Publications by authors named "Henrik Toft Sørensen"

612 Publications

Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study.

BMJ 2021 05 5;373:n1114. Epub 2021 May 5.

Pharmacovigilance Research Centre, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

Objective: To assess rates of cardiovascular and haemostatic events in the first 28 days after vaccination with the Oxford-AstraZeneca vaccine ChAdOx1-S in Denmark and Norway and to compare them with rates observed in the general populations.

Design: Population based cohort study.

Setting: Nationwide healthcare registers in Denmark and Norway.

Participants: All people aged 18-65 years who received a first vaccination with ChAdOx1-S from 9 February 2021 to 11 March 2021. The general populations of Denmark (2016-18) and Norway (2018-19) served as comparator cohorts.

Main Outcome Measures: Observed 28 day rates of hospital contacts for incident arterial events, venous thromboembolism, thrombocytopenia/coagulation disorders, and bleeding among vaccinated people compared with expected rates, based on national age and sex specific background rates from the general populations of the two countries.

Results: The vaccinated cohorts comprised 148 792 people in Denmark (median age 45 years, 80% women) and 132 472 in Norway (median age 44 years, 78% women), who received their first dose of ChAdOx1-S. Among 281 264 people who received ChAdOx1-S, the standardised morbidity ratio for arterial events was 0.97 (95% confidence interval 0.77 to 1.20). 59 venous thromboembolic events were observed in the vaccinated cohort compared with 30 expected based on the incidence rates in the general population, corresponding to a standardised morbidity ratio of 1.97 (1.50 to 2.54) and 11 (5.6 to 17.0) excess events per 100 000 vaccinations. A higher than expected rate of cerebral venous thrombosis was observed: standardised morbidity ratio 20.25 (8.14 to 41.73); an excess of 2.5 (0.9 to 5.2) events per 100 000 vaccinations. The standardised morbidity ratio for any thrombocytopenia/coagulation disorders was 1.52 (0.97 to 2.25) and for any bleeding was 1.23 (0.97 to 1.55). 15 deaths were observed in the vaccine cohort compared with 44 expected.

Conclusions: Among recipients of ChAdOx1-S, increased rates of venous thromboembolic events, including cerebral venous thrombosis, were observed. For the remaining safety outcomes, results were largely reassuring, with slightly higher rates of thrombocytopenia/coagulation disorders and bleeding, which could be influenced by increased surveillance of vaccine recipients. The absolute risks of venous thromboembolic events were, however, small, and the findings should be interpreted in the light of the proven beneficial effects of the vaccine, the context of the given country, and the limitations to the generalisability of the study findings.
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http://dx.doi.org/10.1136/bmj.n1114DOI Listing
May 2021

Rectal Cancer Risk and Survival After Total Colectomy for IBD: A Population-Based Study.

Dis Colon Rectum 2021 May;64(5):583-591

1 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark 2 Department of Surgery, Section of Coloproctology, Aarhus University Hospital, Aarhus N, Denmark 3 Department of Surgery, Randers Regional Hospital, Randers, Denmark.

Background: Patients undergoing total colectomy for IBD may develop cancer in the rectal remnant, but the association is poorly understood.

Objectives: This study aimed to examine the risk and prognosis of rectal cancer after total colectomy for IBD.

Design: This is a nationwide population-based study.

Setting: Treatment of the patients took place in Denmark from 1977 to 2013.

Patients: Patients with IBD undergoing total colectomy were included.

Main Outcome Measures: We examined the incidence of rectal cancer among patients with IBD and total colectomy and compared cancer stage to that of other patients with rectal cancer in Denmark. We used Kaplan-Meier methodology to estimate survival and Cox regression to estimate adjusted mortality rate ratios following a rectal cancer diagnosis, comparing patients with and without IBD and a rectal remnant.

Results: We identified 4703 patients with IBD (1026 Crohn's disease; 3677 ulcerative colitis) who underwent total colectomy with a rectal remnant. During 29,725 years of follow-up, 30 rectal cancers were observed, compared with 8 rectal cancers expected (standardized incidence ratio = 3.6 (95% CI, 2.4-5.1)). Cancer stage distributions were similar. Risk of rectal cancer 35 years after total colectomy was 1.9% (95% CI, 1.1%-2.9%). Five years after rectal cancer diagnosis, survival was 28% (95% CI, 12%-47%) and 38% (95% CI, 37%-38%) for patients with and without IBD and a rectal remnant. The adjusted mortality rate ratio 1 to 5 years after a rectal cancer diagnosis was 2.5 (95% CI, 1.6-3.9). Median time from last recorded nondiagnostic proctoscopy to rectal cancer diagnosis for patients with IBD and total colectomy was 1.1 years.

Limitations: This study was limited by the few outcomes and the use of administrative and not clinical data.

Conclusion: Long-term risk of rectal cancer following total colectomy for IBD was low. Survival following a diagnosis of rectal cancer was poorer for patients with IBD and total colectomy than for patients who had rectal cancer without IBD and total colectomy. Endoscopic surveillance, as it appeared to be practiced in this cohort, may be inadequate. See Video Abstract at http://links.lww.com/DCR/B497. RIESGO DE CÁNCER DE RECTO Y SUPERVIVENCIA DESPUÉS DE UNA COLECTOMÍA TOTAL POR ENFERMEDAD INFLAMATORIA INTESTINAL: UN ESTUDIO POBLACIONAL: Los pacientes sometidos a colectomía total por enfermedad inflamatoria intestinal (EII) pueden desarrollar cáncer en el remanente rectal, pero la asociación es poco conocida.Examinar el riesgo y el pronóstico del cáncer de recto después de una colectomía total para la EII.Estudio poblacional a nivel nacional.Dinamarca 1977-2013.Pacientes con EII sometidos a colectomía total.Examinamos la incidencia de cáncer de recto entre pacientes con EII y colectomía total y comparamos el estadio del cáncer con el de otros pacientes con cáncer de recto en Dinamarca. Utilizamos la metodología de Kaplan-Meier para estimar la supervivencia y la regresión de Cox para estimar las tasas de mortalidad ajustadas (aMRR) después de un diagnóstico de cáncer de recto, comparando pacientes con y sin EII y un remanente rectal.Identificamos 4.703 pacientes con EII (1.026 enfermedad de Crohn; 3.677 colitis ulcerosa) que se sometieron a colectomía total con remanente rectal. Durante 29,725 años de seguimiento, se observaron 30 cánceres de recto, en comparación con los 8 esperados [razón de incidencia estandarizada (SIR) = 3.6, (intervalo de confianza (IC) del 95%: 2.4-5.1)]. Las distribuciones de las etapas del cáncer fueron similares. El riesgo de cáncer de recto 35 años después de la colectomía total fue del 1,9% (IC del 95%: 1,1% -2,9%). Cinco años después del diagnóstico de cáncer de recto, la supervivencia fue del 28% (IC del 95%: 12% -47%) y del 38% (IC del 95%: 37% -38%) para los pacientes con y sin EII y un remanente rectal, respectivamente. La aMRR 1-5 años después de un diagnóstico de cáncer de recto fue de 2,5 (IC del 95%: 1,6-3,9). La mediana de tiempo desde la última proctoscopia no diagnóstica registrada hasta el diagnóstico de cáncer de recto en pacientes con EII y colectomía total fue de 1,1 años.Pocos resultados, uso de datos administrativos y no clínicos.El riesgo a largo plazo de cáncer de recto después de una colectomía total para la EII fue bajo. La supervivencia después de un diagnóstico de cáncer de recto fue más pobre para los pacientes con EII y colectomía total que para los pacientes con cáncer de recto sin EII y colectomía total. La vigilancia endoscópica, como parecía practicarse en esta cohorte, puede ser inadecuada. Consulte Video Resumen en http://links.lww.com/DCR/B497. (Traducción-Dr. Adrian Ortega).
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http://dx.doi.org/10.1097/DCR.0000000000001810DOI Listing
May 2021

Rectal Cancer Risk and Survival After Total Colectomy for IBD: A Population-Based Study.

Dis Colon Rectum 2021 May;64(5):583-591

1 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark 2 Department of Surgery, Section of Coloproctology, Aarhus University Hospital, Aarhus N, Denmark 3 Department of Surgery, Randers Regional Hospital, Randers, Denmark.

