Nationwide Danish Health Registries Research Articles

An algorithm for drug-resistant epilepsy in Danish national registers.

Patients with drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. Identification of persons with DRE in administrative data can allow for effective large-scale research, and we therefore aimed to construct an algorithm for identification of DRE in Danish nation-wide health registers. We used a previously generated sample of 525 persons with medical record-validated incident epilepsy between 2010-2019, of which 80 (15%) fulfilled International League Against Epilepsy (ILAE) criteria of DRE at the time of the latest contact - this cohort was considered the gold standard. We linked information in the validated cohort to Danish national health registers and constructed register-based algorithms for identification of DRE-cases. The accuracy of each algorithm was validated against the medical record-validated gold standard. We applied the best performing algorithm according to test accuracy (F1 score) to a large cohort with incident epilepsy identified in the Danish National Patient Registry between 1995 and 2013 and performed descriptive and logistic regression analyses to characterize the cohort with DRE as identified by the algorithm. The best performing algorithm in terms of F1 score was defined as 'fillings of prescriptions for ≥ 3 distinct antiseizure medications (ASMs) within 3 years or acute hospital visit with epilepsy/convulsions following fillings of prescriptions for two distinct ASMs' (sensitivity 0.59, specificity 0.93, positive predictive value 0.59, negative predictive value 0.92, area under the receiver operating characteristic curve 0.77, and F1 score 0.595). Applying the algorithm to a register-based cohort of 83,682 individuals with incident epilepsy yielded 8,650 cases (10.3 %) with DRE. In multivariable logistic regression analysis, early onset of epilepsy, focal or generalized epilepsy, somatic co-morbidity, and substance abuse, were independently associated with risk of being classified with DRE. We developed an algorithm for the identification of DRE in Danish national registers, which can be applied for a variety of research questions. We identified early onset of epilepsy, focal or generalized epilepsy, somatic co-morbidity, and substance abuse as risk factors for DRE.

Use of proton pump inhibitors after laparoscopic gastric bypass and sleeve gastrectomy: a nationwide register-based cohort study.

L-RYGB and L-SG are the dominant bariatric procedures worldwide. While L-RYGB is an effective treatment of coexisting gastroesophageal reflux disease (GERD), L-SG is associated with an increased risk of de-novo or worsening of GERD. The study aimed to evaluate the long-term use of proton pump inhibitors (PPI) following laparoscopic Roux-en-Y gastric bypass (L-RYGB) and sleeve gastrectomy (L-SG). This nationwide register-based study included all patients undergoing L-RYGB or L-SG in Denmark between 2008 and 2018. In total, 17,740 patients were included in the study, with 16,096 and 1671 undergoing L-RYGB and L-SG, respectively. The median follow up was 11 years after L-RYGB and 4 years after L-SG. Data were collected through Danish nationwide health registries. The development in PPI use was assessed through postoperative redeemed prescriptions. GERD development was defined by a relevant diagnosis code associated with gastroscopy, 24 h pH measurement, revisional surgery or anti-reflux surgery. The risk of initiation of PPI treatment or GERD diagnosis was evaluated using Kaplan-Meier plots and COX regression models. The risk of continuous PPI treatment was examined using logistic regression modeling. The risk of initiating PPI treatment was significantly higher after L-SG compared with L-RYGB (HR 7.06, 95% CI 6.42-7.77, p < 0.0001). The risk of continuous PPI treatment was likewise significantly higher after L-SG (OR 1.45, 95% CI 1.36-1.54, p < 0.0001). The utilization of PPI consistently increased after both procedures. The risk of GERD diagnosis was also significantly higher after L-SG compared with L-RYGB (HR 1.93, 95% CI 1.27-2.93, p < 0.0001). The risk of initiating and continuing PPI treatment was significantly higher after L-SG compared with L-RYGB, and a continuous increase in the utilization of PPI was observed after both procedures.

Mortality after major lower extremity amputation and association with index level: a cohort study based on 11,205 first-time amputations from nationwide Danish databases.

