8 mL/min/1.73 m². Choice of eGFR equation significantly influenced the recommended dose (p < 0.0001). Shifting to BIS, FAS, or LMR equations led to a lower recommended dose in 20% to 31% of patients. Choice of eGFR equation significantly influenced dosing of ibuprofen, morphine, and gabapentin.