Danish National Prescription Registry Research Articles

Incidence and prognosis of superficial vein thrombosis during pregnancy and the post-partum period: a Danish nationwide cohort study

The incidence of superficial vein thrombosis (SVT) of the legs and the subsequent risk of venous thromboembolism during pregnancy and the post-partum period is unknown. To better understand the clinical course of SVT during these times, we aimed to estimate the incidence rate of SVT during pregnancy and in the post-partum period, as well as the risk of subsequent venous thromboembolism. In this nationwide cohort study, we collected data on all pregnant women who delivered between Jan 1, 1997, and Dec 31, 2017, in Denmark were extracted from the Danish Medical Birth Register, the Danish National Patient Registry, and the Danish National Prescription Registry. Data on ethnicity were not available. Incidence rates per 1000 person-years were calculated for each trimester and the antepartum and post-partum period. Among women with a pregnancy-related SVT, risk of subsequent venous thromboembolism within the same pregnancy or post-partum period were calculated and compared with a matched cohort of pregnant women without SVT using Cox proportional hazards analysis. During 1 276 046 deliveries, 710 diagnoses of lower extremity SVT occurred from conception up to 12 weeks postpartum (0·6 per 1000 person-years [95% CI 0·5-0·6]). The incidence rates of SVT per 1000 person-years were 0·1 (95% CI 0·1-0·2) during the during the first trimester, 0·2 (0·2-0·3) during the second trimester, and 0·5 (0·5-0·6) during the third trimester. The incidence rate was 1·6 per 1000 person-years (95% CI 1·4-1·7) during the post-partum period. Of the 211 women with antepartum SVT included in the analysis, 22 (10·4%) were diagnosed with venous thromboembolism, compared with 25 (0·1%) in women without SVT (hazard ratio 83·3 [95% CI 46·3-149·7]). The incidence rate of SVT during pregnancy and the post-partum period was low. However, if SVT during pregnancy was diagnosed, the risk of developing venous thromboembolism during the same pregnancy was high. These results might help physicians and patients to make decisions about anticoagulant management of pregnancy-related SVT. None.

Abstract P4-03-02: Low-dose aspirin prescriptions and breast cancer recurrence: a Danish nationwide cohort study with up to 23 years of follow-up

Abstract Background Low-dose aspirin irreversibly inhibits the cyclooxygenase enzymes COX-1 and COX-2, which catalyze the formation of prostaglandins and thromboxanes, inhibiting platelet aggregation. Platelets are thought to play a role in tumorigenesis. As such, aspirin may have a beneficial effect on breast cancer prognosis, but results to date are conflicting. Objectives To evaluate the association between aspirin use and breast cancer recurrence up to 23 years after primary diagnosis. Methods We included all women diagnosed with non-metastatic breast cancer during 1996-2004 registered in the Danish Breast Cancer Group (DBCG) clinical database. We obtained information on aspirin prescriptions (>= 2 prescriptions filled between cancer diagnosis and the landmark) from the Danish National Prescription Registry. Information on early and late (>10 years after primary diagnosis) recurrence was obtained using the DBCG database (for recurrence within the first 10 years after diagnosis) and for late recurrence via a previously described and validated algorithm, drawing on data from the Danish National Patient Registry, the Danish Pathology Registry, the Danish Cancer Registry and a contralateral breast cancer database. We used Cox regression to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CI) employing landmark analyses starting follow-up at years 5, 10, 15, and 20 after primary diagnosis. We adjusted for potential confounders including calendar year of diagnosis, menopausal status, comorbidities, estrogen receptor status, clinical stage, grade, surgery type, chemo- and endocrine therapy, diagnostic codes for alcoholism and obesity, as well as co-medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, bisphosphonates, metformin, digoxin, hormone replacement therapy, non-steroidal anti-inflammatory drugs, and vitamin K antagonists). We followed patients until recurrence, death, second cancer, loss to follow-up, or 31 December 2018. Results Among 21,684 women with non-metastatic breast cancer, 4,902 experienced recurrence during 242,427 person-years of follow-up. Our landmark analyses showed a reduced hazard of recurrence in the 5-, 10-, and 15-year landmark cohorts (5-year landmark adjusted HR = 0.80, 95% CI = 0.68, 0.94; 10-year landmark adjusted HR = 0.84, 95% CI = 0.71, 1.00, 15-year landmark adjusted HR = 0.83, 95% CI = 0.61, 1.14). The 20-year landmark analysis revealed an adjusted HR of 1.09 (95% CI = 0.49, 2.46). Conclusions The potential anti-cancer effect of aspirin appears most pronounced in the first 15 years after breast cancer diagnosis. Funding Elisabeth Solmunde is funded by the Danish Cancer Society (R320-A18464-B5768) and the Independent Research Fund Denmark (1149-00013B). This work was supported by grants to Deirdre Cronin-Fenton from the Danish Cancer Society (“Knæk Cancer” R147-A10100). Citation Format: Elisabeth Solmunde, Rikke N Pedersen, Mette Nørgaard, Lene Mellemkjær, Søren Friis, Bent Ejlertsen, Thomas P. Ahern, Deirdre Cronin-Fenton. Low-dose aspirin prescriptions and breast cancer recurrence: a Danish nationwide cohort study with up to 23 years of follow-up [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-02.