Mortality after major lower extremity amputations is high and may depend on amputation level. We aimed to examine the mortality risk in the first year after major lower extremity amputation divided into transtibial and transfemoral amputations. This observational cohort study used data from the Danish Nationwide Health registers. 11,205 first-time major lower extremity amputations were included from January 1, 2010, to December 31, 2021, comprising 3,921 transtibial amputations and 7,284 transfemoral amputations. The 30-day mortality after transtibial amputation was overall 11%, 95% confidence interval (CI) 10-12 (440/3,921) during the study period, but declined from 10%, CI 7-13 (37/381) in 2010 to 7%, CI 4-11 (15/220) in 2021. The 1-year mortality was 29% overall, CI 28-30 (1,140 /3,921), with a decline from 31%, CI 21-36 (117/381) to 20%, CI 15-26 (45/220) during the study period. For initial transfemoral amputation, the 30-day mortality was overall 23%, CI 22-23 (1,673/7,284) and declined from 27%, CI 23-31 (138/509) to 22%, CI 19-25 (148/683) during the study period. The 1-year mortality was 48% overall, CI 46-49 (3,466/7,284) and declined from 55%, CI 50-59 (279/509) to 46%, CI 42-50 (315/638). The mortality after major lower extremity amputation declined in the 12-year study period; however, the 1-year mortality remained high after both transtibial and transfemoral amputations (20% and 46% in 2021). Hence, major lower extremity amputation patients constitute one of the most fragile orthopedic patient groups, emphasizing an increased need for attention in the pre-, peri-, and postoperative setting.

Cardiovascular Risk in Young Patients Diagnosed With Obstructive Sleep Apnea.

In older adults, obstructive sleep apnea (OSA) has been associated with several cardiovascular complications. Whether young patients diagnosed with OSA also are at higher risk of developing subsequent cardiovascular disease is uncertain. We aimed to estimate the risk of developing an incident cardiovascular event among young patients diagnosed with OSA. We linked nationwide Danish health registries to identify a cohort of patients aged ≤50 years with OSA using data from 2010 through 2018. Cases without OSA from the general population were matched as controls (1:5). The main outcome was any cardiovascular event (including hypertension, diabetes, atrial fibrillation, ischemic heart disease, ischemic stroke, heart failure, and venous thromboembolism). All-cause mortality was a secondary outcome. The study included 20 240 patients aged ≤50 years with OSA (19.6% female; mean±SD age 39.9±7.7 years) and 80 314 controls. After 5-year follow-up, 31.8% of the patients with OSA developed any cardiovascular event compared with 16.5% of the controls, with a corresponding relative risk (RR) of 1.96 (95% CI, 1.90-2.02). At 5-year follow-up, 27.3% of patients with OSA developed incident hypertension compared with 15.0% of the controls (RR, 1.84 [95% CI, 1.78-1.90]). Incident diabetes occurred in 6.8% of the patients with OSA and 1.4% of controls (RR, 5.05 [95% CI, 4.60-5.54]). Similar to older adults, young adults with OSA demonstrate increased risk of developing cardiovascular events. To prevent cardiovascular disease progression, accumulation of cardiovascular risk factors, and mortality, risk stratification and prevention strategies should be considered for these patients.

Time to pregnancy and life expectancy: a cohort study of 18 796 pregnant couples.