Background: Patients undergoing total colectomy for IBD may develop cancer in the rectal remnant, but the association is poorly understood.

Objectives: This study aimed to examine the risk and prognosis of rectal cancer after total colectomy for IBD.

Design: This is a nationwide population-based study.

Setting: Treatment of the patients took place in Denmark from 1977 to 2013.

Patients: Patients with IBD undergoing total colectomy were included.

Main Outcome Measures: We examined the incidence of rectal cancer among patients with IBD and total colectomy and compared cancer stage to that of other patients with rectal cancer in Denmark. We used Kaplan-Meier methodology to estimate survival and Cox regression to estimate adjusted mortality rate ratios following a rectal cancer diagnosis, comparing patients with and without IBD and a rectal remnant.

Results: We identified 4703 patients with IBD (1026 Crohn's disease; 3677 ulcerative colitis) who underwent total colectomy with a rectal remnant. During 29,725 years of follow-up, 30 rectal cancers were observed, compared with 8 rectal cancers expected (standardized incidence ratio = 3.6 (95% CI, 2.4-5.1)). Cancer stage distributions were similar. Risk of rectal cancer 35 years after total colectomy was 1.9% (95% CI, 1.1%-2.9%). Five years after rectal cancer diagnosis, survival was 28% (95% CI, 12%-47%) and 38% (95% CI, 37%-38%) for patients with and without IBD and a rectal remnant. The adjusted mortality rate ratio 1 to 5 years after a rectal cancer diagnosis was 2.5 (95% CI, 1.6-3.9). Median time from last recorded nondiagnostic proctoscopy to rectal cancer diagnosis for patients with IBD and total colectomy was 1.1 years.

Limitations: This study was limited by the few outcomes and the use of administrative and not clinical data.

Conclusion: Long-term risk of rectal cancer following total colectomy for IBD was low. Survival following a diagnosis of rectal cancer was poorer for patients with IBD and total colectomy than for patients who had rectal cancer without IBD and total colectomy. Endoscopic surveillance, as it appeared to be practiced in this cohort, may be inadequate. See Video Abstract at http://links.lww.com/DCR/B497. RIESGO DE CÁNCER DE RECTO Y SUPERVIVENCIA DESPUÉS DE UNA COLECTOMÍA TOTAL POR ENFERMEDAD INFLAMATORIA INTESTINAL: UN ESTUDIO POBLACIONAL: Los pacientes sometidos a colectomía total por enfermedad inflamatoria intestinal (EII) pueden desarrollar cáncer en el remanente rectal, pero la asociación es poco conocida.Examinar el riesgo y el pronóstico del cáncer de recto después de una colectomía total para la EII.Estudio poblacional a nivel nacional.Dinamarca 1977-2013.Pacientes con EII sometidos a colectomía total.Examinamos la incidencia de cáncer de recto entre pacientes con EII y colectomía total y comparamos el estadio del cáncer con el de otros pacientes con cáncer de recto en Dinamarca. Utilizamos la metodología de Kaplan-Meier para estimar la supervivencia y la regresión de Cox para estimar las tasas de mortalidad ajustadas (aMRR) después de un diagnóstico de cáncer de recto, comparando pacientes con y sin EII y un remanente rectal.Identificamos 4.703 pacientes con EII (1.026 enfermedad de Crohn; 3.677 colitis ulcerosa) que se sometieron a colectomía total con remanente rectal. Durante 29,725 años de seguimiento, se observaron 30 cánceres de recto, en comparación con los 8 esperados [razón de incidencia estandarizada (SIR) = 3.6, (intervalo de confianza (IC) del 95%: 2.4-5.1)]. Las distribuciones de las etapas del cáncer fueron similares. El riesgo de cáncer de recto 35 años después de la colectomía total fue del 1,9% (IC del 95%: 1,1% -2,9%). Cinco años después del diagnóstico de cáncer de recto, la supervivencia fue del 28% (IC del 95%: 12% -47%) y del 38% (IC del 95%: 37% -38%) para los pacientes con y sin EII y un remanente rectal, respectivamente. La aMRR 1-5 años después de un diagnóstico de cáncer de recto fue de 2,5 (IC del 95%: 1,6-3,9). La mediana de tiempo desde la última proctoscopia no diagnóstica registrada hasta el diagnóstico de cáncer de recto en pacientes con EII y colectomía total fue de 1,1 años.Pocos resultados, uso de datos administrativos y no clínicos.El riesgo a largo plazo de cáncer de recto después de una colectomía total para la EII fue bajo. La supervivencia después de un diagnóstico de cáncer de recto fue más pobre para los pacientes con EII y colectomía total que para los pacientes con cáncer de recto sin EII y colectomía total. La vigilancia endoscópica, como parecía practicarse en esta cohorte, puede ser inadecuada. Consulte Video Resumen en http://links.lww.com/DCR/B497. (Traducción-Dr. Adrian Ortega).
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http://dx.doi.org/10.1097/DCR.0000000000001810DOI Listing
May 2021

Predictors for and outcomes after bone marrow biopsy in Scandinavian patients with chronic immune thrombocytopenia.

Eur J Haematol 2021 Apr 13. Epub 2021 Apr 13.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.

Objectives: To examine predictors for bone marrow biopsy (BMB) and the outcome following BMB in patients with chronic immune thrombocytopenia (cITP).

Methods: We identified patients diagnosed with cITP during 2009-2017 and obtained information on BMB, cITP treatment and subsequent thrombotic events, hospitalized bleeding, hematological cancer, and death using data from population-based healthcare databases and medical records in Denmark, Norway, and Sweden.

Results: Among 4471 adults (≥18 years) with cITP, 1683 (37.6%) underwent BMB before cITP diagnosis, while cumulative BMB incidence after cITP diagnosis date was 3.1% at 1 year and 7.5% at 5 years. Predictors of having a BMB after cITP diagnosis included older age, male sex, low baseline platelet count, splenectomy, and number of cITP treatments. Compared with patients without BMB, patients with BMB had higher rates of thrombotic events (1 year adjusted hazard ratio [HR] 1.53 [95% CI, 0.92-2.54]), hospitalized bleeding episodes (1 year adjusted HR 1.72 [95% CI, 1.15-2.58]), hematological cancer (1 year adjusted HR 35.26 [95% CI 17.67-70.34]), and all-cause mortality (1 year adjusted HR 1.97 [95% CI, 1.44-2.68]).

Conclusion: Patients who undergo BMB after cITP diagnosis represent a subset of patients with more severe disease and increased rates of complications as well as hematological malignancies.
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http://dx.doi.org/10.1111/ejh.13635DOI Listing
April 2021

Long-term risk of epilepsy, cerebral palsy and attention-deficit/hyperactivity disorder in children affected by a threatened abortion in utero.

Int J Epidemiol 2021 Apr 13. Epub 2021 Apr 13.

Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark.

Background: The birth of a child affected by a threatened abortion (TAB) in utero is associated with autism spectrum disorder; association with other neurological disorders is unknown.

Methods: This nationwide registry-based cohort study included singletons live-born in Denmark (1979-2010), followed through 2016. The outcomes were epilepsy, cerebral palsy (CP) and attention-deficit/hyperactivity disorder (ADHD). We used Cox regression to compute hazard ratios (HRs), adjusted for birth year, birth order, parental age, morbidity, medication use and maternal socio-economic factors. To remove time-invariant family-shared confounding, we applied sibling analyses.

Results: The study population included 1 864 221 singletons live-born in 1979-2010. Among the TAB-affected children (N = 59 134) vs TAB-unaffected children, at the end of follow-up, the cumulative incidence was 2.2% vs 1.6% for epilepsy, 0.4% vs 0.2% for CP and 5.5% vs 4.2% for ADHD (for children born in 1995-2010). The adjusted HRs were 1.25 [95% confidence interval (CI) 1.16-1.34] for epilepsy, 1.42 (95% CI 1.20-1.68) for CP and 1.21 (95% CI 1.14-1.29) for ADHD. In the sibling design, the adjusted HRs were unity for epilepsy (full siblings: 0.96, 95% CI 0.82-1.12; maternal: 1.04, 95% CI 0.90-1.20; paternal: 1.08, 95% CI 0.93-1.25) and ADHD (full: 1.08, 95% CI 0.92-1.27; maternal: 1.04, 95% CI 0.90-1.20; paternal: 1.08, 95% CI 0.93-1.25). For CP, HRs shifted away from unity among sibling pairs (full: 2.92, 95% CI 1.33-6.39; maternal: 2.03, 95% CI 1.15-3.57; paternal: 3.28, 95% CI 1.36-7.91).

