Search

Objectives: To inform researchers of central considerations and limitations when applying biochemical laboratory-generated registry data in clinical and public health research., Study Design and Setting: After review of literature on registry-based studies and the utilization of clinical laboratory registry data, relevant paragraphs and their applicability toward the creation of considerations for the use of biochemical registry data in research were evaluated. This led to the creation of an initial ten considerations. These were elaborated, edited, and merged after several read-throughs by all authors and discussed thoroughly under influence by the authors' personal experiences with laboratory databases and research registries in Denmark, leading to the formulation of five central considerations with corresponding items and illustrative examples., Results: We recommend that the following considerations should be addressed in studies relying on biochemical laboratory-generated registry data: why are biochemical laboratory data relevant to examine the hypothesis, and how were the variable(s) utilized in the study? What were the primary indications for specimen collection in the study population of interest? Were there any pre-analytical circumstances that could influence the test results? Are data comparable between producing laboratories and within the single laboratory over time? Is the database representative in terms of completeness of study populations and key variables?, Conclusion: It is crucial to address key errors in laboratory registry data and acknowledge potential limitations., Competing Interests: Declaration of competing interest The authors report no conflicts of interest regarding the study presented in this paper. K.A.D. is now an employee of Novo Nordisk A/S., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neighborhood socioeconomic disadvantage is associated with cardiovascular health, although it is unclear which specific aspects of neighborhoods matter most. We leveraged a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998, creating variation in exposure to various aspects of neighborhood disadvantage. The cohort was followed through December 2018. Exposures included neighborhood-level family income, educational attainment, unemployment, and welfare transfers measured in the first neighborhood after arrival to Denmark. Outcomes included cardiovascular risk factors (hyperlipidemia, hypertension, diabetes and anxiety/depression) and cardiovascular disease (acute myocardial infarction and ischemic heart disease). Neighborhood-level income and education were most consistently associated with cardiovascular risk factors, whereas welfare transfers were most consistently associated with cardiovascular disease. Addressing these specific aspects of neighborhood disadvantage could therefore lower the risk of poor cardiovascular health among refugees. Future research is warranted to examine if results are generalizable to other immigrant groups, countries or time periods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: People with mental disorders exhibit increased mortality due to colorectal cancer, despite having a similar incidence to the general population. We aimed to evaluate the extent to which people with mental disorders participate in organised colorectal cancer screening., Methods: We conducted a population-based cohort study of all Danish residents aged 50-74 years who were invited to undergo biennial faecal immunochemical testing between March 1, 2014, and Sept 30, 2018. We used national registry data from all first-time invitees. The primary endpoint was participation within 90 days of invitation. We calculated the proportion who participated and assessed their screening results and adherence to and completeness of follow-up colonoscopy according to their history of mental disorders, classified as none, mild or moderate, or severe. We computed crude and adjusted participation differences in percentage points and participation ratios using the pseudo-observations method., Findings: Of 2 036 704 people who were invited, we included 2 036 352 in the final cohort, of whom 1 008 045 (49·5%) were men and 1 028 307 (50·5%) were women, with a mean age of 60·7 years (SD 8·3, range 49-78). Data on ethnicity were not collected. Compared with people with no mental disorders, the adjusted analysis showed lower participation among people with mild or moderate mental disorders (men: participation difference -4·4 percentage points [95% CI -4·7 to -4·1]; women: -3·8 percentage points [-4·1 to -3·6]) and severe mental disorders (men: participation difference -13·8 percentage points [-14·3 to -13·3]; women: -15·4 percentage points [-15·8 to -14·9]). People with mental disorders had a higher proportion of positive faecal immunochemical test results, lower adherence to colonoscopy, and more incomplete colonoscopies than people without mental disorders., Interpretation: People with mental disorders were less likely to participate in colorectal cancer screening than those without these disorders. Patients with mental disorders could benefit from support or encouragement from their general practitioner or mental health-care facility to participate in cancer screening. Potential interventions should consider type of mental disorder, as needs might differ., Funding: Danish Cancer Society, Danish Health Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The psychologic consequences of acute venous thromboembolism (VTE) have not been investigated in depth., Objectives: We aimed to examine the association between VTE and the risk of subsequent depression., Methods: Using Danish nationwide registries, we established a population-based cohort of 64 596 individuals with incident VTE during 1996 to 2016 and a comparison cohort (n = 322 999) selected randomly from the general population and individually matched by birth year, sex, and calendar year of VTE. The participants were followed up for 3 years, and depression was defined as any hospital diagnosis of depression or ≥1 prescription for antidepressants. Incidence rates were computed as the number of events per 1000 person-years, and hazard ratios with 95% CIs were computed as estimates of the risk conferred by VTE using the comparison cohort as reference. We estimated absolute risks using cumulative incidence functions, treating death as a competing event., Results: Depression was observed in 6225 individuals after VTE and 16 363 members of the comparison cohort (incidence rates of 44.4 and 19.4 per 1000 person-years, respectively). The absolute risk of depression was 10.3% (95% CI, 10.1%-10.6%) in the VTE cohort and 5.6% (95% CI, 5.5%-5.6%) in the comparison cohort, corresponding to 4.7 excess cases of depression per 100 individuals with VTE. VTE was associated with a 2.35-fold (95% CI, 2.28-2.43) increased risk of depression compared with that in the comparison cohort. The association was attenuated after adjustments for socioeconomic status and comorbidities (hazard ratio, 1.91; 95% CI, 1.85-1.97)., Conclusion: VTE was associated with an increased risk of depression after adjustment for comorbidities., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Patients with venous thromboembolism (VTE) are commonly classified by the presence or absence of provoking factors at the time of VTE to guide treatment decisions. This approach may not capture the heterogeneity of the disease and its prognosis., Objectives: To evaluate clinically important novel phenotypic clusters among patients with VTE without cancer and to explore their association with anticoagulant treatment and clinical outcomes., Methods: Latent class analysis was performed with 18 baseline clinical variables in 3062 adult patients with VTE without active cancer participating in PREFER in VTE, a noninterventional disease registry. The derived latent classes were externally validated in a post hoc analysis of Hokusai-VTE (n = 6593), a randomized trial comparing edoxaban with warfarin. The associations between cluster membership and anticoagulant treatment, recurrent VTE, bleeding, and mortality after initial treatment were studied., Results: The following 5 clusters were identified: young men cluster (n = 1126, 37%), young women cluster (n = 215, 7%), older people cluster (n = 1106, 36%), comorbidity cluster (n = 447, 15%), and history of venous thromboembolism cluster (n = 168, 5%). Patient characteristics varied by age, sex, medical history, and treatment patterns. Consistent clusters were evident on external validation. In Cox proportional hazard models, recurrence risk was lower in the young women cluster (hazard ratio [HR], 0.27; 95% CI, 0.12-0.61) compared with the comorbidity cluster, after adjusting for extended anticoagulation. The risk of bleeding was lower in young men, young women, and older people clusters (HR, 0.50; 95% CI, 0.38-0.66; HR, 0.23; 95% CI, 0.11-0.46; and HR, 0.55; 95% CI 0.41-0.73, respectively)., Conclusion: The heterogeneity of VTE cases extends beyond the distinction between provoked and unprovoked VTE., (Copyright © 2022 International Society on Thrombosis and Haemostasis. All rights reserved.)

