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Aurélie Mailhac,1 Lars Pedersen,1 Anton Pottegård,2 Jens Søndergaard,3 Torben Mogensen,4 Henrik Toft Sørensen,1 Reimar W Thomsen1 1Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; 2Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 3Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense, Denmark; 4Danish Pharmacovigilance Council, Danish Medicines Agency, Copenhagen, DenmarkCorrespondence: Reimar W Thomsen, Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark, Email rwt@clin.au.dkPurpose: A surge in the use of semaglutide injection (Ozempic®) approved to treat type 2 diabetes (T2D) has led to a global supply shortage. We investigated contemporary user rates and clinical characteristics of semaglutide (Ozempic®) users in Denmark, and the extent of “off-label” prescribing for weight loss.Patients and Methods: Nationwide population-based cross-sectional study based on linked health registries January 2018 through December 2023. All adults who received a first prescription of semaglutide once weekly (Ozempic®) were included. We examined quarterly rates of new users and total user prevalences, using other glucagon-like peptide-1 receptor agonists and weight loss medications as comparison. We also investigated user characteristics including T2D, glucose control, comedications, and cardiorenal disease.Results: The new user rate of semaglutide (Ozempic®) remained stable at approximately 4 per 1000 adult person-years between 2019 and 2021 and then accelerated, peaking at 10 per 1000 in the first quarter of 2023 after which it declined sharply. User prevalence increased to 91,626 users in Denmark in 2023. The proportion of semaglutide (Ozempic®) new users who had a record of T2D declined from 99% in 2018 to only 67% in 2022, increasing again to 87% in 2023. Among people with T2D who initiated semaglutide (Ozempic®) in 2023, 52% received antidiabetic polytherapy before initiation, 39% monotherapy, and 8% no antidiabetic therapy. Most T2D initiators had suboptimal glucose control, with 83% having an HbA1c ≥ 48 mmol/mol and 68% ≥ 53 mmol/mol despite use of antidiabetic medication, and 29% had established atherosclerotic cardiovascular disease or kidney disease.Conclusion: The use of semaglutide (Ozempic®) in Denmark has increased dramatically. Although not approved for weight loss without T2D, one-third of new users in 2022 did not have T2D. Conversely, most initiators with T2D had a clear medical indication for treatment intensification, and “off-label” use can only explain a minor part of the supply shortage.Keywords: drug utilization, epidemiology, anti-obesity drugs, glucose-lowering drugs, obesity, type 2 diabetes

Objectives Studies have reported high incidences of stroke in patients hospitalised with SARS-CoV-2, but the impact of disease severity is unexplored. We aimed to estimate the risk of incident ischaemic stroke in SARS-CoV-2 test-positive individuals compared with test-negative individuals stratified by disease severity during acute infection and post infection.Design A register-based cohort study.Setting A Danish nationwide study.Participants All Danish adults who had PCR tests for SARS-CoV-2 performed between 1 March 2020 and 30 November 2021. Test-positive individuals were included at their first positive test. For individuals tested prior to 30 November 2021, we randomly sampled an index date from the distribution of test dates among SARS-CoV-2 test-positive individuals. Test-positive individuals were followed during the acute phase of infection (days 0–14) and post infection (180 days after the acute phase). Test-negative individuals were followed in equivalent time periods.Primary and secondary outcome measures Incident ischaemic stroke risk in SARS-CoV-2 test-positive individuals compared with test-negative individuals during acute infection and post infection. We calculated subdistribution HRs (SHR) with death as a competing risk using propensity score weighting as confounder control. The risk was stratified according to disease severity: community managed, hospitalised, or admission to the intensive care unit.Results Among 3 910 219 SARS-CoV-2 PRC-tested individuals, 356 421 test-positive and 3 067 456 test-negative individuals were included. A positive SARS-CoV-2 test was associated with an SHR of 3.32 (95% CI 2.60 to 4.25) overall for stroke compared with test negative in the acute phase. In the postinfection period, the risk of stroke remained increased in individuals hospitalised during the acute phase (SHR 1.85, 95% CI 1.45 to 2.37). Individuals with community-managed SARS-CoV-2 had no increased long-term risk of stroke (SHR 1.01, 95% CI 0.88 to 1.16).Conclusion SARS-CoV-2 infection is associated with increased stroke risk. Disease severity seems to be an important factor. Individuals with community-managed SARS-CoV-2 had no increased stroke risk.

