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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

Purpose: Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population. Methods: Two parallel nested case-control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP. Cancer cases were matched to 10 controls by age and gender through risk-set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). Results: In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26–1.34) in SIDIAP and 1.20 (1.12–1.30) in BIFAP, with a lower risk for BCC (1.11 [1.02–1.21]) than for SCC (1.71 [1.45–2.02]). A dose–response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09–1.43) in SIDIAP and 0.85 (0.64–1.13) in BIFAP. Conclusions: In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose–response pattern.

This population-based cohort study will evaluate the risk of appendicitis following mRNA vaccination against COVID-19 using Danish nationwide registries.

AimsThe Danish authorities implemented a differential rollout of the COVID-19 vaccines where individuals at high risk of COVID-19 were prioritized. We describe the temporal uptake of COVID-19 vaccines and changing characteristics of vaccine recipients in Denmark.MethodsUsing the Danish national health care registries, we identified all Danish residents ≥5 years of age who received at least one dose of a COVID-19 vaccine from December 27th, 2020, to January 29th, 2022. We charted the daily number of newly vaccinated individuals and the cumulative vaccine coverage over time, stratified by vaccine type, age groups, and vaccination priority groups. In addition, we described characteristics of vaccine recipients during 2-months-intervals and in vaccination priority groups.ResultsBy January 29th, 2022, 86%, 84% and 63% of Danish residents ≥5 years had received a first, second, and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84% of vaccinated individuals). Vaccine uptake ranged from 48% in 5-11-year-olds up to 98% in 65-74-year-olds. Individuals vaccinated before June 2021 were older (median age 61-70 years vs. 10-35 years in later periods) and had more comorbidities such as hypertension (22-28% vs. 0.77-2.8% in later periods), chronic lung disease (9.4-15% vs. 3.7-4.6% in later periods), and diabetes (9.3-12% vs. 0.91-2.4% in later periods).ConclusionsThe uptake of the COVID-19 vaccines is high in Denmark. We document substantial changes over time in characteristics of vaccine recipients which should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines.

Lack of clinical guidance constitutes a significant barrier to deprescribing. Within Danish clinical guidelines on treatment of dementia, type 2 diabetes, hypertension, and osteoporosis, only limited attention was given to deprescribing. For dementia, type 2 diabetes, and osteoporosis, guidance was primarily focused on when to consider and implement deprescribing, with limited practical guidance on how to deprescribe. No guidance for deprescribing antihypertensives was identified. This highlights a need to consider deprescribing more broadly when developing and updating clinical guidelines, as argued in this review.

The main tool in drug safety monitoring, spontaneous reporting of adverse effects, is unlikely to detect delayed adverse drug effects including cancer. Hypothesis-free screening studies based on administrative data could improve ongoing drug safety monitoring. Using Danish health registries, we conducted a series of case–control studies by identifying individuals with incident cancer in Denmark from 2001 to 2018, matching each case with 10 population controls on age, sex, and calendar time. ORs were estimated using conditional logistic regression accounting for matching factors, educational level, and selected comorbidities. A total of 13,577 drug–cancer associations were examined for individual drugs and 8,996 for drug classes. We reviewed 274 drug–cancer pairs where an association with high use and a cumulative dose–response pattern was present. We classified 65 associations as not readily attributable to bias of which 20 were established as carcinogens by the International Agency for Research on Cancer and the remaining 45 associations may warrant further study. The screening program identified drugs with known carcinogenic effects and highlighted a number of drugs that were not established as carcinogens and warrant further study. The effect estimates in this study should be interpreted cautiously and will need confirmation targeted epidemiologic and translational studies. Significance: This study provides a screening tool for drug carcinogenicity aimed at hypothesis generation and explorative purposes. As such, the study may help to identify drugs with unknown carcinogenic effects and, ultimately, improve drug safety as part of the ongoing safety monitoring of drugs.