DOP21 Disease activity patterns of paediatric Inflammatory Bowel Disease – A Danish nationwide cohort study 1996-2018

Abstract Background Inflammatory bowel diseases (IBD) are heterogenous diseases in terms of their clinical presentation including frequency and severity of flares. We aimed to describe disease activity (DA) patterns in a Danish nationwide cohort including all IBD patients diagnosed < 18 years of age between 1996 and 2018. Methods Paediatric patients diagnosed with Crohn’s disease (pCD) or ulcerative colitis (pUC) were identified from national registers (Danish Civil Registration System, National Patient Registry, Danish National Prescription Registry and Danish Pathology Data Bank). DA was assessed in both incident and prevalent pIBD patients and categorised as mild-moderate in case of a course of topical corticosteroids, oral budesonide, or topical 5-ASA. Episodes were categorised as severe if they involved hospitalization, surgery, oral corticosteroids or biological therapy. DA patterns in incident patients were assessed for 5- and 10-year periods from diagnosis as follows: The 5-year DA pattern: A) No years with DA. B) 1 or 2 years with at least one episode of DA in each year. C) 3 or 4 years with at least one episode of DA in each year. D) All 5 years with at least one yearly episode of DA. The 10-year DA pattern: A) Decreasing: First 5 years with 2 or more years with DA; following 5 years with 2 years or less with DA. B) Increasing: First 5 years with less than 2 years with DA; following 5 years with 2 or more years with DA. C) Chronic continuous: First 10 years with at least 8 years with DA. D) Quiescent: First 10 years with one year or less with DA. E) Chronic intermittent: DA pattern that does not meet the criteria above. Results 1,965 pCD and 1,838 pUC incident patients were included. At diagnosis severe DA was found in 87% in pCD and 80% in pUC, in addition to 6.1% of pUC patients who had a colectomy the first year. After 5 years of disease the annual proportion of pCD and pUC with no DA 70% and 61%. This remained constant after 10 years (pCD:72% and pUC: 64%). In pUC, 12% and 16% required colectomy 5 and 10 years after diagnosis. In prevalent pCD (N=2,515) and pUC (N=2,428) the proportion with no DA each calendar year was stable (pCD: 59%-73% and pUC: 50%-60%, prior to 2010). The majority of both pCD and pUC patients experienced one or two years with at least one episode of DA within the first five years (pCD: 51%, pUC: 53%). During the first 10 years from diagnosis, the decreasing DA pattern was the most common in both pCD and pUC (43% and 47%, respectively) (Figure). Conclusion DA patterns in pIBD are characterised by a high proportion of severe activity initially with a decreasing pattern after 5 and 10 years follow-up. No change in the proportion of patients with no DA was seen despite the introduction of biologic therapy in the period.

P850 Co-medication before and after onset of inflammatory bowel disease in adults or elderly

Abstract Background The incidence of Inflammatory Bowel Disease (IBD) is increasing. Co-medication is clinically important in addition to the treatment of IBD. However, real-world data on co-medication is sparse. Thus, we aimed to describe whether a diagnosis of IBD affects the prescription pattern of co-medication used to treat other diseases in adult-onset and elderly-onset IBD. Methods This nationwide cohort study utilized data from Danish Health Registers. We included patients with adult-onset of IBD (18-59 years of age) and elderly-onset of IBD (+60 years of age) from 1998-2018 with three years of follow-up after the diagnosis for all patients. We identified patients who had at least two diagnoses of IBD in The National Patient Register. We described redeemed prescriptions of 11 common groups for medication used to treat conditions other than IBD using data from The Danish National Prescription Registry. Results We identified 36,165 incident patients. We created two cohorts; 27,386 (75%) had adult-onset IBD, and 8,779 (25%) patients had elderly-onset IBD, Table 1. The proportion of patients with redeemed prescriptions in both cohorts was statistically significantly increased one and three years after onset of IBD for antidepressants, antipsychotics, sedatives/hypnotics, opioids, non-opioid analgesics, antidiabetics, and proton pump inhibitors, compared to one and three years before diagnosis, Figure 1 & Figure 2. Conclusion The proportion of patients with redeemed prescriptions for antidepressants, antipsychotics, sedatives/hypnotics, opioids, non-opioid analgesics, antidiabetics, and proton pump inhibitors was significantly increased one and three years after a diagnosis of IBD compared to one and three years before diagnosis.

Heavy prenatal alcohol exposure and overall morbidities: a Danish nationwide cohort study from 1996 to 2018