Kamille Herskind,1 Peter Bjødstrup Jensen,1 Christina Anne Vinter,2– 4 Lone Krebs,5,6 Lene Friis Eskildsen,5 Anne Broe,1,7 Anton Pottegård,1 Mette Bliddal1,8 1Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Gynaecology and Obstetrics, Odense University Hospital, Odense, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 4Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; 5Department of Obstetrics and Gynecology, Copenhagen University Hospital-Amager and Hvidovre, Copenhagen, Denmark; 6Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 7IQVIA, London, UK; 8Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Mette Bliddal, OPEN, Heden 16, St.tv, Odense, 5000, Denmark, Tel +45 2943 7912, Email mette.bliddal@rsyd.dkPurpose: This study aimed to systematically evaluate the validity of variables related to pregnancy, delivery, and key characteristics of the infant in the Danish National Patient Register using maternal medical records as the reference standard.Patients and Methods: We reviewed medical records of 1264 women giving birth in the Region of Southern Denmark during 2017. We calculated positive (PPV) and negative (NPV) predictive values, sensitivity, and specificity to estimate the validity of 49 selected variables.Results: The PPV was ≥ 0.90 on most pregnancy-related variables including parity, pre-gestational BMI, diabetes disorders, and previous cesarean section, while it was lower for hypertensive disorders, especially mild to moderate preeclampsia (0.49, 95% CI 0.32– 0.66). Sensitivity ranged from 0.80 to 1.00 on all pregnancy-related variables, except hypertensive disorders (sensitivity 0.38– 0.71, lowest for severe preeclampsia). On most delivery-related variables including obstetric surgical procedures (eg cesarean section and induction of labor), pharmacological pain-relief, and gestational age at delivery, PPV’s ranged from 0.98 to 1.00 and the corresponding sensitivities from 0.87 to 1.00. Regarding infant-related variables, both the APGAR score registered five minutes after delivery and birthweight yielded a PPV of 1.00.Conclusion: Obstetric coding in the Danish National Patient Register shows very high validity and completeness making it a valuable source for epidemiologic research.Plain Language Summary: Danish register data are often used for epidemiological research in reproduction. The registers are based on coded information to the registers based on information from medical records. The quality of the register data is highly dependent of the validity of the codes. Yet there is a lack in our knowledge of the validity of data related to pregnancy, childbirth, and the characteristics of the newborn baby. We therefore aimed to validate the Danish National Patient Registry data related to pregnancy and childbirth by comparing the registered code with information from the medical records.We scrutinized medical records from 1264 women giving birth in the Region of Southern Denmark during 2017. We compared the registration in the medical record with the registered code in the Danish National Patient Registry by calculating how accurate the register data are according to 49 different variables.Results showed that registered codes in the Patient Registry for pregnancy- and childbirth-related conditions and key infant characteristics were to a high degree in agreement with the data from the medical report with few exceptions.In conclusion, the study revealed that the Danish National Patient Register provides highly accurate and comprehensive data for most pregnancy, delivery, and infant-related variables. This underscores the register’s value as a reliable source for epidemiologic research in reproductive health.Keywords: registries, sensitivity and specificity, validity, epidemiology, pregnancy, delivery

Patients with primary immune thrombocytopenia (ITP) suffer from reduced survival and quality of life, but the underlying reasons for this are largely undescribed. Mental health and the use of psychotropic drugs in ITP is unknown. We investigated the risk of hospital registered mental health events including fatigue and the use of psychotropic drugs in adult patients with ITP compared with the general population, using nationwide registry-data. We identified 3,749 patients with ITP and 149,849 age-sex matched general population comparators in the Danish Health Registries in the period 1997-2016. The median age was 60 years (IQR 40-73) and 53% were women. We followed the individuals for incident mental health events and estimated the use of psychotropic drugs over calendar-years and in temporal relation to diagnosis of ITP. The first year cumulative incidence of any mental health event was 2.3% (95% confidence interval, 1.9-2.9) in patients and 0.7% (0.6-0.7) in comparators, yielding an adjusted cause-specific hazard ratio (csHR) of 3.57 (2.84-4.50). The corresponding estimates for depression were 1.2% (0.9-1.6) and 0.3% (0.3-0.4) respectively, with an adjusted csHR of 3.53 (2.56-4.85). We found similar findings for anxiety and fatigue, but risks generally diminished after 1-5 years. The use of opioids, antidepressants, and benzodiazepines increased in temporal relation to diagnosis of ITP. The risk of mental health events and the use of psychotropic drugs is higher in adult patients with ITP compared with the general population, and has a temporal relation to diagnosis of ITP emphasizing that mental health in ITP is a concern.