Background: Breast cancer survivors may have increased risk of subsequent haematologic cancer. We compared their risk of haematologic cancers with the general population during 38 years of follow-up., Methods: Using population-based Danish medical registries, we assembled a nationwide cohort of women diagnosed with incident non-metastatic breast cancer during 1980-2017, with follow-up through 2018. We compared breast cancer survivors with the general population by computing standardised incidence ratios (SIR) and 95% confidence intervals (CI)., Results: Among 101,117 breast cancer survivors, we observed 815 incident haematologic cancers (median follow-up: 7.9 years). We observed excess risk of acute myeloid leukaemia (AML) (SIR: 1.65, 95%CI: 1.33-2.01), particularly in women who received chemotherapy (SIR: 3.33, 95%CI: 2.24-4.75) and premenopausal women (SIR: 3.23, 95%CI: 2.41-4.25). The risk of acute lymphoid leukaemia (ALL) was increased (SIR: 2.25, 95%CI: 1.29-3.66), whereas the risk of chronic lymphoid leukaemia (CLL) was decreased (SIR: 0.66, 95%CI: 0.53-0.82). An additional analysis showed elevated risk of CLL 0-6 months after breast cancer diagnosis (SIR: 3.00 95%CI: 1.75-4.80)., Conclusion: Compared to the general population, breast cancer survivors had elevated risk of AML, particularly when treated with chemotherapy. The risk of ALL was elevated, whereas the risk of CLL was lower. The higher risk of CLL in the first six months after diagnosis likely reflects surveillance bias-due to intensified diagnostic efforts at breast cancer diagnosis and treatment-prompting earlier detection. This has likely reduced the long-term risk of CLL in breast cancer survivors., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: We examined the impact of liver cirrhosis on the risk of thromboembolic events and bleeding complications in patients with atrial fibrillation or flutter (AFF)., Methods: This population-based cohort study used data from Danish health registries. We identified all patients with a first-time diagnosis of AFF during 1995 to 2015, and followed them from their AFF diagnosis until the end of 2016. Patients were categorized according to the presence or absence of liver cirrhosis. We computed incidence rates per 1000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) based on Cox regression analyses, adjusting for age, CHA 2 DS 2 VASc score, and Charlson Comorbidity Index score., Results: We identified 273 225 patients with AFF. Of these, 1463 (0.54%) had liver cirrhosis. During 0 to 5 years of follow-up, compared to patients without liver cirrhosis, patients with liver cirrhosis had higher incidence rates and hazards of ischemic stroke (29.7 vs 21.6; HR, 1.3; 95% CI, 1.1-1.6), venous thromboembolism (9.2 vs 5.5; HR, 1.5; 95% CI, 1.2-2.3), but not myocardial infarction (10.2 vs 11.2; HR, 0.9; 95% CI, 0.7-1.2). Patients with liver cirrhosis also had higher rates of hemorrhagic stroke (5.8 vs 3.3; HR, 1.7; 95% CI, 1.1-2.6), subdural hemorrhage (5.3 vs 1.6; HR, 3.2; 95% CI, 2.1-4.9), hemorrhage of the lung or urinary tract (24.6 vs 15.2; HR, 1.6; 95% CI, 1.3-2.0), and gastrointestinal hemorrhage (34.5 vs 10.4; HR, 3.3; 95% CI, 2.7-3.9)., Conclusion: In patients with AFF, liver cirrhosis was associated with an elevated risk of ischemic stroke, venous thromboembolism, and all evaluated bleeding complications., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Cardiovascular disease (CVD) is increasing in youths, but there is limited knowledge about the etiology of early-onset CVD. We aimed to examine the association between maternal education before childbirth and CVD risk in offspring during early adulthood (20 to 40 years of age)., Methods: This population-based cohort study included 112,3600 subjects born in Denmark during 1977 to 1996., Results: Compared with offspring born to mothers with high education, offspring born to mothers with low or medium education had 27% (hazard ratio, 1.27; 95% confidence interval, 1.23-1.30) or 12% (1.12; 1.09-1.15) increased overall risk of early-onset CVD, respectively. Increased risks were observed for most type-specific CVDs: in particular, for myocardial infarction (low [2.03; 1.55-2.65] or medium education [1.52; 1.16-1.99]), heart failure (low [1.59; 1.24-2.03] or medium education [1.51; 1.19-1.92]), and ischemic stroke (low [1.50; 1.28-1.76] or medium education [1.29; 1.10-1.51]). We observed high incidences of CVD in offspring of mothers with comorbid CVD (low [1.67; 1.51-1.86] or medium education [1.46; 1.29-1.64]), compared with those of mothers with high education and no history of CVD., Conclusions: Low maternal education before childbirth, especially with maternal comorbid CVD, is significantly associated with increased risk of overall CVD and most type-specific CVDs in offspring in early adulthood. The influence of maternal education on future offspring CVD should be taken into consideration in the assessment of CVD risks from early decades of life., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although venous thromboembolism (VTE) is a leading cause of morbidity and mortality, and socioeconomic status (SES) affects human health and health behavior, few studies have examined the association between SES and VTE., Objectives: We aimed to investigate the association between SES, assessed individually and in a composite score by levels of education, income, and employment status, and incident VTE., Methods: We used Danish national registries to identify 51 350 persons aged 25-65 years with incident VTE during 1995-2016. For each case, we used incidence density sampling to select five age-, sex-, and index-year-matched controls from the general Danish population (n = 256 750). SES indicators, including education, income, and employment status, were assessed 1 and 5 years before the VTE. We used conditional logistic regression to compute odds ratios (ORs) with 95% confidence intervals (CIs) for VTE according to individual SES indicators and a composite SES score in analyses adjusted for age, sex, and comorbidities., Results: Compared with low levels, high educational level (OR 0.74; 95% CI 0.71-0.77), high income (OR 0.70; 95% CI 0.68-0.72), and high employment status (OR 0.66; 95% CI 0.64-0.68) were associated with decreased risk of VTE, even after adjusting for comorbidities. A composite SES score was superior to the individual indicators in assessing VTE risk (OR for high vs. low score: 0.61; 95% CI 0.59-0.63). In sensitivity analysis with SES indicators measured 5 years before the VTE, the risk estimates remained essentially the same., Conclusion: High levels of both individual SES indicators and a composite SES score were associated with decreased VTE risk., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Objectives: The aim of this study was to examine prevalence, predictors, and impact of coronary artery calcium (CAC) across different risk factor burdens on the prevalence of obstructive coronary artery disease (CAD) and future coronary heart disease (CHD) risk in young patients., Background: The interplay of risk factors and CAC for predicting CHD in young patients aged ≤45 years is not clear., Methods: The study included 3,691 symptomatic patients (18-45 years of age) from the WDHR (Western Denmark Heart Registry) undergoing coronary computed tomographic angiography. CHD events were myocardial infarction and late revascularization., Results: During a median of 4.1 years of follow-up, 57 first-time CHD events occurred. In total, 3,180 patients (86.1%) had CAC = 0 and 511 patients (13.9%) had CAC >0. Presence of CAC increased with number of risk factors (odds ratio: 4.5 [95% CI: 2.7-7.3] in patients with >3 vs 0 risk factors). The prevalence of obstructive CAD at baseline and the rate of future CHD events increased in a stepwise manner with both higher CAC and number of risk factors. The CHD event rate was lowest at 0.5 (95% CI: 0.1-3.6) per 1,000 person-years in patients with 0 risk factors and CAC = 0. Among patients with >3 risk factors, the event rate was 3.1 (95% CI: 1.0-9.7) in patients with CAC = 0 compared with 36.3 (95% CI: 17.3-76.1) in patients with CAC >10., Conclusions: In young patients, there is a strong interplay between CAC and risk factors for predicting the presence of obstructive CAD and for future CHD risk. In the presence of risk factors, even a low CAC score is a high-risk marker. These results demonstrate the importance of assessing risk factors and CAC simultaneously when assessing risk in young patients., Competing Interests: Funding Support and Author Disclosures This study was funded by Aarhus University Hospital. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The incidence of venous thromboembolism (VTE) in cancer patients may have changed in the past decade, possibly due to novel cancer therapies, improved survival, and high-resolution imaging. Danish medical registries were used to identify 499 092 patients with a first-time cancer diagnosis between 1997 and 2017, who were matched to 1 497 276 comparison individuals without cancer from the general population. We computed cumulative incidences of VTE 6 and 12 months after the diagnosis/index date. Hazard ratios (HRs) were calculated using Cox regression. Risk factors were examined by computing subdistribution hazard ratios (SHRs) in a competing-risk analysis. Cumulative incidence of VTE 12 months after the cancer diagnosis/index date was 2.3% (95% confidence interval [CI], 2.2% to 2.3%) in the cancer cohort and 0.35% (95% CI, 0.34% to 0.36%) in the comparison cohort (HR, 8.5; 95% CI, 8.2-8.8). Important risk factors for cancer patients were prior VTE (SHR, 7.6; 95% CI, 7.2-8.0), distant metastasis (SHR, 3.2; 95% CI, 2.9-3.4), and use of chemotherapy (SHR, 3.4; 95% CI, 3.1-3.7), protein kinase inhibitors (SHR, 4.1; 95% CI, 3.4-4.9), antiangiogenic therapy (SHR, 4.4; 95% CI, 3.8-5.2), and immunotherapy (SHR, 3.6; 2.8-4.6). Twelve-month incidence in the cancer cohort increased from 1.0% (95% CI, 0.9% to 1.2%) in 1997 to 3.4% (95% CI, 2.9% to 4.0%) in 2017, which was paralleled by improved 12-month survival and increased use of computed tomography scans, chemotherapy, and targeted therapies. In conclusion, the risk of VTE in cancer patients is increasing steadily and is ninefold higher than in the general population., (© 2021 by The American Society of Hematology.)

