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Recommendations for the treatment of chronic obstructive pulmonary disease (COPD) have shifted towards a more restrictive use of inhaled corticosteroids (ICS). We aimed to identify the nationwide development over time in the use of ICS treatment in COPD. We conducted a register-based repeated cross-sectional study using Danish nationwide registers. On a yearly basis from 1998 to 2018, we included all patients in Denmark ≥ 40 years of age with an ICD-10 diagnosis of COPD (J44). Accumulated ICS use was calculated for each year based on redeemed prescriptions. Patients were divided into the following groups: No ICS, low-dose ICS, medium-dose ICS, or high-dose ICS. From 1998 to 2018, the yearly proportion of patients without ICS treatment increased (from 50.6% to 57.6%), the proportion of patients on low-dose ICS treatment increased (from 11.3% to 14.9%), and the proportion of patients on high-dose ICS treatment decreased (from 17.0% to 9.4%). We demonstrated a national reduction in the use of ICS treatment in COPD from 1998 to 2018, with an increase in the proportion of patients without ICS and on low-dose ICS treatment and a decrease in the proportion of patients on high-dose ICS treatment. [ABSTRACT FROM AUTHOR]

Background Direct oral anticoagulants (DOACs) are recommended as first-line treatment of atrial fibrillation. Whether DOAC use is associated with lower risks of kidney complications compared with vitamin K antagonists (VKAs) remains unclear. We examined this association in a nationwide, population-based cohort study. Methods We conducted a cohort study including patients initiating oral anticoagulant treatment within 3 months after an atrial fibrillation diagnosis in Denmark during 2012–18. Using routinely collected creatinine measurements from laboratory databases, we followed patients in an intention-to-treat approach for acute kidney injury (AKI) and chronic kidney disease (CKD) progression. We used propensity-score weighting to balance baseline confounders, computed weighted risks and weighted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing DOACs with VKAs. We performed several subgroup analyses and a per-protocol analysis. Results We included 32 781 persons with atrial fibrillation initiating oral anticoagulation (77% initiating DOACs). The median age was 75 years, 25% had a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2, and median follow-up was 2.3 (interquartile range 1.1–3.9) years. The weighted 1-year risks of AKI were 13.6% in DOAC users and 15.0% in VKA users (HR 0.86, 95% CI 0.82; 0.91). The weighted 5-year risks of CKD progression were 13.9% in DOAC users and 15.4% in VKA users (HR 0.85, 95% CI 0.79; 0.92). Results were similar across subgroups and in the per-protocol analysis. Conclusions Initiation of DOACs was associated with a decreased risk of AKI and CKD progression compared with VKAs. Despite the potential limitations of observational studies, our findings support the need for increased clinical awareness to prevent kidney complications among patients who initiate oral anticoagulants. [ABSTRACT FROM AUTHOR]

INTRODUCTION: There is growing interest in the prediagnostic phase of inflammatory bowel disease (IBD) and in the overlap of IBD with other diseases. We described and compared use of any prescription medication between individuals with and without IBD in a 10-year period preceding diagnosis. METHODS: Based on cross-linked nationwide registers, we identified 29,219 individuals diagnosed with IBD in Denmark between 2005 and 2018 and matched to 292,190 IBD-free individuals. The primary outcome was use of any prescription medication in years 1-10 before IBD diagnosis/matching date. Participants were considered as medication users if they redeemed ≥1 prescription for any medication in the World Health Organization Anatomical Therapeutic Chemical (ATC) main groups or subgroups before diagnosis/matching. RESULTS: The IBD population had a universally increased use of medications compared with the matched population before IBD diagnosis. At 10 years before diagnosis, the proportion of users was 1.1-fold to 1.8-fold higher in the IBD population in 12 of 14 ATC main groups of medication (P-value < 0.0001). This applied across age, sex, and IBD subtypes, although it was the most pronounced for Crohn's disease (CD). Two years before diagnosis, the IBD population had a steep increase in medication use for several organ systems. When analyzing therapeutic subgroups of medication, the CD population exhibited 2.7, 2.3, 1.9, and 1.9 times more users of immunosuppressants, antianemic preparations, analgesics, and psycholeptics, respectively, than the matched population 10 years before diagnosis (P-value < 0.0001). DISCUSSION: Our findings demonstrate universally increased medication use years before IBD, especially CD, diagnosis and indicates multiorgan involvement in IBD. [ABSTRACT FROM AUTHOR]

Aims: Drug‐induced diabetes is underreported in conventional drug safety monitoring and may contribute to the increasing incidence of type 2 diabetes. Therefore, we used routinely collected prescription data to screen all commonly used drugs for diabetogenic effects. Methods: Leveraging the Danish nationwide health registries, we used a case‐only symmetry analysis design to evaluate all possible associations between drug initiation and subsequent diabetes. The study was conducted among individuals aged ≥40 years with a first‐ever prescription for any antidiabetic drug 1996‐2018 (n = 348 996). Sequence ratios (SRs) and 95% confidence intervals (CIs) were obtained for all possible drug class‐diabetes combinations. A lower bound of the 95% CI >1.00 was considered a signal. Signals generated in Denmark were replicated using the Services Australia, Pharmaceutical Benefits Scheme 10% data extract. Results: Overall, 386 drug classes were investigated, of which 70 generated a signal. In total, 43 were classified as previously known based on the SIDER database or a literature review, for example, glucocorticoids (SR 1.67, 95% CI 1.62‐1.72) and β‐blockers (SR 1.20, 95% CI 1.16‐1.23). Of 27 new signals, three drug classes yielded a signal in both the Danish and Australian data source: digitalis glycosides (SR 2.15, 95% CI 2.04‐2.27, and SR 1.76, 95% CI 1.50‐2.08), macrolides (SR 1.20, 95% CI 1.16‐1.24, and SR 1.11, 95% CI 1.06‐1.16) and inhaled β2‐agonists combined with glucocorticoids (SR 1.35, 95% CI 1.28‐1.42, and SR 1.14, 95% CI 1.06‐1.22). Conclusion: We identified 70 drug‐diabetes associations, of which 27 were classified as hitherto unknown. Further studies evaluating the hypotheses generated by this work are needed, particularly for the signal for digitalis glycosides. [ABSTRACT FROM AUTHOR]

Aim: To investigate changes in the pattern of drugs used to treat type 2 diabetes in Denmark from 2005 to 2021. Materials and Methods: A nationwide, population‐based drug utilization study based on medical databases covering the Danish population was conducted. We assessed incident and prevalent use patterns among all 441 205 individuals initiating at least one non‐insulin, glucose‐lowering drug. Results: The rate of new users of non‐insulin, glucose‐lowering drugs increased from 2005, peaked in 2011, decreased to stable levels during 2013 to 2019, then increased dramatically during 2020‐2021. The prevalence of use increased from 2.1% (in 2005) to 5.0% (in 2021) of the entire adult population. In 2021, metformin comprised 39% of all glucose‐lowering drug consumption, followed by insulin (17%), sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) (17%), glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) (16%) and dipeptidyl peptidase‐4 inhibitors (7.5%). Overall, 56% of users were on monotherapy, 28% used dual therapy, while 13% and 2.8% used three and four drug classes, respectively. Both the intensity and diversity of therapies increased substantially over time, with 15 different treatment regimens each covering more than 1% of users in 2021. General practitioners prescribed 88% of all glucose‐lowering drugs. Marked shifts towards GLP‐1RA initiation by general practitioners and SGLT‐2i initiation by specialists were observed, and changing user profiles suggested increasing use for non‐diabetes indications. Conclusions: The rate of new users of non‐insulin, glucose‐lowering drugs has increased in recent years and the prevalence of glucose‐lowering drug use increases steadily. Glucose‐lowering drugs are mainly prescribed by general practitioners, and the intensity, diversity and indications of glucose‐lowering treatment are increasing. [ABSTRACT FROM AUTHOR]

Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ‐sedatives, BZ‐hypnotics, and benzodiazepine‐related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000–2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55–78% of BZ use in 2020, followed by BZ sedatives at 20–44%, BZ‐hypnotics at <1–5%, and clonazepam at <1–2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups—despite warnings against their use in this population. [ABSTRACT FROM AUTHOR]

