Incidence rate of venous thrombosis in women switching combined oral contraceptives: a cohort study.

Background: The incidence rate of venous thrombosis (VT) in women switching combined oral contraceptives (COCs) is unknown. Objectives: We hypothesize that women switching COCs may have a similar increased incidence rate of VT as women who start COCs. Switching means starting with a new COC, which may biologically approximate starting. Methods: We conducted a cohort study with data from the Netherlands and Denmark. First, we identified starters who were defined as women who did not use COCs in the 2 years prior to the start of their first COC prescription within the study period. Switchers were a subset of COC starters who redeemed a COC formulation different from their initial COC during follow-up but not longer than 12 months after starting. We estimated incidence rate ratios (adjusted incidence rate ratio [aIRR]) of VT with 95% CIs among COC switchers as compared with COC starters using Poisson regression adjusted for age, COC progestogen generation, and preexisting obesity. Results: In both countries, we found an increased risk of VT among switchers as compared with starters during the first 3 months of the follow-up (aIRR = 1.77; 95% CI, 1.22-2.56 in the Netherlands and aIRR = 1.50; 95% CI, 1.04-2.16 in Denmark). Conclusion: Switchers, particularly in the first 3 months after switching, may experience a renewed starter effect thereby increasing the risk of VT.

The Epidemiology of Hospital-Treated Alopecia Areata in Denmark, 1995-2016.

INTRODUCTION: Alopecia areata (AA) is an autoimmune skin disease presenting as nonscarring hair loss. Information on the epidemiology of AA, especially the occurrence of AA and its subtypes within the general population, is scarce. The study aimed to estimate the incidence rates and prevalence of hospital-treated AA and its subtypes in Denmark and to examine the demographic and clinical characteristics of patients with AA, including comorbidities and use of prescription medications. METHODS: This was a cohort study based on data from administrative and health registers in Denmark in 1995-2016. The study included individuals who were (1) registered with a hospital inpatient or hospital-based outpatient clinic diagnosis of AA between 1995 and 2016 in the Danish National Patient Registry covering encounters at all Danish hospitals, (2) alive and resided in Denmark anytime between 1995 and 2016, (3) aged ≥ 12 years, and (4) resided uninterrupted in Denmark during the 12 months before the first AA diagnosis during the study period. RESULTS: During the study period, 2778 individuals with an incident hospital-based diagnosis of AA were identified; 63.1% were female and 28.7% of the patients were aged ≥ 50 years. Over the study period, the overall incidence rate for any hospital-treated AA per 100,000 person-years was 2.62 (95% confidence interval [CI], 2.53-2.72), and the overall prevalence in 2016 was 71.7 (95% CI 69.4-74.1) per 100,000 persons. Both incidence rate and prevalence increased over time. Prevalence of most hospital-treated comorbidities or history of medication use was below 10% and was similar in the alopecia totalis (AT)/alopecia universalis (AU) and non-AT/AU subtypes of AA. CONCLUSION: This cohort study reported incidence rates and prevalence over time and characteristics of individuals with hospital-treated AA in Denmark, which are in agreement with those previously reported in this population.

Evaluating the comparability of osteoporosis treatments using propensity score and negative control outcome methods in UK and Denmark electronic health record databases.