Is fecundity, measured as time to pregnancy (TTP), associated with mortality in parents? Prolonged TTP is associated with increased mortality in both mothers and fathers in a dose-response manner. Several studies have linked both male and female fecundity to mortality. In women, infertility has been linked to several diseases, but studies suggest that the underlying conditions, rather than infertility, increase mortality. A prospective cohort study was carried out on 18 796 pregnant couples, in which the pregnant women attended prophylactic antenatal care between 1973 and 1987 at a primary and tertiary care unit. The couples were followed in Danish mortality registers from their child's birth date until death or until 2018. The follow-up period was up to 47 years, and there was complete follow-up until death, emigration or end of study. At the first antenatal visit, the pregnant women were asked to report the time to the current pregnancy. Inclusion was restricted to the first pregnancy, and TTP was categorised into <12 months, ≥12 months, not planned, and not available. In sub-analyses, TTP ≥12 was further categorized into 12-35, 36-60, and >60 months. Information for parents was linked to several Danish nationwide health registries. Survival analysis was used to estimate the hazard ratios (HRs) with a 95% CI for survival and adjusted for age at the first attempt to become pregnant, year of birth, socioeconomic status, mother's smoking during pregnancy, and mother's BMI. Mothers and fathers with TTP >60 months survived, respectively, 3.5 (95% CI: 2.6-4.3) and 2.7 (95% CI: 1.8-3.7) years shorter than parents with a TTP <12 months. The mortality was higher for fathers (HR: 1.21, 95% CI: 1.09-1.34) and mothers (HR: 1.29, 95% CI: 1.12-1.49) with TTP ≥12 months compared to parents with TTP <12 months. The risk of all-cause mortality during the study period increased in a dose-response manner with the highest adjusted HR of 1.98 (95% CI: 1.62-2.41) for fathers and 2.03 (95% CI: 1.56-2.63) for mothers with TTP >60 months. Prolonged TTP was associated with several different causes of death in both fathers and mothers, indicating that the underlying causes of the relation between fecundity and survival may be multi-factorial. A limitation is that fecundity is measured using a pregnancy-based approach. Thus, the cohort is conditioned on fertility success and excludes sterile couples, unsuccessful attempts and spontaneous abortions. The question used to measure TTP when the pregnant woman was interviewed at her first attended prophylactic antenatal care: 'From the time you wanted a pregnancy until it occurred, how much time passed?' could potentially have led to serious misclassification if the woman did not answer on time starting unprotected intercourse but on the start of wishing to have a child. We found that TTP is a strong marker of survival, contributing to the still-emerging evidence that fecundity in men and women reflects their health and survival potential. The authors acknowledge an unrestricted grant from Ferring. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. M.L.E. is an advisor to Ro, VSeat, Doveras, and Next. N/A.

Validation of the DANCAMI, the Charlson Comorbidity Index, and the Elixhauser Comorbidity Index for predicting mortality in patients with infective endocarditis

Abstract Introduction Comorbidity scores are often used to adjusted for confounding by comorbidity burden in population-based research as they increase statistical efficiency in smaller study populations. However, there is currently no comorbidity index available for predicting infective endocarditis prognosis. This gap in the literature hinders the ability to accurately adjust for confounding in studies investigating the prognosis of infective endocarditis, highlighting the need of validating existing comorbidity indices for this purpose. Purpose To validate the discriminatory ability of the Danish Comorbidity Index for Acute Myocardial Infarction (DANCAMI), the Charlson Comorbidity Index (CCI), and the Elixhauser Comorbidity Index (ECI) for predicting in-hospital, 1-year, and 10-year all-cause mortality after infective endocarditis. Methods We used nationwide Danish health registries to identify all patients with a first-time inpatient, primary or secondary diagnosis for infective endocarditis between 1995 and 2021 and their comorbidities. When identifying the comorbidities, we used all in and outpatient hospital information in the 10 years before the infective endocarditis diagnosis. Based on the presence of comorbidities, we estimated the DANCAMI, the CCI, and the ECI scores for each patient. Using a logistic regression model, we calculated area under the receiver operating curves (AUCs) for a baseline model including age and sex and for models including the scores from the comorbidity indices plus age and sex for in-hospital, 1-year, and 10-year all-cause mortality. The AUC describes the probability that for a pair of random patients, the model will assign a greater predicted risk to the patient dying. Results Overall, we identified 12,530 patients with infective endocarditis. The median age was 71 years and 35% were females. For the individual analyses, we had complete follow-up on 12,493 patients when predicting in-hospital mortality, 11,587 when predicting 1-year mortality, and 5,880 patients when predicting 10-year mortality. For in-hospital mortality, the AUCs were 0.62 for the baseline model, 0.65 for the DANCAMI, 0.64 for the CCI, and 0.65 for the ECI. For 1-year mortality, the AUCs were 0.66 for the baseline model, 0.71 for the DANCAMI, 0.70 for the CCI, and 0.70 for the ECI. For 10-year mortality, the AUCs were 0.76 for the baseline model, 0.82 for the DANCAMI, 0.81 for the CCI, and 0.81 for the ECI. Conclusions After accounting for sex and age, adding either the DANCAMI, the CCI, or the ECI did not increase the discriminatory ability for predicting in-hospital all-cause mortality after infective endocarditis but did increase the discriminatory ability for predicting 1-year and 10-year all-cause mortality. Consequently, comorbidity scores might be beneficial in reducing confounding by comorbidity burden when predicting 1-year or 10-year infective endocarditis mortality, depending on their association with the exposure of interest.