Objectives: The authors sought to assess the distribution of 5-year risk of cardiovascular disease (CVD) events (myocardial infarction, revascularizations, ischemic stroke) and death among symptomatic patients with varying degrees of coronary artery disease (CAD) ascertained from computed tomography angiography (CTA)., Background: CTA is used increasingly as the first-line test for evaluating patients with symptoms suggestive of CAD. This creates the daily clinical challenge of best using the information available from CTA to guide appropriate downstream allocation of preventive treatments., Methods: Among 21,275 patients from the Western Denmark Heart Registry, the authors developed a model predicting 5-year risk for CVD and death based on traditional risk factors and CAD severity. Only events occurring >90 days after CTA were included., Results: During a median follow-up of 4.2 years, 1,295 CVD events and deaths occurred. The median 5-year risk for events was 4% (interquartile range: 3% to 8%), and ranged from <5% to >50% in individual patients. The degree of CAD severity was the strongest risk factor; however, traditional risk factors also contributed significantly to risk. Thus, risk distributions in patients with varying degree of CAD overlapped considerably, and patients with extensive nonobstructive CAD could have higher estimated risk than patients with obstructive CAD (stenosis >50%). Among patients with obstructive CAD, 12% had 5-year risk <10% whereas 24% had risk >20%. A similar large overlap in risk was found when revascularizations were excluded from the endpoint., Conclusions: The 5-year risk for CVD events and death varies substantially in symptomatic patients undergoing CTA, even in the presence of obstructive CAD. These results provide support for individual risk assessment to improve potential benefit when allocating preventive therapies following CTA., Competing Interests: Funding Support and Author Disclosures This study was funded by Aarhus University Hospital. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Accurate estimates of hepatocellular carcinoma (HCC) risk in patients with cirrhosis are important to guide surveillance strategies. We described HCC risk among outpatients with alcohol-related cirrhosis and contrasted the risk of death from HCC with the risk of death from variceal bleeding or trauma., Methods: This was a nationwide, registry-based historical cohort study between 2006 and 2018. We included all Danish outpatients with a hospital diagnosis of alcohol-related cirrhosis, except those with cancer, those with chronic viral hepatitis or autoimmune liver disease, and those older than 80 years. We followed them through 2018 and described the cumulative risk of HCC and the cumulative risk of death from HCC, variceal bleeding, or trauma., Results: Of the 4,553 patients included, 181 developed HCC and 2,274 died. The cumulative risk of HCC was 0.9% (95% CI 0.7-1.3) after 1 year, 3.6% (95% CI 3.0-4.2) after 5 years, and 6.0% (95% CI 5.1-7.0) after 10 years, or approximately 0.7% per year. Male sex, older age, and decompensated cirrhosis predicted a higher HCC risk. After 10 years, 6.9% of deaths in the cohort could be attributed to HCC, whereas 6.5% could be attributed to variceal bleeding, and 5.0% to trauma., Conclusions: In 2006-2018, Danish outpatients with alcohol-related cirrhosis had an HCC risk of 0.7% per year, and they were nearly as likely to die from variceal bleeding or from trauma as from HCC. The implications are that many potentially harmful examinations are required for every HCC found through surveillance, so interventions targeting the prevention of other causes of death might be more cost-effective., Lay Summary: We described the risk of hepatocellular carcinoma (HCC, the most common form of liver cancer originating in the liver) in Danish outpatients with cirrhosis due to harmful alcohol consumption. Accurate data on that risk are important for patient counselling and decisions about screening for HCC. The risk was about 0.7% per year, which is lower than might be expected and suggests that many potentially harmful screening examinations are required for every HCC found through surveillance., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to assess if information on CAD severity from coronary computed tomography angiography (CTA) can identify patients that benefit most from treating low-density lipoprotein-cholesterol (LDL-C) to American Heart Association/American College of Cardiology (ACC/AHA) and European Society of Cardiology (ESC) guidelines targets., Background: Current treatment guidelines for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) disregard severity of coronary artery disease (CAD) for treatment choices. It is unclear whether severity of CAD should be considered in treatment recommendations., Methods: Among 20,241 symptomatic patients undergoing diagnostic CTA from the Western Denmark Heart Registry, we assessed the number needed to treat (NNT) in 6 years to prevent 1 ASCVD event as well as the proportion of all events that could be prevented by treating LDL-C to targets. We assumed a 22% relative reduction of ASCVD events per 1 mmol/l reduction in LDL-C., Results: In multivariable analysis with no CAD as the reference, the subdistribution hazard ratio for ASCVD events was 4.0 (95% confidence interval [CI]: 3.3 to 4.9) for 1-vessel disease, 4.6 (3.5 to 6.0) for 2-vessel disease, and 5.6 (4.0 to 8.0) for 3-vessel disease. Consequently, the NNT to prevent 1 ASCVD event in 6 years by treating LDL-C to targets varied greatly from 233 (ESC) and 110 (ACC/AHA) for patients with no CAD to 8-9 for patients with 3-vessel disease (both ACC/AHA and ESC). The estimated percentage of ASCVD events that could be prevented by achieving guideline targets was 30% to 36% for patients with obstructive disease. However, <20% of patients achieved targets., Conclusions: An individualized approach based on CAD severity can identify symptomatic patients that are likely to derive most and least benefit from treating LDL-C to ACC/AHA and ESC treatment targets., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Myocardial infarction (MI) is a risk factor for venous thromboembolism (VTE). Although comorbidities affect MI prognosis, it is unclear whether they affect VTE risk after MI., Objectives: We examined the impact of comorbidity on VTE risk after MI., Methods: We used nationwide population-based registries to identify first-time hospitalizations for MI and subsequent occurrence of VTE in Denmark (1995-2013). We included a comparison cohort from the general population matched 5:1 with MI patients by sex, age, and comorbidities. We computed 30-day and 1- to 12-month cumulative risks, rates, and hazard ratios of VTE. We also assessed the interaction between MI and comorbidity, defined as excess VTE risk in patients with both MI and comorbidity, by computing interaction contrasts and attributable fractions relating to the interaction., Results: Thirty-day and 1- to 12-month VTE risks were 0.6% and 0.5% in the MI cohort (n = 160 338) and 0.03% and 0.3% in the comparison cohort (n = 792 384). The 30-day hazard ratio for VTE in the MI cohort was 23 (95% confidence interval, 20-27), which decreased during 1-year follow-up. Thirty days after MI, interactions between MI and comorbidity accounted for 16% and 39% of VTE rates in MI patients with low-to-moderate and high comorbidity, respectively. The interactions were driven primarily by hemiplegia and cancer., Conclusions: Thirty-day VTE risk was substantially increased after MI compared with the general population. Although the absolute VTE risk was low, comorbidity substantially increased this risk, especially hemiplegia and cancer. VTE prophylaxis might be indicated in such high-risk patients but warrants further investigation., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Whether the prognostic impact of comorbidity on myocardial infarction (MI) mortality is due to comorbidity alone or/and its interaction effect is unknown., Methods: We used Danish medical registries to conduct a nationwide cohort study of all first-time MIs during 1995-2016 (n = 179,515) and a comparison cohort matched on age, sex, and individual comorbidities (n = 880,347). We calculated age-standardized 5-year all-cause mortality rates. Interaction was examined on an additive scale by calculating interaction contrasts (difference in rate differences)., Results: Among individuals without comorbidity, the 30-day mortality rate per 1000 person-years was 1851 (95% CI: 1818-1884) for MI patients and 22 (21-24) for comparison cohort members (rate difference = 1829). For individuals with low comorbidity, corresponding baseline mortality rates were 2498 (2436-2560) in the MI and 54 (50-57) in the comparison cohort (rate difference = 2444). The interaction contrast (616) indicated that the interaction accounted for 25% (616/2498) of the total 30-day mortality rate in MI patients with low comorbidity. This percentage increased further for moderate (35%) and severe (45%) comorbidity levels. Absolute and relative interaction effects were largest within the first 30 days and younger individuals. Dose-response patterns were also observed during 31-365 days and 1-5 years of follow-up (p-values for trends<0.002). The interaction differed substantially between individual types of cardiac and non-cardiac comorbidities., Conclusion: Cardiac and non-cardiac comorbidities interact with MI to increase short- and