Abstract Background Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants in pregnancy. Animal and some clinical studies have suggested potential increases in depression and anxiety following prenatal SSRI exposure, but the extent to which these are driven by the medication remains unclear. We used Danish population data to test associations between maternal SSRI use during pregnancy and children outcomes up to age 22. Methods We prospectively followed 1,094,202 single-birth Danish children born 1997–2015. The primary exposure was ≥ 1 SSRI prescription filled during pregnancy; the primary outcome, first diagnosis of a depressive, anxiety, or adjustment disorder, or redeemed prescription for an antidepressant medication. We used propensity score weights to adjust potential confounders, and incorporated data from the Danish National Birth Cohort (1997–2003) to further quantify potential residual confounding by subclinical factors. Results The final dataset included 15,651 exposed and 896,818 unexposed, children. After adjustments, SSRI-exposed had higher rates of the primary outcome than those of mothers who either did not use an SSRI (HR = 1.55 [95%CI:1.44,1.67] or discontinued the SSRI use ≥ 3 months prior to conception (HR = 1.23 [1.13,1.34]). Age of onset was earlier among exposed (9 [IQR:7–13] years) versus unexposed (12 [IQR:12–17] years) children (p

Objective Patients receiving immunosuppressives have been excluded from trials for SARS-CoV-2 vaccine efficacy. Investigation of immunosuppressants’ impact on effectiveness of vaccines, particularly in patients with immune-mediated inflammatory diseases (IMID), is therefore required.Design We performed a nationwide cohort study to assess the risk of COVID-19 infection in vaccinated patients with IMID exposed to immunosuppressives compared with IMID unexposed to immunosuppressives. Exposure to immunosuppressives in the 120 days before receiving the second SARS-CoV-2 mRNA vaccination was assessed. Patients were followed from date of second vaccination and weighted Cox models were used to estimate the risk of infection associated with immunosuppressives. Secondary outcomes included hospitalisation and death associated with a positive SARS-CoV-2 test. Risk of infection by immunosuppressant drug class was also analysed.Setting This study used population-representative data from Danish national health registries in the period from 1 January to 30 November 2021.Results Overall, 152 440 patients were followed over 19 341 person years. Immunosuppressants were associated with a significantly increased risk of infection across IMID (HR: 1.4, 95% CI 1.2 to 1.5), in inflammatory bowel disease (IBD) (HR: 1.6, 95% CI 1.4 to 1.9) and arthropathy (HR: 1.3, 95% CI 1.1 to 1.4) but not psoriasis (HR: 1.1, 95% CI 0.9 to 1.4). Immunosuppressants were also associated with an increased risk of hospitalisation across IMID (HR: 1.4, 95% CI 1.1 to 2.0), particularly in IBD (HR: 2.1, 95% CI 1.0 to 4.1). No significantly increased risk of death in immunosuppressant exposed patients was identified. Analyses by immunosuppressant drug class showed increased COVID-19 infection and hospitalisation with anti-tumour necrosis factor (TNF), systemic corticosteroid, and rituximab and other immunosuppressants in vaccinated patients with IMID.Conclusion Immunosuppressive therapies reduced effectiveness of mRNA SARS-CoV-2 vaccination against infection and hospitalisation in patients with IMID. Anti-TNF, systemic corticosteroids, and rituximab and other immunosuppressants were particularly associated with these risks.

Aim: We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism. Methods: In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P‐glycoprotein (P‐gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P‐gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators. Results: Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10 days of 0.67 (95% confidence interval [CI]: 0.42–1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39–1.4), suggesting reduced oral absorption via increased P‐gp expression. In vitro, dicloxacillin raised P‐gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72–1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51–1.5). Conclusions: Dicloxacillin increases expression of intestinal P‐gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug–drug interaction between dicloxacillin/flucloxacillin and DOACs. [ABSTRACT FROM AUTHOR]

The article published in the Journal of Internal Medicine explores the increased risk of hypereosinophilia following the initiation of glucagon-like peptide 1 receptor agonists (GLP1-RA) using Danish health registries. The study found that individuals who initiated GLP1-RA were three times more likely to experience hypereosinophilia compared to before initiation, with no similar association observed for other antidiabetic drugs. The research highlights the need for larger studies to further investigate the potential link between GLP1-RA and clinically manifest hypereosinophilic syndrome. [Extracted from the article]