Evidence on the comparative effectiveness of osteoporosis treatments is heterogeneous. This may be attributed to different populations and clinical practice, but also to differing methodologies ensuring comparability of treatment groups before treatment effect estimation and the amount of residual confounding by indication. This study assessed the comparability of denosumab vs oral bisphosphonate (OBP) groups using propensity score (PS) methods and negative control outcome (NCO) analysis. A total of 280 288 women aged ≥50 years initiating denosumab or OBP in 2011-2018 were included from the UK Clinical Practice Research Datalink (CPRD) and the Danish National Registries (DNR). Balance of observed covariates was assessed using absolute standardised mean difference (ASMD) before and after PS weighting, matching, and stratification, with ASMD >0.1 indicating imbalance. Residual confounding was assessed using NCOs with ≥100 events. Hazard ratio (HR) and 95% confidence interval (CI) between treatment and NCO was estimated using Cox models. Presence of residual confounding was evaluated with two approaches1: >5% of NCOs with 95% CI excluding 1,2 >5% of NCOs with an upper CI <0.75 or lower CI >1.3. The number of imbalanced covariates before adjustment (CPRD 22/87; DNR 18/83) decreased, with 2-11% imbalance remaining after weighting, matching or stratification. Using approach 1, residual confounding was present for all PS methods in both databases (≥8% of NCOs), except for stratification in DNR (3.8%). Using approach 2, residual confounding was present in CPRD with PS matching (5.3%) and stratification (6.4%), but not with weighting (4.3%). Within DNR, no NCOs had HR estimates with upper or lower CI limits beyond the specified bounds indicating residual confounding for any PS method. Achievement of covariate balance and determination of residual bias were dependent upon several factors including the population under study, PS method, prevalence of NCO, and the threshold indicating residual confounding.

Treatment groups in clinical practice may not be comparable as patient characteristics differ according to the need for the prescribed medication, known as confounding. We assessed comparability of two common osteoporosis treatments, denosumab and oral bisphosphonate, in 280 288 postmenopausal women using electronic health records from UK Clinical Practice Research Datalink (CPRD) and Danish National Registries (DNR). We evaluated comparability of recorded patient characteristics with three propensity score (PS) methods, matching, stratification, and weighting. We assessed residual confounding from unrecorded patient characteristics via negative control outcomes (NCO), events known not to be associated with treatment such as delirium. We found that achieving comparability of osteoporosis treatment groups depended on the study population, PS method, and definition of residual confounding. Weighting and stratification performed the best in DNR and CPRD, respectively. Using a stricter threshold based on statistical significance for the NCO suggested the treatment groups were not comparable, except for PS stratification in DNR. Applying clinically significant thresholds of treatment effect size showed comparability using weighting in CPRD and all PS methods in DNR. Studies should consider more than one PS method to test robustness and identify the largest number of NCO to give the greatest flexibility in detecting residual confounding.

COVID-19 and pregnancy: A European study on pre- and post-infection medication use.

PURPOSE: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location. METHODS: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK). The prevalence of primary care prescribing or dispensing was compared in the 30-day periods before and after a positive COVID-19 test or diagnosis. RESULTS: The study included 294,126 pregnant women, of whom 8943 (3.0%) tested positive for, or were diagnosed with, COVID-19 during their pregnancy. A significantly higher use of antithrombotic medications was observed particularly after COVID-19 infection in the second and third trimesters. The highest increase was observed in the Valencia region where use of antithrombotic medications in the third trimester increased from 3.8% before COVID-19 to 61.9% after the infection. Increases in other countries were lower; for example, in Norway, the prevalence of antithrombotic medication use changed from around 1-2% before to around 6% after COVID-19 in the third trimester. Smaller and less consistent increases were observed in the use of other drug classes, such as antimicrobials and systemic corticosteroids. CONCLUSION: Our findings highlight the substantial impact of COVID-19 on primary care medication use among pregnant women, with a marked increase in the use of antithrombotic medications post-COVID-19. These results underscore the need for further research to understand the broader implications of these patterns on maternal and neonatal/fetal health outcomes.

Association between pregnancy affected by vaginal bleeding and women's mortality: A cohort study.