Heavy prenatal alcohol exposure is harmful and can lead to fetal alcohol spectrum disorders. A systematic review and meta-analysis identified 428 comorbidities in individuals with fetal alcohol spectrum disorders, and reported pooled prevalence estimates. We aimed to investigate overall risk of morbidities in heavy prenatal alcohol-exposed children by estimating risk of the identified comorbidities, and previously unidentified diseases and health-related problems. Our Danish nationwide register-based cohort study included all singleton births. Individuals were followed up to age 18 years, between 1996 and 2018. Stillbirths and children of immigrants were not included in the study, and births of women who migrated within 1 year before or during pregnancy were also excluded due to loss to follow-up. Data on health and education were extracted from the Danish Medical Birth Register, the Danish National Patient Registry, the Danish National Prescription Registry, the Danish Civil Registration System, and the Population Education Register. We estimated crude and standardised risk differences of hospital diagnoses. Heavy prenatal alcohol exposure was defined by hospital contacts with alcohol-attributable diagnoses given to the mother or her child, or by maternal redeemed prescriptions for drugs to treat alcohol dependence 1 year before or during pregnancy. Of 1 407 689 identified singleton births, 219 186 were excluded for reasons including they were born to immigrants, lost to follow-up, or were stillbirths. Of the remaining 1 188 503 children, 4799 (0·4%) had heavy prenatal alcohol exposure and 1 183 704 (99·6%) were classified as non-alcohol-exposed births. 578 179 (48·6%) babies were female and 610 324 (51·4%) were male. We found 234 of 428 previously identified comorbidities in individuals with fetal alcohol spectrum disorder, of which 29 conditions had a standardised risk difference of at least 0·5%, predominantly related to brain function, behavioural disorders, infections, and neonatal conditions. The four highest standardised risk differences were found for low birthweight (4·70% [95% CI 3·70-5·71]), small for gestational age (4·63% [3·72-5·55]), delayed milestone (3·81% [2·99-4·64]), and other preterm infants (2·69% [1·71-3·68]). Of previously unidentified diseases and health-related problems, 32 of 719 had a standardised risk difference of at least 1·0%, mainly related to brain function, some injuries, substance-related conditions, and childhood adversities. Heavy prenatal alcohol exposure is associated with an overall increased risk of child morbidities and previously unrecognised alcohol-related health problems. Prenatal alcohol exposure is a key public health issue with a potential negative impact on child and adolescent health. This study urges for renewed efforts and substantiates the profound degree to which pre-conceptional care is mandatory. The Obel Family Foundation, The Health Foundation, TrygFonden, Aase and Ejnar Danielsens Foundation, The North Denmark Region Health Science and Research Foundation, Holms Memorial Foundation, Dagmar Marshalls Foundation, the A.P. Møller Foundation, King Christian X Foundation, Torben and Alice Frimodts Foundation, the Axel and Eva Kastrup-Nielsens Foundation, and the A.V. Lykfeldts Foundation.

Heavy prenatal alcohol exposure and obstetric and birth outcomes: a Danish nationwide cohort study from 1996 to 2018

Heavy alcohol use during pregnancy can harm the fetus, but the relation to most obstetric outcomes remains unclear. We therefore aimed to describe maternal characteristics and estimate the association between heavy prenatal alcohol exposure and 22 adverse obstetric and birth outcomes. We carried out a Danish nationwide register-based historical cohort study, including all singleton births from Jan 1, 1996, to Dec 31, 2018. Births of women who had emigrated to Denmark were excluded from the study due to missing data and women who migrated within 1 year before or during pregnancy were also excluded due to loss to follow-up. Data were extracted from the Danish Medical Birth Register, the Danish National Patient Registry, the Danish National Prescription Registry, the Danish Civil Registration System, and the Population Education Register. Logistic regression models were used to estimate crude and adjusted odds ratios (ORs) of obstetric and birth outcomes. Heavy alcohol use was defined by hospital contacts for alcohol-attributable diagnoses given to the mother, her infant, or both, or maternal redeemed prescriptions for drugs to treat alcohol dependence within 1 year before or during pregnancy. Of 1 191 295 included births, 4823 (0·40%) were defined as heavily alcohol-exposed and 1 186 472 were categorised as a reference group with no identified heavy prenatal alcohol exposure. Heavy-alcohol-exposed births more often had mothers with psychiatric diagnoses (49·8% vs 9·6%), substance use (22·0% vs 0·4%), tobacco use (64·3% vs 15·8%), and low educational level (64·1% vs 17·6%) than did the reference group. For heavy-alcohol-exposed births, significantly increased adjusted ORs were found for small for gestational age (OR 2·20 [95% CI 1·97-2·45]), preterm birth (OR 1·32 [1·19-1·46]), haemorrhage in late pregnancy (OR 1·25 [1·05-1·49]), and preterm prelabour rupture of membranes (OR 1·18 [1·00-1·39]). Decreased adjusted ORs were found for postpartum haemorrhage (500-999 mL; OR 0·80 [95% CI 0·69-0·93]), gestational diabetes (OR 0·81 [0·67-0·99]), planned caesarean section (OR 0·82 [0·72-0·94]), pre-eclampsia and eclampsia (OR 0·83 [0·71-0·96]), and abnormalities of forces of labour (OR 0·92 [0·86-0·99]). Heavy prenatal alcohol exposure is associated with adverse obstetric and birth outcomes and high proportions of maternal low educational level, psychiatric disease, and lifestyle risk behaviours. These findings highlight a need for holistic public health programmes and policy attention on improving pre-conceptional care and antenatal care. The Obel Family Foundation, The Health Foundation, TrygFonden, Aase and Ejnar Danielsens Foundation, The North Denmark Region Health Science and Research Foundation, Holms Memorial Foundation, Dagmar Marshalls Foundation, the A.P. Møller Foundation, King Christian X Foundation, Torben and Alice Frimodts Foundation, the Axel and Eva Kastrup-Nielsens Foundation, the A.V. Lykfeldts Foundation.

Sedative drug-use in Denmark, 2000 to 2019: a nationwide drug utilization study.