Cotinine concentrations in maternal serum and amniotic fluid during pregnancy and risk of testicular germ cell cancer in the offspring: A prospective nested case-control study.

Maternal smoking in pregnancy may increase the risk of testicular germ cell cancer (TGCC) in offspring, but current evidence remains inconclusive. We performed a nested case-control study using cotinine measurements in maternal serum and amniotic fluid as a biomarker for tobacco exposure during pregnancy. A total of 654 males with maternal serum (n = 359, ncases/controls = 71/288) and/or amniotic fluid (n = 295, ncases/controls = 66/229) samples were included. Data on TGCC diagnoses and relevant covariates were derived from nationwide Danish health registries. Cotinine was quantified by liquid chromatography tandem mass spectrometry. An adapted cox regression model estimated the risk of TGCC considering active and inactive tobacco use defined according to cotinine concentrations of <, ≥15 ng/ml. Overall, the concentrations of cotinine were comparable in maternal serum and amniotic fluid (medianserum/amniotic fluid : 2.1/2.6 ng/ml). A strong statistically significant correlation was detected in 14 paired samples (Spearman rho: 0.85). Based on maternal serum cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC in offspring (HR 0.88, 95% CI 0.51; 1.52). Similarly, based on amniotic fluid cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC (HR 1.11, 95% CI 0.64; 1.95). However, different risks were observed for seminomas and nonseminomas in both matrices, but none were statistically significant. Our findings did not provide convincing evidence supporting that exposure to tobacco during pregnancy is associated with TGCC.

PSYCHIATRIC ADVERSE EFFECTS OF MONTELUKAST - A NATIONWIDE COHORT STUDY.

Recent observational studies suggest that the leukotriene receptor antagonist montelukast may have neuropsychiatric adverse effects, however, results are conflicting. To assess if montelukast exposure in adults with asthma is associated with onset of neuropsychiatric adverse events using data from the Danish nationwide health registers. Individuals ≥18 years with either ≥1 prescription redemption of inhaled corticosteroids (ICS) or with at least one hospital contact with asthma as the main diagnosis between January 1, 2011 and December 31, 2018 were included. Montelukast exposure was assessed as a time-dependent variable. The two outcomes of interest were: use of neuropsychiatric medicine including antidepressants, antipsychotics, anxiolytics, lithium and medication used for attention-deficit/hyperactivity disorder (outcome 1), and hospital contacts with a neuropsychiatric diagnosis (outcome 2), within 90 days of exposure to montelukast. Initiation of montelukast was significantly associated with outcome 1: use of neuropsychiatric medicine (HR (95% CI) = 1.14 (1.08-1.20, p <0.0001). In the assessment of outcome 2: hospital contacts with a neuropsychiatric diagnosis, a significant risk associated with montelukast initiation was found only in the youngest age groups (HR (95% CI) = 1.28 (1.12-1.47), p<0.001 and 1.16 (1.02-1.31), p<0.05, for age group 18-29 and 30-44, respectively). Age-stratified analyses showed that the risk of both outcomes increased with decreasing age, with the highest risk seen in patients aged 18-29. Among younger individuals, montelukast use was significantly associated with an increased risk of neuropsychiatric events such as use of neuropsychiatric medicine and hospital treatment. Clinicians should increase awareness of such adverse effects when prescribing montelukast.

Revisiting the association between treatment with antidepressants and mania: A nationwide within-individual study of 3554 patients with bipolar disorder.