Kasper Bruun Kristensen,1 Lars Christian Lund,1 Peter Bjødstrup Jensen,1 Anne Broe,1 Emelie Rotbain,2 Per Damkier,1,3,4 Anton Pottegård,1 Jacob Harbo Andersen,1 Mikkel Højlund,1,5 Morten Olesen,1 Lotte Rasmussen,1 Morten Rix Hansen,1,3,4 Martin Thomsen Ernst,1 Rikke Wesselhoeft,1,6 Daniel Pilsgaard Henriksen,3 Mette Reilev,1 Mette Bliddal,1,7 Jesper Hallas1 1Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark; 6Child and Adolescent Psychiatry Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark; 7Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Jesper Hallas, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 2, Odense, 5000, Denmark, Tel +4565503010, Email jhallas@health.sdu.dkPurpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices.Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥ 40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables.Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883– 0.890) exceeded that of the CCI (0.871, 95% CI 0.868– 0.874) and ECI (0.866, 95% CI 0.863– 0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779– 0.784) to 0.838 (95% CI 0.834– 0.842).Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.Keywords: multimorbidity, comorbidity, pharmacoepidemiology, prognosis, risk score

Objectives To examine valsartan, losartan and irbesartan usage and switching patterns in the USA, UK, Canada and Denmark before and after July 2018, when the first Angiotensin-Receptor-Blocker (ARB) (valsartan) was recalled.Design Retrospective cohort study.Setting USA, Canadian administrative healthcare data, Danish National Prescription Registry and UK primary care electronic health records.Participants Patients aged 18 years and older between January 2014 and December 2020.Intervention Valsartan, losartan and irbesartan.Main outcome Monthly percentages of individual ARB episodes, new users and switches to another ARB, ACE inhibitors (ACEI) or calcium channel blockers containing products.Results We identified 10.8, 3.2, 1.8 and 1.2 million ARB users in the USA, UK, Canada and Denmark, respectively. Overall proportions of valsartan, losartan and irbesartan use were 18.4%, 67.9% and 5.2% in the USA; 3.1%, 48.3% and 10.2% in the UK, 16.3%, 11.4% and 18.3% in Canada, 1%, 93.5% and 0.6% in Denmark. In July 2018, we observed an immediate steep decline in the proportion of valsartan use in the USA and Canada. A similar trend was observed in Denmark; however, the decline was only minimal. We observed no change in trends of ARB use in the UK. Accompanying the valsartan decline was an increase in switching to other ARBs in the USA, Canada and Denmark. There was a small increase in switching to ACEI relative to the valsartan-to-other-ARBs switch. We also observed increased switching from other affected ARBs, losartan and irbesartan, to other ARBs throughout 2019, in the USA and Canada, although the usage trends in the USA remained unchanged.Conclusion The first recall notice for valsartan resulted in substantial decline in usage due to increased switching to other ARBs. Subsequent notices for losartan and irbesartan were also associated with increased switching around the time of the recall, however, overall usage trends remained unchanged.

AimThe aim of this study was to study potential cytochrome P450 (CYP) induction by dicloxacillin.MethodsWe performed an open-label, randomized, two-phase, five-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1 g dicloxacillin three times daily for 10 days. Plasma and urine were collected over 24 h and the concentration of all five drugs and their primary metabolites was determined using a liquid chromatography coupled to triple quadrupole mass spectrometry method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48 h and changes in gene expression and the activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 were investigated. The activation of nuclear receptors by dicloxacillin was assessed using luciferase assays.ResultsA total of 10 days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0 to 24 h for omeprazole (CYP2C19) {geometric mean ratio [GMR] [95% confidence interval (CI)]: 0.33 [0.24, 0.45]}, tolbutamide (CYP2C9) [GMR (95% CI): 0.73 (0.65, 0.81)] and midazolam (CYP3A4) [GMR (95% CI): 0.54 (0.41, 0.72)]. Additionally, other relevant pharmacokinetic parameters were affected, indicating the induction of CYP2C- and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed a statistically significant dose-dependent increase in CYP expression and activity by dicloxacillin, caused by activation of the pregnane X receptor.ConclusionsDicloxacillin is an inducer of CYP2C- and CYP3A-mediated drug metabolism, and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window.