To describe trends in and characteristics of sedative drug use from 2000 through 2019 in relation to the introduction of central regulations and new drugs. In this descriptive study, we used individual prescription data on the entire Danish population from the Danish National Prescription Registry to calculate yearly incidence and prevalence of use of benzodiazepines, benzodiazepine-related drugs (Z-drugs), melatonin, olanzapine, low-dose quetiapine, mianserin/mirtazapine, pregabalin, and promethazine from 2000 through 2019. From the Danish National Patient Registry, we obtained data on drug users' psychiatric and somatic comorbidity. The use of benzodiazepines and Z-drugs declined gradually from 2000 through 2019, whereas the newer alternatives, melatonin, low-dose quetiapine, pregabalin and promethazine, increased in use, while the use of olanzapine and mianserin/mirtazapine was relatively stable. This development was seen in both men and women and across all age groups except for hypnotic benzodiazepines which showed a steep increase in the oldest age group from 2010. For all sedative drugs depression, anxiety, alcohol and misuse disorder, pain and cancer were the most prevalent comorbidities. During our study period, the number of individuals without any of the selected diagnoses increased. In Denmark different central regulations have influenced prescription practice toward more restrictive use of Z-drugs and benzodiazepines, except for hypnotic benzodiazepine prescriptions increased after the introduction of special palliative care. An increase in use of newer sedative drugs, however, indicates that the regulations do not remove the need for sedative drugs in the population.

Risk and Subtypes of Stroke Following New-Onset Postoperative Atrial Fibrillationin Coronary Bypass Surgery: APopulation-Based Cohort Study.

Background New-onset postoperative atrial fibrillation (POAF) develops in approximately one-third of patients undergoing cardiac surgery and is associated with a higher incidence of ischemic stroke and increased mortality. However, it remains unknown to what extent ischemic stroke events in patients with POAF are cardioembolic and whether anticoagulant therapy is indicated. We investigated the long-term risk and pathogenesis of postoperative stroke in patients undergoing coronary artery bypass grafting experiencing POAF. Methods and Results This was a register-based cohort study. Data from the WDHR (Western Denmark Heart Registry) were linked with the DNPR (Danish National Patient Register), the Danish National Prescription Register, and the Cause of Death Register. All stroke diagnoses were verified, and ischemic stroke cases were subclassified according to pathogenesis. Furthermore, investigations of all-cause mortality and the use of anticoagulation medicine for the individual patient were performed. A total of 7813 patients without a preoperative history of atrial fibrillation underwent isolated coronary artery bypass grafting between January 1, 2010, and December 31, 2018, in Western Denmark. POAF was registered in 2049 (26.2%) patients, and a postoperative ischemic stroke was registered in 195 (2.5%) of the patients. After adjustment, there was no difference in the risk of ischemic stroke (hazard ratio [HR], 1.08 [95% CI, 0.74-1.56]) or all-cause mortality (HR, 1.09 [95% CI, 0.98-1.23]) between patients who developed POAF and non-POAF patients. Although not statistically significant, patients with POAF had a higher incidence rate (IR; per 1000 patient-years) of cardioembolic stroke (IR, 1 [95% CI, 0.6-1.6] versus IR, 0.5 [95% CI, 0.3-0.8]), whereas non-POAF patients had a higher incidence rate of large-artery occlusion stroke (IR, 1.1 [95% CI, 0.8-1.5] versus IR, 0.7 [95% CI, 0.4-1.4]). Early initiation of anticoagulation medicine was not associated with a lower risk of ischemic stroke. However, patients with POAF were more likely to die of cardiovascular causes than non-POAF patients (P<0.001). Conclusions We found no difference in the adjusted risk of postoperative stroke or all-cause mortality in POAF versus non-POAF patients. Patients with POAF after coronary artery bypass grafting presented with a higher, although not significant, proportion of ischemic strokes of the cardioembolic type.

Bidirectional 5-year risks of diabetic retinopathy, glaucoma and/or ocular hypertension: Results from a national screening programme.

We aimed to investigate if diabetic retinopathy (DR), glaucoma and/or ocular hypertension (OHT) are prospectively linked, as previous studies have proposed cross-sectional associations, but longitudinal data from larger cohorts are lacking. We performed a bidirectional 5 years prospective, registry-based cohort study. We extracted data from national registers, including the Danish Registry of Diabetic Retinopathy, the Danish Civil Registration System, the Danish National Patient Register and the Danish National Prescription Registry. DR level was defined by the highest level of the two eyes. Glaucoma and/or OHT was defined by diagnostic codes (H40*) or at least three redeemed prescriptions of glaucoma medication (S01E*) within 1 year. We included 205 970 persons with diabetes and 1 003 170 age- and gender-matched non-diabetes controls. Exposures were level-specific DR (i) and glaucoma and/or OHT (ii), and outcomes were hazard ratios (HRs) for 5 years incident glaucoma and/or OHT (i) and DR (ii). Persons with diabetes were more likely to develop glaucoma and/or OHT (multivariable adjusted HR 1.11, 95% CI 1.06-1.15), but this did not depend on the level of DR. In persons with diabetes, those with glaucoma and/or OHT were more likely to develop DR (multivariable adjusted HR 1.12, 95% CI 1.03-1.23) within 5 years. In a national cohort, diabetes associated with a little higher risk of upcoming glaucoma and/or OHT, and, inversely, the presence of the latter predicted a higher risk of incident DR. Nevertheless, our data do not seem to justify including glaucoma evaluation in the national Danish DR-screening programme.