Background: Phenotype classification contributes to risk assessment of asthma. Previous studies have applied this concept primarily to adult populations and in the setting of research protocol assessments which may not be applicable to clinical settings., Objective: Exploring the value of routinely collected clinical data for phenotype classification and risk assessment of childhood asthma., Methods: Using hospital and laboratory data, 29,851 children in a Danish nationwide database aged 2-17 years with ICS-treated asthma in 2015 followed for two years (730 days) were classified to have T2 (elevated blood eosinophils (>300 cells/μL) and/or elevated total- or specific-IgE), and/or non-T2 risk factors (in utero tobacco exposure and/or severe viral infections). Logistic regression was applied to quantify associations of risk factors with asthma severity, control, and exacerbation risk., Results: In a complete case analysis, 85.8 % children had at least one T2 risk factor and 29.3 % had mixed T2/non-T2 risk factors. Elevated blood eosinophils and total/specific IgE were associated with exacerbations (ORs 1.55 (1.38-1.73) and 1.41 (1.20-1.66) and higher asthma severity (1.42 (1.24-1.63) and 1.31 (1.08-1.60)), respectively. Dose-dependency was observed between blood eosinophil counts, total IgE levels, and risk of adverse outcomes. Furthermore, accumulation of risk factors demonstrated an increasing risk, with children with all four risk factors having a high risk of any adverse asthma-related outcome (OR 3.13 (2.03-4.82) CONCLUSION: Asthma phenotypic markers defined in research protocols can be reliably applied in real-world settings by utilizing data collected during routine clinical care and enable better classification of risk of adverse asthma outcomes., Competing Interests: Declaration of competing interest KEJH has received personal fees from AstraZeneca, Chiesi, GSK, Sanofi and TEVA. NA, SCG declares no conflicts of interest. DR declares no conflicts of interest but does serve on a DSMB for the National Institute of Health. CSU has received personal fees from AstraZeneca, GSK, TEVA, Chiesi, Sanofi Genzyme, Boehringer-Ingelheim, Orion Pharma, Novartis, ALK-Abello, Mundipharma, Berlin Chemie, Pfizer, TFF Pharmaceuticals, Covis Pharma and Actelion. VB has received personal fees from AstraZeneca, GSK, TEVA, Sanofi Genzyme, MSD, Chiesi, Boehringer-Ingelheim, Novartis, ALK-Abello, Mundipharma, BIRK NPC and Pharmaxis., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: The healthcare systems in Scandinavia inform nationwide registers and the Scandinavian populations are increasingly combined in research. We aimed to compare Norway (NO), Sweden (SE), and Denmark (DK) regarding sociodemographic factors and healthcare., Methods: In this cross-sectional study, we analyzed aggregated data from the nationwide Scandinavian registers. We calculated country-specific statistics on sociodemographic factors and healthcare use (general practitioner visits, admissions to somatic hospitals, and use of medicines)., Results: In 2018, population were 5295,619 (NO), 10,120,242 (SE), and 5781,190 (DK). The populations were comparable regarding sex, age, education, and income distribution. Overall, medication use was comparable, while there was more variation in hospital admissions and general practitioner visits. For example, per 1000 inhabitants, 703 (NO), 665 (SE), and 711 (DK) individuals redeemed a prescription, whereas there were 215 (NO), 134 (SE), and 228 (DK) somatic hospital admissions per 1000 inhabitants. General practitioner contacts per 1000 inhabitants were 7082 in DK and 5773 in NO (-data from SE)., Conclusion: The Scandinavian countries are comparable regarding aggregate-level sociodemographic factors and medication use. Variations are noted in healthcare utilisation as measured by visits to general practitioners and admissions to hospitals. This variation should be considered when comparing data from the Scandinavian countries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Symptoms and treatment of benign prostatic hyperplasia (BPH) or erectile dysfunction (ED) may lead to prostate cancer workup, and patterns of prescriptions before diagnosis may affect findings of pharmacoepidemiological studies. Usage of BPH and ED drugs after diagnosis may be related to prostate cancer treatment. We investigated differences in prescription rates of BPH and ED drugs among prostate cancer patients and cancer-free comparisons and between patients with localized and non-localized disease. A nationwide register-based study, including all Danish men aged 50–85 years diagnosed with prostate cancer during 1998–2015 and an age-matched comparison cohort without cancer. We calculated rates of new and total prescriptions in 1-month intervals from 3 years before to 3 years after cancer diagnosis for drugs used to treat BPH and ED, overall and stratified by clinical stage. We identified 54,286 men with prostate cancer and a comparison cohort of 249,645 age-matched men. The new prescription rate for BPH drugs increased for men with prostate cancer in the year before diagnosis and peaked 1 month before diagnosis with an 18-fold higher rate. Men with prostate cancer had a higher total prescription rate of BPH drugs 3 years before diagnosis, notably among men with localized disease. Before diagnosis, the new prescription rates for ED drugs were similar among men with prostate cancer and comparisons. After diagnosis, men with prostate cancer had a 7-fold higher rate of new prescriptions for ED drugs. Among men with localized disease, the total prescription rate of ED drugs increased in the months following diagnosis. Differences in prescription rates suggest increased prostate cancer surveillance among men receiving BPH drugs, whereas the post-diagnostic increase in ED drugs among men with localized disease is compatible with the increased risk of ED following prostate cancer treatment. [ABSTRACT FROM AUTHOR]

• Antidepressant use was associated with an overall decreased risk of ovarian cancer. • The risk reduction was larger among postmenopausal women and long-term users. • The effect was most prominent for serous ovarian cancers. • Selective serotonin reuptake inhibitors showed the strongest risk reduction. • Oral contraceptive use and hormone replacement therapy both modified the association. Given that the evidence regarding the link between antidepressant use and ovarian cancer risk is equivocal, we investigated this research question by conducting two nationwide nested case-control studies among the Danish and Swedish populations. Altogether, 14,121 women with epithelial ovarian cancer (30–84 years old) (Denmark: 8976 diagnosed 2000–2019, Sweden: 5145 diagnosed 2010–2018) were randomly age-matched with 564,840 female controls (359,040 from Denmark, and 205,800 from Sweden) using risk set sampling. We used conditional logistic regression to estimate odds ratios (OR) with 95 % confidence intervals (CI) and combined the estimates based on the fixed-effect assumption. We also investigated potential effect modification by well-established risk factors for ovarian cancer. Antidepressant use was associated with an overall reduced risk of ovarian cancer (OR = 0.92, 95%CI: 0.88–0.96), and that reduction was more pronounced in postmenopausal women and long-term users. The effect was most pronounced for serous ovarian tumors (OR = 0.90, 95%CI: 0.86–0.95) but was also observed in other subtypes, although not statistically significant. Among different types of antidepressants, selective serotonin reuptake inhibitors in general and citalopram in particular exhibited a noteworthy reduction in ovarian cancer risk (OR = 0.89, 95%CI: 0.82–0.96). Additionally, use of oral contraceptives and hormone replacement therapy individually modified the association between antidepressant use and ovarian cancer risk. Use of an antidepressant was associated with a slight, but statistically significant, decrease in ovarian cancer risk. Given the morbidity and mortality associated with ovarian cancer, and increasing use of antidepressants, these findings may be of significance to cancer prevention and should be studied in more detail mechanistically. [ABSTRACT FROM AUTHOR]

Chlorprothixene is commonly used off‐label in low doses for sedative‐hypnotic purposes although it might carry a risk of cardiometabolic adverse events due to its pharmacodynamic profile. We investigated the risk of diabetes and major adverse cardiovascular events (MACE) with use of low‐dose chlorprothixene, compared with use of low‐dose quetiapine in a nationwide cohort study, including all new users of low‐dose chlorprothixene (n = 81 328) and low‐dose quetiapine (n = 91 163) in Denmark 2000–2017. Main outcomes were diabetes and MACE (myocardial infarction, stroke and death from cardiovascular causes). The association between cumulative dose of chlorprothixene and the outcomes was tested in a case–control analysis. Low‐dose chlorprothixene use was associated with increased risk of diabetes (intention‐to‐treat [ITT]‐hazard ratio [HR]: 1.16; 95% CI: 1.08–1.25), compared with low‐dose quetiapine use. This association strengthened when follow‐up was restricted to time on treatment (as‐treated [AT]‐HR: 1.34; 95% CI: 1.14–1.56). Low‐dose chlorprothixene use was also associated with increased risk of MACE (ITT‐HR: 1.12; 95% CI: 1.04–1.21) and stroke (ITT‐HR: 1.21; 95% CI: 1.06–1.37) but not with myocardial infarction (ITT‐HR: 1.11; 95% CI: 0.95–1.30) nor death from cardiovascular causes (ITT‐HR: 1.07; 95% CI: 0.96–1.20). Cumulative dose of chlorprothixene ≥6000 mg was associated with increased risk of diabetes (OR: 1.15–1.63; test for trend: p < 0.001), whereas cumulative dose of chlorprothixene ≥1500 mg was associated with increased risk of MACE (OR: 1.10–1.85; test for trend: p < 0.001). In conclusion, low‐dose chlorprothixene use is associated with increased risk of cardiometabolic adverse events compared with low‐dose quetiapine use. [ABSTRACT FROM AUTHOR]

Purpose: There is an increasing need for national and international pharmacoepidemiological studies based on high-quality real-world data of which the Danish registries are a valuable source. In lack of a complete overview of which data are used to assess real-world drug safety and effectiveness outcomes, we aimed to map the outcomes, data sources, and the reporting of outcome quality in recent pharmacoepidemiological studies. Methods: We conducted a systematic mapping review of pharmacoepidemiological studies based on Danish registries investigating drug safety and/or effectiveness, published in the period 2018– 2019, identified in PubMed and Scopus. Extraction included: Anatomical Therapeutic Chemical level 2 code for drug exposures, outcomes, outcome data sources, and quality of outcomes. Results: Of the 210 included studies, 96% used outcomes categorized as Clinical, 4% utilized outcomes categorized as Society-related, 5% used outcomes categorized as Healthcare cost and utilization, and 3% of the studies applied outcomes categorized as Patient-reported in which the percentages are not mutually exclusive. Diagnosis (66%) and Mortality (38%) were the two most utilized subcategories among those categorized as Clinical outcomes. Danish Health Data Authority and Statistics Denmark registries were the most reported outcome data sources (90%). Ninety-six studies (46%) reported one or more quality parameters related to their outcomes of interest with accuracy/validity being the most reported parameter (22%). Conclusion: The Danish registries support a wide range of outcomes. Across therapeutic areas, most studies investigate traditional clinical outcomes of disease and mortality based on data from a small number of available registries. In contrast, clinical and biochemical databases, despite potentially offering outcomes with high responsiveness, and the high-quality social and healthcare cost registries were rarely used as outcome data sources. [ABSTRACT FROM AUTHOR]