Antidepressants are commonly used "off-label" for bipolar depression, despite concerns over the risk of potential treatment-emergent mania (or "manic switch"). Treatment-emergent mania is difficult to study with adequate power in clinical trials as it requires a large group of participants and long follow-up. Therefore, naturalistic register-based studies have been applied to assess this phenomenon. Here, we aimed to replicate previous findings and address key methodological limitations that were not previously taken into account. We utilized data from nationwide Danish health registries to identify patients with bipolar disorder treated with an antidepressant, either with or without concomitant treatment with a mood stabilizer (drug treatment proxied via redeemed prescriptions). We plotted the incidence of manic and depressive episodes relative to the initiation of antidepressant treatment and compared the incidence of mania in the period prior to and following initiation of antidepressant treatment (within-individual design). In 3554 patients with bipolar disorder initiating treatment with an antidepressant, the number of manic episodes peaked approximately 3 months prior to initiation of antidepressant treatment, and the number of depressive episodes peaked around the initiation of antidepressant prescription. This temporal pattern suggests that antidepressants were used to treat post-manic depression. Within-individual designs do not control sufficiently for confounding by indication, when the treatment indication is time-varying. Thus, results from prior within-individual studies of antidepressant treatment in the context of bipolar disorder may be invalid due to time-varying confounding by indication.

Increased mortality in patients with hematologic malignancies treated with proton pump inhibitors: a nationwide cohort study

Proton Pump inhibitors (PPIs) are frequently prescribed to cancer patients to prevent gastric mucosal damage. Post-diagnostic PPI use in patients with solid tumors may be associated with increased cancer mortality. However, the hazardous impact of PPIs in patients with hematologic malignancies remains unknown. This association was investigated in a large, retrospective cohort study using data from the Danish nationwide health registries. The outcomes were cancer-specific or non-cancer deaths. We identified 15,320 patients with hematologic malignancies and of these 1811 were identified as post-diagnostic PPI users. PPI users had significantly increased HRs for cancer-specific mortality (HR 1.31; 95% CI, 1.18–1.44) and 1-year cancer-specific mortality (HR 1.50, 95% CI 1.29–1.74) as compared to nonusers. The association between PPI use and increased cancer-specific mortality in Danish patients with hematologic malignancies supports the raised concerns regarding the frequent use of PPIs in cancer patients.

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.

It is unknown whether the cardiovascular risks associated with non-steroidal anti-inflammatory drug (NSAID) use differ according to lifestyle and socioeconomic position. We examined the association between NSAID use and major adverse cardiovascular events (MACE) within subgroups defined by lifestyle and socioeconomic position. 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. 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). The relative increase in cardiovascular risk associated with NSAID use was not modified by lifestyle or socioeconomic position.

Non-Traumatic Subdural Hematoma and Cancer: A Cohort Study.

Cancer may increase the risk of bleeding. However, whether subdural hematoma is a marker of occult cancer remains unknown. We examined the association between non-traumatic subdural hematoma and cancer risk in a cohort study. Using Danish nationwide health registries, we identified 2713 patients with non-traumatic subdural hematoma and no previous cancer diagnosis, who were hospitalized between April 1, 1996 and December 31, 2019. We computed age-, sex-, and calendar year-standardized incidence ratios (SIRs) as the ratio of the observed to expected number of patients with cancer by using national incidence rates as reference as a measure of relative risk. We identified 77 cancer cases within the first year of follow-up and 272 cancer cases thereafter. The one-year risk of cancer was 2.8% (95% confidence interval: 2.2-3.5), and the one-year SIR was 1.7 (95% confidence interval: 1.3-2.1). During the subsequent years, the SIR was 1.0 (95% confidence interval: 0.9-1.1). The relative risk was elevated for some hematological and liver cancers. The risk of a new cancer diagnosis was clearly increased in patients with non-traumatic subdural hematoma compared with the general population during the first year of follow-up. However, the absolute risk was low, thus limiting the clinical relevance of pursuing early cancer detection in these patients.

Survival in adult patients with chronic primary and secondary immune thrombocytopenia: A population-based study.