OBJECTIVE: To investigate the association between vaginal bleeding (VB) in pregnancy and women's mortality, using VB-unaffected pregnancies, terminations and miscarriages as comparators. DESIGN: Observational cohort study. SETTING: Nationwide registries of Denmark linked at an individual level. POPULATION OR SAMPLE: 1 354 181 women and their 3 162 317 pregnancies (1979-2017), including 70 835 VB-affected pregnancies and comparators: 2 236 359 VB-unaffected pregnancies ending in childbirth; 589 697 terminations; and 265 426 miscarriages. METHODS: We followed pregnancies until the earliest date of woman's death, emigration or end of data. MAIN OUTCOME MEASURES: All-cause and cause-specific mortality rates per 10 000 person-years (PY) and hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted using Cox proportional hazards regression for age, calendar year, pre-existing chronic conditions and socio-economic factors. RESULTS: There were 2320 deaths from any cause among women following VB-affected pregnancy (mortality rate 15.2, 95% CI 14.6-15.9 per 10 000 PY); 55 030 deaths following VB-unaffected pregnancy (mortality rate 12.7, 95% CI 12.6-12.8); 27 500 deaths following a termination (mortality rate 21.9, 95% CI 21.6-22.1), and 10 865 deaths following a miscarriage (mortality rate 19.2, 95% CI 18.8-19.6). For comparison of VB-affected versus VB-unaffected pregnancies, associations with all-cause (HR 1.14, 95% CI 1.09-1.19), natural causes (HR 1.15, 95% CI 1.09-1.22) and non-natural causes (HR 1.27, 95% CI 1.08-1.48) mortality were attenuated in a sensitivity analysis of pregnancies recorded in 1994-2017 (HR 1.00, 95% CI 0.90-1.12, HR 0.98, 95% CI 0.85-1.14 and HR 1.04, 95% CI 0.72-1.51, respectively). Contrasts with remaining comparators did not suggest increased risks of all-cause, natural or non-natural mortality causes. CONCLUSION: We found no evidence of an increased risk of women's mortality following VB-affected versus VB-unaffected pregnancy, termination or miscarriage.

Understanding the impact of non-shared unmeasured confounding on the sibling comparison analysis.

BACKGROUND: The sibling comparison analysis is used to deal with unmeasured confounding. It has previously been shown that in the presence of non-shared unmeasured confounding, the sibling comparison analysis may introduce substantial bias depending on the sharedness of the unmeasured confounder and the sharedness of the exposure. We aimed to improve the awareness of this challenge of the sibling comparison analysis. METHODS: First, we simulated sibling pairs with an exposure, a confounder and an outcome. We simulated sibling pairs with no effect of the exposure on the outcome and with positive confounding. For varying degrees of sharedness of the confounder and the exposure and for varying prevalence of the exposure, we calculated the sibling comparison odds ratio (OR). Second, we provided measures for sharedness of selected treatments based on Danish health data. RESULTS: The confounded sibling comparison OR was visualized for varying degrees of sharedness of the confounder and the exposure and for varying prevalence of the exposure. The confounded sibling comparison OR was seen to increase with increasing sharedness of the exposure and the confounded sibling comparison OR decreased with an increasing prevalence of exposure. Measures for sharedness of treatments based on Danish health data showed that treatments of chronic diseases have the highest sharedness and treatments of non-chronic diseases have the lowest sharedness. CONCLUSIONS: Researchers should be aware of the challenge regarding non-shared unmeasured confounding in the sibling comparison analysis, before applying the analysis in non-randomized studies. Otherwise, the sibling comparison analysis may lead to substantial bias.

Risk of diabetes and cardiovascular diseases in women with vaginal bleeding before 20 gestational weeks: Danish population-based cohort study.