Objective To describe life-time use of current actionable pharmacogenetic (PGx) somatic and psychotropic drugs according to international PGx consortia in people with and without hospital-diagnosed mental disorders in the Danish population. Methods Population- and register-based observational drug utilization study in 56 065 individuals with mental disorders, i. e. attention-deficit/hyperactivity disorder, autism, bipolar disorder, depression and schizophrenia, and a random, representative sample of 29 975 individuals of the Danish population, born between 1981 and 2005. Individuals were followed from 1995 or birth until 2016 (for a maximum of 22 years). We report prevalence and incidence rates of PGx drug use by age, sex and mental disorders based on redeemed prescriptions between 1995 and 2016. Results Of the 69 PGx drugs, prescriptions of 39 drugs had been redeemed by the study population by 35 years of age. The use of at least 1 PGx drug varied between 23.1% in males without mental disorders and 97.2% in females with schizophrenia. Males with ADHD or autism were the youngest first-time PGx drug users at a mean of 11.6 years. The mean number of different PGx drugs used was 1.2 in males without mental disorders and 5.6 in individuals with schizophrenia. The prevalence of different PGx drugs linked to more than one gene was 25.3% in males without mental disorders to 94.1% in females with schizophrenia. Conclusion PGx drugs are commonly used by younger people, more often by individuals with mental disorders and by females. Panel-based PGx testing could contribute to treatment decisions at a very young age. [ABSTRACT FROM AUTHOR]

Oral corticosteroids (OCS) are used in asthma management but can cause serious adverse effects. We aimed to investigate the usage trends in a nationwide asthma cohort in Denmark from 1999 to 2018. Using national registers, we identified young adults (18–45 years) with two or more asthma drug collections within 12 months since the age of 15 years as indicative of active asthma. OCS exposure level was stratified as high use (≥5 mg prednisolone/day/year) and low use (<5 mg/day/year). Lorenz curves were computed to illustrate potential skewness of consumption among the OCS users. We identified 318 950 individuals with a median age of 29 years (IQR 20–38 years) whereof 57% were women. The 1‐year prevalence of OCS users was stable at 4.8% (median, IQR 4.7%–4.8%), but with nearly 40% decrease in high‐users from 0.54% in 1999 to 0.33% in 2018. The median annual exposure decreased from 500 mg/year (1999) to 250 mg/year (2018). We found a substantial skewness in the distribution of OCS usage with 10% of users accounting for almost 50% of all OCS use. The prevalence of OCS users among young adults with active asthma has been relatively stable from 1999 to 2018, but with a decreasing prevalence of high‐users and annual consumption. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer has an average 10-year relative survival reaching 84%. This favorable survival is due, in part, to the introduction of biomarker-guided therapies. We estimated the population-level effect of the introduction of two adjuvant therapies-tamoxifen and trastuzumab-on recurrence using the trend-in-trend pharmacoepidemiologic study design., Methods: We ascertained data on women diagnosed with nonmetastatic breast cancer who were registered in the Danish Breast Cancer Group clinical database. We used the trend-in-trend design to estimate the population-level effect of the introduction of (1) tamoxifen for postmenopausal women with estrogen receptor (ER)-positive breast cancer in 1982, (2) tamoxifen for premenopausal women diagnosed with ER-positive breast cancer in 1999, and (3) trastuzumab for women <60 years diagnosed with human epidermal growth factor receptor 2-positive breast cancer in 2007., Results: For the population-level effect of the introduction of tamoxifen among premenopausal women diagnosed with ER-positive breast cancer in 1999, the risk of recurrence decreased by nearly one-half (OR = 0.52), consistent with evidence from clinical trials; however, the estimate was imprecise (95% confidence interval [CI] = 0.25, 1.85). We observed an imprecise association between tamoxifen use and recurrence from the time it was introduced in 1982 (OR = 1.24 95% CI = 0.46, 5.11), inconsistent with prior knowledge from clinical trials. For the introduction of trastuzumab in 2007, the estimate was also consistent with trial evidence, though imprecise (OR = 0.51; 95% CI = 0.21, 22.4)., Conclusions: We demonstrated how novel pharmacoepidemiologic analytic designs can be used to evaluate the routine clinical care and effectiveness of therapeutic advancements in a population-based setting while considering some limitations of the approach., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We describe the distribution of prescriber types responsible for issuing prescriptions in Denmark. Using a 20% random sample of all Danes alive during 2000–2018 (n = 1 515 025) and all their prescriptions filled at community pharmacies (n = 182 143 707), we found that general practitioners issued 88% of all prescriptions, followed by hospital physicians (7.4%) and private practicing specialists (4.2%). These values were stable over the study period. With increasing patient age, general practitioners were responsible for a larger proportion of prescriptions (e.g. 68% for patients aged 0–17 y and 89% for patients ≥51 y). General practitioners were responsible for 84% of all treatment initiation (first prescription) and 90% of all maintenance treatment. Corresponding values for hospital physicians were 9.5 and 6.3%, and for private practicing specialists 5.3 and 3.6%. In conclusion, general practitioners are responsible for the vast majority of prescribing in Denmark, including both treatment initiation and continuation, in particular among the elderly. [ABSTRACT FROM AUTHOR]

Objectives: The aim was to describe the pre‐diagnostic and post‐diagnostic psychopharmacological treatment of bipolar disorder over the past two decades. Methods: We identified all 16 288 individuals aged ≥ 18 years, who received their first diagnosis of bipolar disorder at a psychiatric hospital in Denmark between 1997 and 2014. For each calendar year, we calculated the proportion of patients (with index date in the respective calendar years) who were prescribed psychopharmacological treatment in the 2 years preceding and the 2 years following the date of the first diagnosis of bipolar disorder. For patients diagnosed with bipolar disorder from 2007 to 2010 (n = 3949), we described the psychopharmacological treatment from 1995 to 2016, that is, from up to 16 years prior to and up to 10 years after the diagnosis. Results: Concomitant use of ≥ 2 antidepressants in the 2 years preceding the bipolar disorder diagnosis increased over the study period. In the 2 years following the diagnosis, the use of lithium decreased, while use of atypical antipsychotics (particularly quetiapine), valproate, and lamotrigine increased over the study period. During the 10 years following the diagnosis, 53%‐90% of the patients received any psychotropic drug while 12%‐26% received treatment with an antidepressant without overlapping treatment with a mood‐stabilizing drug. Conclusion: The increased use of two or more antidepressants suggests more focus on bipolar disorder as a differential diagnosis to treatment‐resistant unipolar depression. The decreased use of lithium (consistent with international trends) and the prevalent use of antidepressants without overlapping treatment with a drug with mood‐stabilizing properties are concerning. [ABSTRACT FROM AUTHOR]

Aims: In the Danish population, we examined whether patients treated with thiopurines, methotrexate, systemic corticosteroids, anti‐tumour necrosis factor (TNF)‐α agents, anti‐interleukin therapeutic agents, selective immunosuppressive agents and cyclosporine/tacrolimus had an increased risk of hospitalization for COVID‐ 19, compared to the background population. Methods: A nationwide cohort study including all people alive in Denmark on 1 March 2020. Exposed patients constituted those exposed to thiopurines (n = 5484), methotrexate (n = 17 977), systemic corticosteroids (n = 55 868), anti‐TNF‐α agents (n = 17 857), anti‐interleukin therapeutic agents (n = 3744), selective immunosuppressive agents (n = 3026) and cyclosporine/tacrolimus (n = 1143) in a period of 12 months prior to 1 March 2020 (estimated time of outbreak in Denmark). We estimated the adjusted risk of hospitalization for COVID‐19 for patients treated with the above‐mentioned categories of medications, compared to the rest of the population. Results: The adjusted odds ratios of hospitalization in patients treated with corticosteroids and cyclosporine/tacrolimus were 1.64 (95% confidence interval [CI] 1.35 to 2.00) and 4.75 (95% CI 1.96 to 11.49), respectively. The risks of hospitalization in patients treated with thiopurines, methotrexate, and anti‐TNF‐α agents, were 1.93 (95% CI 0.91 to 4.08), 0.74 (95% CI 0.43 to 1.28), 1.00 (95% CI 0.52 to 1.94), respectively. The number of outcomes in patients treated with anti‐interleukin therapeutic agents and selective immunosuppressive agents was too small for analysis. Conclusion: Patients treated with systemic corticosteroids and cyclosporine/tacrolimus had a significantly increased risk of being hospitalized for COVID‐19. Our study does not uncover whether the increased risk is related to the drug itself, the underlying condition for which the patient is treated or other factors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: To investigate temporal trends in time to initiation of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide 1 analogues (cardioprotective glucose‐lowering drugs [GLDs]) in patients with a new dual diagnosis of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Materials and methods: In a cohort study, we identified patients with a new dual diagnosis of T2DM and CVD using linked healthcare data from nationwide registries on drug prescriptions and diagnosis codes. For each calendar year between 2012 and 2018, we examined time to initiation and cumulative user proportions (CUPs) for cardioprotective GLD use 1 and 2 years after the dual diagnosis. Results: Among all individuals living in Denmark in the period 2012 to 2018, 41 733 patients with a new dual diagnosis of T2DM and CVD were identified (median [interquartile range] age 71 [64–79] years, 61% male, and 57% with CVD as the latest diagnosis). Incidence curve slopes and 1‐ and 2‐year CUPs for cardioprotective GLDs increased during the study period (1‐year CUP 4.0%, 95% confidence interval [CI] 3.6–4.5) in 2012 to 14.7, 95% CI 13.7–15.7, in 2018; 2‐year CUP 5.5, 95% CI 5.0–6.1, in 2012 to 16.7, 95% CI 15.8–17.7, in 2017). T2DM patients with CVD as the second (latest) diagnosis had higher 1‐year CUPs than CVD patients with T2DM as the latest diagnosis: 2012: 7.0 (95% CI 6.2–8.0) versus 1.4 (95% CI 1.0–1.8); 2018: 18.1 (95% CI 16.8–19.6) versus 10.0 (95% CI 8.8‐11.3). Conclusions: In patients with T2DM and CVD, the incidence of cardioprotective GLD initiation increased between 2012 and 2018, however, within 2 years of dual diagnosis, it remained low. [ABSTRACT FROM AUTHOR]