Few studies have investigated long-term survival in patients with primary immune thrombocytopenia (pITP). Further, changes in prognosis over the past decades and prognosis of secondary immune thrombocytopenia (sITP) are largely unstudied. Our objectives were to study comorbidity-adjusted prognostic changes and causes of death in chronic pITP and sITP patients. Using nationwide Danish health registries 1980-2016, we identified 1762 patients with chronic pITP (median age 58 (IQR, 37-73) years) and 128 with chronic sITP (median age 59 (IQR, 40-73) years). Patients were age-sex-matched to 74,781 general population comparators. Comorbidity was assessed using Charlson Comorbidity Index (CCI). Overall median survival was reduced by 5.1 years (95% CI, 0.7-9.4) (p < .001) for pITP and 11.1 years (95% CI, 5.8-16.4) (p < .001) for sITP. 5-year survival increased from 69% (95% CI, 59-78) in 1980-89 to 80% (95% CI, 75-83) in 2010-16 for pITP, and decreased from 100% (95% CI, 89-98) to 64% (95% CI, 87-91) for sITP. However, numbers were small for sITP. 5-year survival for pITP with high CCI was 41% (95% CI, 32-49), and 85% (95% CI, 83-87) for low CCI. Bleeding, infection and hematological cancer were relatively frequent causes of death with adjusted subhazard ratios of 3.25 (95% CI, 2.33-4.52), 1.53 (95% CI, 1.08-2.16) and 2.16 (95% CI, 1.12-4.16) in pITP respectively, and 10.52 (95% CI, 1.43-77.36) for hematological cancer in sITP. Long-term survival is reduced in chronic ITP but seems to be improving. Comorbidity and sITP are associated with a poor prognosis.

Vitamin D status and severity of COVID-19

We explored the association between COVID-19 severity and vitamin D status using information from Danish nation-wide health registers, the COVID-19 surveillance database and stored blood samples from the national biobank. 25-hydroxyvitamin D (25(OH)D) was measured using tandem mass spectroscopy. The association between 25(OH)D levels and COVID-19 severity, classified hierarchical as non-hospitalized, hospitalized but not admitted to an intensive care unit (ICU), admitted to ICU, and death, was evaluated by proportional odds ratios (POR) assuming proportionality between the four degrees of severity. Among 447 adults tested SARS-CoV-2 positive in the spring of 2020, low levels of 25(OH)D were associated with a higher risk of severe COVID-19. Thus, odds of experiencing more severe COVID-19 among individuals with insufficient (25 to < 50 nmol/L) and sufficient (≥ 50 nmol/L) 25(OH)D levels were approximately 50% of that among individuals with deficient levels (< 25 nmol/L) (POR = 0.49 (95% CI 0.25–0.94), POR = 0.51 (95% CI 0.27–0.96), respectively). Dividing sufficient vitamin D levels into 50 to < 75 nmol/L and ≥ 75 nmol/L revealed no additional beneficial effect of higher 25(OH)D levels. In this observational study, low levels of 25(OH)D were associated with a higher risk of severe COVID-19. A possible therapeutic role of vitamin D should be evaluated in well-designed interventional studies.

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

Maternal Serum α-Fetoprotein Levels during Pregnancy and Testicular Cancer in Male Offspring: A Cohort Study within a Danish Pregnancy Screening Registry.

Testicular cancer is believed to originate from disruptions of normal androgen-estrogen balance in-utero. α-fetoprotein (AFP) may modify fetal response to estrogens via estrogen interaction. In a cohort study, we investigated the association between circulating maternal pregnancy AFP and testicular cancer risk in offspring. Of the 56,709 live-born males from a pregnancy screening registry in 1980-1995, our study included 50,519 singleton males with available second trimester blood samples from their mothers and complete covariate ascertainment. Testicular cancer diagnoses and covariate data were obtained from nationwide Danish health registries. Cox regression and Kaplan-Meier analyses estimated the prospective risk of testicular cancer (all, seminoma, nonseminoma) by AFP multiples of the median. During follow-up, 163 (0.3%) of the included males developed testicular cancer, of which 89 (54.6%) were nonseminomas. Maternal serum AFP levels greater than/equal to the median were associated with a relative risk of testicular cancer close to unity (RR 1.04, 95% CI 0.76; 1.41) compared to AFP below the median. Associations differed by type of testicular cancer (RRseminoma 0.81, 95% CI 0.51; 1.29, RRnonseminoma 1.31, 95% CI 0.85; 2.02). On balance, our findings do not support that serum AFP in pregnancy can be used as a predictor of testicular cancer in offspring.