Purpose: In pharmacoepidemiological studies, the precision of effect estimates usually depends on the lowest number in the underlying two by two table. We denote this the “bottleneck count” (BNC). We describe how to translate the BNC into an achievable precision and provide empirical examples. Methods: First, we derive a theoretical prediction of the precision in a study where only the BNC determines precision. As an illustration, we calculated the expected precision of a null-effect study on retinoids and peptic ulcer bleeding, expressed as the upper/lower confidence limit ratio (ULCLR). Finally, we reviewed 126 effect estimates from the literature, analyzing the relationship between the predicted and achieved precision. Results: The log–log transformed ULCLR was shown to be a simple linear function of log(BNC). The expected annual number of retinoid-users experiencing a peptic ulcer bleeding was 9.8, yielding an estimated ULCLR for a 1-year study of 3.84. The literature review showed an inverse linear relationship between the logarithmic BNC and the log–log transformed ULCLR, which was largely independent of study design, effect measure and category of BNC. Achieved precision deviated little from predictions but was usually lower than predicted, particularly with low BNC. Conclusion: The precision of a study can be predicted simply and with good accuracy from the BNC, which is useful for determining whether a study is worth pursuing or not.

Background Venous thromboembolism (VTE) is a potentially fatal complication of SARS-CoV-2 infection and thromboprophylaxis should be balanced against risk of bleeding. This study aimed to examine risks of VTE and major bleeding in hospitalized and community-managed SARS-CoV-2 patients compared with control populations. Methods Using nationwide population-based registries, 30-day risks of VTE and major bleeding in SARS-CoV-2 positive patients were compared with those of SARS-CoV-2 test-negative patients and with an external cohort of influenza patients. Medical records of all COVID-19 patients at six departments of infectious diseases in Denmark were reviewed in detail. Results The overall 30-day risk of VTE was 0.4% (40/9,460) among SARS-CoV-2 patients (16% hospitalized), 0.3% (649/226,510) among SARS-CoV-2 negative subjects (12% hospitalized), and 1.0% (158/16,281) among influenza patients (59% hospitalized). VTE risks were higher and comparable in hospitalized SARS-CoV-2 positive (1.5%), SARS-CoV-2 negative (1.8%), and influenza patients (1.5%). Diagnosis of major bleeding was registered in 0.5% (47/9,460) of all SARS-CoV-2 positive individuals and in 2.3% of those hospitalized. Medical record review of 582 hospitalized SARS-CoV-2 patients observed VTE in 4% (19/450) and major bleeding in 0.4% (2/450) of ward patients, of whom 31% received thromboprophylaxis. Among intensive care patients (100% received thromboprophylaxis), risks were 7% (9/132) for VTE and 11% (15/132) for major bleeding. Conclusions Among people with SARS-CoV-2 infection in a population-based setting, VTE risks were low to moderate and were not substantially increased compared with SARS-CoV-2 test-negative and influenza patients. Risk of severe bleeding was low for ward patients, but mirrored VTE risk in the intensive care setting. BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and thromboprophylaxis should be balanced against risk of bleeding. This study examined risks of VTE and major bleeding in hospitalized and community-managed SARS-CoV-2 patients compared with control populations. METHODS: Using nationwide population-based registries, 30-day risks of VTE and major bleeding in SARS-CoV-2 positive patients were compared with those of SARS-CoV-2 test-negative patients and with an external cohort of influenza patients. Medical records of all COVID-19 patients at 6 departments of infectious diseases in Denmark were reviewed in detail. RESULTS: The overall 30-day risk of VTE was 0.4% (40/9460) among SARS-CoV-2 patients (16% hospitalized), 0.3% (649/226 510) among SARS-CoV-2 negative subjects (12% hospitalized), and 1.0% (158/16 281) among influenza patients (59% hospitalized). VTE risks were higher and comparable in hospitalized SARS-CoV-2 positive (1.5%), SARS-CoV-2 negative (1.8%), and influenza patients (1.5%). Diagnosis of major bleeding was registered in 0.5% (47/9460) of all SARS-CoV-2 positive individuals and in 2.3% of those hospitalized. Medical record review of 582 hospitalized SARS-CoV-2 patients observed VTE in 4% (19/450) and major bleeding in 0.4% (2/450) of ward patients, of whom 31% received thromboprophylaxis. Among intensive care patients (100% received thromboprophylaxis), risks were 7% (9/132) for VTE and 11% (15/132) for major bleeding. CONCLUSIONS: Among people with SARS-CoV-2 infection in a population-based setting, VTE risks were low to moderate and were not substantially increased compared with SARS-CoV-2 test-negative and influenza patients. Risk of severe bleeding was low for ward patients, but mirrored VTE risk in the intensive care setting.