Alejandro Arana,1 Anton Pottegård,2 Josephina G Kuiper,3 Helen Booth,4 Johan Reutfors,5 Brian Calingaert,6 Lars Christian Lund,2 Elizabeth Crellin,4 Marcus Schmitt-Egenolf,5,7 James A Kaye,8 Karin Gembert,5 Kenneth J Rothman,8 Helle Kieler,5 Daniel Dedman,4 Eline Houben,3 Lia Gutiérrez,1 Jesper Hallas,2 Susana Perez-Gutthann1 1Department of Epidemiology, RTI Health Solutions, Barcelona, 08028, Spain; 2Clinical Pharmacology, Pharmacy and Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense C, 5000, Denmark; 3The PHARMO Institute, Utrecht, 3528 AE, the Netherlands; 4Clinical Practice Research Datalink (CPRD), The Medicines and Healthcare Products Regulatory Agency, London, E14 4PU, UK; 5Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, 171 76, Stockholm, Sweden; 6Department of Epidemiology, RTI Health Solutions, Research Triangle Park, NC, 27709-2194, USA; 7Department of Public Health and Clinical Medicine, Umeå University, Umeå, 901 87, Sweden; 8Department of Epidemiology, RTI Health Solutions, Waltham, MA, 02451-1623, USACorrespondence: Alejandro AranaDepartment of Epidemiology, RTI Health Solutions, Av. Diagonal 605, 9-1, Barcelona, 08028, SpainTel +34 93 362 2805Fax +34 93 414 2610Email aarana@rti.orgPurpose: Evidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately.Patients and Methods: A cohort study in Denmark, Sweden, UK, and the Netherlands was conducted. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for nonmelanoma skin cancer (NMSC), melanoma, cutaneous T-cell lymphoma (CTCL), non-Hodgkin lymphoma (NHL) excluding CTCL, and Hodgkin lymphoma (HL) in new users of TCIs versus users of moderate/high-potency topical corticosteroids.Results: The study included 126,908/61,841 adults and 32,605/27,961 children initiating treatment with tacrolimus/pimecrolimus, respectively. Follow-up was ≥ 10 years for 19% of adults and 32% of children. Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were < 1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25– 2.58) for cutaneous T-cell lymphoma. For pimecrolimus, IRRs in adults were < 1 for non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and Hodgkin’s lymphoma; and 1.21 (1.03– 1.41) for melanoma; and 1.28 (1.20– 1.35) for nonmelanoma skin cancer. In children, results were inconclusive due to few events. In adults, incidence rate ratios ≥ 5 years after first topical calcineurin inhibitor exposure were not higher than in overall analyses.Conclusion: Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results. Even if causal, the public health impact of these excess risks would be low and confined to the first years of exposure.Keywords: tacrolimus, pimecrolimus, cutaneous T-cell lymphoma, malignant melanoma, non-melanoma skin cancer, database study

Background: A previous study in Denmark suggested an increased melanoma risk associated with the use of flecainide.Objective: To study the association between flecainide use and the risk of melanoma and non-melanoma skin cancer in Spain and Denmark.Methods: We conducted a multi-database case–control study in (database/study period) Spain (SIDIAP/2005–2017 and BIFAP/2007–2017) and Denmark (Danish registries/2001–2018). We included incident cases of melanoma or non-melanoma skin cancer (NMSC) aged ≥18 with ≥2 years of previous data (≥10 years for Denmark) before the skin cancer and matched them to controls (10:1 by age and sex). We excluded persons with immunosuppression or previous cancer. We defined ever-use as any prescription fill and high-use as a cumulative dose of at least 200 g (reference: never-use). We categorized a cumulative dose for a dose–response assessment. We used conditional logistic regression to compute ORs (95% CI) adjusted for photosensitizing, anti-neoplastic, disease-specific drugs and comorbidities.Results: The total numbers of melanoma/NMSC cases included were 7,809/64,230 in SIDIAP, 4,661/31,063 in BIFAP, and 27,978/152,821 in Denmark. In Denmark, high-use of flecainide was associated with increased adjusted ORs of skin cancer compared with never-use [melanoma: OR 1.97 (1.38–2.81); NMSC: OR 1.34 (1.15–1.56)]. In Spain, an association between high-use of flecainide and NMSC was also observed [BIFAP: OR 1.42 (1.04–1.93); SIDIAP: OR 1.19 (0.95–1.48)]. There was a non-significant dose–response pattern for melanoma in Denmark and no apparent dose–response pattern for NMSC in any of the three databases. We found similar results for ever-use of flecainide.Conclusion: Flecainide use was associated with an increased risk of melanoma (Denmark only) and NMSC (Denmark and Spain) but without substantial evidence of dose–response patterns. Further studies are needed to assess for possible unmeasured confounders.