The means by which patients acquire their medications differ between countries, and a knowledge of this is essential when conducting and interpreting pharmacoepidemiological studies. The aim of this paper is to provide an overview of how patients obtain medicines in Denmark, to relate these to nationwide registries available for research and to discuss the implications for research. Health services are predominantly tax‐funded in Denmark, with dentistry and some medicine bought at community pharmacies being exceptions, involving partial reimbursement of charges. The paper gives an overview of prescription medicines acquired from community pharmacies (including magistral preparations), over‐the‐counter medicines, vaccinations and in‐hospital medicine including so‐called "free medicine" (in Danish: "vederlagsfri medicin"). "Free medicine" is medicines for a defined list of diseases and indications that is provided free of charge to patients in outpatient clinics. The paper also describes the content of the various Danish data sources about medicine use, summarizes their strengths and limitations, and exemplifies the ways of evaluating their completeness. An example is provided of the regional variation in the means by which medicines are acquired. [ABSTRACT FROM AUTHOR]

Aims: Antipsychotics are primarily labelled for the treatment of severe mental illness and have documented clinical utility in certain neurological disorders or palliative care. However, off-label use of antipsychotics is common and increasing, and prior studies on antipsychotic utilisation have not specifically assessed users in neurology, palliative care or general practice. We aimed to explore diagnoses associated with antipsychotic use, treatment patterns and characteristics of users without diagnoses relevant to antipsychotic treatment. Methods: Population-based study identifiying all users of antipsychotics in Denmark (pop 5.7 mio.) 1997–2018 in the Danish National Prescription Register (DNPR). Possible indications for antipsychotic therapy were evaluated using in- and outpatient contacts from the DNPR. Users were divided hierarchically into six groups: severe mental disorders (schizophrenia, bipolar-spectrum disorders), chronic mental disorders (dementias, mental retardation, autism), other mental disorders (depression-spectrum, anxiety and personality disorders, etc.), selected neurological diseases, cancer and antipsychotic users without any of these diagnoses. This last group was characterised regarding demographics, antipsychotic use, health care utilisation and likely antipsychotic treatment initiator in 2018. Results: Altogether, 630 307 antipsychotic users were identified, of whom 127 649 had filled prescriptions during 2018. Users without diagnoses relevant to antipsychotic treatment comprised of the largest group (37%), followed by schizophrenia and bipolar-spectrum disorders (34%), other mental disorders (15%), dementia, autism and mental retardation (11%), cancer (2.2%) and neurological diagnoses (2.0%). Of 37 478 incident users in 2018, 39% had no diagnosis relevant to antipsychotic treatment, 7.9% had major depression, 7.7% neurotic/stress-related disorders and 7.5% dementia. Quetiapine was most commonly used, both overall (51%) and among users without diagnoses relevant to antipsychotic treatment (58%). Of 14 474 incident users in 2018 without diagnoses relevant to antipsychotic treatment, treatment was most likely initiated by a general practitioner (65%), with only 17% seeing a psychiatrist during the following year. As many as 18% of patients with adjustment disorders and 14% of those without relevant diagnoses for antipsychotic use, remained on antipsychotic treatment 5 years after their first prescription. Conclusions: Over one-third of antipsychotic users in Denmark did not have psychiatric, neurological or cancer diagnoses as possible indications for antipsychotic therapy. Many antipsychotics are initiated or prescribed in general practice, and a concerningly large subgroup without documented diagnoses relevant for antipsychotics continued to receive them. Rational prescribing, adequate side effect monitoring and further research into reasons for the observed antipsychotic use patterns and their risk–benefit ratio are needed. [ABSTRACT FROM AUTHOR]

Background: We examined whether the apparent association between renal cell carcinoma (RCC) and use of dihydropyridine calcium channel blockers (CCBs) was explained by confounding by indication since hypertension, the main indication for CCBs, is a risk factor for RCC.Methods: Using Danish health registries, we conducted a nested case-control study including 7315 RCC cases during 2000-2015. We matched each case with up to 20 controls on age and sex using risk-set sampling. We estimated odds ratios (ORs) for long-term CCB use associated with RCC using conditional logistic regression. We addressed confounding by indication by (1) adjusting for hypertension severity indicators; (2) evaluating dose-response patterns; (3) examining whether other first-line anti-hypertensives were associated with RCC; and (4) using an active comparator new user design by nesting the study in new users of CCBs or angiotensin-converting enzyme inhibitors (ACEIs).Results: The adjusted OR for RCC associated with long-term CCB use compared to non-use was 1.76 (1.63-1.90). After we additionally adjusted for hypertension severity indicators, the OR remained elevated (OR 1.37; confidence interval [CI] 1.25, 1.49) with evidence of a dose-response pattern. Other anti-hypertensives were also associated with RCC, for example, ACEIs (OR 1.27; 95% CI = 1.16, 1.39) and thiazides (OR 1.22; 95% CI = 1.12, 1.34). In the active comparator new user design, the OR was 1.21 (95% CI = 0.95, 1.53) for use of CCBs compared with ACEIs.Conclusions: In this population, confounding by indication appeared to explain at least part of the association between RCC and dihydropyridine CCBs. [ABSTRACT FROM AUTHOR]

Background Data on drug utilisation patterns in nursing home populations is scarce. We aimed to describe drug use patterns in Danish nursing home residents. Methods We established a cohort of 5,179 individuals (63% women; median age of 84 years) admitted into 94 nursing homes across Denmark during 2015–2017. Data on prescription drug use and other census data were obtained from the nationwide Danish health registries. Results The total number of drug classes filled increased from a median of 6 drugs (interquartile range [IQR] 3–9) at 18–24 months before nursing home admission to a median of 8 drugs (IQR 6–11) just after admission, with the most common drug classes comprising paracetamol (61%), platelet inhibitors (41%), proton pump inhibitors (34%), statins (33%) and potassium supplements (31%). The incidence rate of new drug treatments increased from 21 new treatments/100 residents/month at 12–24 months before admission to a peak of 71 new treatments/100 residents/month in the month prior to admission, while it levelled off to about 34 new treatments/100 residents/month after 6–9 months. The drug classes primarily responsible for this peak were laxatives, antibiotics and analgesics. The largest absolute increases were seen for laxatives (53%), paracetamol (43%) and antidepressants (36%), all showing a marked increase up to and following admission. A high proportion of residents remained on therapy in the 3-year period following admission, with users of antidepressants and antidementia drugs being most persistent. Conclusion Nursing home admission is associated with an increase in use of both predominantly preventive and non-preventive drug classes. [ABSTRACT FROM AUTHOR]

Aims: Registries on in-hospital drug use are sparse, especially those that can be linked to nationwide registries. In this study, we present and validate the Electronic Patient Medication module (EPM)—the electronic administrative database on in-hospital drug use covering the Capital Region of Denmark. Methods: The research database (EPM-research) is an adaptation of the database underlying the electronic administrative database for in-hospital drug use (EPM-clinic). The validation study was comprised of two sub-studies. Sub-study 1: Accordance of registration between EPM-clinic and EPM-research was investigated by analyzing randomly chosen retrospective patient records. Sub-study 2: Workflows and real-life registration practices were investigated through visits to three different (two medical and one emergency) departments. An observer followed a nurse while dispensing and administering drugs. This information was compared with EPM-research. The primary endpoint for both sub-studies was accordance of generic name between registrations. Secondary endpoints were exact brand name, dose, and time of each administration. Accordance (proportions) with 95% confidence intervals (CI) using the Clopper-Pearson method were calculated. The study was approved by the Danish Data Protection Agency (BFH-2016-058-04906) and the Danish Patient Safety Authority (3-3013-1884/1/). Results: In sub-study 1 227 retrospective drug administrations were reviewed. Accordance of generic name was 100.0% (CI 98.4%−100.0%). In sub-study 2 176 drug administrations were observed of which 173 were recorded with identical generic name, resulting in 98.3% (CI 95.1%-99.6%) accordance of data. Conclusions: Our validation of the EPM-research showed very high accordance. With detailed information on in-hospital drug use, the EPM-research may be a useful tool in pharmacoepidemiological research. [ABSTRACT FROM AUTHOR]