Exposure to nitrosatable drugs during pregnancy and childhood cancer: A matched case-control study in Denmark, 1996-2016.

Nitrosatable drugs can be synthesized to N-nitroso compounds in human stomach. In a pregnant woman, N-nitroso compounds can be translocated to the fetus through the placenta. Maternal exposure of nitrosatable compounds during pregnancy has been associated with childhood brain tumors and leukemia. However, few studies have investigated an association between nitrosatable drug exposure during pregnancy and childhood cancer. We examined if maternal prescriptions of nitrosatable drugs received during pregnancy are associated with childhood cancer. A matched case-control study was conducted using Danish nationwide registry data from 1995 to 2016. Each childhood cancer case was matched with twenty-five controls. Maternal exposure of nitrosatable drugs during pregnancy was identified from the Danish National Prescription Register. A multivariable conditional logistic regression model was used to estimate adjusted odds ratios (adj.OR) with 95% confidence intervals (CI) for each childhood cancer type. Maternal prescriptions of nitrosatable drugs positively associate with central nervous system tumors (adj.OR = 1.25; 95% CI = 1.04-1.51) and neuroblastoma (adj.OR = 1.96; 95% CI = 1.34-2.85) in offspring. We also observed a positive association between perinatal exposure of nitrosatable drugs and acute lymphoblastic leukemia (adj.OR = 1.31; 95% CI = 1.07-1.59), however, it appeared to be due to confounding by indication, i.e., maternal infections. Nitrosatable drug use during pregnancy potentially increased risk of central nervous system tumors and neuroblastoma. While a positive association between maternal prescriptions of nitrosatable drugs and acute lymphoblastic leukemia should be interpreted cautiously because of confounding by indication.

A register-based study: cough - a frequent phenomenon in the adult population

BackgroundChronic cough, more than 8 weeks, can either be without co-morbidity called unexplained chronic cough (UCC) or with co-morbidity called refractory chronic cough (RCC). Using datasets from the Danish National Prescription Registry (Prescription Registry) and Danish National Patient Registry (Patient Registry) we wanted to investigate the prevalence and factors of importance of cough in a Nationwide registry.Material and methodsInclusion criteria were patients 18–90 years with at least one final cough diagnosis (ICD-10 DR05/DR059) in Patient registry or patients who have redeemed ≥2 prescriptions for relevant cough-medication within a 90-day harvest in the Prescription registry from 2008 to 2017. To validate this study’s chosen proxy on chronic cough an analysis of the Patient registry sub-population with a contact of ≥8 weeks and then final diagnosis code DR05/DR059 was also performed. The population was divided into UCC and RCC.ResultsOf the 104,216 patients from the Prescription registry, 52,727 were classified as having UCC and 51,489 were classified with RCC. From the Patient registry 34,260 were included, of whom 12,278 had UCC and 21,982 had RCC. Cough were frequently found among females (p < 0.0001). Both genders were around 2 years older in RCC than UCC (p < 0.0001) Spirometry was performed in 69 and 57%, X-ray in 73 and 58% and asthma challenge test performed in 13 and 5% (UCC and RCC, respectively, p < 0.0001). The frequency of co-morbidities such as heart failure, rheumatologic disease, pulmonary embolism, and diabetes was < 10%.ConclusionMany patients suffer from chronic cough or cough requiring medications, with or without co-morbidity; frequently found among menopausal women. Most patients had a substantial work-up performed. The high frequency and the resources consuming work-up program call for systematic coding of disease, systematic patient evaluation and more specific treatment options. The study was approved (ID: no. P-2019-191).

Metformin Use and the Risk of Myeloproliferative Neoplasms in a Danish Population Based Cohort