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.

Background Danish health registers are used widely to examine associations between specific risk factors and congenital malformations. Various overall prevalence rates of malformations have been reported in Denmark indicating differences in the underlying data sources or malformation definitions. We described trends in registration of malformations in Denmark 1997-2017 and identified potential caveats for the use of Danish health registries in epidemiological studies. We composed a Danish adaptation of EUROCATs definition of malformations. Methods Using nationwide Danish health registries, we identified all recorded pregnancies and followed livebirths for up to 5 years. We described the different data sources, ways to identify malformations, the overall rate of malformations over time, and identified the 10 most common major malformations. Results A total of 1,340,774 foetuses and infants from 1,313,281 pregnancies among 747,144 women from 1997 to 2017 were analysed. Using primary and secondary diagnoses from all available sources and restricting hip malformations to diagnoses after 6 weeks postpartum, we found that 65,411 (49/1000) foetuses or infants had at least one major malformation defined by our Danish translation of EUROCATs definition of malformations. The prevalence of major malformations increased over time from 39/1000 in 1997 to 53/1000 in 2017. The most common specific malformations were malformations of cardiac septa (Q21) and great arteries (Q25) with a peak of 10 and 6/1000 births in 2010 and 2009, respectively. Conclusion Malformations should be identified using primary and secondary diagnoses from the Birth register, the Patient register, and the Cause of Death register. To increase transparency and external validity, classification of major malformations should be based on the Danish adaptation of EUROCATs classification of malformations.

Background: Customers are commonly seeking information, e.g. via the internet, to achieve information on health, diseases, and treatment options. However, little is known about customers’ information seeking behavior prior to community pharmacy visits. Objective: To quantify and describe customers’ information seeking behavior prior to community pharmacy visits, and to describe how pharmacy staff utilize information obtained by customers. Methods: Six Danish community pharmacies collected data on customers’ information seeking behavior through an online survey for five days in a three week-period in November 2018. Customers were asked about their information seeking behavior regarding their errand at the pharmacy that specific day, what kind of information they had sought, which sources they had used, and their motivation for seeking that information. Hereafter, the pharmacy staff recorded whether they confirmed or disconfirmed the information, and whether they used the information in their counselling. The results were reported using descriptive statistics. Results: A total of 3424 customers were invited to participate in the study. Among 2623 customers agreeing to participate, 14.4% (n = 377) had obtained information prior to the pharmacy visit. Information seeking was more frequent among younger customers (

Background To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a prospective cohort of all Danish residents tested for SARS-CoV-2 in Denmark is established. Data structure All Danish residents tested by reverse transcriptase polymerase chain reactions (RT-PCR) for SARS-CoV-2 in Denmark are included. The cohort is identified using the Danish Microbiology Database. Individual-level record linkage between administrative and health-care registries is facilitated by the Danish Civil Registration System. Information on outcomes related to SARS-CoV-2 infection includes hospital admission, intensive care unit admission, mechanical ventilation, and death and is retrieved from the five administrative Danish regions, the Danish National Patient Registry, and the Danish Register of Causes of Death. The Patient Registry further provides a complete hospital contact history of somatic and psychiatric conditions and procedures. Data on all prescriptions filled at community pharmacies are available from the Danish National Prescription Registry. Health-care authorization status is obtained from the Danish Register of Healthcare Professionals. Finally, selected laboratory values are obtained from the Register of Laboratory Results for Research. The cohort is governed by a steering committee with representatives from the Danish Medicines Agency, Statens Serum Institut, the Danish Health Authority, the Danish Health Data Authority, Danish Patients, the Faculties of Health Sciences at the Danish universities, and Danish regions. The steering committee welcomes suggestions for research studies and collaborations. Research proposals will be prioritized based on timeliness and potential clinical and public health implications. All research protocols assessing specific hypotheses for medicines will be made publicly available using the European Union electronic Register of Post-Authorisation Studies. Conclusion The Danish COVID-19 cohort includes all Danish residents with an RT-PCR test for SARS-CoV-2. Through individual-level linkage with existing Danish health and administrative registries, this is a valuable data source for epidemiological research on SARS-CoV-2.