Objectives: To study chronic headache and medication-overuse headache (MOH) prevalence; to identify groups with high prevalence of these conditions; and to identify the most frequently used pain medications among respondents with chronic headache.Background: Chronic headache and MOH prevalence in Denmark were last estimated in 2010.Methods: In this cross-sectional study, 104,950 individuals aged ≥16 years were randomly sampled for the 2017 Danish Capital Region Health Survey. Responses to questions about headache and use of acute pain medications were linked to demographic registries. MOH was defined as headache ≥15 days/month plus self-report of use of pain medications ≥10 or 15 days/month, in the last three months. Weighted prevalence proportions were calculated.Results: Among 55,185 respondents, chronic headache prevalence was 3.0% (95% CI: 2.3-3.2) and MOH prevalence was 2.0% (95% CI: 1.8-2.1). Both conditions were more common among females and the middle-aged. Respondents on social welfare or receiving early retirement pensions had the highest prevalences. Among those with chronic headache, 44.7% overused over-the-counter analgesics for headache; paracetamol 41.5%; a combination of different pain relievers 25.3%; ibuprofen 21.9%; opioids 17.0%; combination preparations 14.3%; and triptans 9.1%.Conclusions: The highest prevalence of chronic headache and MOH was seen among people with low socioeconomic position. Overuse of paracetamol was most common. Reported opioid use was higher than expected. Groups with high prevalence of MOH should be the focus of public health interventions on rational use of OTC and prescription pain medications. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to assess the association between switching patterns and adherence/persistence in Danish patients over the age of 65, who started their first-ever glaucoma treatment with latanoprost eye drops., Methods: Patients were assigned to three different cohorts: (1) switchers, (2) non-switchers, and (3) preservative-free latanoprost (Monoprost®) users. Patients were followed for 1 year until the end of data coverage or censoring. Study covariates were used to compute the propensity score. In the adjusted analysis, the propensity score was added to the model as an independent variable. The Cox regression model was used to calculate the hazard ratio (HR) of discontinuation for the three cohorts (the non-switchers cohort was the reference level) in both adjusted and unadjusted analyses., Results: Non-switchers had a statistically significant lower adherence (proportion of days covered, PDC 92%) than switchers (PDC 96%; p < 0.001) and users of Monoprost® (PDC 99%; p < 0.001). Switchers had a 53% lower risk of treatment discontinuation compared to the reference group within 1 year after the first redemption of latanoprost in both unadjusted (HR 0.47; 95% Confidence interval, 95% CI: 0.41-0.53; p < 0.001) and adjusted (HR 0.47; 95% CI: 0.42-0.53; p < 0.001) analyses. In comparison to the non-switchers, Monoprost® users had a 78% lower risk for the above result in both unadjusted (HR 0.22; 95% CI: 0.17-0.28; p < 0.001) and adjusted (HR 0.22; 95% CI: 0.17-0.29; p < 0.001) analyses., Conclusion: This study found increased adherence and persistence in latanoprost users among those who redeemed preservative-free latanoprost (Monoprost®) and among those who switched between different latanoprost formulations., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To describe utilization patterns, characteristics of users and prescribers of the new oral antiviral medication, molnupiravir, indicated for mild-to-moderate COVID-19., Methods: Using nationwide registries, we identified all Danish adults who filled a prescription for molnupiravir from December 16th, 2021, to August 31st, 2022. We described weekly incidence rates and patient characteristics over time, prescriber characteristics as well as time between molnupiravir initiation and a positive SARs-CoV-2 test. Patient characteristics were compared to matched, untreated SARS-CoV-2 positive reference groups., Results: By August 31st, 2022, 5847 individuals had filled a prescription for molnupiravir. The incidence rate gradually increased to 16 weekly prescriptions per 1000 RT-PCR SARS-CoV-2 positives. Users of molnupiravir were most often men (55% vs. 45% women). The majority (81%) had a positive RT-PCR SARS-CoV-2 test and few (2.9%) redeemed molnupiravir outside the recommended window of 5 days from the positive test result. Compared to matched, untreated SARS-CoV-2 positive reference groups, users of molnupiravir had a median age of 74 years versus 49 years, a higher proportion resided in a nursing home (12% vs. 1.5%) and had a higher number of comorbidities (median of 3 vs. 0); most commonly hypertension (38%), chronic lung disease (35%), diabetes (20%) and mood disorders (20%). General practitioners were the primary prescribers of molnupiravir (91%)., Conclusions: Molnupiravir was mainly prescribed by general practitioners to RT-PCR SARS-CoV-2 positive individuals who had a potentially increased risk of severe COVID-19. Though some off-label prescribing occurred, our study indicates a high level of adherence to contemporary guidelines., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Asthma is the most common chronic illness in children, carrying a major burden. Socioeconomic position (SEP) affects adult asthma outcomes, but its impact on childhood asthma, particularly in primary versus specialist care, has not been studied thoroughly., Methods: In a Danish cohort consisting of all children aged 2-17 years redeeming inhaled corticosteroids in 2015, parental SEP impact on asthma outcomes was investigated. Workforce attachment, income, education, and metropolitan residence were chosen as covariates in logistic regression. Outcomes were uncontrolled (excessive use of short-acting beta2-agonists), exacerbating (oral corticosteroid use or hospitalization), and severe asthma (according to GINA 2020)., Results: The cohort comprised 29,851 children (median age 8.0, 59% boys). 16% had uncontrolled asthma, 8% had ≥1 exacerbation. Lower income and metropolitan residence correlated with higher odds of poor control, exacerbations, and severe asthma. Lower education correlated with worse asthma outcomes. Education and income were protective factors in primary care, but not in specialist care. Metropolitan residence was the sole factor linked to specialist care referral for severe asthma., Conclusion: Low parental SEP and metropolitan residence associated with poor asthma outcomes. However, specialist care often mitigated these effects, though such care was less likely for at-risk children in non-metropolitan areas., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MRL declares no conflicts of interest. KEJH has received personal fees from AstraZeneca, Chiesi, GSK, Sanofi and TEVA. DP declares no conflicts of interest but does serve on a DSMB for the National Institute of Health. CSU has received personal fees from AstraZeneca, GSK, TEVA, Chiesi, Sanofi Genzyme, Boehringer-Ingelheim, Orion Pharma, Novartis, ALK-Abello, Mundipharma, Berlin Chemie, Pfizer and Actelion outside the submitted work.

Background: Despite its potential value in register-based pharmacoepidemiologic research, recorded information on "indication for use" (INDO) in the Danish National Prescription Registry has rarely been used, likely because of questions about the variable's validity, which to our knowledge no study has systematically assessed., Methods: We extracted data on 80,814 prescriptions from the software systems (PharmaNet and C2) of five Danish community pharmacies filled between 4 and 16 February 2019 and 2020. Using the indication information recorded in the pharmacy software systems as the gold standard, we evaluated the extent and quality of the corresponding information from the Prescription Registry., Results: Of all prescriptions identified, we captured >99% in the Prescription Registry. The proportion of prescriptions with recorded indication codes in the Prescription Registry was 82% (n = 66,164) but was lower for C2 than PharmaNet. Correcting for the overrepresentation of C2 data in our sample, the estimated proportion of registration was ≈88%. Almost 100% (66,158 of 66,164) of the prescriptions with recorded indication codes in the Prescription Registry had correctly recorded indication codes. Nonspecific indication codes were present in 5.6%-36% of selected drugs and drug classes., Conclusions: Prescriptions filled at Danish community pharmacies are accurately captured by the Danish National Prescription Registry, and the recorded information on indication is generally valid and usable in research. However, minor concerns remain about missingness, nonspecific recorded indication codes, and lower validity, and a higher proportion of missingness of recorded indication codes is expected before 2017.A supplementary digital video by the article's co-author, Hanin Harbi, is available at http://links.lww.com/EDE/C89., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Osteoporosis is the most common metabolic bone disease. Aim: This study aimed to measure the utilization of drugs aff ecting bone structure and mineralization in Serbia from 2013 to 2016, and to compare this data with that from countries with well-developed pharmacotherapeutic practice, such as Finland, Norway, and Denmark. Methods: The utilization of drugs is estimated using the Anatomical Therapeutic Chemical/Defined Daily Dose (DDD) methodology. The amount of total drugs consumed has been expressed in the number of Defined Daily Dose on 1000 inhabitants per day (DDD/1000 inhabitants/day). Results: In 2016, a total of 2.91 DDD/1000 inh/day of all drugs was used in Serbia of which 75.26% belonged to bisphosphonates, whereas they made 37.15% in Finland, 81.56% in Norway and 77.84% in Denmark of the total utilization of M05 drugs subclass. The most frequently used bisphosphonate in Serbia in 2013 was alendronic acid, while in 2016 it was ibandronic acid. In three compared countries the rate of utilization among bisphosphonates was the highest for alendronic acid. The level of other bisphosphonates' utilization in Serbia, as well as the utilization of strontium ranelate, is constantly low compared to other drugs. In comparison to other countries, the utilization of denosumab in Serbia is multiple folds lower, however with an upward trend. Conclusions: The utilization of drugs aff ecting bone structure and mineralization in the examined period in Serbia compared to Finland, Norway and Denmark is three to six fold lower. Furthermore, there is a difference between the structure of prescribed and consumed drugs. [ABSTRACT FROM AUTHOR]