INTRODUCTION The peroral antidiabetic drug metformin (MT) is primarily prescribed for hyperglycaemia due to insulin-resistance in type-2 diabetes mellitus or metabolic syndrome and is a widely used drug worldwide. Use of MT has been associated with reduced cancer risk and mortality in meta-analyses (Gandini et al, 2014). Constitutive activation of the JAK-STAT pathway by the recurrent gain-of-function mutation JAK2V617F is a hallmark of MPN and has been related to the formation of bone marrow fibrosis by altering the bone marrow microenvironment. Preclinical studies of MT have shown antileukemic activity in myeloid neoplasms by activating the AMPK-mTOR-pathway, downregulating JAK2/STAT signaling, and mitochondrial activity suggesting MT as a possible treatment option in MPN (Biondani & Peyron, 2018; MacHado-Neto et al, 2018; Kawashima & Kirito, 2016). Recently, the phase II study Fibromet failed to demonstrate effect of MT in reversing bone marrow fibrosis in myelofibrosis. However, significant down regulation of the JAK-STAT-pathway and cytokine production were demonstrated (Campos et al, 2021). Currently, the association between MT use and the risk of MPNs remains to be elucidated. METHODS We conducted a nationwide population-based nested case-control study to compare MT use among patients diagnosed with MPN between 2010 and 2018 and a matched population without MPN in the Danish general population to estimate odds ratios (ORs) for MPN associated with MT use. We utilized five large nationwide Danish health registries to obtain data on exposure, outcome, and covariates for adjustment. The index date was defined as the date of MPN diagnosis and cases were identified using the National Chronic Myeloid Neoplasia Registry covering >90% of MPN cases in Denmark (Bak et al, 2016). Controls were selected by incidence density sampling (five to one) from the Danish general population matched on age, gender, and calendar year. Data on MT exposure were collected from the Danish National Prescription Registry. "Ever-use” was defined as a minimum of one prescription before the index date and "Long-term use” as >5 years of MT use (assuming an intake of the WHOs defined daily dose for MT at 2000 mg plus 25% to account for minor prescription variations and incompliances). Exposure to MT, comorbidity, and concomitant drug use were disregarded 12 months prior to the index date to avoid reverse causation. By conditional logistic regression analysis, we obtained ORs and 95% confidence intervals (95% CIs) adjusted for study design (age, gender, and index date) and fully adjusted ORs (aORs) (see footnote in Table 2 for adjusted variables). RESULTS The study population included a total of 3,816 cases and 19,080 matched controls (Table 1). Exposure assessment categorized 7.0% of cases and 8.2% of controls as "Ever-users” of MT resulting in an aOR for MPN of 0.70 (95% CI, 0.61-0.81). Long-term users were rare and comprised 1.1% of cases and 2.0% of controls resulting in an aOR for MPN 0.45 (0.33-0.63). When assessing the duration of MT exposure, we found a trend towards a dose-response relationship (<1 year: aOR 0.79 [0.62-1.00]; 1-4.99 years: 0.78 [0.64-0.95]; 5-9.99 years: 0.42 [0.29-0.61]; >10 years: 0.56 [0.30-1.03]); however, this was not statistically significant for the >10 years category, most likely due to small numbers. In stratified analyses the protective effect of long-term MT use was consistent according to gender with aOR of 0.37 (0.23-0.60) and 0.56 (0.36-0.89) for males and females, respectively, compared to males and females without MT use. In a subgroup analysis the effect was consistent across all age groups and MPN-subtypes. However, aORs did not reach statistical significance for age <60 years, myelofibrosis, and MPN unclassifiable (Table 2). CONCLUSION In this study we found an inverse association between MT use and risk of MPNs indicating a potential protective effect of MT on the development of MPNs. The protective effect was most pronounced for long-term use, older age (≥60 years) and for polycythemia vera and essential thrombocythemia. Whether this effect is causal should be determined interventional studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Birthweight, childhood body size, and timing of puberty and risks of breast cancer by menopausal status and tumor receptor subtypes

BackgroundAssociations of birthweight, childhood body size and pubertal timing with breast cancer risks by menopausal status and tumor receptor subtypes are inconclusive. Thus, we investigated these associations in a population-based cohort of Danish women.MethodsWe studied 162,419 women born between 1930 and 1996 from the Copenhagen School Health Records Register. The register includes information on birthweight, measured childhood weights and heights at the age of 7–13 years, and computed ages at the onset of the growth spurt (OGS) and at peak height velocity (PHV). The Danish Breast Cancer Cooperative Group database provided information on breast cancer (n = 7510), including estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and menopausal status. Hormone replacement therapy use came from the Danish National Prescription Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regression.ResultsWe found that birthweight was not associated with any breast cancer subtypes. While childhood BMI was not statistically significantly associated with ER+ tumors nor consistently with ER− tumors among pre-menopausal women, consistent inverse associations were found among postmenopausal women. At the age of 7 years, the HRs for postmenopausal ER+ and ER− tumors were 0.90 (95% CI 0.87–0.93) and 0.84 (95% CI 0.79–0.91) per BMI z-score, respectively. Similarly, childhood BMI was inversely associated with pre- and postmenopausal HER2− tumors, but not with HER2+ tumors. Childhood height was positively associated with both pre- and postmenopausal ER+ tumors, but not with ER− tumors. At the age of 7 years, the HRs for postmenopausal ER+ and ER− tumors were 1.09 (95% CI 1.06–1.12) and 1.02 (95% CI 0.96–1.09) per height z-score, respectively. In general, childhood height was positively associated with HER2+ and HER2− tumors among pre- and postmenopausal women. Ages at OGS and PHV were not associated with any breast cancer subtypes.ConclusionsWe showed that a high BMI and short stature in childhood are associated with reduced risks of certain breast cancer subtypes. Thus, childhood body composition may play a role in the development of breast cancer.

Association of Hormone Therapy With Depression During Menopause in a Cohort of Danish Women