long-term mortality beyond that explained by their additive effects. The interaction had a dose-response relation with comorbidity burden and a magnitude of clinical importance., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work. None of the authors has received any fees, honoraria, grants or consultancies that would constitute a conflict of interest with the current study. The Department of Clinical Epidemiology, Aarhus University Hospital, receives funding for other studies from companies in the form of research grants to (and administered by) Aarhus University. None of those studies has any relation to the present study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Ulcerative colitis (UC) is a risk factor for colorectal cancer (CRC). However, available studies reflect older treatment and surveillance paradigms, and most have assessed risks for incident CRC without taking surveillance and lead-time bias into account, such as by assessing CRC incidence by tumour stage, or stage-adjusted mortality from CRC. We aimed to compare both overall and country-specific risks of CRC mortality and incident CRC among patients with UC., Methods: In this population-based cohort study of 96 447 patients with UC in Denmark (n=32 919) and Sweden (n=63 528), patients were followed up for CRC incidence and CRC mortality between Jan 1, 1969, and Dec 31, 2017, and compared with matched reference individuals from the general population (n=949 207). Patients with UC were selected from national registers and included in the analysis if they had two or more records with a relevant International Classification of Disease in the patient register (in the country in question) or one such record plus a colorectal biopsy report with a morphology code suggestive of inflammatory bowel disease. For every patient with UC, we selected matched reference individuals from the total population registers of Denmark and Sweden, who were matched for sex, age, birth year, and place of residence. We used Cox regression to compute hazard ratios (HRs) for incident CRC, and for CRC mortality, taking tumour stage into account., Findings: During follow-up, we observed 1336 incident CRCs in the UC cohort (1·29 per 1000 person-years) and 9544 incident CRCs in reference individuals (0·82 per 1000 person-years; HR 1·66, 95% CI 1·57-1·76). In the UC cohort, 639 patients died from CRC (0·55 per 1000 person-years), compared with 4451 reference individuals (0·38 per 1000 person-years; HR 1·59, 95% CI 1·46-1·72) during the same time period. The CRC stage distribution in people with UC was less advanced (p<0·0001) than in matched reference individuals, but taking tumour stage into account, patients with UC and CRC remained at increased risk of CRC death (HR 1·54, 95% CI 1·33-1·78). The excess risks declined over calendar periods: during the last 5 years of follow-up (2013-17, Sweden only), the HR for incident CRC in people with UC was 1·38 (95% CI 1·20-1·60, or one additional case per 1058 patients with UC per 5 years) and the HR for death from CRC was 1·25 (95% CI 1·03-1·51, or one additional case per 3041 patients with UC per 5 years)., Interpretation: Compared with those without UC, individuals with UC are at increased risk of developing CRC, are diagnosed with less advanced CRC, and are at increased risk of dying from CRC, although these excess risks have declined substantially over time. There still seems to be room for improvement in international surveillance guidelines., Funding: The Swedish Medical Society, Karolinska Institutet, Stockholm County Council, Swedish Research Council, Swedish Foundation for Strategic Research, Independent Research Fund Denmark, Forte Foundation, Swedish Cancer Foundation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months., Methods: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed., Findings: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed., Interpretation: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI., Funding: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The etiology of pericarditis, myocarditis, and endocarditis is predominantly infectious, and infections often show seasonal variation. Little is known, however, about seasonal patterns in these cardiopathies., Methods: Using Danish health care registries, we identified all patients with a first-time hospital-based diagnosis of pericarditis, myocarditis, or endocarditis between 1994 and 2016. We estimated peak-to-trough ratios from fitted sine curves to measure the intensity of seasonal variation in occurrence during the study period. Because randomness will lead to small apparent seasonal patterns, we also conducted a plasmode simulation to assess the degree of seasonality that randomness would produce., Results: Crude peak-to-trough ratios of monthly frequencies summarized over a year were small. We estimated a peak-to-trough ratio of 1.10 (95% confidence interval [CI], 1.05-1.14) for pericarditis, 1.11 (95% CI, 1.02-1.21) for myocarditis, and 1.01 (95% CI, 1.00-1.07) for endocarditis. The simulated mean peak-to-trough ratios found after randomly reassigning the monthly frequencies within each year were 1.04 (95% CI, 1.00-1.09) for pericarditis, 1.04 (95% CI, 1.00-1.13) for myocarditis, and 1.04 (95% CI, 1.00-1.10), for endocarditis., Conclusion: The data indicate no important seasonal variation in the occurrence of pericarditis, myocarditis, and endocarditis in Denmark between 1994 and 2016., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Therapeutic advances have improved survival after hematological cancers. In turn, patients may be at increased risk of thromboembolic and bleeding events., Objectives: To examine the risks of myocardial infarction (MI), ischemic stroke, venous thromboembolism (VTE), and bleeding requiring hospital contact in patients with hematological cancers., Methods: We conducted a Danish population-based cohort study (2000-2013). We identified all adult hematological cancer patients and sampled a general population comparison cohort in a 1:5 ratio matched by age, sex, previous thromboembolic events, bleeding, and solid cancer. Ten-year absolute risks of thromboembolism and bleeding were calculated and hazard ratios (HRs) were computed, controlling for matching factors., Results: Among 32 141 hematological cancer patients, the 10-year absolute risk of any thromboembolic or bleeding complication following hematological cancer was 19%: 3.3% for MI, 3.5% for ischemic stroke, 5.2% for VTE, and 8.5% for bleeding. Except among patients with myeloid leukemia, acute lymphoid leukemia, or myelodysplastic syndrome, the risk of thromboembolic events surpassed that of bleeding. The hematological cancer cohort overall was at increased risk for MI [HR = 1.36, 95% confidence interval (CI): 1.25-1.49], ischemic stroke (HR = 1.22, 95% CI: 1.12-1.33), VTE (HR = 3.37, 95% CI: 3.13-3.64), and bleeding (HR = 2.39, 95% CI: 2.26-2.53) compared with the general population., Conclusions: Approximately 2 of 10 hematological cancer patients experienced MI, ischemic stroke, VTE, or bleeding requiring hospital contact within 10 years. The hematological cancer cohort had higher hazards of MI, ischemic stroke, VTE, and bleeding requiring hospital contact than a general population comparison cohort., (© 2019 International Society on Thrombosis and Haemostasis.)

Essentials Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count. We conducted a cohort study of 3 584 chronic ITP patients from the Nordic countries. Cardiovascular events occurred across all platelet count levels. Cardiovascular or bleeding events were strong prognostic factors for all-cause mortality. Background Among patients with chronic immune thrombocytopenia (cITP), little is known regarding risk factors for cardiovascular and bleeding outcomes and how these events influence mortality. Objectives We examined the rate of cardiovascular events and bleeding requiring a hospital contact according to platelet count levels, as well as the prognostic impact of these events on all-cause mortality in adult patients with cITP. Methods We identified all cITP patients registered in the Nordic Country Patient Registry for Romiplostim during 1996 to 2015. Absolute risks and hazard ratios across platelet count levels based on Cox regression analysis were computed, adjusting for age, sex, prevalent/incident cITP, smoking, and comorbidities. We also compared all-cause mortality rates in cITP patients with and without cardiovascular and bleeding events. Results Among 3 584 cITP patients, 1-year risks were 1.9% for arterial cardiovascular events, 1.2% for venous thromboembolism, and 7.5% for bleeding. Rates of cardiovascular events were similar across platelet counts. Patients with platelet counts <50 × 10 9 /L had >2-fold higher rates of bleeding than patients with normal platelet counts. These associations were unchanged in time-varying analyses that considered changes in platelet counts during follow-up. Occurrences of cardiovascular and bleeding events were associated with 4-fold to 5-fold increases in 1-year mortality. Conclusions Among patients with cITP, the 1-year risks of cardiovascular events were 1% to 2%, while nearly 8% experienced a bleeding event within 1 year. Cardiovascular events occurred across all platelet levels, while low platelet counts were associated with increased hazards of bleeding. Cardiovascular and bleeding events were strong prognostic factors for mortality., (© 2019 International Society on Thrombosis and Haemostasis.)