Conclusions: The birth of a child affected by TAB in utero was associated with a greater risk of CP, but not epilepsy or ADHD.
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http://dx.doi.org/10.1093/ije/dyab069DOI Listing
April 2021

No benefit of more intense follow-up after surgery for colorectal cancer in the risk group with elevated CEA levels - An analysis within the COLOFOL randomized clinical trial.

Eur J Surg Oncol 2021 Mar 26. Epub 2021 Mar 26.

Department of Surgery, Skåne University Hospital, 205 02, Malmö, Sweden. Electronic address:

Background: Patients with colorectal cancer were examined to determine (1) whether elevated carcinoembryonic antigen (CEA) levels, either before treatment or after surgery, was associated with an increased risk of overall or colorectal cancer-specific mortality or recurrence, and (2) whether high intensity follow-up would benefit those patients.

Materials And Methods: Post-hoc analysis based on 2509 patients that underwent surgery for colorectal cancer, stage II or III, in the COLOFOL randomized trial with 5-year follow-up. Serum CEA levels were ascertained before treatment and one month after surgery. Follow-up examinations included computed tomography of the thorax and abdomen and serum CEA sampling. Patients were randomized to examinations at either 6, 12, 18, 24, and 36 months (high-intensity group) or at 12 and 36 months after surgery (low-intensity group). Levels of CEA >5 μg/l were defined as elevated.

Results: Elevated CEA levels before treatment were associated with increased risk of recurrence (hazard ratio [HR], 1.49; 95% confidence interval [CI]: 1.22-1.83), colorectal cancer-specific mortality (HR, 1.44; 95% CI: 1.08-1.91), and overall mortality (HR, 1.38; 95% CI: 1.07-1.78). Elevated CEA levels after surgery were associated with increased colorectal cancer-specific mortality (HR, 1.68; 95% CI: 1.08-2.61) and overall mortality (HR, 1.79; 95% CI: 1.22-2.63). The intensity of the follow-up regimen had no effect on 5-year outcomes in patients with elevated CEA levels.

Conclusion: Both pre-treatment and post-surgery elevated serum CEA levels were associated with increased overall and cancer-specific mortality. Intensified follow-up showed no benefit over low-intensity follow-up in this high-risk group of patients with elevated CEA levels.
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http://dx.doi.org/10.1016/j.ejso.2021.03.235DOI Listing
March 2021

Mortality Among Parents of Children With Major Congenital Anomalies.

Pediatrics 2021 May 2;147(5). Epub 2021 Apr 2.

Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada;

Background: A mother whose child has a chronic condition, such as a major congenital anomaly, often experiences poorer long-term health, including earlier mortality. Little is known about the long-term health of fathers of infants with a major congenital anomaly.

Methods: In this population-based prospective cohort study, we used individual-linked Danish registry data. Included were all mothers and fathers with a singleton infant born January 1, 1986, to December 31, 2015. Cox proportional hazards regression was used to generate hazard ratios for all-cause and cause-specific mortality among mothers and fathers whose infant had an anomaly and fathers of unaffected infants, relative to mothers of unaffected infants (referent), adjusted for child's year of birth, parity, parental age at birth, parental comorbidities, and sociodemographic characteristics.

Results: In total, 20 952 of 965 310 mothers (2.2%) and 20 655 of 951 022 fathers (2.2%) had an infant with a major anomaly. Median (interquartile range) of parental follow-up was 17.9 (9.5 to 25.5) years. Relative to mothers of unaffected infants, mothers of affected infants had adjusted hazard ratios (aHRs) of death of 1.20 (95% confidence interval [CI]: 1.09 to 1.32), fathers of unaffected infants had intermediate aHR (1.62, 95% CI: 1.59 to 1.66), and fathers of affected infants had the highest aHR (1.76, 95% CI: 1.64 to 1.88). Heightened mortality was primarily due to cardiovascular and endocrine/metabolic diseases.

Conclusions: Mothers and fathers of infants with a major congenital anomaly experience an increased risk of mortality, often from preventable causes. These findings support including fathers in interventions to support the health of parental caregivers.
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http://dx.doi.org/10.1542/peds.2020-028571DOI Listing
May 2021

Thromboembolism and the Oxford-AstraZeneca COVID-19 vaccine: side-effect or coincidence?

Lancet 2021 04 30;397(10283):1441-1443. Epub 2021 Mar 30.

Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

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http://dx.doi.org/10.1016/S0140-6736(21)00762-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009607PMC
April 2021

Sleep disruption and Alzheimer's disease risk: Inferences from men with benign prostatic hyperplasia.

EClinicalMedicine 2021 Feb 3;32:100740. Epub 2021 Feb 3.

Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, DK-8200 Aarhus N, Denmark.

Background: Sleep disturbances may increase risks of Alzheimer's disease (AD) and other dementias. Benign prostatic hyperplasia (BPH) is usually associated with lower urinary tract symptoms, including nocturia, and thereby disturbed sleep. We examined if men with BPH are at increased risk of AD and all-cause dementia.

Methods: In a Danish nationwide cohort (1996-2016), we identified 297,026 men with BPH, defined by inpatient or outpatient hospital diagnosis or by BPH-related surgical or medical treatment, and 1,107,176 men from the general population matched by birth year. We computed rates, cumulative incidences, and adjusted hazard ratios (HRs) of AD and all-cause dementia. Follow-up started 1 year after BPH diagnosis date/index date.

Findings: Median follow-up was 6·9 years (Interquartile range (IQR), 3·6 - 11·6 years] in the BPH cohort and 6·4 years (IQR: 3·4 - 10·8 years) in the comparison cohort. The cumulative 1-10 year risk of AD was 1·15% [95% confidence interval (CI), 1·11-1·20], in the BPH cohort and 1·00% (95% CI, 0·98 - 1·02) in the comparison cohort. The adjusted 1-10-year hazard ratios were 1·16 (95% CI: 1·10-1·21) for AD and 1·21 (95% CI: 1·17-1·25) for all-cause dementia. From >10 years up to 21 years of follow-up, BPH remained associated with 10%- 20% increased risk of AD and all-cause dementia.

Interpretation: During up to 21 years of follow-up, men with BPH had persistently higher risk of AD and all-cause dementia compared with men in the general population. Our results identify BPH as a common, potentially remediable disorder associated with dementia risk.

Funding: Lundbeckfonden, Aarhus University Research Foundation, and the National Institutes of Health.
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http://dx.doi.org/10.1016/j.eclinm.2021.100740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910709PMC
February 2021

Thirteen-Year Trends in Cardiovascular Risk in Men and Women with Chronic Coronary Syndrome.

Eur Heart J Qual Care Clin Outcomes 2021 Feb 24. Epub 2021 Feb 24.

Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.

Aims: To examine combined and sex-specific temporal changes in risks of adverse cardiovascular events and coronary revascularization in patients with chronic coronary syndrome undergoing coronary angiography.

Methods: We included all patients with stable angina pectoris and coronary artery disease examined by coronary angiography in Western Denmark from 2004 to 2016. Patients were stratified by examination year interval: 2004-2006, 2007-2009, 2010-2012, and 2013-2016. Outcomes were two-year risk of myocardial infarction, ischemic stroke, cardiac death, and all-cause death estimated by adjusted incidence rate ratios using patients examined in 2004-2006 as reference.

Results: A total of 29,471 patients were included, of whom 70% were men. The two-year risk of myocardial infarction (2.8% versus 1.9%, adjusted incidence rate ratio 0.65, 95% CI 0.53-0.81), ischemic stroke (1.8% versus 1.1%, adjusted incidence rate ratio 0.48, 95% CI 0.37-0.64), cardiac death (2.1% versus 0.9%, adjusted incidence rate ratio 0.38, 95% CI 0.29-0.51), and all-cause death (5.0% versus 3.6%, adjusted incidence rate ratio 0.65, 95% CI 0.55-0.76) decreased from the first examination interval (2004-2006) to the last examination interval (2013-2016). Coronary revascularizations also decreased (percutaneous coronary intervention: 51.6% versus 42.5%; coronary artery bypass grafting: 24.6% versus 17.5%). Risk reductions were observed in both men and women, however, women had a lower absolute risk.