During menopause, the levels of estrogen and progesterone decrease and 60% to 70% of women experience menopausal symptoms, including mood disturbances. The latter might be prevented by hormone therapy (HT), yet some studies have suggested that use of HT might be associated with increased risk of depression. To examine whether use of HT during menopause was associated with a subsequent diagnosis of depression. This nationwide register-based cohort and self-controlled case series study included all women in Denmark aged 45 years between January 1, 1995, through December 31, 2017 (n = 825 238), without prior oophorectomy, breast cancer, or cancer in reproductive organs. Follow-up was completed on December 31, 2018. The statistical analysis was performed from September 1, 2021, through May 31, 2022. Redeemed prescriptions of different types of HT identified by the Anatomical Therapeutic Chemical classification system codes (G03C [estrogen] and G03F [estrogen combined with progestin]) in the Danish National Prescription Registry between 1995 and 2017. Type of administration was divided into systemic (oral or transdermal) and local (intravaginal or intrauterine). A hospital diagnosis of depression (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F32-F33 and International Classification of Diseases, Eighth Revision, codes 296.09, 296.29, 298.0, and 300.49) between 1995 through 2018. Associations were examined in cohort and self-controlled case series analysis using Cox proportional hazards and fixed-effects Poisson regression models. During follow-up from 45 years of age to a mean of 56.0 (range, 45.1-67.7) years, 189 821 women (23.0%) initiated systemically or locally administered HT and 13 069 (1.6%) were diagnosed with depression. Systemically administered HT was mainly initiated before 50 years of age and was associated with a higher risk of a subsequent depression diagnosis (hazard ratio [HR] for 48-50 years of age, 1.50 [95% CI, 1.24-1.81]). The risk was especially elevated the year after initiation of both treatment with estrogen alone (HR, 2.03 [95% CI, 1.21-3.41]) and estrogen combined with progestin (HR, 2.01 [95% CI,1.26-3.21]). Locally administered HT was initiated across all ages and was not associated with depression risk (HR, 1.15 [95% CI, 0.70-1.87]). It was, however, associated with a lower risk of depression when initiated after 54 years of age (HR for 54-60 years of age, 0.80 [95% CI, 0.70-0.91]). In self-controlled analysis, which efficiently accounts for time-invariant confounding, users of systemically administered HT had higher rates of depression in the years after initiation compared with the years before treatment (incidence rate ratio for 0-1 year after initiation, 1.66 [95% CI, 1.30-2.14]). These findings suggest that systemically administered HT before and during menopause is associated with higher risk of depression, especially in the years immediately after initiation, whereas locally administered HT is associated with lower risk of depression for women 54 years or older.

Risk factors for cardiac implantable electronic device infections: a nationwide Danish study.

Cardiac implantable electronic device (CIED) infection is a severe complication to modern management of cardiac arrhythmias. The CIED type and the type of surgery are recognized as risk factors for CIED infections, but knowledge of patient-related risk factors is scarce. This study aimed to identify lifelong patient-related risk factors for CIED infections. Consecutive Danish patients undergoing a CIED implantation or reoperation between January 1996 and April 2018 were included. The cohort consisted of 84 429 patients undergoing 108 494 CIED surgeries with a combined follow-up of 458 257 CIED-years. A total of 1556 CIED explantations were classified as either pocket (n = 1022) or systemic CIED infection (n = 534). Data were cross-linked with records from the Danish National Patient Registry and the Danish National Prescription Registry. Using multiple-record and multiple-event per subject proportional hazard analysis, specific patient-related risk factors were identified but with several variations amongst the subtypes of CIED infection. CIED reoperations were associated with the highest risk of pocket CIED infection but also CIED type, young age, and prior valvular surgery [hazard ratio (HR): 1.62, 95% confidence interval (CI): 1.29-2.04]. Severe renal insufficiency/dialysis (HR: 2.40, 95% CI: 1.65-3.49), dermatitis (HR: 2.80, 95% CI: 1.92-4.05), and prior valvular surgery (HR: 2.09, 95% CI: 1.59-2.75) were associated with the highest risk of systemic CIED infections. Congestive heart failure, ischaemic heart disease, malignancy, chronic obstructive pulmonary disease, and temporary pacing were not significant at multivariate analysis. Specific comorbidities and surgical procedures were associated with a higher risk of CIED infections but with variations amongst pocket and systemic CIED infection. Pocket CIED infections were associated with CIED reoperations, young age and more complex type of CIED, whereas systemic CIED infections were associated with risk factors predisposing to bacteraemia.

The risk of major osteoporotic fractures with GLP-1 receptor agonists when compared to DPP-4 inhibitors: A Danish nationwide cohort study.

BackgroundType 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin.MethodsWe conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen’s Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects.ResultsIn total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76–1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73–1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49–0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis.ConclusionIn our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture.

The road to biologics in patients with hidradenitis suppurativa: a nationwide drug utilization study.

Prolonged systemic antibiotic treatment is often a part of management of hidradenitis suppurativa (HS). Although biologic therapies are now available, the patient's treatment journey leading to biologic therapy is unclear. To examine treatment patterns and duration of systemic treatment use in patients with HS preceding biologic therapy. We identified all patients with HS receiving treatment with biologics in the Danish National Patient Registry from 2010 to 2018 and extracted their entire prescription history of specific systemic treatments from the Danish National Prescription Registry since its inception in 1995. The patients' treatment journeys are graphically displayed through Sankey diagrams and box plots generated to show temporal distributions. Descriptive patient characteristics were presented as frequencies with percentages for categorical variables and as means with SDs or medians with interquartile ranges (IQRs) for continuous variables. A total of 225 patients with HS were included. Patients had most frequently been treated with penicillin (n = 214; 95·1%), dicloxacillin (n = 194; 86·2%), tetracycline (n = 145; 64·4%) and rifampicin/clindamycin (n = 111; 49·3%), as well as the retinoids isotretinoin and acitretin, and dapsone. Prior to biologic therapy, patients received a mean of 4·0 (SD 1·3) different systemic therapies, across a mean of 16·9 (SD 11·3) different treatment series. The mean time from first systemic therapy until biologic therapy was initiated was 15·3 (SD 5·1) years [8·2 (SD 5·9) years when excluding penicillin and dicloxacillin]. Patients with HS who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS. Delay in the initiation of biologic therapy may represent a missed opportunity to prevent disease progression. What is already known about this topic? The treatment journey leading to biologic therapy in patients with HS has not previously been investigated. What does this study add? Our data from 225 patients with HS illustrate that patients who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS.