Objectives: Urinary tract infections have been linked with urinary tract cancer, but the association remains controversial. We examined whether pyelonephritis is a clinical marker of urogenital cancer., Methods: We used Danish medical databases to create a population-based cohort of patients with an incident hospital-based pyelonephritis diagnosis during 1994-2013. Follow-up for cancer began at pyelonephritis diagnosis and ended on 30 November 2013. We restricted the cohort to patients older than 50 years, as urogenital cancer risk in the younger population is low. We calculated the absolute risk of urogenital cancer and the standardized incidence ratio (SIR) comparing risk observed in pyelonephritis patients to risk expected in the general population of Denmark., Results: Among 15 070 patients with pyelonephritis, we observed 197 urinary tract cancers and 374 genital organ cancers over a 20-year follow-up period. The absolute risk of urogenital cancer was 1.5% 6 months after a pyelonephritis diagnosis, and the cumulative risk was 3.0% at 5 years. During the first 6 months following a pyelonephritis diagnosis, the SIR of urogenital cancer was 8.56 (95% CI 7.49-9.75). Between 6 and 12 months following this diagnosis, the SIR was 1.75 (95% CI 1.26-2.35), and beyond 1 year the SIR was approximately unity for most cancers. Notably, the SIR for bladder cancer among women remained elevated beyond 1 year of follow-up., Conclusions: Patients presenting with a hospital-based diagnosis of pyelonephritis had a higher 6-month risk of urogenital cancer than expected. However, causation cannot be inferred because of the study design., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Essentials The risk of thrombosis among ischemic stroke patients using glucocorticoids is unknown. We examined the risk of thrombosis in 98 487 ischemic stroke patients, by glucocorticoid use. Myocardial infarction and venous thromboembolism risk was increased in glucocorticoid users. Hemorrhagic stroke risk was lower and recurrent ischemic stroke the same in glucocorticoid users. SUMMARY: Background Glucocorticoid users have a high mortality rate following stroke, but the underlying clinical pathways are poorly understood. Objectives To examine the risk of cardiovascular events among ischemic stroke patients using glucocorticoids. Methods We conducted a nationwide population-based cohort study by using medical registries in Denmark. We identified all patients hospitalized with a first-time ischemic stroke (2004-2013). We categorized glucocorticoid use into current use (last prescription redemption ≤ 90 days before admission), former use, and non-use. With non-users as reference, we studied the risks of recurrent ischemic stroke, hemorrhagic stroke, myocardial infarction and venous thromboembolism associated with glucocorticoid use. Comorbidity and comedication-adjusted 1-year hazard ratios (aHRs) with 95% confidence intervals (CIs) were computed on the basis of Cox regression analysis. Results We identified 98 487 patients with a first-time (index) ischemic stroke. After the index stroke, the 1-year cumulative incidence of recurrent ischemic stroke was 16.4% among current glucocorticoid users, whereas risks were lower for hemorrhagic stroke (0.46%), myocardial infarction (1.35%), and venous thromboembolism (0.98%). Among current glucocorticoid users, aHRs were increased for myocardial infarction (1.32, 95% CI 0.98-1.76) and venous thromboembolism (1.39, 95% CI 0.99-1.94), whereas the risk of hemorrhagic stroke was reduced (aHR 0.60, 95% CI 0.38-0.93). There was no association with recurrent ischemic stroke (aHR 1.01, 95% CI 0.94-1.09). Conclusions During the first year after ischemic stroke, current glucocorticoid use was associated with moderately increased risks of myocardial infarction and venous thromboembolism, and a lower risk of hemorrhagic stroke, whereas the risk of recurrent ischemic stroke was not affected., (© 2018 Aarhus University Hospital. Journal of Thrombosis and Haemostasis © 2018 International Society on Thrombosis and Haemostasis.)

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 classification separates the spirometric 1-4 staging from the ABCD groups defined by symptoms and exacerbations. Little is known about how this new classification predicts mortality in patients with chronic obstructive pulmonary disease (COPD). We aimed to establish the predictive ability of the GOLD 2017 classification, compared with earlier classifications, for all-cause and respiratory mortality, both when using its main ABCD groups and when further subdividing according to spirometric 1-4 staging., Methods: In this nationwide cohort study, we enrolled patients with COPD with data available in the Danish registry for COPD. To be included in this registry, individuals must have been outpatients in hospital-based pulmonary clinics in Denmark. Eligible patients were aged 30 years or older; had received a primary diagnosis of COPD (International Classification of Diseases [ICD]-10 J44.X) or acute respiratory failure (ICD-10 J96.X) in combination with COPD (ICD-10 J44.X) as a secondary diagnosis; and had complete data on FEV 1 , body-mass index, modified Medical Research Council dyspnoea scale score, and smoking status. We categorised eligible patients with complete data according to the 2007, 2011, and 2017 GOLD classifications at the first contact with an outpatient clinic. For the GOLD 2017 classification, we further subdivided the patients by spirometry into 16 subgroups (1A to 4D). We calculated adjusted hazard ratios (HRs) for all-cause and respiratory mortality and compared the predictive ability of the three GOLD classifications (2007, 2011, and 2017) using receiver operating curves., Findings: We enrolled 33 765 patients with COPD, who were outpatients in Danish hospitals between Jan 1, 2008, and Nov 30, 2013, in the main cohort assessed for all-cause mortality. 22 621 of these patients had data available on cause-specific mortality (respiratory) and were included in a subcohort followed from Jan 1, 2008, to Dec 31, 2011. For the GOLD 2017 classification, 3 year mortality increased with increasing exacerbations and dyspnoea from group A (all-cause mortality 10·0%, respiratory mortality 3·0%) to group D (all-cause mortality 36·9%, respiratory mortality 18·0%). However, 3 year mortality was higher for group B patients (all-cause mortality 23·8%, respiratory mortality 9·7%) than for group C patients (all-cause mortality 17·4%, respiratory mortality 6·4%). Compared with group A, adjusted HRs for all-cause mortality ranged from 2·05 (95% CI 1·87-2·26) for group B, to 1·47 (1·31-1·65) for group C, and to 3·01 (2·75-3·30) for group D. Area under the curve for all-cause mortality was 0·61 (95% CI 0·60-0·61) for GOLD 2007, 0·61 (0·60-0·62) for GOLD 2011, and 0·63 (0·53-0·73) for GOLD 2017. Area under the curve for respiratory mortality was 0·64 (0·62-0·65) for GOLD 2007, 0·63 (0·62-0·64) for GOLD 2011, and 0·65 (0·53-0·78) for GOLD 2017. The GOLD 2017 classification based on ABCD groups only did not predict mortality better than the earlier 2007 and 2011 GOLD classifications. However, when 16 subgroups (1A to 4D) were defined, the new classification predicted mortality more accurately than the previous systems (p<0·0001)., Interpretation: We showed that the new GOLD 2017 ABCD classification does not predict all-cause and respiratory mortality more accurately than the previous GOLD systems from 2007 and 2011., Funding: Danish Lung Association, Program for Clinical Research Infrastructure., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Essentials Comorbidity is prevalent in the stroke population and affects post-stroke survival. A stroke patient cohort (n = 201 691) and a general population cohort were followed for survival. Cancer and advanced renal/liver disease substantially increased one-year stroke mortality. Tailoring stroke interventions according to comorbidity may reduce excess mortality., Summary: Background Comorbidity is prevalent among stroke patients, affecting post-stroke survival. It remains unknown whether comorbidity impacts post-stroke mortality beyond the combined individual effects of stroke and comorbidity. Methods Using nationwide Danish databases, we performed a cohort study of 201 691 patients ≥ 18 years old with incident ischemic stroke, intracerebral or subarachnoid hemorrhage, or unspecified stroke during 1995-2012, and 992 942 adults from the general population, matched to stroke patients by birth year, sex and individual comorbidities in the Charlson Comorbidity Index. During up to 5 years of follow-up, we computed standardized mortality rates (SMRs) to assess interaction contrasts as a measure of excess mortality not explained by the additive effects of stroke and comorbidity acting alone. Results Five-year post-stroke mortality was 48%, corresponding to an SMR of 187 deaths per 1000 person-years. During the 30-day peak post-stroke mortality (SMR, 180 per 1000 person-months), interaction with comorbidity represented 23%, 34% and 51% of post-stroke mortality rates among patients with low (score = 1), moderate (score = 2-3) and high (score = 4+) comorbidity based on Charlson Comorbidity Index scores. The interaction accounted for 5% to 32% of subsequent 31-365-day post-stroke mortality rates, depending on comorbidity level. The interaction contrasts were most notable among comorbid patients with cancer, particularly with hematological or metastatic disease, followed by patients with moderate-to-severe liver or renal disease. Conclusion Comorbidity, notably cancer and advanced renal or liver disease, increased 1-year mortality after stroke beyond the combined effects expected from either disease acting alone., (© 2017 International Society on Thrombosis and Haemostasis.)

