Nationwide Danish Health Registries Research Articles

Implementation of sodium-glucose co-transporter 2 inhibitors in patients with heart failure through a new digital strategy (EMAIL-HF): a randomised clinical trial study design

Abstract Introduction Delayed implementation of new medical discoveries remains a global healthcare challenge and is mainly due to the complexity of cross-institutional patient care. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors is the latest medical discovery in heart failure (HF) and have recently been added to clinical guidelines as they have proven to reduce the risk of adverse cardiovascular outcomes in patients with HF across the ejection fraction spectrum. Whether a new digital strategy can optimise and accelerate the implementation of SGLT2 inhibitors in patients living with HF is of great importance for public health. Purpose To evaluate whether a new and streamlined digital strategy can optimise and accelerate the implementation of SGLT2 inhibitors in patients with HF. Design and methods: The trial is a multicentre, parallel group, register-based randomised clinical study, evaluating the effect and potential of a new digital strategy to implement new guideline therapies to patients living with a chronic disease, specifically SGLT2 inhibitors to patients with HF (figure 1). The setup employs data from nationwide health registers and official digital letters to inform patients about the new therapy option and invite them to have their eligibility evaluated by a HF specialist and start therapy. A total of ~10,000 patients with HF across the ejection fraction spectrum (with and without diabetes), who have not yet been started on SGLT2 inhibitors, are identified through Danish nationwide health registers, and randomised 1:1 to receive the digital letter (figure 2). The primary outcome is the proportion of patients redeeming a prescription of a SGLT2 inhibitor within six months. Secondary outcome is a composite HF endpoint consisting of all-cause death or HF hospitalisation. Other outcome measures are renal failure, stroke and myocardial infarction, safety outcomes, adherence to therapy and proportion of vulnerable patient groups initiating therapy including immigrants, elderly, frail patients, patients with lower socioeconomic level and lower educational level. A total of 4689 patients have been randomised (February 2024) and data will be presented in 2025. Conclusions The trial will determine the efficacy and safety of a new and streamlined digital strategy to implement SGLT2 inhibitors to patients with chronic HF. The setup has the potential to be used in a broad spectrum of patients living with chronic diseases and is expected to be highly cost-effective.Figure 1.Study hypothesisFigure 2.Study design

Risk and timing of postpartum depression in parents of twins compared to parents of singletons.

Parents of twins appear to be at increased risk of postpartum depression (PPD), yet little is known about the magnitude and timing of onset in the postpartum period compared to singleton parents. We conducted a cohort study using the Danish nationwide health registers. We defined a study population of parents that is, mothers and fathers of all twin and singleton livebirths between 1997 and 2019. Postpartum depression was defined as incident depression diagnosis or a redeemed antidepressant prescription from childbirth through 365 days postpartum. We performed a parametric time-to-event analysis based on Poisson regression. The time scale was time since birth, modeled using restricted cubic splines. From this we estimated the hazard ratio (HR) representing the momentary risk, and the cumulative risk ratio (RR) over the first year postpartum, in twin compared to singleton parents. The study population was based on 27,095 twin and 1,350,046 singleton births. In adjusted analyses, the HR of twins compared to singletons was highest around 2 months postpartum (HR 1.28, 95% CI 1.10-1.49) for mothers, and around 6 months (1.20, 95% CI 1.02-1.42) for fathers. The 6 months adjusted cumulative RR of PPD in twins compared to singletons was 1.24 (95% CI 1.10-1.40) for mothers and 1.11 (95% CI 0.95-1.30) for fathers. Twin mothers had increased risk of PPD compared to singleton mothers, which was driven by an immediate increase after childbirth. The risk among twin fathers was not increased immediately after childbirth, but we found slightly elevated risk around 6 months postpartum. This could suggest diverse patterns of PPD symptomatology in twin parents compared to singleton parents and between mothers and fathers. Our findings underline parents of twins as a potentially vulnerable group to PPD and emphasize the need for increased awareness of their mental health.

Treatment trajectories for Danish individuals with type 2 diabetes in the era of emerging glucose-lowering therapies.

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

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.

Dicloxacillin is an inducer of intestinal P-glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke/systemic embolism in direct oral anticoagulant users.

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

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

Background/ObjectivesL-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).Subjects/MethodsThis 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.ResultsThe 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).ConclusionsThe 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.