Using nationwide Danish registries, we conducted a population-based case-crossover study evaluating the association between switching from a vitamin K antagonist (VKA) to a direct oral anticoagulant (DOAC), and vice versa, and 30-day risks of bleeding and arterial thromboembolism in patients with atrial fibrillation (AF). The case-crossover population was identified among oral anticoagulant users during 2011–2018 (n = 123,217) as patients with AF with 1) a case-defining outcome and 2) an anticoagulant switch during the 180 days preceding the outcome. Odds ratios were estimated using conditional logistic regression by comparing the occurrence of switching during the 30-day window immediately preceding the outcome to that in reference windows in the same individual 60–180 days before the outcome. The case-crossover populations for switching from VKA to DOAC and DOAC to VKA comprised 1,382 and 287 case patients, respectively. Switching from VKA to DOAC, but not from DOAC to VKA, was associated with an increased short-term risk of bleeding (odds ratio = 1.42; 95% confidence intervals: 1.13, 1.79, and 1.06; and 0.64, 1.75, respectively) and ischemic stroke (odds ratio = 1.74; 95% confidence intervals: 1.21, 2.51, and 0.92; and 0.46, 1.83, respectively). Our findings suggest that switching from VKA to DOAC is an intermittent risk factor of bleeding and ischemic stroke in patients with AF.

In this review paper, I outline the principles of the cohort as a sampling frame and provide a basic introduction to the cohort study design and the case-control study design, two of the most important designs in the pharmacoepidemiologist's toolbox. Further, I discuss when to prefer one design over the other. The paper is intended as a primer for people new to the field of pharmacoepidemiology and contains a range of suggestions for additional reading regarding the study designs and related epidemiological topics.

BackgroundRepeated oral corticosteroid use indicates uncontrolled disease among asthma patients, and referral for asthma specialist assessment is recommended. We aimed to describe trends and predictors associated with specialist contacts among young adults with asthma and repeated oral corticosteroid use.MethodsIndividuals aged 18–45 years with two or more dispensed asthma medication prescriptions and two dispended oral corticosteroid prescriptions (including short-term and long-term treatments) within 12 months during 1999–2018 were identified by use of Danish healthcare registers. The frequency of specialist contacts within 1 year of follow-up was assessed among individuals without previous specialist contacts within 5 years of inclusion. Factors associated with specialist contact were identified using logistic regression models. Furthermore, oral corticosteroid prescriber sources were assessed.ResultsFor the 11 223 individuals included, 2444 (22%) had previous specialist-contact care within 5 years prior of inclusion, and additionally 926 (8.3%) within 1 year of follow-up. Among those without previous specialist contacts (n=8779), the frequency of incident specialist contacts within 1 year of follow-up increased from 6.3% in 1999 to 18% in 2017. Factors associated with incident specialist contacts included dispensing ≥12 short-acting β-agonist canisters and previous asthma-related emergency department visits and hospitalisations. The majority of oral corticosteroid prescriptions at baseline (71%) were prescribed by general practitioners, although with decreasing proportions from 1999 to 2018.ConclusionsThe majority (70%) of young adults with asthma and repeated oral corticosteroid use do not seem to receive specialist assessment in Denmark. This highlights a potential room for improvement in the patient referral pathway for at-risk asthma patients.