Dwelling type and risk of chronic obstructive lung disease

BACKGROUND AND AIM Previous research has shown an association between dwelling type and chronic obstructive lung disease (COPD). However, existing research has primarily been based on cross-sectional data making the temporal relation between dwelling type and COPD uncertain. The temporal relation is of importance since people with existing COPD might move into a more COPD friendly type of dwelling (e.g., without stairs) or move due to consequences of their COPD (e.g., financial strains). Hence, we aimed to test the hypothesis that dwelling type was associated with risk of developing COPD. METHODS We performed a cohort study of participants who replied to the Danish Health and Morbidity survey in 2000. Participants were followed from inclusion in 2000 until end of 2018 for incident COPD based on information from the Danish National Patient Register and the Danish National Prescription Registry. Incidence rate ratios (IRR) of COPD with 95% confidence intervals (CI) were estimated using Poisson Regressions of incidence rates (IR). Analyses were adjusted for construction-year, urbanization, educational level, age, sex, smoking status and calendar year. RESULTS A total of 12,054 participants, free of COPD at inclusion, were included. Most participants lived in detached houses (56%) whereas 17%, 16% and 11 % lived in semi-detached houses, apartments, or other dwelling types, respectively. A total of 1,078 developed COPD during follow-up corresponding to an overall IR of COPD at 8.6. The IRR was 1.45 (95% CI: 1.21-1.73), 1.51 (95% CI: 1.26-1.81), 1.14 (95% CI: 0.86-1.52) and 1.45 (95%: CI 0.81-2.59) for people living in semi-detached houses, apartments, farms and others dwelling types, respectively, as compared to people living in detached houses. CONCLUSIONS The IR of developing COPD was significantly higher among participants living in semi-detached houses and in apartments as compared to participant living in detached houses. KEYWORDS: Dwelling type; COPD; Cohort study

SGLT2 inhibitor treatment is not associated with an increased risk of osteoporotic fractures when compared to GLP-1 receptor agonists: A nationwide cohort study.

BackgroundType 2 diabetes mellitus (T2D) is associated with an increased fracture risk. It is debated whether sodium-glucose cotransporter 2 (SGLT2) inhibitors influence fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) with SGLT2 inhibitors compared to glucagon-like peptide 1 (GLP-1) receptor agonists when used as add-on therapies to metformin.MethodsWe conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either SGLT2 inhibitors or GLP-1 receptor agonists were identified and enrolled from 2012 to 2018. Subjects were then propensity-score matched 1:1 based on age, sex, and index date. Major osteoporotic fractures (MOF) were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator.ResultsIn total, 27,543 individuals treated with either combination were identified and included. After matching, 18,390 individuals were included in the main analysis (9,190 in each group). Median follow-up times were 355 [interquartile range (IQR) 126-780] and 372 [IQR 136-766] days in the SGLT2 inhibitor and GLP-1 receptor agonist group, respectively. We found a crude HR of 0.77 [95% CI 0.56-1.04] for MOF with SGLT2 inhibitors compared to GLP-1 receptor agonists. In the fully adjusted model, we obtained an unaltered HR of 0.77 [95% CI 0.56-1.05]. Results were similar across subgroup- and sensitivity analyses.ConclusionThese results suggest that SGLT2 inhibitors have no effect on fracture risk when compared to GLP-1 receptor agonists. This is in line with results from previous studies.

Free-of-charge dispensing of antipsychotics for schizophrenia in Denmark: Impact on the nationwide prescription registry and redemption of somatic medications.

ObjectiveFree‐of‐charge dispensing of antipsychotics for schizophrenia was introduced in Denmark around 2008. However, free‐of‐charge dispensing is not recorded in the Danish National Prescription Register (DNPR), potentially introducing bias and misclassification.MethodsWe identified all 30 275 individuals with a first‐episode schizophrenia diagnosis in Denmark between 1 January 1999 and 1 March 2017 including all redeemed prescriptions registered in the DNPR during the 2 years after the schizophrenia diagnosis. For each calendar year, we calculated the proportion of individuals who had filled ≥1 prescription for psychotropic and/or somatic medications within the first 2 years after the schizophrenia diagnosis.ResultsFrom 2007 to 2017, the proportion of individuals with prescription‐records for any psychotropic medication during the 2 years after the schizophrenia diagnosis decreased from 88% to 74%, particularly antipsychotics (from 83% to 61%) and antidepressants (from 49% to 35%). This was particularly observed among those aged 18–30 years at the schizophrenia diagnosis. A similar decrease was not observed for prescription‐records of somatic medications.ConclusionThe introduction of free‐of‐charge antipsychotics has affected the redemption of specific psychotropic drugs in the DNPR in first‐episode schizophrenia. This limitation needs to be considered in register‐based studies and emphasizes the need to identify solutions.