BACKGROUND: Women's reproductive health is associated with cardiovascular morbidity. However, an association of vaginal bleeding (VB) in pregnancy with diabetes and cardiovascular outcomes has scarcely been investigated. METHODS: We conducted a population-based cohort study in Denmark (1994-2018). Using nationwide registries, among 903 327 women we identified 1 901 725 pregnancies: 39 265 ended in childbirth and were affected by VB; 1 389 285 ended in childbirth and were unaffected by VB; 333 785 ended in a termination, and 139 390 ended in a miscarriage. The outcomes were diabetes types 1 and 2, hypertension, ischaemic heart disease including myocardial infarction, atrial fibrillation or flutter, heart failure and ischaemic and haemorrhagic stroke. We computed incidence rates and hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, calendar year of pregnancy end, morbidities and reproductive and socioeconomic factors, using inverse probability of treatment-weighted Cox proportional hazards regression. RESULTS: In analyses of VB-affected vs VB-unaffected pregnancies, aHRs were 1.15 (1.03-1.28) for diabetes type 1, 1.19 (1.13-1.26) for diabetes type 2, 1.19 (1.14-1.25) for hypertension, 1.26 (1.16-1.37) for ischaemic heart disease, 1.21 (1.03-1.42) for myocardial infarction, 1.32 (1.14-1.51) for atrial fibrillation or flutter and 1.23 (0.99-1.52) for heart failure. aHRs were 1.41 (1.26-1.57) and 1.46 (1.23-1.72) for ischaemic and haemorrhagic stroke, respectively. When contrasting VB-affected pregnancies with terminations, aHRs were up to 1.3-fold increased for diabetes and hypertension; however, when contrasting VB-affected pregnancies with miscarriages, estimates were below or close to the null value. CONCLUSIONS: Women's risks of diabetes and cardiovascular outcomes later in life were increased following VB-affected vs VB-unaffected pregnancy or termination, but not following VB-affected pregnancy vs miscarriage.

Association between vaginal bleeding in pregnancy that resulted in delivery and risk of cancer: A Danish registry-based cohort study.

BACKGROUND: Vaginal bleeding (VB) before 20 gestational weeks of a viable pregnancy is a manifestation of a threatened miscarriage. VB is associated with increased levels of pro-inflammatory cytokines such as interferon-gamma, tumour necrosis factor-alpha and interleukin-6. Increased levels of these cytokines and oxidative stress are risk factors for cancer. The risk of cancer following a VB-affected pregnancy that ended in childbirth is unknown. OBJECTIVES: To investigate the associations between VB in pregnancy that resulted in delivery and risk of incident cancer. METHODS: We conducted a cohort study (1995-2018) in Denmark using administrative and healthcare registries. We included 37,082 VB-affected deliveries, 1,363,614 VB-unaffected deliveries, 324,328 pregnancies ending in terminations, and 137,104 miscarriages. We computed the absolute risk of cancer and hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, calendar year, morbidities, and socio-economic factors using Cox proportional hazards regression. Multiple pregnancies to the same woman were accounted for in the analysis. RESULTS: The median (25th-75th percentile) follow-up in the study was 12.6 (6.9, 18.2) years. The prevalence of VB in the present study was 3%. At the end of the follow-up, there were 1320 cancer cases among the VB-affected delivery cohort, 40,420 among the VB-unaffected delivery cohort, 10,300 among the termination cohort and 4790 among the miscarriage cohort. HRs for any cancer among VB-affected deliveries were 1.03 (95% CI 0.97, 1.08) compared with VB-unaffected deliveries, 1.03 (95% CI 0.97, 1.09) compared with terminations and 0.90 (95% CI 0.84, 0.95) compared with miscarriages. There were no increased risks of premenopausal breast cancer, cervical cancer, ovary and fallopian tube cancer or uterine cancer following VB-affected deliveries vs. comparison cohorts. CONCLUSIONS: We found no evidence of an association between vaginal bleeding in pregnancy and an increased risk of cancer.

A Road Map for Peer Review of Real-World Evidence Studies on Safety and Effectiveness of Treatments.