Conclusion: The risk for adverse cardiovascular events decreased substantially in both men and women with chronic coronary syndrome from 2004 to 2016. These results most likely reflect the cumulative effect of improvements in the management of chronic coronary artery disease.
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http://dx.doi.org/10.1093/ehjqcco/qcab015DOI Listing
February 2021

Hepatobiliary Cancer Risk in Patients with Inflammatory Bowel Disease: A Scandinavian Population-Based Cohort Study.

Cancer Epidemiol Biomarkers Prev 2021 May 24;30(5):886-894. Epub 2021 Feb 24.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Background: Inflammatory bowel disease (IBD) has been associated with hepatobiliary cancer, but existing evidence is poor. We evaluated risk of death from hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC) among patients with IBD.

Methods: This Swedish/Danish population-based cohort study (1969-2017) followed patients with IBD and 1:10 matched population comparators from their diagnosis/match date until death, emigration, or end of follow-up.

Results: Among the 97,496 patients with ulcerative colitis/963,026 comparators, we found 66/390 HCC-deaths, 120/173 ICC-deaths, and 91/220 ECC-deaths (median follow-up 10 years); the 10-year-mortality was 0.5‰ (per mille) for HCC, 0.6‰ for ICC, and 0.4‰ for ECC, which decreased to 0.3‰, 0.4‰, and 0.2‰, respectively, in 2003-2017. Overall hazard ratios (HR) were 1.83 [95% confidence interval (CI), 1.41-2.38] for HCC-, 7.33 (95% CI, 5.81-9.25) for ICC-, and 4.46 (95% CI, 3.49-5.70) for ECC-deaths. A total of 22/66 HCC-deaths, 87/120 ICC-deaths, and 55/91 ECC-deaths occurred among patients with ulcerative colitis with primary sclerosing cholangitis (PSC), corresponding to 10-year-mortality of 6.7‰, 26.2‰, and 17.2‰, respectively. Among 47,399 patients with Crohn's disease (median follow-up 11 years), 10-year-mortality from HCC ( = 28), ICC ( = 28), and ECC ( = 24) were 0.3‰, 0.1‰, and 0.3‰, respectively, and corresponding HRs were 1.96 (95% CI, 1.31-2.93), 3.33 (95% CI, 2.19-5.09), and 3.10 (95% CI, 1.97-4.87). One of 28 HCC-deaths, 14/28 ICC-deaths (10-year-mortality 19‰), and 12/24 ECC-deaths (10-year-mortality 14‰) occurred after PSC.

Conclusions: Risk of HCC-, ICC-, and ECC-deaths was low in patients with IBD and decreased over time. However, a large proportion of deaths occurred after PSC.

Impact: Guidelines on specific surveillance strategies for patients with IBD with PSC, but not those without PSC, are needed.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1241DOI Listing
May 2021

Mannose-binding lectin and risk of infections in type 2 diabetes: A Danish cohort study.

J Diabetes Complications 2021 May 26;35(5):107873. Epub 2021 Jan 26.

Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Aims: In individuals at increased risk of infections, e.g., patients with type 2 diabetes, low MBL may have detrimental effects. We used the Mendelian randomization principle to examine whether genetically low MBL is a risk factor for developing infections in patients with type 2 diabetes.

Methods: Serum MBL (n = 7305) and MBL genotype (n = 3043) were determined in a nationwide cohort of patients with new type 2 diabetes and up to 8 years follow-up for hospital-treated infections and community-based antimicrobial prescriptions. The associations were examined in spline and Cox regression analyses.

Results: 1140 patients (16%) were hospitalized with an infection and 5077 patients (70%) redeemed an antimicrobial prescription. For low (≤100 μg/L) versus intermediate (101-1000 μg/L) serum MBL concentration, the adjusted hazard ratios (aHRs) were 1.13(95% confidence interval, 0.96-1.33) for any hospital-treated infections and 1.19(1.01-1.41) for bacterial infections. Low MBL expression genotype was not associated with risk of any hospital-treated infections except for diarrheal diseases (aHR 2.23[1.04-4.80]). Low MBL expression genotype, but not low serum MBL, was associated with increased risk for antimicrobial prescriptions (aHR 1.18[1.04-2.34] and antibacterial prescriptions 1.20[1.05-1.36]).

Conclusions: Low MBL is a weak causal risk factor for developing infections in patients with type 2 diabetes.
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http://dx.doi.org/10.1016/j.jdiacomp.2021.107873DOI Listing
May 2021

Venous thromboembolism and risk of cancer in users of statins: A Danish population-based cohort study.

Thromb Res 2021 May 18;201:1-5. Epub 2021 Feb 18.

Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark.

Background: Venous thromboembolism (VTE) may be the first symptom of cancer. Statins are suggested to prevent VTE, but the risk of cancer in VTE patients using statins remains poorly understood.

Objectives: To examine if VTE is a marker of cancer in users of statins.

Methods: We identified all Danish patients during 1996-2017 with a first-time diagnosis of VTE and a filled prescription for a statin within 90 days prior to the VTE diagnosis. We classified patients as prevalent users if the first filling of a statin occurred more than one year preceding the VTE diagnosis, and as new users if the first filling occurred within the preceding year. We computed cumulative incidences of cancer, with death as a competing risk, and age-, sex-, and calendar-period standardized incidence ratios (SIRs), comparing the observed cancer incidence with the expected based on national cancer statistics.

Results: Among 9280 (85%) prevalent users of statin and 1580 (15%) new users, the one-year cumulative incidence of any cancer was 6.6 (95% CI: 6.1-7.2) for prevalent users and 6.4 (95% CI: 5.2-7.6) for new users; the corresponding SIRs were 3.1 (95% CI: 2.9-3.3) and 3.5 (95% CI: 2.9-4.3). In the second and subsequent years, the SIRs diminished and approached unity for both prevalent (1.1 [95% CI: 1.1-1.2]) and new users (1.1 [95% CI: 0.9-1.3]).

Conclusions: VTE patients using statins had a 3-fold increased rate of cancer in the first year after diagnosis. A first VTE serves as an important marker of cancer, regardless of statin use.
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http://dx.doi.org/10.1016/j.thromres.2021.02.015DOI Listing
May 2021

Venous thromboembolism and risk of cancer in users of statins: A Danish population-based cohort study.

Thromb Res 2021 May 18;201:1-5. Epub 2021 Feb 18.

Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark.

Background: Venous thromboembolism (VTE) may be the first symptom of cancer. Statins are suggested to prevent VTE, but the risk of cancer in VTE patients using statins remains poorly understood.

Objectives: To examine if VTE is a marker of cancer in users of statins.

Methods: We identified all Danish patients during 1996-2017 with a first-time diagnosis of VTE and a filled prescription for a statin within 90 days prior to the VTE diagnosis. We classified patients as prevalent users if the first filling of a statin occurred more than one year preceding the VTE diagnosis, and as new users if the first filling occurred within the preceding year. We computed cumulative incidences of cancer, with death as a competing risk, and age-, sex-, and calendar-period standardized incidence ratios (SIRs), comparing the observed cancer incidence with the expected based on national cancer statistics.

Results: Among 9280 (85%) prevalent users of statin and 1580 (15%) new users, the one-year cumulative incidence of any cancer was 6.6 (95% CI: 6.1-7.2) for prevalent users and 6.4 (95% CI: 5.2-7.6) for new users; the corresponding SIRs were 3.1 (95% CI: 2.9-3.3) and 3.5 (95% CI: 2.9-4.3). In the second and subsequent years, the SIRs diminished and approached unity for both prevalent (1.1 [95% CI: 1.1-1.2]) and new users (1.1 [95% CI: 0.9-1.3]).

Conclusions: VTE patients using statins had a 3-fold increased rate of cancer in the first year after diagnosis. A first VTE serves as an important marker of cancer, regardless of statin use.
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http://dx.doi.org/10.1016/j.thromres.2021.02.015DOI Listing
May 2021

Statins and risk of diverticular disease: Nested case-control study.