Charles Vesteghem,1– 3 Rasmus Froberg Brøndum,1– 3 Ursula G Falkmer,1,3,4 Anton Pottegård,5 Laurids Østergaard Poulsen,1,3,4 Martin Bøgsted1– 3 1Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 2Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; 3Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark; 4Department of Oncology, Aalborg University Hospital, Aalborg, Denmark; 5Department of Public Health, University of Southern Denmark, Odense, DenmarkCorrespondence: Charles VesteghemDepartment of Clinical Medicine, Aalborg University, Søndre Skovvej 15, Aalborg, 9000, DenmarkTel +45 97 66 38 72Fax +45 97 66 63 23Email charles.vesteghem@rn.dkBackground: The Danish National Patient Registry is a major resource for Danish epidemiology. Only a few studies have been conducted to check the validity of the reporting of systemic anticancer treatments. In this study, we assessed this validity for a range of cancer types over a long period of time.Patients and Methods: We extracted systemic anticancer treatment procedures from the Danish National Patient Registry for patients with solid malignant tumors treated at the Department of Oncology at Aalborg University Hospital between 2009 and 2019 (12,014 patients with 215,293 drug records). These data were compared to records obtained from the antineoplastic prescription database used at the department. We estimated the sensitivity, positive predictive value (PPV), and F1-score defined as the harmonic mean of the sensitivity and the PPV.Results: There was an overall high concordance between the two datasets with a sensitivity and a PPV > 92%. Treatments for brain, ovarian and endometrial cancers displayed lower concordance (81– 89%). The validity was stable over the study period, with a slight drop during 2016– 2017. Most drugs had a high validity with F1-scores above 90%. Fluorouracil, gemcitabine, pemetrexed, pembrolizumab, and nivolumab had F1-scores above 97%. Drugs that were introduced in the study period, such as lapatinib, palbociclib, erlotinib, pertuzumab, and panitumumab, yielded lower F1-scores due to the absence of specific registry codes early after introduction.Conclusion: The Danish National Patient Registry can be used to reliably obtain information about systemic anticancer treatments, keeping in mind limitations for recently introduced drugs and for some types of cancer.Keywords: antineoplastic agents, registries, Danish National Patient Registry, epidemiology, sensitivity and specificity, validity

Abstract Background Lipid levels in blood have decreased considerably during the past decades in the general population partly due to use of statins. This study aims to investigate the trends in lipid levels between 2001 and 2018 in a statin-free population from primary health care, overall and by sex and age. Methods In a cohort of 634,119 patients from general practice with no diagnoses or medical treatments that affected lipid levels of total cholesterol (TC; n = 1,574,339) between 2001 and 2018 were identified. Similarly, measurements of low-density lipoprotein cholesterol (LDL-C; n = 1,302,440), high-density lipoprotein cholesterol (HDL-C; n = 1,417,857) and triglycerides (TG; n = 1,329,477) were identified. Results Mean TC decreased from 5.64 mmol/L (95% CI: 5.63–5.65) in 2001 to 5.17 mmol/L (95% CI: 5.16–5.17) in 2018 while LDL-C decreased from 3.67 mmol/L (95% CI: 3.66–3.68) to 3.04 mmol/L (95% CI: 3.03–3.04). Women aged 70–74 years experienced the largest decreases in TC levels corresponding to a decrease of 0.7 mmol/L. The decrease in LDL-C levels was most pronounced in men ≥85 years with a decrease of 0.9 mmol/L. For both genders, TC and LDL-C levels increased with advancing age until around age 50. After menopause the women had higher TC and LDL-C levels than the men. The median (geometric mean) TG level decreased by 0.4 mmol/L from 2001 to 2008, after which it increased slightly by 0.1 mmol/L until 2018. During life the TG levels of the men were markedly higher than the women’s until around age 65–70. HDL-C levels showed no trend during the study period. Conclusions The levels of TC and LDL-C decreased considerably in a statin-free population from primary health care from 2001 to 2018. These decreases were most pronounced in the elderly population and this trend is not decelerating. For TG, levels have started to increase, after an initial decrease.

Abstract Background Case–control studies based on pharmaco-epidemiological databases typically use decision rules to determine exposure status from information on dates of prescription redemptions, although this induces misclassification. The reverse Waiting Time Distribution has been suggested as a likelihood based model to estimate the latent exposure status, and we therefore suggest to extend this into a joint likelihood based model, which incorporates both the latent exposure status and the exposure-outcome association. This will achieve consistency and efficiency of the estimates, i.e. they can be expected to be asymptotically unbiased and have optimal precision. Methods We established a joint likelihood for the observed case–control status and last prescription redemption before the index date. The likelihood combines the ordinary logistic regression likelihood and the reverse Waiting Time Distribution, and allows inclusion of covariates in both parts to adjust for observed confounders. We conducted a simulation study of the new model and standard models based on decision rules for exposure and the probability of being exposed, respectively, to assess the relative bias and variability of estimates. Lastly, we applied the models to a case–control study on use of nonsteroidal anti-inflammatory drugs and risk of upper-gastrointestinal bleeding. Results In simulation studies the new model had low relative bias (