The growing acceptance of real-world evidence (RWE) in clinical and regulatory decision-making, coupled with increasing availability of health care data and advances in automated analytic approaches, has contributed to a marked expansion of RWE studies of diabetes and other diseases. However, a recent spate of high-profile retractions highlights the need for improvements in the conduct of RWE research as well as in the associated peer review and editorial processes. We review best pharmacoepidemiologic practices and common pitfalls regarding design, measurement, analysis, data validity, appropriateness, and generalizability of RWE studies. To enhance RWE study assessments, we propose that journal editors require 1) study authors to complete RECORD-PE, a reporting guideline for pharmacoepidemiological studies on routinely collected data, 2) availability of predetermined study protocols and analysis plans, 3) inclusion of pharmacoepidemiologists on the peer review team, and 4) provision of detail on data provenance, characterization, and custodianship to facilitate assessment of the data source. We recognize that none of these steps guarantees a high-quality research study. Collectively, however, they permit an informed assessment of whether the study was adequately designed and conducted and whether the data source used was fit for purpose.

Impact of hemoglobin A1c level on the association between non-steroidal anti-inflammatory drug use and cardiovascular events in patients with type 2 diabetes: A population-based cohort study.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) should be used cautiously in patients with type 2 diabetes. We examined whether the cardiovascular risks associated with NSAID use depended on HbA1c level in patients with type 2 diabetes. METHODS: We conducted a population-based cohort study of all adult Danes with a first-time HbA1c measurement ≥48 mmol/mol during 2012-2020 (n = 103 308). We used information on sex, age, comorbidity burden, and drug use to calculate time-varying inverse probability of treatment weights. After applying these weights in a pooled logistic regression, we estimated hazard ratios (HRs) of the association between use of NSAIDs (ibuprofen, naproxen, or diclofenac) and cardiovascular events (a composite of myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation or flutter, and all-cause death). We stratified all analyses by HbA1c level (<53 or ≥53 mmol/mol). RESULTS: For ibuprofen use, the HR of a cardiovascular event was 1.53 (95% confidence interval [CI]: 1.34-1.75) in patients with HbA1c <53 and 1.24 (95% CI: 1.00-1.53) in patients with HbA1c ≥53 mmol/mol. For naproxen use, the HR was 1.14 (95% CI: 0.59-2.21) in patients with HbA1c <53 and 1.30 (95% CI: 0.49-3.49) in patients with HbA1c ≥53 mmol/mol. For diclofenac use, the HR was 2.40 (95% CI: 1.62-3.56) in patients with HbA1c <53 and 2.89 (95% CI: 1.65-5.04) in patients with HbA1c ≥53 mmol/mol. CONCLUSIONS: In patients with type 2 diabetes, glycemic dysregulation did not affect the cardiovascular risk associated with NSAID use.

Quantifying the impact of unmeasured confounding in observational studies with the E value.

The E value method deals with unmeasured confounding, a key source of bias in observational studies. The E value method is described and its use is shown in a worked example of a meta-analysis examining the association between the use of antidepressants in pregnancy and the risk of miscarriage.

Impact of Lifestyle and Socioeconomic Position on the Association Between Non-steroidal Anti-inflammatory Drug Use and Major Adverse Cardiovascular Events: A Case-Crossover Study.

INTRODUCTION: It is unknown whether the cardiovascular risks associated with non-steroidal anti-inflammatory drug (NSAID) use differ according to lifestyle and socioeconomic position. OBJECTIVE: We examined the association between NSAID use and major adverse cardiovascular events (MACE) within subgroups defined by lifestyle and socioeconomic position. METHODS: We conducted a case-crossover study of all adult first-time respondents to the Danish National Health Surveys of 2010, 2013, or 2017, without previous cardiovascular disease, who experienced a MACE from survey completion through 2020. We used a Mantel-Haenszel method to obtain odds ratios (ORs) of the association between NSAID use (ibuprofen, naproxen, or diclofenac) and MACE (myocardial infarction, ischemic stroke, heart failure, or all-cause death). We identified NSAID use and MACE via nationwide Danish health registries. We stratified the analyses by body mass index, smoking status, alcohol consumption, physical activity level, marital status, education, income, and employment. RESULTS: Compared with non-use, the OR of MACE was 1.34 (95% confidence interval: 1.23-1.46) for ibuprofen, 1.48 (1.04-2.43) for naproxen, and 2.18 (1.72-2.78) for diclofenac. When comparing NSAID use with non-use or the individual NSAIDs with each other, we observed no notable heterogeneity in the ORs within subgroups of lifestyle and socioeconomic position for any NSAID. Compared with ibuprofen, diclofenac was associated with increased risk of MACE in several subgroups with high cardiovascular risk, e.g., individuals with overweight (OR 1.52, 1.01-2.39) and smokers (OR 1.54, 0.96-2.46). CONCLUSIONS: The relative increase in cardiovascular risk associated with NSAID use was not modified by lifestyle or socioeconomic position.