Background: There is a well-documented decline in fertility treatment success with increasing female age; however, there are few preconception cohort studies that have examined female age and natural fertility. In addition, data on male age and fertility are inconsistent. Given the increasing number of couples who are attempting conception at older ages, a more detailed characterization of age-related fecundability in the general population is of great clinical utility., Objective: The purpose of this study was to examine the association between female and male age with fecundability., Study Design: We conducted a web-based preconception cohort study of pregnancy planners from the United States and Canada. Participants were enrolled between June 2013 and July 2017. Eligible participants were 21-45 years old (female) or ≥21 years old (male) and had not been using fertility treatments. Couples were followed until pregnancy or for up to 12 menstrual cycles. We analyzed data from 2962 couples who had been trying to conceive for ≤3 cycles at study entry and reported no history of infertility. We used life-table methods to estimate the unadjusted cumulative pregnancy proportion at 6 and 12 cycles by female and male age. We used proportional probabilities regression models to estimate fecundability ratios, the per-cycle probability of conception for each age category relative to the referent (21-24 years old), and 95% confidence intervals., Results: Among female patients, the unadjusted cumulative pregnancy proportion at 6 cycles of attempt time ranged from 62.0% (age 28-30 years) to 27.6% (age 40-45 years); the cumulative pregnancy proportion at 12 cycles of attempt time ranged from 79.3% (age 25-27 years old) to 55.5% (age 40-45 years old). Similar patterns were observed among male patients, although differences between age groups were smaller. After adjusting for potential confounders, we observed a nearly monotonic decline in fecundability with increasing female age, with the exception of 28-33 years, at which point fecundability was relatively stable. Fecundability ratios were 0.91 (95% confidence interval, 0.74-1.11) for ages 25-27, 0.88 (95% confidence interval, 0.72-1.08) for ages 28-30, 0.87 (95% confidence interval, 0.70-1.08) for ages 31-33, 0.82 (95% confidence interval, 0.64-1.05) for ages 34-36, 0.60 (95% confidence interval, 0.44-0.81) for ages 37-39, and 0.40 (95% confidence interval, 0.22-0.73) for ages 40-45, compared with the reference group (age, 21-24 years). The association was stronger among nulligravid women. Male age was not associated appreciably with fecundability after adjustment for female age, although the number of men >45 years old was small (n=37)., Conclusion: In this preconception cohort study of North American pregnancy planners, increasing female age was associated with an approximately linear decline in fecundability. Although we found little association between male age and fecundability, the small number of men in our study >45 years old limited our ability to draw conclusions on fecundability in older men., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Essentials Can venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients be marker of cancer? RA patients with VTE and comparison cohorts from population-based registries were compared. Increased risk of cancer in RA patients with VTE during the first year of VTE was observed. Risk of cancer in RA patients was increased also during the longer period following VTE., Summary: Background It is unknown whether venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients can be a marker of occult cancer. Objectives To examine risk of cancer subsequent to VTE among RA patients compared with risk of cancer in an RA cohort without VTE and in a general population without RA and without VTE. Patients/Methods All RA patients with a first-time diagnosis of VTE (index date) during 1978-2013 and comparison cohorts were identified from population-based registries in Denmark. Results We identified three cohorts: 2497 RA patients with VTE, 11 672 RA patients without VTE and 12 730 persons from the general population. The cumulative incidence of cancer within the first year of the index date was 3.2% among RA with VTE, 2.2% among RA without VTE, and 2.0% in the general population cohort. Incidence rate ratios (IRRs) were 1.79 (95% confidence interval [CI], 1.37-2.33) for RA patients with VTE vs. RA patients without VTE and 2.12 (95% CI, 1.63-2.76) for RA patients with VTE vs. the general population. The IRR of cancer at > 1 to 36 years from the index date among RA patients with VTE was 1.16 (95% CI, 1.00-1.34) compared with the RA patients without VTE and 1.33 (95% CI, 1.15-1.53) compared with the general population. Conclusions We found an increased risk of cancer in RA patients with VTE during the first year following VTE and also during the longer follow-up period. Thus, VTE may not only be a result of inflammation and immunological dysfunctions associated with RA, but may also be a marker for occult cancer., (© 2017 International Society on Thrombosis and Haemostasis.)

Background: Patients with atrial fibrillation or flutter (AFF) are at increased risk of ischemic stroke, but their risk of other thromboembolic events remains less clear., Methods: During 2004-2013, we conducted a nationwide population-based cohort study using Danish medical registries. We identified all patients with first-time AFF and sampled a sex-, age-, and calendar year-matched general population comparison cohort without AFF. For myocardial infarction, peripheral embolism, ischemic stroke, hemorrhagic stroke, deep venous thrombosis, and pulmonary embolism, we computed cumulative risks and adjusted incidence rate ratios (aIRRs) adjusted for comorbidity and medication., Results: The study population consisted of 103,989 patients with AFF and 519,935 individuals without AFF from the general population. Ten-year cumulative risks in the AFF cohort were 3.5% for myocardial infarction, 0.5% for peripheral embolism, 6.7% for ischemic stroke, 1.3% for hemorrhagic stroke, 1.0% for deep venous thrombosis, and 1.3% for pulmonary embolism. During the first 30days following AFF, aIRRs were markedly (4 to 16-fold) increased for all outcomes and similarly elevated for myocardial infarction (aIRR=8.0, 95% confidence interval (CI): 6.8-9.5) and ischemic stroke (aIRR=9.9, 95% CI: 8.5-11.5). Thereafter, aIRRs decreased gradually, reaching unity after 5years for myocardial infarction, deep venous thrombosis, and pulmonary embolism, but remained 1.6 to 3.5-fold increased for peripheral embolism, ischemic stroke, and hemorrhagic stroke., Conclusions: AFF was a risk factor for all arterial and venous outcomes during the first year of follow-up, but only for peripheral embolism, ischemic stroke, and hemorrhagic stroke thereafter., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: To investigate breast cancer prognosis (disease-free (DFS) and overall survival (OS)) among carriers of germline BRCA mutations (BRCAm) in Denmark., Methods: We identified all women in Central and Northern Denmark diagnosed with breast cancer during 2004-2011. We retrieved information on germline BRCAm testing from Clinical Genetics departments and clinical/treatment characteristics from population-based medical registries. Follow-up for recurrence, new primary cancer, and mortality extended from 180days after diagnosis until 31/12/2012. We estimated median DFS and OS and five-year cumulative incidence and incidence rates (IR/1000 person-years), and 95% confidence intervals (95% CI), for each outcome., Results: Among 9874 patients, 523 (5%) underwent BRCA testing-90 were BRCAm carriers, 433 were BRCA wildtype (BRCAwt). Compared with BRCAwt women, BRCAm carriers were younger, had lower stage, and ER- and HER2- tumors. Median time from diagnosis to BRCA testing was 0.91 years and 1.3 years in BRCAm and BRCAwt women; median follow-up to first event was 3.9 and 3.4 years, respectively. Five-year DFS and OS were higher in BRCAm than BRCAwt women: 88% (95%CI=78.3-93.5) vs. 75.3% (95%CI=70.2-79.6) and 97.8% (95%CI=91.4-99.4) vs 92.2% (95%CI=88.5-94.7), respectively. Five-year IRs of recurrence were 36.7/1000 person-years (95%CI=15.8-72.2) in the BRCAm cohort vs. 58.4 (95%CI=42.9-77.6) in the BRCAwt cohort., Conclusions: BRCAm carriers may have a better prognosis than BRCAwt women. However, limited testing conducted mainly during follow-up, yielded low numbers for precise estimations, and may be attributable to selection bias., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Essentials Risk of pregnancy-related venous thromboembolism may be increased in inflammatory bowel disease. We performed a study on inflammatory bowel disease and pregnancy-related venous thromboembolism. Inflammatory bowel disease is a risk factor for pregnancy-related venous thromboembolism. Proper disease control before conception is pivotal to avoid venous thromboembolism., Summary: Background The incidence of inflammatory bowel disease (IBD) increases, and thus is more common, in pregnant women. IBD is a risk factor for venous thromboembolism (VTE) but it is not clear whether IBD predisposes women to an excess risk of VTE during pregnancy and the postpartum period. Methods This was a nationwide population-based cohort study of all deliveries during 1980-2013 in Denmark, using data from two nationwide health registries: the Danish National Patient Registry and the Medical Birth Registry. We computed incidence rates (IRs) per 1000 person-years, and crude and adjusted relative risks (RRs) with 95% confidence intervals (CIs) for VTE during pregnancy and the first 12 postpartum weeks in women with and without IBD. Results We included 1 046 754 women with 1 978 701 deliveries. We identified 3465 VTE events during pregnancy and 1302 VTE events postpartum. The IR for VTE during pregnancy was 4.20 (95% CI, 2.83-5.58) in IBD patients and 2.41 (95% CI, 2.33-2.50) in women without IBD, corresponding to an RR of 1.72 (95% CI, 1.22-2.43). Adjustment for maternal age and smoking (pregnancies during 1991-2013) yielded an adjusted RR of 1.67 (95% CI, 1.15-2.41). IBD flare was associated with an RR of 2.64 (95% CI, 1.69-4.14) for VTE during pregnancy. The IR for postpartum VTE was 7.03 (95% CI, 3.87-10.20) among IBD patients and 2.88 (95% CI, 2.72-3.04) in women without IBD, corresponding to an adjusted RR of 2.10 (95% CI, 1.33-3.30). Conclusions IBD is a risk factor for VTE during pregnancy and postpartum., (© 2017 International Society on Thrombosis and Haemostasis.)