Introduction: To investigate the impact of a polygenic risk score for schizophrenia (PRS-SZ) and urbanicity on the risk of treatment-resistant schizophrenia (TRS) in people diagnosed with schizophrenia and to evaluate the association between PRS-SZ and TRS across levels of urbanicity.Methods: Cohort study of people born after 1981 with a first registered diagnosis of schizophrenia between 1996 and 2012 using Danish population registry data. Through linkage to genome-wide data, we calculated PRS-SZ based on a Psychiatric Genomics Consortium meta-analysis. We assessed urbanicity at birth (capital, provincial and rural areas). TRS was defined using prescription and hospital data. Performing Cox regression analysis, we calculated hazard rate ratios (HRs) and 95% confidence intervals (CI).Results: Among 4475 people with schizophrenia, we identified 593 (13.3%) with TRS during 17,558 person years of follow-up. The adjusted HR for TRS associated with one standard deviation (SD) increase in the PRS-SZ was 1.11 (95% CI: 1.00-1.24). The adjusted HRs for TRS across levels of urbanicity were 1.20 (95% CI: 0.98-1.47) for provincial areas and 1.19 (95% CI 0.96-1.47) for rural areas compared with the capital area. Within strata of urbanicity, the adjusted HR for TRS was 1.39 (95% CI: 1.14-1.70) in the capital area with 1 SD increase in the PRS-SZ, 0.99 (95% CI 0.84-1.17) in provincial areas, and 1.03 (95% CI: 0.86-1.25) in rural areas.Conclusion: The effect of genetic liability (i.e. PRS) on risk of TRS varied across urbanicity levels and was highest for people with schizophrenia born in the capital areas. [ABSTRACT FROM AUTHOR]

Purpose: Multi-morbidity and polypharmacy are common among older people. It is essential to provide a better understanding of the complexity of prescription drug use among older adults to optimise rational pharmacotherapy. Population-based utilisation data in this age group is limited. Using the Danish nationwide health registries, we aimed to characterise drug use among Danish individuals ≥ 60 years. Methods: This is a descriptive population-based study assessing drug prescription patterns in 2015 in the full Danish population aged ≥ 60 years. The use of specific therapeutic subgroups and chemical subgroups and its dependence on age were described using descriptive statistics. Profiles of drug combination patterns were evaluated using latent class analysis. Results: We included 1,424,775 residents (median age 70 years, 53% women). Of all the older adults, 89% filled at least one prescription during 2015. The median number of drug groups used was five per person. The most used single drug groups were paracetamol and analogues (34%), statins (33%) and platelet aggregation inhibitors (24%). Eighteen drug profiles with different drug combination patterns were identified. One drug profile with expected use of zero drugs and 11 drug profiles expected to receive more than five different therapeutic subgroup drugs were identified. Conclusion: The use of drugs is extensive both at the population level and increasing with age at an individual level. Separating the population into different homogenous groups related to drug use resulted in 18 different drug profiles, of which 11 drug profiles received on average more than five different therapeutic subgroup drugs. [ABSTRACT FROM AUTHOR]

Objective: This study investigated how desmopressin is prescribed to adults in Denmark. Methods: All adult users of desmopressin over an 8‐year period were identified from the Danish National Prescription Registry. Adult patients with nocturia or nocturnal enuresis (NE) were identified by indication codes for "frequent nocturnal voiding" or "involuntary nocturnal voiding", respectively. Patient demographics, desmopressin formulation and dose, and concomitant medication were investigated. Results: In all, 13 871 adults with nocturia and 2872 adults with chronic (i.e. >10 prescriptions) NE were given 102 547 and 43 712 desmopressin prescriptions, respectively. Across the entire patient cohort, 57% were women and mean patient age was 62 years. Over 40% of prescriptions were to elderly patients (≥65 years), and desmopressin use for adult enuresis increased with age. Orally disintegrating tablets were the most frequently used formulation (57%–65% of prescriptions), and a greater proportion of women than men used low‐dose desmopressin (60 μg). Concomitant use of painkillers (opioids: 18%–26.7% of prescriptions; non‐steroidal anti‐inflammatory drugs: 14.2%–16.4% of prescriptions) and antidepressants (14.4%–18.1% of prescriptions) was common in both conditions, and 5.4%–9.2% of concomitant prescriptions were for overactive bladder medications. Conclusions: This study provides insights into desmopressin use among Danish adults. Nearly half the prescriptions were to patients aged ≥65 years, despite historical manufacturer recommendations that desmopressin be restricted to patients <65 years of age. NE is considered a childhood condition, but desmopressin use for adult NE increased with age. A greater proportion of desmopressin prescriptions to women than men were for the lowest dose, consistent with greater sensitivity to desmopressin in women. [ABSTRACT FROM AUTHOR]

Abstract Purpose To evaluate the development in the use of medications associated with an increased risk of developing osteoporosis over the time period from 1999 to 2016. Methods We extracted data on total sale, sales rate and usage rate for the medications of interest from www.medstat.dk , which is an online, open-source database reporting the monthly sale of both over-the-counter and prescription-based medications in Denmark. The dataset covers both the primary and secondary health sectors. Results Most medications exhibited an increasing use from 1999 to 2016, though some had stable (e.g. glucocorticoids) or declining use. Notably, some medications showed widespread and increasing use, including proton pump inhibitors (PPI), selective serotonine reuptake inhibitors (SSRI) and venlafaxine. For PPI, sales rates increased by 461% from 1999 to 2016, with 9% of men and 11.4% of women filling at least one prescription in 2016. The use of SSRI and venlafaxine increased by 114% and 613%, respectively. This was more pronounced in women and for SSRI also in the elderly (80+ years). The sale of aromatase inhibitors was moderate (1–10 DDD per 1000 capita per day) in 2016, yet grew by 2400% from 1999, almost exclusively in women aged 80 years or older. Conclusion We found a trend of increasing use from 1999 to 2016 of most medications with a potential for causing osteoporosis, often most pronounced in fracture risk groups (postmenopausal women and/or in the elderly). This may play a clinically relevant role in both current and future causality of osteoporosis. Highlights • In Denmark, the use of most medications associated with an increased risk of osteoporosis has increased from 1999 to 2016 • Total sale of proton pump inhibitors (PPI) per 1,000 capita per day increased from 11.9 to 66.8 DDD in 2016 • During 2016, 9.0% of men and 11.4% of women collected ≥1 prescription of PPI (3.0% and 3.4%, respectively, in 1999) • Total sale of selective serotonin reuptake inhibitors doubled from 1999 to 2016, driven by primary sector prescriptions • Total sale of venlafaxine increased by 613% from 1999 to 2016, primarily driven by the increase in the female subgroup [ABSTRACT FROM AUTHOR]

Background: Polypharmacy, the use of multiple medications, has become increasingly widespread. Information on time trends in polypharmacy in people with dementia is limited, although they may be more susceptible to risks associated with polypharmacy.Objective: To examine changes in the prevalence of polypharmacy and excessive polypharmacy in people with dementia compared to changes in people without dementia.Methods: Repeated cross-sectional study of the entire Danish population aged≥65 from 2000 (n = 790,717) to 2014 (n = 1,028,377) using linked register data on diagnoses, filled prescriptions, and demographic data. Multivariate analyses were performed to explore changes in the prevalence of polypharmacy and excessive polypharmacy (≥5 and≥10 different prescription drugs). This was done before and after 2011 to examine whether increasing awareness of potential problems associated with polypharmacy has altered the trend. Estimates for people with and without dementia were compared.Results: In people with dementia, the prevalence of polypharmacy increased from 47.3% to 69.4% from 2000 to 2011 and excessive polypharmacy from 7.4% to 20.9%. In people without dementia, polypharmacy increased from 22.7% to 36.1% and excessive polypharmacy from 3.5% to 7.7%. The increase was significantly more marked in people with dementia across all age groups. From 2011 to 2014, the prevalence of polypharmacy and excessive polypharmacy remained relatively stable: Polypharmacy decreased negligibly from 69.4% to 68.1% in people with dementia and from 36.1% to 35.2% in people without dementia.Conclusion: Although the increasing trend has halted, polypharmacy remains widespread in people with dementia. Further research is needed to explore possible implications. [ABSTRACT FROM AUTHOR]

Glucocorticoids can have psychosis as a potential side effect, but have also been suggested to yield protective effects due to anti-inflammatory properties. Nonetheless, knowledge is sparse on the association between glucocorticoid treatment and development of psychosis, which we aimed to study in this first large-scale longitudinal study. Among all individuals born in Denmark 1995-2003 (n=597,257), we compared individuals who had redeemed ≥1 prescription for glucocorticoids to an active comparator group and a non-exposed group concerning subsequent development of schizophrenia spectrum disorders until 2013. Hazard rate ratios (HRR) were estimated using Cox regression adjusted for calendar year, age, gender, urbanization, somatic diseases, parental educational level and psychiatric history. The risk for a subsequent diagnosis of early-onset schizophrenia spectrum disorder (N=1141) was increased after exposure to both non-systemic (HRR=1.47; 95%-CI=1.25-1.73; N=371) and systemic glucocorticoids (HRR=1.66; 95%-CI=1.13-2.43; N=34), when compared to non-exposed individuals. Similar elevated risks were observed when comparing to the active comparator group, for schizophrenia and acute psychosis, and within an older cohort. The risk of psychosis was elevated the most within the first year after exposure to glucocorticoids (P<0.001) without any indication for a dose-response association. However, in individuals with asthma, exposure to glucocorticoids did not further increase the risk of psychosis. Glucocorticoid exposure was associated with an increased risk for psychotic disorders, which may be explained by an effect of the underlying somatic disease, such as asthma. A potential beneficial effect of glucocorticoids on psychotic symptoms should be investigated in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Long-term iodine exposure may influence the frequency of thyroid disease treatments through fluctuations in thyroid diseases. Yet, the long-term fluctuations in thyroid disease treatments upon iodine fortification (IF) are not fully known. We aimed to examine the development in thyroid disease treatments in Denmark before and following the implementation of IF in 2000. Methods: Nationwide data on antithyroid medication, thyroid hormone therapy, thyroid surgery, and radioiodine treatment were obtained from Danish registries. Negative binominal regression was applied to analyze annual changes in treatment rates adjusted for region of residence, sex, and age. Results: Incidence of antithyroid medication transiently increased but fell and reached steady state from 2010 at an incidence rate ratio (RR) of 0.72 (95% confidence interval [CI] 0.67–0.77) compared to year 2000. Thyroid hormone therapy increased and reached steady state in 2010 at an incidence RR of 1.75 (95% CI 1.62–1.89) compared to year 2000. Thyroid surgery was constant except for higher rates in 2014–2015, and radioiodine treatment fluctuated with no apparent pattern. Conclusion: Ten years after IF, a steady state was observed for incident antithyroid medication below the level at IF, and thyroid hormone therapy above the level at IF. Only small changes were observed in thyroid surgery and radioiodine treatment. In the same period, changes in diagnostic and treatment practices and lifestyle factors are likely to have occurred and should be considered when evaluating the effects of IF on treatment of thyroid diseases. [ABSTRACT FROM AUTHOR]