Prenatal exposure to pregabalin, birth outcomes and neurodevelopment - a population-based cohort study in four Nordic countries.

INTRODUCTION: Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. OBJECTIVE: To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. METHODS: This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005-2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel-Haenszel (MH) meta-analyses. RESULTS: The total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98-1.34) for major congenital malformations and 1.72 (1.02-2.91) for stillbirth, which attenuated to 1.25 (0.74-2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03-1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67-1.42) for autism spectrum disorders, and 1.00 (0.78-1.29) for intellectual disability. CONCLUSIONS: Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis.

Prenatal Antidepressant Exposure and the Risk of Attention-Deficit/Hyperactivity Disorder in Childhood: Accounting for Misclassification of Exposure.

BACKGROUND: Many studies of prenatal antidepressant exposure and the risk of attention-deficit/hyperactivity disorder (ADHD) have done little to reduce bias from exposure misclassification. We assessed the prenatal antidepressant-ADHD effect by incorporating information on repeatedly redeemed prescriptions and redemptions of drug classes commonly used in pregnancy in the analyses to reduce bias from exposure misclassification. METHODS: Using population-based registries, we conducted a nationwide cohort study of all children born in Denmark from 1997 to 2017. In a former-user analysis, we compared children prenatally exposed, defined by a redeemed prescription by the mother during pregnancy, to a comparison cohort consisting of prenatally unexposed children whose mothers had redeemed a prescription before pregnancy. We incorporated information on repeatedly redeemed prescriptions and redemptions of drug classes commonly used in pregnancy in the analyses to reduce bias from exposure misclassification. We used incidence rate ratios (IRRs) and incidence rate differences (IRDs) as effect measures. RESULTS: The cohort included 1,253,362 children, among whom 24,937 were prenatally exposed to antidepressants. The comparison cohort consisted of 25,698 children. During follow-up, 1,183 exposed children and 1,291 children in the comparison cohort developed ADHD yielding an IRR of 1.05 (95% confidence interval [CI] = 0.96, 1.15) and an IRD of 0.28 (95% CI = -0.20, 0.80) pr. 1,000 person-years. IRRs from analyses attempting to reduce exposure misclassification varied from 1.03 to 1.07. CONCLUSIONS: Our results were not consistent with the hypothesized effect of prenatal antidepressant exposure on the risk of ADHD. Attempts to reduce exposure misclassification did not alter this finding.

Epidemiology of male osteoporosis in Denmark (1996-2018).

Osteoporosis in men may be underdiagnosed. One in four men in Denmark will develop osteoporosis after age of 50 years, with fracture as a common presenting symptom. PURPOSE: The aim of this study was to describe epidemiology of male osteoporosis in Denmark. METHODS: In this nationwide registry-based cohort study, we identified men with osteoporosis, 50 years or older, residing in Denmark, during the years 1996-2018. Osteoporosis was defined as one of the following: a hospital diagnosis of osteoporosis; a hospital diagnosis of osteoporosis fracture; or an outpatient dispensing of an anti-osteoporosis medication. We reported annual incidence and prevalence and described the distribution of fractures, comorbidities, socioeconomic status, and initiation of anti-osteoporosis therapy among men with osteoporosis. Selected characteristics were also described among men without osteoporosis of similar age. RESULTS: There were 171,186 men fulfilling the study criteria for osteoporosis. The overall age-standardized incidence rate of osteoporosis was 8.6 per 1000 person-years (95% confidence interval (CI), 8.5-8.6), varying between 7.7 and 9.7, while the prevalence increased from 4.3% (95% CI, 4.2-4.3) to 7.1% (95% CI, 7.0-7.1) during the 22-year period. The remaining-lifetime risk of developing osteoporosis after age of 50 years was close to 30%. The proportion of men initiating anti-osteoporosis treatment within 1 year of diagnosis increased from 6.9% to 29.8%. Men with osteoporosis had more comorbidities and redeemed more medication than did men without osteoporosis of similar age. CONCLUSION: Osteoporosis among men may be undertreated despite increasing treatment initiation.