Background: Animal studies have shown that a high intake of galactose, a breakdown product of lactose, increases ovarian toxicity. Few epidemiologic studies, to our knowledge, have examined the association between dairy intake and fertility, and they have had conflicting findings., Objective: We prospectively evaluated dairy intake in relation to fecundability among women who were planning for pregnancy., Design: Data were derived from preconception cohort studies in Denmark (Snart Foraeldre) and North America [PRESTO (Pregnancy Study Online)] in which women completed a validated food-frequency questionnaire 10 d after enrollment. The dietary intake of dairy foods and their constituents was calculated based on reported frequencies, mean serving sizes, and standard recipes for mixed foods. Outcome data were updated every 8 wk for 12 mo or until reported conception. Analyses were restricted to 2426 women attempting pregnancy for ≤6 cycles at study entry. Fecundability ratios (FRs) and 95% CIs were estimated with the use of proportional probabilities regression models adjusted for potential confounders., Results: FRs for total dairy intake (≥18 compared with <7 servings/wk) were 1.37 (95% CI: 1.05, 1.78) among 1126 Snart Foraeldre participants and 1.04 (95% CI: 0.78, 1.38) among 1300 PRESTO participants (pooled FR: 1.11; 95% CI: 0.94, 1.31). The elevated FR for total dairy intake among Snart Foraeldre participants was limited to milk consumption and found only among women aged <30 y. There was no clear association between low- or high-fat dairy intake and fecundability in either cohort. Although there was little evidence of an association between dietary intake of calcium, potassium, magnesium, or vitamin D and fecundability, a greater consumption of phosphorus and lactose was associated with slightly higher fecundability in both cohorts., Conclusions: Associations between dairy intake and fecundability were generally small and inconsistent across cohorts. Our findings do not support the hypotheses that a greater consumption of high-fat dairy improves fertility or that a greater consumption of lactose or low-fat dairy harms fertility., (© 2017 American Society for Nutrition.)

Background: Long-term nationwide trends in atrial fibrillation (AF) incidence and 5-year outcomes are rare., Methods: We conducted a population-based cohort study using the Danish National Patient Registry covering all Danish hospitals. We computed standardized incidence rates during 1983-2012. We used Cox regression to estimate hazard ratios (HRs) of heart failure, stroke, and death within 5years, comparing 5-year calendar periods with the earliest period (1983-1987) as reference., Results: We identified 312,420 patients with first-time hospital-diagnosed AF. The incidence rate per 100,000person-years increased from 98 in 1983 to 307 in 2012. The mean annual increase during the 30-year study period was 4%, with a 6% increase annually until 2000 and a 1.4% increase annually thereafter. The incidence trends were most pronounced among men and persons above 70years. Among high-risk subgroups, AF incidence was consistently highest in patients with valvular heart disease or heart failure. The rate of heart failure following AF declined by 50% over the entire study period (HR: 0.49, 95% confidence interval (CI): 0.48-0.51) and the mortality rate declined by 40% (HR: 0.62, 95% CI: 0.61-0.63). Within the last two decades, the rate for ischemic stroke declined by 20% (HR 0.81, 95% CI: 0.78-0.84), but increased almost as much for haemorrhagic stroke (HR: 1.14, 95% CI: 1.01-1.29)., Conclusions: The long-term risk of heart failure, ischemic stroke, and death following onset of AF has decreased remarkably over the last three decades. Still, the threefold increased incidence of hospital-diagnosed AF during the same period is a major public health concern., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease., Methods: In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651., Findings: Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1·48 (95% CI 1·11-1·96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0066). As-treated estimates were 28% versus 19% (1·55, 1·18-2·04, p=0·0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1·07, 0·67-1·72, p=0·77) for all-cause mortality, 7% versus 2% (2·88, 1·40-5·90, p=0·0040) for non-procedural myocardial infarction, 16% versus 10% (1·50, 1·04-2·17, p=0·032) for any revascularisation, and 5% versus 2% (2·25, 0·93-5·48, p=0·073) for stroke., Interpretation: The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease., Funding: Biosensors, Aarhus University Hospital, and participating sites., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: We aimed to investigate the prevalence and prognostic impact of tumor mesenchymal epithelial transition factor (MET) expression in stage IV gastric cancers in a real-world clinical setting because existing evidence is sparse., Methods: The study included archived cancer specimens from 103 stage IV gastric cancer patients (2003-2010). We analyzed MET-protein expression by immunohistochemistry (MET-positive if ≥25% of tumor cells showed MET expression). We calculated overall survival using the Kaplan-Meier method and hazard ratios comparing mortality among MET-positive and MET-negative patients using Cox regression adjusted for age, gender, and comorbidity., Results: We found that 62.1% (95% confidence interval, 52.0-71.5) of patients had MET-positive tumors. Median survival was lower among patients with MET-positive tumors (3.5 months) than among patients with MET-negative tumors (9.6 months), corresponding to an adjusted hazard ratio of 2.2 (95% confidence interval, 1.3-3.7)., Conclusions: Tumor MET expression is prevalent and has substantial prognostic impact in stage IV gastric cancer patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Bladder cancer (BC) is associated with venous thromboembolism (VTE), but data on the effect of comorbidities are scarce., Materials and Methods: Population-based cohort study with 13,809 patients with BC diagnosed in Denmark (1995-2011) and a general population comparison cohort matched on age, sex, and comorbidities (n = 132,421). Risk of VTE, pulmonary embolism and deep venous thrombosis was computed for the first month, 3 months, 1 year, and 5 years following cancer diagnosis and stratified by Charlson Comorbidity Index (CCI) scores, cystectomy, and metastases., Results: VTE risk was higher among the patients with BC than in the comparison cohort during five years of follow-up (risk difference = 20 per 1,000 persons [95% CI: 16-23]). Excess risk was relatively stable with increasing comorbidity score. In the first year, the risk difference was 17 per 1,000 persons (95% CI: 14-21) and 16 (95% CI: 4.8-27) for CCI score = 0 and CCI score = 4, respectively, and similar results were observed by stratification on pulmonary embolism and deep venous thrombosis. For patients with BC undergoing cystectomy, VTE risk was 70-fold higher than in the general population cohort within 3 months after diagnosis., Conclusions: BC is associated with increased risk of VTE, compared with the general Danish population. Risks are particularly high for VTE after cystectomy. Risk did not increase with higher comorbidity burden, as the relative risk of VTE was greatest among patients without comorbidity. Clinical attention to VTE risk, particularly cystectomy-related VTE, in patients with BC is appropriate irrespective of comorbidities., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Elevated plasma vitamin B12 levels (cobalamin, Cbl) are associated with increased short-term cancer risk among patients referred for this laboratory measurement. We aimed to assess prognosis in cancer patients with elevated plasma Cbl., Methods: We conducted a population-based cohort study using data from Danish medical registries during 1998-2014. The study included 25,017 patients with a cancer diagnosis and Cbl levels of 200-600 pmol/L (reference/normal range), 601-800 pmol/L and >800 pmol/L measured up to one year prior to diagnosis, and a comparison cohort of 61,988 cancer patients without a plasma Cbl measurement. Patients treated with Cbl were excluded. Survival probability was assessed using Kaplan-Meier curves. Mortality risk ratios (MRR) were computed using Cox proportional hazard regression, adjusted for age, sex, calendar year, cancer stage and comorbidity, scored using the Charlson comorbidity index., Results: Survival probabilities were lower among patients with elevated Cbl levels than among patients with normal levels and among members of the comparison cohort [(1-year survival,%) Cbl: 200-600 pmol/L: 69.3%; 601-800 pmol/L: 49.6%; >800 pmol/L: 35.8%; comparison cohort: 72.6%]. Thirty-day mortality was elevated for patients with Cbl levels of 601-800 pmol/L or >800 pmol/L, compared to patients with levels of 200-600 pmol/L [(MRR (95% confidence interval): 601-800 pmol/L vs. 200-600 pmol/L: 1.9 (1.6-2.2); >800 pmol/L vs. 200-600 pmol/L: 2.7 (2.4-3.1)]. This association remained robust for 31-90-day and 91-365-day mortality, showing similar dose-response patterns., Conclusion: Cancer patients with elevated Cbl levels had higher mortality than those with normal Cbl levels. These findings may have clinical significance for assessing the prognosis of cancer patients., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To examine the association between pregravid oral contraceptive (OC) use and spontaneous abortion (SAB)., Methods: In an Internet-based preconception cohort study of 4862 Danish pregnancy planners, we used Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals (CIs) for the association between OC use and SAB. We controlled for maternal age, physical activity, parity, education, alcohol and caffeine consumption, body mass index, and smoking., Results: Compared with women who discontinued OCs >1 year before conception, HRs were 0.95 (95% confidence interval (CI) = 0.77-1.17), 0.99 (95% CI = 