Study Question: Does phthalate exposure from prescription drugs affect semen quality?Summary Answer: Exposure to phthalate-containing drugs is associated with poor semen quality.What Is Known Already: Phthalates and their metabolites have been shown to disrupt the hormone signalling in animal studies. One study has shown associations between medicinal phthalate exposure and poor semen quality, suggesting similar effects in humans.Study Design, Size, Duration: We included 18 515 males with poor semen quality (cases) and 31 063 males with normal semen quality (controls) registered in the Danish IVF Registry from 2006 to 2016.Participants/materials, Setting, Methods: Exposure to phthalate-containing drugs was assessed from the Danish Register of Medicinal Product Statistics. Outcome measures were obtained at the first contact with the fertility clinic, and categorized according to the International Classification of Diseases (ICD-10). The association between current use of phthalate-containing medications <90 days prior to semen sampling and reduced semen quality was analysed using unconditional logistic regression, adjusting for potential confounders.Main Results and the Role Of Chance: In total, 57 cases and 72 controls redeemed at least one prescription for a drug containing ortho-phthalates in the 90 days before their first semen sample, yielding an adjusted odds ratio (OR) of 1.30 (95% CI: 0.91-1.85) for poor semen quality when compared to males exposed to phthalate-free generic drugs. Similarly, 81 cases and 78 controls exposed to a drug containing polymers had increased odds of poor semen quality (OR = 1.71, 95% CI: 1.24-2.35). Current exposure to polymer containing products from alimentary tract and metabolism drugs was associated with the highest OR of 2.80 (95% CI: 1.63-4.84). Comparing males exposed to drugs containing ortho-phthalates or polymers with males unexposed to prescription drugs, we found adjusted ORs of 1.32 (95% CI: 0.93-1.87) and 1.73 (95% CI: 1.26-2.36), respectively. We saw no clear relationship between degree of exposure and odds of poor semen quality.Limitations, Reasons For Caution: The reliance on ICD-10 based register data restricted our ability to relate phthalate exposure to detailed semen parameters. Furthermore, due to imperfections in the registry, we could only include the first semen sample and could not follow semen quality over time.Wider Implications Of the Findings: Our results support the likely negative effect of phthalate exposure from medicinal drugs on semen quality. As exposures from medicinal products are readily avoidable, our findings may be of relevance to regulatory authorities.Study Funding/competing Interest(s): This work was supported by Odense University Hospital, Denmark (Grant number A1003). None of the authors declare conflict of interest. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to explore the cardiovascular safety of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark. Methods: This was a cohort study using data recorded in Danish registries from patients newly exposed to darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium in 2004-2012. We estimated crude and standardized incidence rates (IRs) for acute myocardial infarction (AMI); stroke; cardiovascular mortality; major adverse cardiac events (MACE, a combined endpoint of the previous three outcomes); and all-cause death for the individual and combined drugs. We also estimated crude, standardized, and propensity score-stratified incidence rate ratios (IRRs) comparing individual antimuscarinic drugs to tolterodine as the reference. Results: Among 72,917 new users of OAB drugs (mean age, 66 years; 60% women), the standardized IR (95% confidence interval) per 1000 person-years for current use of any OAB drug was 2.7 (2.5-2.9) for AMI, 1.3 (1.2-1.5) for stroke, 7.8 (7.5-8.1) for MACE, 4.8 (4.5-5.0) for cardiovascular mortality, and 15.2 (14.8-15.6) for all-cause mortality. Propensity score-stratified IRRs for current use (reference, tolterodine) were close to the null for all drugs and endpoints. Conclusions: We did not identify differences in the risk of cardiovascular events or mortality among users of individual antimuscarinic OAB drugs. [ABSTRACT FROM AUTHOR]

Purpose: Montelukast is a leukotriene receptor antagonist used in asthma and rhinitis treatment. Despite being marketed nearly two decades ago, little is known about its utilisation pattern. Methods: Using the Danish National Prescription Registry, we identified subjects filling a montelukast prescription between 1998 and 2017. Using descriptive statistics, we reported the development in incidence, and prevalence, as well as a measure of treatment duration, and concomitant use of asthma- or anti-allergic therapy. Results: We identified 147,247 individuals filling 1,327,489 montelukast prescriptions. A total of 54,349 users (37%) filled only one montelukast prescription. The prevalence increased from 0.9/1000 persons in 1998 to 3.3/1000 persons in 2016. The rate of new users reached its maximum of 2.1/1000 person-years in 2009. Among new montelukast users, 28% were still users after 1 year. Among all montelukast initiators, 60% filled at least one prescription of short-acting beta-2-agonists (SABA) up to a year prior to montelukast initiation, and 49% filled a prescription of inhaled corticosteroids (ICS). Only 0.8% ( n = 1148) of all individuals initiated montelukast without a redeemed prescription of short- or long-term inhalation therapy, systemic antihistamines, or nasal topical anti-allergic treatment. Conclusions: The usage of montelukast has increased over threefold since its market entry in 1998, mainly driven by an increased number of prevalent users. The majority of individuals who initiated montelukast filled a prescription of SABA up to a year prior to montelukast initiation, whereas almost half filled a prescription of ICS. [ABSTRACT FROM AUTHOR]

Anticholinergic medications are used to treat extrapyramidal adverse effects induced by antipsychotics. Anticholinergics are associated with adverse effects: constipation, dry mouth and worsening of cognitive function. Anticholinergics have potential for abuse and are not recommended for long term-treatment. We aimed to investigate the use of anticholinergics in patients with schizophrenia. The national health registers in Denmark were used to examine: The prevalence of anticholinergics in 1996–2012 using a cross-sectional design; geographic variations in the prescription of anticholinergics in 2012; correlates of treatment with anticholinergics. The proportion of patients using anticholinergics decreased significantly from 11.7% in 1996 to 5.7% in 2012. The prescription pattern varied considerably between national regions in 2012, ranging from 4.0% in the Capital Region to 8.1% in the Northern Denmark Region. Long-term use of anticholinergics was predicted by older age, age at debut of schizophrenia, receiving early retirement pension, typical antipsychotic use, antipsychotic polypharmacy, typical + atypical antipsychotics, antidepressant treatment, high doses of antipsychotics measured in defined-daily-dose, physical comorbidity and psychiatrists` greater caseload. Use of anticholinergics declined during the study period, and showed substantial variation across the regions in 2012. Long-term use was linked to typical antipsychotic use and variables that are associated with greater illness severity. [ABSTRACT FROM AUTHOR]

The Odense University Pharmacoepidemiological Database ( OPED) is a prescription database established in 1990 by the University of Southern Denmark, covering reimbursed prescriptions from the county of Funen in Denmark and the region of Southern Denmark (1.2 million inhabitants). It is still active and thereby has more than 25 years of continuous coverage. In this MiniReview, we review its history, content, quality, coverage, governance and some of its uses. OPED's data include the Danish Civil Registration Number ( CPR), which enables unambiguous linkage with virtually all other health-related registers in Denmark. Among its research uses, we review record linkage studies of drug effects, advanced drug utilization studies, some examples of method development and use of OPED as sampling frame to recruit patients for field studies or clinical trials. With the advent of other, more comprehensive sources of prescription data in Denmark, OPED may still play a role as in certain data-intensive regional studies. [ABSTRACT FROM AUTHOR]

Background: antipsychotic drugs (APs) have been associated with falls and fractures in elderly individuals but limited knowledge on specific drugs exist. Objective: to investigate the association between individual APs and fractures in elderly persons. Design and setting: nationwide register-based cohort study. Subjects: all Danish individuals aged ≥65 who had not been in treatment with any AP in the year before inclusion. Methods: incidence rate ratios (IRRs) of fractures of hip, pelvis or upper extremities during treatment with commonly used APs were assessed in multivariable Poisson models. Exposure was divided into time periods from initiation of treatment: 0-30 days, 31-365 days or >365 days. Results: one year prior to inclusion, 1,540,915 individuals ≥65 years had not received APs and of these 93,298 initiated treatment with APs. Mean follow-up was 9.6 years. During follow-up, 246,057 (16%) experienced a fracture. Associations were for all APs highest in the initial treatment period (0-30 days) with IRRs for risperidone 1.97 (95% CI: 1.70-2.28), olanzapine 2.31 (95% CI: 1.96-2.73), quetiapine 2.09 (95% CI: 1.73-2.52), zuclopenthixol 2.19 (95% CI: 1.82-2.63), chlorprothixen 1.62 (95% CI: 1.18-2.24), flupenthixol 1.43 (95% CI: 1.06-1.93), levomepromazine 1.19 (95% CI 0.86-1.66), haloperidol 2.98 (95% CI 2.57-3.45), compared with the background population. Conclusions: use of APs is associated with fractures in elderly persons especially in the initial treatment period. If AP use in an elderly person is deemed necessary, individual falls prophylaxis should be considered. [ABSTRACT FROM AUTHOR]