Pharmacoepidemiol Drug Saf 2021 Jun 21;30(6):770-778. Epub 2021 Feb 21.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.

Background: Statins exert pleiotropic anti-inflammatory effects and may prevent diverticular disease. However, the association remains poorly understood with previous studies obtaining conflicting results.

Aims: To examine the effect of statin on the subsequent risk of diverticular disease.

Methods: We conducted a nested case-control study in Denmark among respondents (>18 years) of the 2010 or the 2013 Danish National Health Survey. Among these, we identified 8809 cases of hospital-diagnosed diverticular disease and risk-set sampled population controls without diverticular disease. Using complete prescription and hospital records, we used conditional logistic regression to compute odds ratios (ORs) associating statin use with diverticular disease. In adjusted analyses, we controlled for hospital-based diagnoses, medication use other than statins, and lifestyle and socioeconomic factors.

Results: The fully adjusted OR for diverticular disease associated with ever use (≥1 statin prescription filling) was 1.19 (95% CI: 1.12-1.27) compared with never use. However, we observed no dose-response relation. For example, among short-term users (<5 years), the OR was 1.18 (95% CI: 1.04-1.35) for low intensity users and 1.13 (95% CI: 1.01-1.26) for high intensity users. Among long-term users (≥5 years), the respective ORs were 1.25 (95% CI: 1.13-1.38) and 1.11 (95% CI: 0.98-1.24). In analyses restricting to cases and controls with a previous colonoscopy, associations were null (OR: 1.01 [95% CI: 0.85-1.20]).

Conclusions: The observed association of a higher risk of diverticular disease associated with statins could be explained by diagnostic bias. Our study did not support a protective nor harmful effect of statins on the risk of diverticular disease.
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http://dx.doi.org/10.1002/pds.5205DOI Listing
June 2021

Lifestyle and Anthropometric Factors and Risk of Herpes Zoster: A Nationwide Population-Based Cohort Study.

Am J Epidemiol 2021 Feb 11. Epub 2021 Feb 11.

Research Unit for General Practice, Aarhus University, Aarhus, Denmark.

The role of lifestyle in development of herpes zoster remains unclear. We examined whether smoking status, alcohol consumption, body mass index (BMI), or physical activity were associated with zoster risk. We followed a population-based cohort of 101,894 respondents to the 2010 Danish National Health Survey (baseline May 1, 2010) until zoster diagnosis, death, emigration, or July 1, 2014, whichever occurred first. We computed hazard ratios for zoster associated with each exposure, using Cox regression with age as the time-scale and adjusting for potential confounders. Compared with never smokers, hazards for zoster were increased in former smokers [1.17; 95% confidence interval (CI): 1.06, 1.30], but not in current smokers (1.00; 95% CI: 0.89, 1.13). Compared with low-risk alcohol consumption, neither intermediate-risk (0.95; 95% CI: 0.84, 1.07) nor high-risk alcohol consumption (0.99; 95% CI: 0.85, 1.15) were associated with zoster. We also found no increased hazard associated with weekly binge drinking vs. not (0.93; 95% CI: 0.77, 1.11). Risk of zoster varied little by BMI (referent=normal weight) and physical activity levels (referent=light level), with HRs between 0.96 and 1.08. We observed no dose-response association between the exposures and zoster. The examined lifestyle and anthropometric factors thus were not risk factors for zoster.
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http://dx.doi.org/10.1093/aje/kwab027DOI Listing
February 2021

Nationwide Trends in Incidence and Mortality of Stroke Among Younger and Older Adults in Denmark.

Neurology 2021 03 10;96(13):e1711-e1723. Epub 2021 Feb 10.

From the Department of Clinical Epidemiology (N.S., K.A., E.H.-P., K.J.R., V.W.H., H.T.S.) and Department of Clinical Biochemistry (K.A.), Thrombosis and Haemostasis Research Unit, Aarhus University Hospital; National Institute of Public Health (N.S., L.C.T.), University of Southern Denmark, Copenhagen; Department of Epidemiology (K.J.R., H.T.S.), Boston University School of Public Health, MA; RTI Health Solutions (K.J.R.), Research Triangle Institute, Research Triangle Park, NC; and Department of Epidemiology and Population Health (V.W.H., H.T.S.) and Department of Neurology and Neurological Sciences, Stanford University, CA.

Objective: To investigate the extent to which the incidence and mortality of a first-time stroke among younger and older adults changed from 2005 to 2018 in Denmark using nationwide registries.

Methods: We used the Danish Stroke Registry and the Danish National Patient Registry to identify patients 18 to 49 years of age (younger adults) and those ≥50 years of age (older adults) with a first-time ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. We computed age-standardized incidence rates and 30-day and 1-year mortality risks separately for younger and older adults and according to smaller age groups, stroke subtype, sex, and severity (Scandinavian Stroke Scale score). Average annual percentage changes (AAPCs) were computed to assess temporal trends.

Results: We identified 8,680 younger adults and 105,240 older adults with an ischemic stroke or intracerebral hemorrhage. The incidence rate per 100,000 person-years of ischemic stroke (20.8 in 2005 and 21.9 in 2018, AAPC -0.6 [95% confidence interval (CI) -1.5 to 0.3]) and intracerebral hemorrhage (2.2 in 2005 and 2.5 in 2018, AAPC 0.6 [95% CI -1.0 to 2.3]) remained steady in younger adults. In older adults, rates of ischemic stroke and intracerebral hemorrhage declined, particularly in those ≥70 years of age. Rates of subarachnoid hemorrhage declined, but more so in younger than older adults. Stroke mortality declined over time in both age groups, attributable largely to declines in the mortality after severe strokes. Most trends were similar for men and women.

Conclusion: The incidence of ischemic stroke and intracerebral hemorrhage was steady in younger adults from 2005 to 2018, while it dropped in adults >70 years of age. Stroke mortality declined during this time.
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http://dx.doi.org/10.1212/WNL.0000000000011636DOI Listing
March 2021

Association of α1-Blocker Receipt With 30-Day Mortality and Risk of Intensive Care Unit Admission Among Adults Hospitalized With Influenza or Pneumonia in Denmark.

JAMA Netw Open 2021 02 1;4(2):e2037053. Epub 2021 Feb 1.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Importance: Alpha 1-adrenergic receptor blocking agents (α1-blockers) have been reported to have protective benefits against hyperinflammation and cytokine storm syndrome, conditions that are associated with mortality in patients with coronavirus disease 2019 and other severe respiratory tract infections. However, studies of the association of α1-blockers with outcomes among human participants with respiratory tract infections are scarce.

Objective: To examine the association between the receipt of α1-blockers and outcomes among adult patients hospitalized with influenza or pneumonia.

Design, Setting, And Participants: This population-based cohort study used data from Danish national registries to identify individuals 40 years and older who were hospitalized with influenza or pneumonia between January 1, 2005, and November 30, 2018, with follow-up through December 31, 2018. In the main analyses, patients currently receiving α1-blockers were compared with those not receiving α1-blockers (defined as patients with no prescription for an α1-blocker filled within 365 days before the index date) and those currently receiving 5α-reductase inhibitors. Propensity scores were used to address confounding factors and to compute weighted risks, absolute risk differences, and risk ratios. Data were analyzed from April 21 to December 21, 2020.

Exposures: Current receipt of α1-blockers compared with nonreceipt of α1-blockers and with current receipt of 5α-reductase inhibitors.

Main Outcomes And Measures: Death within 30 days of hospital admission and risk of intensive care unit (ICU) admission.