Utilization patterns and factors associated with persistence of new users of anti-osteoporosis treatment in Denmark: a population-based cohort study.

Persistence with initial treatment was highest after 1 year, decreasing afterwards. Persistence was highest for denosumab followed by alendronate. We identified several factors associated with treatment persistence, some of which were the same irrespective of OTx agent, which could help target subgroups of patients in terms of social and healthcare support. PURPOSE: To describe patient characteristics, persistence, and factors associated with the persistence of new users of the bisphosphonates (alendronate, risedronate, and ibandronate) and the RANKL inhibitor denosumab in Denmark. METHODS: A population-based cohort study using health registries (2010-2018). We included alendronate (n = 128,590), risedronate (n = 892), ibandronate (n = 5,855), and denosumab (n = 16,469) users, aged ≥ 50 years. RESULTS: The 1-year persistence was 68.2% in the alendronate cohort; 39.3% in the risedronate cohort; 56.3% in the ibandronate cohort; and 84.0% in the denosumab cohort. The 2-year persistence was 58.7% in the alendronate cohort; 28.0% in the risedronate cohort; 42.9% in the ibandronate cohort; and 71.9% in the denosumab cohort. The 4-year persistence was 46.3%, 15.4%, 29.6%, and 56.9%, respectively. Later years of treatment initiation were associated with lower persistence for alendronate (adjusted odds ratio (OR) with 95% CI was 0.86 (0.81-0.91) in 2016 compared to 2010), but not for risedronate (OR was 1.56 (0.60-4.06), ibandronate (OR was 0.92 (0.71-1.19) or denosumab (OR was 1.11 (0.87-1.43). Older age was associated with higher persistence for all medications and the same goes for the female sex except for ibandronate. Dementia was associated with higher persistence for alendronate but not denosumab, whereas prior osteoporosis treatment (OT) was the opposite. Several comorbidities were associated with lower persistence for alendronate, but not denosumab. CONCLUSION: Persistence was highest for denosumab followed by alendronate. We identified several factors associated with treatment persistence, some of which were the same irrespective of OTx agent, which could help target subgroups of patients in terms of social and healthcare support.

Impact of lifestyle and socioeconomic position on use of non-steroidal anti-inflammatory drugs: A population-based cohort study.

PURPOSE: Lifestyle and socioeconomic position may confound the link between non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular events, if associated with NSAID use. We examined this association. METHODS: We conducted a cohort study of all adult first-time responders to the Danish National Health Surveys of 2010, 2013, or 2017 without an NSAID prescription within 3 months before survey completion (n = 407 395). Study exposures were weight, smoking status, alcohol consumption, binge drinking frequency, physical activity level, marital status, highest achieved level of education, income, and employment status. We used a Cox model to compute hazard ratios of time to first redemption of an NSAID prescription and a cumulative odds model to compute odds ratios (ORs) of redeeming one additional NSAID prescription in the year after survey completion. RESULTS: Total follow-up time was 1 931 902 years. The odds of redeeming one additional NSAID prescription in the year after survey completion varied within all categories of lifestyle and socioeconomic position. The largest ORs were observed within categories of weight (1.70, 95% CI: 1.65-1.74 for obesity vs. normal weight), smoking status (1.24, 95% CI: 1.21-1.27 for current vs. never use), and education (1.44, 95% CI: 1.39-1.49 for primary or other vs. university or higher education). The Cox model showed consistent results. CONCLUSIONS: Markers of unhealthy lifestyle and low socioeconomic position were associated with initiation and prolonged NSAID use. Consideration of lifestyle and socioeconomic markers as potential confounders in NSAID studies is therefore recommended.