Natascha Gaster,1 Jesper Hallas,2 Anton Pottegård,2 Søren Friis,3 Morten Schmidt1,4 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 3Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark; 4Department of Cardiology, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Natascha GasterDepartment of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N, DK-8200, DenmarkTel +45 87168063Fax +45 87167215Email ng@clin.au.dkPurpose: To evaluate the potential of Danish prescription registries to capture aspirin and non-aspirin non-steroidal anti-inflammatory drug (NSAID) use and to quantitatively evaluate the magnitude of bias from misclassification of true NSAID and aspirin use as apparent non-use in drug outcome studies.Patients and Methods: In a population-based cohort study, we retrieved sales statistics for NSAIDs and aspirins based on nationwide data from the Danish Health Data Authority and the Danish National Prescription Registry. We estimated prevalence of recorded and non-recorded NSAID use in the prescription registry and resulting proportions of true NSAID and aspirin use misclassified as apparent non-use from 1999 to 2019 at population and patient levels.Results: The prevalence of true use misclassified as non-use (mainly due to over-the-counter use) peaked at 4.7% in 2012 for NSAIDs overall, 5.5% in 2012 for ibuprofen, and at 5.9% in 2002 for high-dose aspirin. Misclassification of other individual NSAIDs was near null. Misclassification of true low-dose aspirin use as non-use declined during the study period but remained around 1% since 2005. In subgroups of cardiac patients, the highest prevalence of true NSAID use misclassified as non-use was 5.0% in 2002 and 4.3% in 2017. Quantitative bias analyses showed how such misclassification of true NSAID and aspirin use as non-use remained minimal both at population and patient levels. In hypothetical examples simulating real study populations with differing exposure prevalence and prevalence of true NSAID and aspirin use misclassified as apparent non-use, the approximate percentage change due to misclassification of use as non-use did not exceed 5% and in most scenarios stayed around 1%.Conclusion: The Danish prescription registries are valid data sources for assessing the effects of aspirin and NSAID use. The influence of non-recorded NSAID and aspirin use on estimates of association is virtually negligible.Keywords: registries, over-the-counter, bias epidemiology

Abstract Randomised controlled trials have shown a neutral or even unfavourable risk–benefit balance of aspirin for primary prevention of cardiovascular events. Using Danish nationwide registries, we investigated aspirin use and associated risks during the past two decades (1998–2018). We linked individual patient data on repeated aspirin redemptions with registered hospital ICD-10 diagnoses of atherosclerotic cardiovascular disease and bleedings. The prevalence of aspirin use among 1.1 million Danish adults fluctuated over the 20-year study period peaking in 2008 with 8.5% (5.4% primary prevention) and dropping to 5.1% (3.1% primary prevention) in 2018. Aspirin use showed strong age dependency, and 21% of individuals > 80 years were treated with aspirin for primary prevention in 2018. Medication adding to bleeding risk was used concurrently by 21% of all aspirin users in 2018. The incidence of major bleedings were similar with primary and secondary prevention aspirin use and highest in elderly (2 per 100 patient years among individuals > 80 years in 2018). In conclusion, low-dose aspirin use for primary prevention of cardiovascular events remains prevalent. The widespread use of aspirin, especially among older adults, and substantial concomitant use of medications adding to bleeding risk warrant increased focus on discontinuation of inappropriate aspirin use.

Aim: To analyse patterns of glucose‐lowering therapies among people with type 2 diabetes (T2D) in Denmark from 2016 to 2023. Materials and Methods: We examined time trends in the clinical profiles of people with T2D who initiated different glucose‐lowering therapy classes for the first time. We furthermore investigated individual‐level treatment trajectories following first‐ever glucose‐lowering therapy in people with or without cardiorenal disease. The study utilized data from the nationwide Danish health registries and included all individuals who filled a first‐ever prescription for metformin, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) or insulin, excluding those without HbA1c‐confirmed T2D or probable type 1 diabetes. Results: We included 260 393 individuals initiating a new glucose‐lowering therapy class from 2016 to 2023, during which there were 6‐ and 3‐fold increases in initiators of GLP‐1RAs and SGLT‐2is, respectively. The median HbA1c level at treatment initiation with GLP‐1RAs or SGLT‐2is decreased, from 67‐68 mmol/mol in 2016‐2017 to 57‐58 mmol/mol in 2022‐2023. Among individuals who initiated metformin as first‐line therapy, the proportion who started additional glucose‐lowering therapy within 2 years increased from 25% in 2016 to 40% in 2021. Among the 38% of individuals who had established cardiorenal disease when they initiated first‐ever glucose‐lowering therapy in 2020, 22% used SGLT‐2is and 18% GLP‐1RAs after 2.5 years, compared with 17% and 21% among initiators without cardiorenal disease, respectively. Conclusions: Our study documents a trend towards earlier T2D treatment intensification and an increase in the use of GLP‐1RAs and SGLT‐2is in Denmark. However, optimal T2D treatment is still not received by most individuals with early T2D and established cardiorenal disease. [ABSTRACT FROM AUTHOR]