Results: A total of 528 467 adult patients (median age, 75.0 years; interquartile range, 64.4-83.6 years; 273 005 men [51.7%]) were hospitalized with influenza or pneumonia in Denmark between 2005 and 2018. Of those, 21 772 patients (4.1%) were currently receiving α1-blockers compared with a population of 22 117 patients not receiving α1-blockers who were weighted to the propensity score distribution of those receiving α1-blockers. In the propensity score-weighted analyses, patients receiving α1-blockers had lower 30-day mortality (15.9%) compared with patients not receiving α1-blockers (18.5%), with a corresponding risk difference of -2.7% (95% CI, -3.2% to -2.2%) and a risk ratio (RR) of 0.85 (95% CI, 0.83-0.88). The risk of ICU admission was 7.3% among patients receiving α1-blockers and 7.7% among those not receiving α1-blockers (risk difference, -0.4% [95% CI, -0.8% to 0%]; RR, 0.95 [95% CI, 0.90-1.00]). A comparison between 18 280 male patients currently receiving α1-blockers and 18 228 propensity score-weighted male patients currently receiving 5α-reductase inhibitors indicated that those receiving α1-blockers had lower 30-day mortality (risk difference, -2.0% [95% CI, -3.4% to -0.6%]; RR, 0.89 [95% CI, 0.82-0.96]) and a similar risk of ICU admission (risk difference, -0.3% [95% CI, -1.4% to 0.7%]; RR, 0.96 [95% CI, 0.83-1.10]).

Conclusions And Relevance: This cohort study's findings suggest that the receipt of α1-blockers is associated with protective benefits among adult patients hospitalized with influenza or pneumonia.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.37053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876591PMC
February 2021

Rectal Cancer Risk and Survival after Total Colectomy for Inflammatory Bowel Disease: A Population-Based Study.

Dis Colon Rectum 2021 Jan 22. Epub 2021 Jan 22.

Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark & Department of Surgery, Section of Coloproctology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark, Department of Surgery, Randers Regional Hospital, Skovlyvej 15, 8930, Randers, Denmark Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark Department of Surgery, Section of Coloproctology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark.

Background: Patients undergoing total colectomy for inflammatory bowel disease (IBD) may develop cancer in the rectal remnant, but the association is poorly understood.

Objectives: To examine risk and prognosis of rectal cancer after total colectomy for IBD.

Design: Nationwide population-based study.

Setting: Denmark 1977-2013.

Patients: Patients with IBD undergoing total colectomy.

Main Outcome Measures: We examined incidence of rectal cancer among patients with IBD and total colectomy and compared cancer stage to that of other rectal cancer patients in Denmark. We used Kaplan-Meier methodology to estimate survival and Cox regression to estimate adjusted mortality rate ratios (aMRRs) following a rectal cancer diagnosis, comparing patients with and without IBD and a rectal remnant.

Results: We identified 4,703 patients with IBD (1,026 Crohn's disease; 3,677 ulcerative colitis) who underwent total colectomy with a rectal remnant. During 29,725 years of follow-up, 30 rectal cancers were observed, compared to 8 expected [standardized incidence ratio (SIR)=3.6, (95% confidence interval (CI): 2.4-5.1)]. Cancer stage distributions were similar. Risk of rectal cancer 35 years after total colectomy was 1.9% (95% CI:1.1%-2.9%). Five years after rectal cancer diagnosis, survival was 28% (95% CI: 12%-47%) and 38% (95% CI: 37%-38%) for patients with and without IBD and a rectal remnant, respectively. The aMRR 1-5 years after a rectal cancer diagnosis was 2.5 (95% CI: 1.6-3.9). Median time from last recorded non-diagnostic proctoscopy to rectal cancer diagnosis for patients with IBD and total colectomy was 1.1 years.

Limitations: Few outcomes, use of administrative and not clinical data.

Conclusion: Long-term risk of rectal cancer following total colectomy for IBD was low. Survival following a diagnosis of rectal cancer was poorer for patients with IBD and total colectomy than for rectal cancer patients without IBD and total colectomy. Endoscopic surveillance, as it appeared to be practiced in this cohort, may be inadequate. See Video Abstract at http://links.lww.com/DCR/B497 .
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http://dx.doi.org/10.1097/DCR.0000000000001810DOI Listing
January 2021

Ten-year cardiovascular risk in diabetes patients without obstructive coronary artery disease: a retrospective Western Denmark cohort study.

Cardiovasc Diabetol 2021 Jan 21;20(1):23. Epub 2021 Jan 21.

Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.

Background: Diabetes patients without obstructive coronary artery disease as assessed by coronary angiography have a low risk of myocardial infarction, but their myocardial infarction risk may still be higher than the general population. We examined the 10-year risks of myocardial infarction, ischemic stroke, and death in diabetes patients without obstructive coronary artery disease according to coronary angiography, compared to risks in a matched general population cohort.

Methods: We included all diabetes patients without obstructive coronary artery disease examined by coronary angiography from 2003 to 2016 in Western Denmark. Patients were matched by age and sex with a cohort from the Western Denmark general population without a previous myocardial infarction or coronary revascularization. Outcomes were myocardial infarction, ischemic stroke, and death. Ten-year cumulative incidences were computed. Adjusted hazard ratios (HR) then were computed using stratified Cox regression with the general population as reference.

Results: We identified 5734 diabetes patients without obstructive coronary artery disease and 28,670 matched individuals from the general population. Median follow-up was 7 years. Diabetes patients without obstructive coronary artery disease had an almost similar 10-year risk of myocardial infarction (3.2% vs 2.9%, adjusted HR 0.93, 95% CI 0.72-1.20) compared to the general population, but had an increased risk of ischemic stroke (5.2% vs 2.2%, adjusted HR 1.87, 95% CI 1.47-2.38) and death (29.6% vs 17.8%, adjusted HR 1.24, 95% CI 1.13-1.36).

Conclusions: Patients with diabetes and no obstructive coronary artery disease have a 10-year risk of myocardial infarction that is similar to that found in the general population. However, they still remain at increased risk of ischemic stroke and death.
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http://dx.doi.org/10.1186/s12933-021-01212-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819163PMC
January 2021

Plasma Vitamin B12 Levels, High-Dose Vitamin B12 Treatment, and Risk of Dementia.

J Alzheimers Dis 2021 ;79(4):1601-1612

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Background: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia.

Objective: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer's disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes).

Methods: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000-2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200-600 pmol/L). We used multivariable Cox regression to compute 0-15-year hazard ratios for dementia.

Results: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia.

Conclusion: We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.
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http://dx.doi.org/10.3233/JAD-201096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990402PMC
January 2021

MANAGEMENT OF ENDOCRINE DISEASE: Glucocorticoid-induced adrenal insufficiency: replace while we wait for evidence?

Eur J Endocrinol 2021 Apr;184(4):R111-R122

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.

Glucocorticoids are, besides non-steroidal anti-inflammatory drugs, the most widely used anti-inflammatory medications. Prevalence studies indicate substantial use of both systemic and locally acting agents. A recognised adverse effect of glucocorticoid treatment is adrenal insufficiency, which is highly prevalent based on biochemical testing, but its clinical implications are poorly understood. Current evidence, including randomised trials and observational studies, indicates substantial variation among patients in both risk and course of glucocorticoid-induced adrenal insufficiency, but both are currently unpredictable. Oral and intra-articular formulations, as well as long-term and high-dose treatments, carry the highest risk of glucocorticoid-induced adrenal insufficiency defined by biochemical tests. However, no route of administration, treatment duration, or dose can be considered without risk. More research is needed to estimate the risk and temporal pattern of glucocorticoid-induced adrenal insufficiency, to investigate its clinical implications, and to identify predictors of risk and prognosis. Randomized trials are required to evaluate whether hydrocortisone replacement therapy mitigates risk and symptoms of glucocorticoid-induced adrenal insufficiency in patients discontinuing glucocorticoid treatment. This review aims to provide an overview of the available evidence, pointing to knowledge gaps and unmet needs.
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http://dx.doi.org/10.1530/EJE-20-1199DOI Listing
April 2021

Unspecified stress disorders and risk of arterial and venous thromboembolic disease in the Danish population.

J Affect Disord 2021 03 30;282:712-716. Epub 2020 Dec 30.

Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA; Department of Psychiatry, Boston University, Boston, MA, USA.

Background: Posttraumatic stress disorder is a well-documented risk factor for cardiovascular disease. Whether non-specific stress-related psychopathology also increases risk is less well known.

Methods: In a cohort of adult Danish-born residents of Denmark with an incident diagnosis of unspecified reaction to severe stress ("unspecified stress reaction") between 1995 and 2011 (N = 24,534), we assessed incidence of seven arterial and venous cardiovascular events/conditions between 1996 and 2013. We calculated standardized incidence ratios (SIRs) comparing incidence of each outcome among the cohort to expected incidence based on sex-, age-, and calendar-time-specific national rates. We conducted stratified analyses by demographic characteristics, comorbidities, and length of follow-up time.