Intake of dietary flavonoids and incidence of ischemic heart disease in the Danish Diet, Cancer, and Health cohort

Background/ObjectivesFew studies have investigated the association between dietary flavonoid intake, including all major subclasses, and the long-term risk of ischemic heart disease (IHD). We examined whether dietary flavonoid intake associated with IHD incidence, assessing the possible modifying role of sex and smoking, in participants from the Danish Diet, Cancer, and Health study.Subjects/MethodsIn a cohort study design, 54,496 adults (46.8% male), aged 50–64 years, without a history of IHD, were followed for up to 23 years. Habitual dietary flavonoid intake was estimated from food frequency questionnaires using Phenol-Explorer. Incident cases of IHD were identified within Danish nationwide health registries. Restricted cubic splines in Cox proportional hazards models were used to examine associations between flavonoid intake and IHD risk.ResultsDuring follow-up, 5560 IHD events were recorded. No overall association was seen between total flavonoid intake, nor any subclass, and IHD, following adjustment for demographics, lifestyle, and dietary confounders. Stratified by sex and smoking status, higher intakes of specific subclasses associated with lower IHD risk among ever-smokers [Q5 vs. Q1 flavonols HR (95% CI): 0.90 (0.82, 0.99); flavanol oligo+polymers: 0.88 (0.80, 0.97)], but not among never-smokers, nor either sex specifically.ConclusionsWhile we did not find clear evidence that higher habitual dietary flavonoid intake was associated with lower IHD risk, these results do not exclude the possibility that certain subclasses may have a protective role in prevention of IHD among population sub-groups; this was evident among smokers, who are at a higher risk of atherosclerosis.

Dose-dependency of diclofenac's cardiovascular risks: a series of nationwide emulated trials

Abstract Background The dose dependency of the adverse effects of diclofenac remains poorly understood. Purpose To examine the dose-related cardiovascular risks associated with diclofenac initiation Methods We used Danish nationwide health registries (1999–2018) to conduct a series of emulated trials (n=285). Eligible adults had no recent NSAID fillings, contraindications, or conditions with low adherence. Individuals eligible for inclusion were ≥18 years with (1) ≥90 days continuous prescription records prior to diclofenac initiation (baseline); (2) no NSAID prescriptions ≤90 days before enrollment, and (3) no exclusion criteria. Exclusion criteria reflected likelihood of low adherence to treatment (dementia, schizophrenia, or antipsychotic drug use) and labeled contraindications (ulcer disease/anti-ulcer drugs, gastrointestinal bleeding, inflammatory bowel disease, thrombocytopenia, or heart failure). Initiators of diclofenac were compared to healthcare-seeking non-initiators, but also head-to-head for initiators of high (≥75 mg pills as proxy for ≥150 mg/daily) vs. low dose (≤50 mg pills as proxy for &amp;lt;150 mg/daily). Cox proportional-hazards regression was used to compute the intention-to-treat hazard ratio, as measure of the incidence rate ratio (IRR), of major adverse cardiac and cerebrovascular events (MACCE) within 30 days from initiation. Results Among 3,177,484 diclofenac initiatiors, 31% used high and 69% used low dose. Compared with non-initiators, diclofenac initiatiors had a 70% increased rate for MACCE (IRR 1.70, 95% CI: 1.55–1.86), reflecting for the individual MACCE components an increased IRRs of 1.66 (95% CI: 1.54–1.79) for myocardial infaction, 1.32 (1.20–1.45) for ischemic stroke, and 1.69 (1.54–1.86) for cardiac death. The effect for MACCE did not differ between initiators of high (IRR 1.73, 95% CI: 1.51–1.97) and low dose (IRR 1.68, 95% CI: 1.52–1.86) (Figure 1). When comparing high and low dose diclofenac head-to-head, we found no meaningful difference in the IRR for MACCE (1.03, 95% CI: 0.89–1.19), MI (0.99, 0.87–1.11), ischemic stroke (0.95, 0.81–1.11) or cardiac death (1.04, 0.90–1.21) (Figure 2). Conclusion Initiation of low- and high-dose diclofenac was associated with a consistent and comparable increase in cardiovascular risk. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation

Risk of Recurrent Venous Thromboembolism in Selected Subgroups of Men: A Danish Nationwide Cohort Study.