Real-world evidence (RWE) studies are increasingly used to inform policy and clinical decisions. However, there remain concerns about the credibility and reproducibility of RWE studies. While there is universal agreement on the critical importance of transparent and reproducible science, the building blocks of open science practice that are common across many disciplines have not yet been built into routine workflows for pharmacoepidemiology and outcomes researchers. Observational researchers should highlight the level of transparency of their studies by providing a succinct statement addressing study transparency with the publication of every paper, poster, or presentation that reports on an RWE study. In this paper, we propose a framework for an explicit transparency statement that declares the level of transparency a given RWE study has achieved across 5 key domains: (1) protocol, (2) preregistration, (3) data, (4) code-sharing, and (5) reporting checklists. The transparency statement outlined in the present paper can be used by research teams to proudly display the open science practices that were used to generate evidence designed to inform public health policy and practice. While transparency does not guarantee validity, such a statement signals confidence from the research team in the scientific choices that were made. [ABSTRACT FROM AUTHOR]

This article examines the early adoption of semaglutide, a drug used to treat type 2 diabetes, in Scandinavia, with a focus on Denmark. The study analyzes nationwide prescription data from Denmark, Norway, and Sweden to compare the use of semaglutide with other glucose-lowering drugs and to compare the characteristics of semaglutide initiators with initiators of other drugs. The findings reveal that semaglutide is widely used in Scandinavia and that the characteristics of semaglutide initiators differ slightly from initiators of other drugs. The study also identifies differences between early and late initiators of semaglutide, suggesting potential off-label use for weight loss. However, the study acknowledges limitations, such as the lack of data on specific indications for use. [Extracted from the article]

We aimed to map tasks related to medication management and time consumption in Danish home health care. Nursing staff (n = 30) from five municipalities were followed during a 10‐week period and tasks related to medication management, time consumption and information on citizens' medication were registered. A total of 269 courses were registered, including 163 (61%) home visits, 76 (28%) in‐office courses, 29 (11%) in‐clinic courses and 1 (0.4%) acute visit. Of defined categories related to medication management, 'record‐keeping and communication' (62%, n = 167), 'dispensing' (48%, n = 129) and 'identification' (30%, n = 81) were most often performed. During half of courses (55%, n = 147), the nursing staff was interrupted at least one time. The median time spent on medication management was less than the time allocated in most of allocated time slots (82%), with a median excess time of 5.1 min (range 0.02–24 min). Citizens (n = 32) used a median of 11 (interquartile range [IQR] 9–13) regular medications and 2 (IQR 1–4) as‐needed, and 69% (n = 22) used high‐risk situation medications. In conclusion, employees in Danish home health care perform diverse medication‐related tasks and are frequently interrupted in their work. Employees spend less time than allocated but do not fully solve all tasks according to best practice guidance. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine patient characteristics and dose titration patterns of real-world semaglutide (Wegovy) users. RESEARCH DESIGN AND METHODS: We used a population-based cohort study including Danish adults who filled semaglutide prescriptions from 12 December 2022 to 31 December 2023. Outcomes were patient characteristics, prescriber type, and dose titration patterns. RESULTS: We identified 110,748 individuals (median age 49 years; 70% female) filling 773,708 prescriptions for semaglutide. General practitioners initiated treatment in 86%. Common comorbidities included hypertension (30%), dyslipidemia (17%), and arthrosis (17%). Only 13% reached the maximum dose of 2.4 mg by their fifth prescription, while 5.7% stopped after the first prescription. Few users (10%) followed recommended dose increases every 4 weeks. Overall, 25% filled at least one prescription of 2.4 mg, while 33–48% continued with the 1.0-mg dosage from the fourth prescription onward. CONCLUSIONS: Real-world semaglutide users generally resembled trial participants, but few follow the dose titration schemes tested in premarket clinical trials. [ABSTRACT FROM AUTHOR]