Characteristics and overall survival of patients with early-stage non-small cell lung cancer: A cohort study in Denmark.

Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer diagnoses, and approximately 35% of patients with NSCLC are diagnosed at an early stage (I-IIIA). This study aimed to describe epidermal growth factor receptor (EGFR) testing, patient characteristics, and overall survival (OS) among patients with early-stage NSCLC in Denmark. Patients with early-stage NSCLC registered in the Danish Lung Cancer Registry in 2013-2018 were followed through 2019. We described EGFR testing, descriptively summarised patient characteristics, and calculated OS by EGFR testing and mutation status. The association between EGFR mutation (EGFRm) and all-cause mortality was estimated using Cox proportional-hazards regression, in subgroups defined by stage at diagnosis, age at diagnosis, comorbidity, and receipt of surgery. In 2013-2018, 21,282 patients with NSCLC were registered in the Danish Lung Cancer Registry, of whom 8758 were diagnosed at an early stage. Of those, 4071 (46%) were tested for EGFRm at diagnosis. Median OS was 5.7 years among patients with EGFRm-positive status (n = 361) and 4.4 years among patients with EGFRm-negative status (n = 3710). EGFRm-positive status was associated with lower all-cause mortality in all subgroups. This study contributes to population-based evidence on the epidemiology of early-stage NSCLC treated in routine clinical practice.

Risk of Major Cardiovascular and Cerebrovascular Events in Users of Lisdexamfetamine and Other Medications for Attention-Deficit/Hyperactivity Disorder in Denmark and Sweden: A Population-Based Cohort Study.

INTRODUCTION: This study aimed to estimate risks of cardiovascular and cerebrovascular events in patients treated with lisdexamfetamine dimesylate (LDX) compared with patients previously treated with other attention-deficit/hyperactivity disorder (ADHD) medications (amphetamine, dexamphetamine, methylphenidate or atomoxetine). METHODS: This population-based cohort study used data from Danish and Swedish medical and administrative national registers. The LDX cohort included adult patients initiating LDX with at least 12 months' data preceding first LDX dispensing (index date). A random sample of patients treated with at least one non-LDX ADHD medication in the 6-24 months (but not less than 6 months) before index date (previous-users cohort) were matched to LDX users on age, sex, region and calendar year. The primary outcome, a composite of major adverse cardiovascular and cerebrovascular events (MACE), included first hospitalisation for acute myocardial infarction or stroke and out-of-hospital coronary heart disease or cerebrovascular disease death. Incidence rates (IRs) and IR ratios (IRRs) with 95% confidence intervals (CIs) of MACE were estimated using Poisson regression. RESULTS: From Denmark/Sweden, 5516/40,163 LDX users and 27,494/200,389 previous users were included. In Denmark, IRs of MACE/1000 person-years (95% CI) were similar for LDX (1.63 [0.85-3.14]) and previous users (1.61 [1.28-2.01]). In Sweden, IRs (95% CI) were 1.40 (1.09-1.79) in LDX users and 1.17 (1.00-1.38) in previous users. Adjusted MACE IRRs (95% CI) for LDX versus previous use were 1.01 (0.48-2.13) in Denmark, 1.13 (0.75-1.71) in Sweden, and 1.10 (0.77-1.58) in the pooled analysis. CONCLUSION: Our findings suggest little to no increased risk of cardiovascular and cerebrovascular events in patients treated with LDX compared with patients previously treated with other ADHD medications.