Background Although men are considered at high risk for recurrent venous thromboembolism (VTE), sex-specific data on prognostic factors are lacking. We estimated the cumulative recurrence risks associated with clinical characteristics and comorbidities known or suspected to be associated with the development of VTE recurrence: major surgery, trauma, history of cancer, rheumatic disorder, ischemic heart disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes, chronic renal disease, varicose veins, alcohol-related diseases, and arterial hypertension. Methods We linked nationwide Danish health registries to identify all incident VTE in- and outpatients in men from 2008 through 2018. Recurrent VTE risk 2 years after anticoagulant discontinuation was calculated using the Aalen-Johansen estimator, stratified by age above/below 50 years. Results The study included 13,932 men with VTE, of whom 21% ( n = 2,898) were aged <50 years. For men aged <50 years with at least one of the clinical characteristics, 2-year recurrence risk ranged from 6% (major surgery) to 16% (history of cancer). For men ≥50 years with at least one of the characteristics, recurrence risk ranged from 7% (major surgery) to 12% (ischemic heart disease, chronic obstructive pulmonary disease, and chronic renal disease). Men aged <50 and ≥50 years without the clinical characteristics all had a recurrence risk of 10%. Discussion We demonstrated a 2-year recurrence risk of at least 6%, regardless of age category and disease status, in this nationwide cohort of men with VTE. The recurrence risk must be balanced against bleeding risk. However, the high recurrence risk across all subgroups might ultimately lead to greater emphasis on male sex in future guidelines focusing on optimized secondary VTE prevention.

Cardiovascular Risks of Diclofenac Versus Other Older COX-2 Inhibitors (Meloxicam and Etodolac) and Newer COX-2 Inhibitors (Celecoxib and Etoricoxib): A Series of Nationwide Emulated Trials.

Diclofenac has increased cardiovascular risks, but its risk profile compared with other COX-2 inhibitors remains unknown. The aim of this study was to compare the cardiovascular risks of diclofenac versus other older and newer COX-2 inhibitors (coxibs). Using Danish nationwide health registries (1999-2020), we conducted a series of emulated trials (n=264). Eligible adults had no recent NSAID prescriptions, contraindications or conditions with low adherence. We included initiators of diclofenac (n=1,600,202), meloxicam (n=10,903), etodolac (n=238,538), celecoxib (n=77,591), and etoricoxib (n=12,122). We computed the adjusted intention-to-treat incidence rate ratio (aIRR) with 95% confidence interval (CI) of major adverse cardiovascular events (MACE) within 30 days of initiation (5562 events). MACE was 20% increased among initiators of diclofenac compared with other older COX-2 inhibitors (aIRR 1.19, 95% CI 1.10-1.28), driven by cardiac death (aIRR 1.57, 95% CI 1.21-2.03). The effect appeared strongest for women (aIRR 1.28, 95% CI 1.15-1.43), individuals with high baseline cardiovascular risk (aIRR 1.32, 95% CI 1.05-1.66), and when comparing high-dose diclofenac with low doses of the other older COX-2 inhibitors (aIRR 1.31, 95% CI 1.13-1.52). The results reflected increased rates compared with both meloxicam (aIRR 1.46, 95% CI 0.94-2.26) and etodolac (aIRR 1.18, 95% CI 1.09-1.28). Diclofenac initiators had similar increased rates of MACE compared with coxibs (aIRR 0.96, 95% CI 0.85-1.08), consistent for celecoxib (aIRR 1.02, 95% CI 0.88-1.19) and etoricoxib (aIRR 0.85, 95% CI 0.66-1.10). The increased cardiovascular risks associated with diclofenac initiation were higher than for other older COX-2 inhibitors (meloxicam/etodolac) and comparable to coxibs (celecoxib/etoricoxib).