Results: Incidence over the study period ranged from 1.1% for provoked VTE to 5.7% for stroke, adjusting for competing risk of death. Unspecified stress reaction was associated with all outcomes (SIRs ranging from 1.3, 95% confidence interval (CI): 1.1-1.4 for atrial fibrillation/flutter to 1.9, 95% CI: 1.7-2.2 for unprovoked VTE and 1.9, 95% CI: 1.6-2.3 for provoked VTE). Associations persisted, but were attenuated, when restricting to persons without alcohol use disorder and to persons without physical health comorbidities.

Limitations: Unspecified stress reaction has less precise criteria than other stress-related diagnoses, and we could not adjust for some potential confounders.

Conclusions: Our results augment literature on stress disorders and cardiovascular disease by highlighting the additional importance of unspecified stress disorders. Further research on this diagnostic category, which may represent subsyndromal psychopathology, is warranted. These findings support considering persons with non-specific stress-related psychopathology in treatment and tertiary prevention activities.
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http://dx.doi.org/10.1016/j.jad.2020.12.180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889626PMC
March 2021

Unspecified stress disorders and risk of arterial and venous thromboembolic disease in the Danish population.

J Affect Disord 2021 03 30;282:712-716. Epub 2020 Dec 30.

Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA; Department of Psychiatry, Boston University, Boston, MA, USA.

Background: Posttraumatic stress disorder is a well-documented risk factor for cardiovascular disease. Whether non-specific stress-related psychopathology also increases risk is less well known.

Methods: In a cohort of adult Danish-born residents of Denmark with an incident diagnosis of unspecified reaction to severe stress ("unspecified stress reaction") between 1995 and 2011 (N = 24,534), we assessed incidence of seven arterial and venous cardiovascular events/conditions between 1996 and 2013. We calculated standardized incidence ratios (SIRs) comparing incidence of each outcome among the cohort to expected incidence based on sex-, age-, and calendar-time-specific national rates. We conducted stratified analyses by demographic characteristics, comorbidities, and length of follow-up time.

Results: Incidence over the study period ranged from 1.1% for provoked VTE to 5.7% for stroke, adjusting for competing risk of death. Unspecified stress reaction was associated with all outcomes (SIRs ranging from 1.3, 95% confidence interval (CI): 1.1-1.4 for atrial fibrillation/flutter to 1.9, 95% CI: 1.7-2.2 for unprovoked VTE and 1.9, 95% CI: 1.6-2.3 for provoked VTE). Associations persisted, but were attenuated, when restricting to persons without alcohol use disorder and to persons without physical health comorbidities.

Limitations: Unspecified stress reaction has less precise criteria than other stress-related diagnoses, and we could not adjust for some potential confounders.

Conclusions: Our results augment literature on stress disorders and cardiovascular disease by highlighting the additional importance of unspecified stress disorders. Further research on this diagnostic category, which may represent subsyndromal psychopathology, is warranted. These findings support considering persons with non-specific stress-related psychopathology in treatment and tertiary prevention activities.
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http://dx.doi.org/10.1016/j.jad.2020.12.180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889626PMC
March 2021

Maternal health, in-utero, and perinatal exposures and risk of thyroid cancer in offspring: a Nordic population-based nested case-control study.

Lancet Diabetes Endocrinol 2021 02 18;9(2):94-105. Epub 2020 Dec 18.

Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Cancer Registry of Norway, Oslo, Norway.

Background: Thyroid cancer tends to be diagnosed at a younger age (median age 51 years) compared with most other malignancies (such as breast cancer [62 years] or lung cancer [71 years]). The incidence of thyroid cancer is higher in women than men diagnosed from early adolescence. However, few in-utero and early life risk exposures associated with increased risk of thyroid cancer have been identified.

Methods: In this population-based nested case-control study we used registry data from four Nordic countries to assess thyroid cancer risk in offspring in relation to maternal medical history, pregnancy complications, and birth characteristics. Patient with thyroid cancer (cases) were individuals born and subsequently diagnosed with first primary thyroid cancer from 1973 to 2013 in Denmark, 1987 to 2014 in Finland, 1967 to 2015 in Norway, or 1973 to 2014 in Sweden. Each case was matched with up to ten individuals without thyroid cancer (controls) based on birth year, sex, country, and county of birth. Cases and matched controls with a previous diagnosis of any cancer, other than non-melanoma skin cancer, at the time of thyroid cancer diagnosis were excluded. Cases and matched controls had to reside in the country of birth at the time of thyroid cancer diagnosis. Conditional logistic regression models were used to calculate odds ratios (ORs) with 95% CIs.

Results: Of the 2437 cases, 1967 (81·4%) had papillary carcinomas, 1880 (77·1%) were women, and 1384 (56·7%) were diagnosed before age 30 years (range 0-48). Higher birth weight (OR per kg 1·14 [95% CI 1·05-1·23]) and congenital hypothyroidism (4·55 [1·58-13·08]); maternal diabetes before pregnancy (OR 1·69 [0·98-2·93]) and postpartum haemorrhage (OR 1·28 [1·06-1·55]); and (from registry data in Denmark) maternal hypothyroidism (18·12 [10·52-31·20]), hyperthyroidism (11·91 [6·77-20·94]), goiter (67·36 [39·89-113·76]), and benign thyroid neoplasms (22·50 [6·93-73·06]) were each associated with an increased risk of thyroid cancer in offspring.

Interpretation: In-utero exposures, particularly those related to maternal thyroid disorders, might have a long-term influence on thyroid cancer risk in offspring.

Funding: Intramural Research Program of the National Cancer Institute (National Institutes of Health).
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http://dx.doi.org/10.1016/S2213-8587(20)30399-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875310PMC
February 2021

Early Discontinuation of Endocrine Therapy and Recurrence of Breast Cancer among Premenopausal Women.

Clin Cancer Res 2021 Mar 17;27(5):1421-1428. Epub 2020 Dec 17.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.

Purpose: Premenopausal women diagnosed with estrogen receptor (ER)-positive breast cancer are prescribed 5-10 years of endocrine therapy to prevent or delay recurrence. In this study, we evaluated the association between early discontinuation of endocrine therapy and breast cancer recurrence in a cohort of premenopausal women.

Experimental Design: We identified 4,503 patients with premenopausal ER-positive breast cancer who initiated adjuvant endocrine therapy and were registered in the Danish Breast Cancer Group clinical database (2002-2011). Women were excluded if they had a recurrence or were lost to follow-up less than 1.5 years after breast cancer surgery. Endocrine therapy was considered complete if the patient received at least 4.5 years of treatment or discontinued medication less than 6 months before recurrence. Exposure status was updated annually and modeled as a time-dependent variable. We accounted for baseline and time-varying confounders via time-varying weights, which we calculated from multivariable logistic regression models, and included in regression models to estimate HRs and 95% confidence intervals (CIs) associating early discontinuation with recurrence.

Results: Over the study follow-up, 1,001 (22%) women discontinued endocrine therapy. We observed 202 (20%) recurrences among those who discontinued endocrine therapy, and 388 (11%) among those who completed the recommended treatment. The multivariable-adjusted estimated rate of recurrence was higher in women who discontinued endocrine therapy relative to those who completed their treatment (hazard ratio, 1.67; 95% CI, 1.25-2.14).

Conclusions: These results highlight the importance of clinical follow-up and behavioral interventions that support persistence of adjuvant endocrine therapy to prevent breast cancer recurrence.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925421PMC
March 2021

Impact of Plaque Burden Versus Stenosis on Ischemic Events in Patients With Coronary Atherosclerosis.

J Am Coll Cardiol 2020 12;76(24):2803-2813

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

Background: Patients with obstructive coronary artery disease (CAD) are at high risk for cardiovascular disease (CVD) events. However, it remains unclear whether the high risk is due to high atherosclerotic disease burden or if presence of stenosis has independent predictive value.

Objectives: The purpose of this study was to evaluate if obstructive CAD provides predictive value beyond its association with total calcified atherosclerotic plaque burden as assessed by coronary artery calcium (CAC).

Methods: Among 23,759 symptomatic patients from the Western Denmark Heart Registry who underwent diagnostic computed tomography angiography (CTA), we assessed the risk of major CVD (myocardial infarction, stroke, and all-cause death) stratified by CAC burden and number of vessels with obstructive disease.