Bckground: Clinical epidemiology research studies, including pharmacoepidemiology and pharmacovigilance studies, use routinely collected health data, such as diagnoses recorded in national health and administrative registries, to assess clinical effectiveness and safety of treatments. We estimated positive predictive values (PPVs) of International Classification of Diseases, 10th revision (ICD-10) codes for primary diagnoses of dermatologic events and hypersensitivity recorded at hospitalization or emergency room visit in the national patient registries of Denmark and Sweden among women with postmenopausal osteoporosis (PMO). Methods: This validation study included women with PMO identified from the Danish and Swedish national patient registries (2005-2014). Medical charts of the potential cases served as the gold standard for the diagnosis confirmation and were reviewed and adjudicated by physicians. Results: We obtained and reviewed 189 of 221 sampled medical records (86%). The overall PPV was 92.4% (95% confidence interval [CI], 85.1%-96.3%) for dermatologic events, while the PPVs for bullous events and erythematous dermatologic events were 52.5% (95% CI, 37.5%-67.1%) and 12.5% (95% CI, 2.2%-47.1%), respectively. The PPV was 59.0% (95% CI, 48.3%-69.0%) for hypersensitivity; however, the PPV of hypersensitivity increased to 100.0% (95% CI, 67.6%-100.0%) when restricting to diagnostic codes for anaphylaxis. The overall results did not vary by country. Conclusion: Among women with PMO, the PPV for any dermatologic event recorded as the primary diagnosis at hospitalization or at an emergency room visit was high and acceptable for epidemiologic research in the Danish and Swedish national patient registries. The PPV was substantially lower for hypersensitivity leading to hospitalization or emergency room visit. [ABSTRACT FROM AUTHOR]

Background: Antipsychotics and other psychotropics are frequently used to treat neuropsychiatric symptoms in patients with dementia, even though the evidence for effect is limited. Concerns have been raised about the safety of antipsychotics, but concomitant use of multiple psychotropic drug classes (psychotropic polypharmacy) may also pose a risk for patients.Objective: To investigate the prevalence and predictors associated with use of psychotropic polypharmacy in patients with dementia.Methods: A population-based study using nationwide registers. Patients with dementia were identified among all Danish residents ≥65 years on January 1, 2012. Data on prescriptions and comorbidity was included in the analysis. Overlapping prescriptions for different psychotropic drug classes were used to determine psychotropic polypharmacy. A multivariable logistic regression analysis was conducted to evaluate factors independently associated with the prescription of other psychotropic drug classes among patients already using antipsychotics.Results: Among all patients registered with dementia (34,553), 25.3% (8,728) used ≥2 psychotropic drugs. Among patients treated with antipsychotics 75.8% (5,403) used at least one other psychotropic drug during the antipsychotic treatment period. Nursing home residency, number of non-psychotropic medications used in 2011, and prior psychiatric diagnosis were associated with psychotropic polypharmacy among antipsychotic drug users. The most frequent combination of psychotropic drugs was antipsychotics and antidepressants.Conclusion: Concomitant use of psychotropic drugs was frequent in dementia patients. Patients living in nursing homes had the highest risk of receiving a combination of antipsychotics and other psychotropic drugs. Concomitant use of psychotropics may cause adverse events, and potential consequences for patients' safety call for further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Laboratory and epidemiological evidence have suggested that statin use may protect against the development of certain cancers, including endometrial cancer. In a nationwide registry-based case-control study, we examined the association between statin use and risk of endometrial cancer.Material and Methods: Cases were female residents of Denmark with a primary diagnosis of endometrial cancer during 2000-2009. For each case, we selected 15 female population controls matched on date of birth (±one month) using risk-set sampling. Ever use of statin was defined as two or more prescriptions on separate dates. Conditional logistic regressions were used to estimate age-matched (by design) and multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CI) for endometrial cancer associated with statin use. The multivariable-adjusted models included parity, hormone replacement therapy (HRT), obesity, diabetes, chronic obstructive pulmonary disease and education. We evaluated whether the association between statin use and endometrial cancer varied with duration and intensity of statin use, type of endometrial cancer or patient characteristics.Results: The study population comprised 5382 endometrial cancer cases and 72 127 population controls. We observed no association between ever use of statins and endometrial cancer risk (OR 1.03, 95% CI 0.94-1.14). In addition, endometrial cancer risk did not vary substantially with duration or intensity of statin use. Stratification by type of endometrial cancer also yielded neutral ORs.Conclusions: In our nationwide case-control study, we found no association between statin use and risk of endometrial cancer. [ABSTRACT FROM AUTHOR]

PHARMACOM-EPI is a novel framework to predict plasma concentrations of drugs at the time of occurrence of clinical outcomes. In early 2021, the U.S. Food and Drug Administration (FDA) issued a warning on the antiseizure drug lamotrigine claiming that it has the potential to increase the risk of arrhythmias and related sudden cardiac death due to a pharmacological sodium channel-blocking effect. We hypothesized that the risk of arrhythmias and related death is due to toxicity. We used the PHARMACOM-EPI framework to investigate the relationship between lamotrigine's plasma concentrations and the risk of death in older patients using real-world data. Danish nationwide administrative and healthcare registers were used as data sources and individuals aged 65 years or older during the period 1996 - 2018 were included in the study. According to the PHARMACOM-EPI framework, plasma concentrations of lamotrigine were predicted at the time of death and patients were categorized into non-toxic and toxic groups based on the therapeutic range of lamotrigine (3-15 mg/L). Over 1 year of treatment, the incidence rate ratio (IRR) of all-cause mortality was calculated between the propensities score matched toxic and non-toxic groups. In total, 7286 individuals were diagnosed with epilepsy and were exposed to lamotrigine, 432 of which had at least one plasma concentration measurement The pharmacometric model by Chavez et al. was used to predict lamotrigine's plasma concentrations considering the lowest absolute percentage error among identified models (14.25 %, 95 % CI: 11.68-16.23). The majority of lamotrigine associated deaths were cardiovascular-related and occurred among individuals with plasma concentrations in the toxic range. The IRR of mortality between the toxic group and non-toxic group was 3.37 [95 % CI: 1.44-8.32] and the cumulative incidence of all-cause mortality exponentially increased in the toxic range. Application of our novel framework PHARMACOM-EPI provided strong evidence to support our hypothesis that the increased risk of all-cause and cardiovascular death was associated with a toxic plasma concentration level of lamotrigine among older lamotrigine users., Competing Interests: Declaration of Competing Interest All authors declare that there is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Gabapentin and pregabalin have been associated with an increased risk of fragility fractures. Due to differences in pharmacokinetics, we aimed to assess the fracture-risk difference between the two medicines. We performed a Danish nationwide new user, high-dimensional propensity score-matched cohort study to assess the 90-day risk of fragility fractures among adults, from January 1996 to December 2018. We applied a high-dimensional propensity score to match new users of gabapentin with new users of pregabalin in a 1:1 intention-to-treat approach. Hazard ratios (HRs), incidence rates (IRs) and incidence rate difference (IRD) were obtained. We identified 388 236 eligible patients of which 294 223 and 98 869 initiated gabapentin and pregabalin, respectively. We included 48 272 matched pairs for further analysis. The mean age was 56 (IQR 44-69) years, and the average follow-up was approximately 11 500 person-years (PY). The IRs of fragility fractures were 23.7 (95%CI 21.0-26.7) and 23.2 (95%CI 20.5-26.2) per 1000 PY for gabapentin and pregabalin-exposed patients, respectively. This yielded an HR of 1.02 (95%CI 0.86-1.21) when using gabapentin as the intervention drug and pregabalin as the reference drug. The IRD was estimated to 0.5 PY (95%CI -3.5-4.5). In conclusion, short-term risk of fragility fractures among gabapentin initiators was not different compared to those initiating pregabalin., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Studying the effect of chronic medication exposure by means of a case-crossover design may result in an upward-biased odds ratio. In this study, our aim was to assess the occurrence of this bias and to evaluate whether it is remedied by including a control group (the case-time-control design). Using Danish data resources from 1995-2012, we conducted case-crossover and case-time-control analyses for 3 medications (statins, insulin, and thyroxine) in relation to 3 outcomes (retinal detachment, wrist fracture, and ischemic stroke), all with assumed null associations. Controls were matched on age, sex, and index date, and exposure over the preceding 12 months was ascertained. For retinal detachment, the case-crossover odds ratio was 1.60 (95% confidence interval (CI): 1.42, 1.80) for statins, 1.40 (95% CI: 1.02, 1.92) for thyroxine, and 1.53 (95% CI: 1.04, 2.24) for insulin. Estimates for the retinal detachment controls were similar, leading to near-null case-time-control estimates for all 3 medication classes. For wrist fracture and stroke, the odds ratios were higher for cases than for controls, and case-time-control odds ratios were consistently above unity, thus implying significant residual bias. In case-crossover studies of medications, contamination by persistent users confers a moderate bias upward, which is partly remedied by using a control group. The optimal strategy for dealing with this problem is currently unknown. [ABSTRACT FROM AUTHOR]