Results: During a median follow-up of 4.3 years, 1,054 patients experienced a first major CVD event. The event rate increased stepwise with both higher CAC scores and number of vessels with obstructive disease (by CAC scores: 6.2 per 1,000 person-years (PY) for CAC = 0 to 42.3 per 1,000 PY for CAC >1,000; by number of vessels with obstructive disease: 6.1 per 1,000 PY for no CAD to 34.7 per 1,000 PY for 3-vessel disease). When stratified by 5 groups of CAC scores (0, 1 to 99, 100 to 399, 400 to 1,000, and >1,000), the presence of obstructive CAD was not associated with higher risk than presence of nonobstructive CAD.

Conclusions: Plaque burden, not stenosis per se, is the main predictor of risk for CVD events and death. Thus, patients with a comparable calcified atherosclerosis burden generally carry a similar risk for CVD events regardless of whether they have nonobstructive or obstructive CAD.
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http://dx.doi.org/10.1016/j.jacc.2020.10.021DOI Listing
December 2020

SARS-CoV-2 infection and adverse outcomes in users of ACE inhibitors and angiotensin-receptor blockers: a nationwide case-control and cohort analysis.

Thorax 2020 Dec 8. Epub 2020 Dec 8.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.

Objective: To examine the impact of ACE inhibitor (ACE-I)/angiotensin receptor blocker (ARB) use on rate of SARS-CoV-2 infection and adverse outcomes.

Methods: This nationwide case-control and cohort study included all individuals in Denmark tested for SARS-CoV-2 RNA with PCR from 27 February 2020 to 26 July 2020. We estimated confounder-adjusted ORs for a positive test among all SARS-CoV-2 tested, and inverse probability of treatment weighted 30-day risk and risk ratios (RRs) of hospitalisation, intensive care unit (ICU) admission and mortality comparing current ACE-I/ARB use with calcium channel blocker (CCB) use and with non-use.

Results: The study included 13 501 SARS-CoV-2 PCR-positive and 1 088 695 PCR-negative individuals. Users of ACE-I/ARB had a marginally increased rate of a positive PCR when compared with CCB users (aOR 1.17, 95% CI 1.00 to 1.37), but not when compared with non-users (aOR 1.00 95% CI 0.92 to 1.09).Among PCR-positive individuals, 1466 (11%) were ACE-I/ARB users. The weighted risk of hospitalisation was 36.5% in ACE-I/ARB users and 43.3% in CCB users (RR 0.84, 95% CI 0.70 to 1.02). The risk of ICU admission was 6.3% in ACE-I/ARB users and 5.4% in CCB users (RR 1.17, 95% CI 0.64 to 2.16), while the 30-day mortality was 12.3% in ACE-I/ARB users and 13.9% in CCB users (RR 0.89, 95% CI 0.61 to 1.30). The associations were similar when ACE-I/ARB users were compared with non-users.

Conclusions: ACE-I/ARB use was associated neither with a consistently increased rate nor with adverse outcomes of SARS-CoV-2 infection. Our findings support the current recommendation of continuing use of ACE-Is/ARBs during the SARS-CoV-2 pandemic.

Trial Registration Number: EUPAS34887.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725106PMC
December 2020

Cancer risk in individuals with major birth defects: large Nordic population based case-control study among children, adolescents, and adults.

BMJ 2020 12 2;371:m4060. Epub 2020 Dec 2.

Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.

Objective: To examine associations between birth defects and cancer from birth into adulthood.

Design: Population based nested case-control study.

Setting: Nationwide health registries in Denmark, Finland, Norway, and Sweden.

Participants: 62 295 cancer cases (0-46 years) and 724 542 frequency matched controls (matched on country and birth year), born between 1967 and 2014.

Main Outcome Measures: Relative risk of cancer in relation to major birth defects, estimated as odds ratios with 99% confidence intervals from logistic regression models.

Results: Altogether, 3.5% (2160/62 295) of cases and 2.2% (15 826/724 542) of controls were born with major birth defects. The odds ratio of cancer for people with major birth defects compared with those without was 1.74 (99% confidence interval 1.63 to 1.84). For individuals with non-chromosomal birth defects, the odds ratio of cancer was 1.54 (1.44 to 1.64); for those with chromosomal anomalies, the odds ratio was 5.53 (4.67 to 6.54). Many structural birth defects were associated with later cancer in the same organ system or anatomical location, such as defects of the eye, nervous system, and urinary organs. The odds ratio of cancer increased with number of defects and decreased with age, for both non-chromosomal and chromosomal anomalies. The odds ratio of cancer in people with any non-chromosomal birth defect was lower in adults (≥20 years: 1.21, 1.09 to 1.33) than in adolescents (15-19 years: 1.58, 1.31 to 1.90) and children (0-14 years: 2.03, 1.85 to 2.23). The relative overall cancer risk among adults with chromosomal anomalies was markedly reduced from 11.3 (9.35 to 13.8) in children to 1.50 (1.01 to 2.24). Among adults, skeletal dysplasia (odds ratio 3.54, 1.54 to 8.15), nervous system defects (1.76, 1.16 to 2.65), chromosomal anomalies (1.50, 1.01 to 2.24), genital organs defects (1.43, 1.14 to 1.78), and congenital heart defects (1.28, 1.02 to 1.59) were associated with overall cancer risk.

Conclusions: The increased risk of cancer in individuals with birth defects persisted into adulthood, both for non-chromosomal and chromosomal anomalies. Further studies on the molecular mechanisms involved are warranted.
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http://dx.doi.org/10.1136/bmj.m4060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708828PMC
December 2020

The DANish Comorbidity Index for Acute Myocardial Infarction (DANCAMI): Development, Validation and Comparison with Existing Comorbidity Indices.

Clin Epidemiol 2020 20;12:1299-1311. Epub 2020 Nov 20.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Objective: To develop and validate the DANish Comorbidity index for Acute Myocardial Infarction (DANCAMI) for adjustment of comorbidity burden in studies of myocardial infarction prognosis.

Methods: Using medical registries, we identified patients with first-time myocardial infarction in Denmark during 2000-2013 (n=36,685). We developed comorbidity indices predicting 1-year all-cause mortality from all comorbidities (DANCAMI) and restricted to non-cardiovascular comorbidities (rDANCAMI). For variable selection, we eliminated comorbidities stepwise using hazard ratios from multivariable Cox models. We compared DANCAMI/rDANCAMI with Charlson and Elixhauser comorbidity indices using standard performance measures (Nagelkerke's R, Harrell's C-statistic, the Integrated Discrimination Improvement, and the continuous Net Reclassification Index). We assessed the significance of the novel DANCAMI variables not included in the Charlson Comorbidity Index. External validation was performed in patients with myocardial infarction in New Zealand during 2007-2016 (n=75,069).

Results: The DANCAMI included 24 comorbidities. The rDANCAMI included 17 non-cardiovascular comorbidities. In the Danish cohort, the DANCAMI indices outperformed both the Charlson and the Elixhauser comorbidity indices on all performance measures. The DANCAMI indices included multiple variables that were significant predictors of 1-year mortality even after controlling for all variables in the Charlson Comorbidity Index. These novel variables included valvular heart disease (hazard ratio for 1-year mortality=1.25, 95% CI: 1.14-1.35), coagulopathy (1.13, 95% CI: 1.05-1.22), alcohol and drug abuse (1.35, 95% CI: 1.15-1.58), schizophrenia (1.60, 95% CI: 1.46-1.76), affective disorder (1.29, 95% CI: 1.22-1.36), epilepsy (1.26, 95% CI: 1.05-1.50), neurodegenerative disorder (1.30, 95% CI: 1.10-1.54) and chronic pancreatitis (1.71, 95% CI: 1.14-2.56). The results were supported by the external validation in New Zealand.

Conclusion: DANCAMI assessed comorbidity burden of patients with first-time myocardial infarction, outperformed existing comorbidity indices, and was generalizable to patients outside Denmark. DANCAMI is recommended as a standard approach for comorbidity adjustment in studies of myocardial infarction prognosis.
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http://dx.doi.org/10.2147/CLEP.S277325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685362PMC
November 2020