0.82-1.19), and 0.80 (95% CI = 0.60-1.06) for women who discontinued OCs 7-12, 2-6, and 0-1 months before conception, respectively. Compared with less than 4 years of OC use, HRs for 4-7, 8-11, and 12 years or more of OC use were 1.05 (95% CI = 0.80-1.37), 0.92 (95% CI = 0.71-1.19), and 0.88 (95% CI = 0.65-1.19), respectively. Dose of estrogen and generation of progestin were not materially associated with SAB risk., Conclusions: We found no evidence that pregravid OC use is associated with an increase in SAB. Use within 1 month of conception was associated with a slightly lower risk of SAB, but this may be due to increased reproductive fitness in women who conceive quickly after discontinuation of OCs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Previous research suggests that patients using glucocorticoids may be at increased risk of postoperative bleeding and infection after major surgery. The objective was to investigate the association between preoperative glucocorticoid use and risk of bleeding and infection after Roux-en-Y gastric bypass surgery (RYGB)., Setting: Nationwide cohort study of 13,195 patients, who underwent RYGB 2006-2012 using Danish population-based medical databases., Methods: Information was obtained on current (redeemed prescription<60 d before surgery), recent (prescription 60-180 d before surgery), or no glucocorticoid use, and postoperative bleeding or infection within 30 days of surgery. We computed risk differences and odds ratios (ORs) as a measure of relative risk with 95% confidence intervals (95% CIs) for the association between glucocorticoid use and bleeding or infection, adjusting for gender, age, and co-morbidities by logistic regression., Results: Among RYGB patients, 325 (2.5%) were current glucocorticoid users, and 365 (2.8%) were recent users. The risk of bleeding was increased in current users: 2.8% versus 1.6% among nonusers (risk difference: 1.2%, 95% CI: -.6, 3.0) corresponding to an adjusted OR of 1.5 (95% CI: .8, 3.0). For recent users, the adjusted OR for bleeding was 1.2 (95% CI: .5, 2.5). The risk of infection did not differ materially between current (1.8%), recent (1.0%) and nonusers (1.7%), corresponding to an adjusted OR of .9 (95% CI: .4, 2.1) among current versus nonusers., Conclusions: Current use of glucocorticoids is associated with a slightly increased risk of postoperative bleeding, but not infection, after RYGB. No increased risks were found for recent users., (Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the association between folic acid (FA) supplementation obtained through either single FA tablets or multivitamins (MVs) and menstrual cycle characteristics among 5386 women aged 18-40 years, enrolled in an Internet-based study of Danish women attempting pregnancy during 2007-2011., Methods: In a cross-sectional study, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of FA supplementation with menstrual cycle regularity; short (<27 days), long (30-33 days), and very long (≥34 days) cycle lengths; and duration and intensity of menstrual bleeding., Results: Compared with nonuse, FA supplementation was associated with reduced odds of short cycle length (OR = 0.80, 95% CI: 0.68-0.94) and a trend toward increased odds of very long cycle length (OR = 1.21, 95% CI: 0.87-1.68) compared with cycle length of 27-29 days. The inverse association with short cycle length was stronger among 18- to 30-year-old women (OR = 0.68, 95% CI: 0.53-0.87), nulliparous women (OR = 0.66, 95% CI: 0.52-0.84), and women who used both FA and MVs (OR = 0.75, 95% CI: 0.60-0.95). We found no clear association between FA supplementation and cycle regularity and duration and intensity of menstrual bleeding., Conclusions: FA supplementation was inversely associated with short menstrual cycle length. This association was strongest among women aged 18-30 years, nulliparous women, and women who used both FA and MVs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Placenta-mediated complications are leading causes of maternal and fetal morbidity and mortality. We hypothesized that a preconception history of venous thromboembolism (VTE) is associated with increased risk of placenta-mediated pregnancy complications., Methods: A nationwide population-based cohort study of all singleton pregnancies leading to delivery from 1997 to 2012 (n = 964 967). We obtained data on placenta-mediated pregnancy complications from the Danish Medical Birth Registry and data on VTE before pregnancy from the Danish National Patient Registry. We computed absolute risks, crude and adjusted risk differences (RDs) using a binomial regression model, and crude and adjusted risk ratios (RRs) from a modified Poisson regression model., Results: Overall, 1419 women had a preconception history of VTE, while 578 112 did not. Preeclampsia occurred in 4.2% of pregnancies in the VTE group and in 2.7% of pregnancies in a comparison cohort (adjusted RD = 1.3%, 95% confidence interval (CI) 0.6-2.0%; adjusted RR = 1.5, 95% CI 1.3-1.8). Stillbirth occurred in 0.7% of pregnancies in the VTE group and in 0.4% of pregnancies in the comparison cohort (adjusted RD = 0.3%, 95% CI 0.02-0.6%; adjusted RR = 1.8, 95% CI 1.1-3.0). Placental abruption occurred in 0.8% of pregnancies in the VTE group and in 0.5% of pregnancies in the comparison cohort (adjusted RD = 0.3%, 95% CI - 0.05-0.6%; adjusted RR = 1.6, 95% CI 1.1-2.4). Small-for-gestational-age infants accounted for 10.9% of live births in the VTE group and 9.8% of live births in the comparison cohort (adjusted RD = 0.6%, 95% CI - 0.5-1.7%; adjusted RR = 1.1, 95% CI 0.9-1.3)., Conclusion: Women with a history of VTE were at increased risk of placenta-mediated complications., (© 2015 International Society on Thrombosis and Haemostasis.)

Background: Long-term trends in use of implantable cardioverter-defibrillators (ICDs) and outcomes are rare., Objective: We examined 13-year nationwide trends in ICD implantation and survival rates in Denmark., Methods: Using medical databases, we identified all first time ICD recipients in Denmark during 2000-2012 (N = 8460) and ascertained all-cause mortality. We computed standardized annual implantation rates and mortality rate ratios according to age, sex, comorbidity level, indication, and device type., Results: The standardized annual implantation rate increased from 42 per million persons in 2000 to 213 per million persons in 2012 (from 34 to 174 for men and from 8 to 39 for women). The increase was driven by secondary prophylactic ICDs until 2006 and primary prophylactic ICDs thereafter. The increase occurred particularly in older patients and those with a high level of comorbidity. Independent of indication, 76% of all patients with ICD were alive after 5 years. Men had a higher mortality rate compared with women (mortality rate ratio 1.28; 95% confidence interval 1.10-1.49). Compared with low comorbidity level, moderate, severe, and very severe comorbidity levels were associated with 1.6-, 2.5-, and 4.9-fold increased mortality rates, respectively. The most influential individual comorbidities were heart failure, diabetes, liver disease, and renal disease., Conclusion: The annual implantation rate of ICDs increased 5-fold in Denmark between 2000 and 2012. The rate increase occurred for both men and women, but particularly in the elderly and patients with severe comorbidity. Five-year survival probability was high, but severe comorbidity and male sex were associated with shorter survival., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

It is unknown if splanchnic venous thrombosis (SVT) is a marker of occult cancer and a prognostic factor for cancer survival. Using Danish medical registries, we conducted a nationwide cohort study including all patients with first-time SVT (n = 1191) between 1994 and 2011. We followed the patients for subsequent cancer diagnoses and calculated absolute risks and standardized incidence ratios (SIRs). We formed a matched comparison cohort of cancer patients without SVT, and assessed the prognostic impact of SVT on cancer survival by applying the Kaplan-Meier method and Cox regression. We followed the patients for a median of 1.6 years, and found that SVT was a marker of occult cancer. The 3-month cancer risk was 8.0% and the SIR was 33 (95% confidence interval, 27-40), compared with the general population. Increased risk was mainly found for liver cancer (risk = 3.5%; SIR = 1805), pancreatic cancer (risk = 1.5%; SIR = 256), and myeloproliferative neoplasms (risk = 0.7%; SIR = 764). The overall SIR remained increased twofold after 1 or more years of follow-up. SVT was also a prognostic factor for survival in patients with liver and pancreatic cancer. The clinical impact may be a more thorough diagnostic work-up in patients presenting with SVT., (© 2015 by The American Society of Hematology.)

Background: Few studies have examined the risk of developing castration-resistant prostate cancer (CRPC), metastasis, and mortality among nonmetastatic prostate cancer (M0-PC) patients treated with androgen deprivation therapy (ADT). We estimated the incidence of these outcomes among M0-PC patients on ADT and identified prostate-specific antigen (PSA) based biomarkers for mortality and metastasis., Methods: This population-based cohort study included all nonmetastatic prostate cancer patients in Northern and Central Denmark Regions during 1997-2010, identified through registry data. Primary outcomes were metastasis, overall survival, and bone metastasis-free survival (BMFS). We estimated relative risks (RR) associated with PSA and PSA doubling-time (PSA-DT), measured as time-varying variables beginning at ADT treatment start., Results: We included 2494 M0-PC patients treated with ADT, of whom 1617 (80%) developed CRPC during follow-up. One-fourth of the patients developed metastases within 5 years; bone metastases (BM) accounted for 81% of all metastases. Median survival time was 4.4 years. Compared with PSA <8 ng/mL, PSA ≥8 ng/mL was associated with an adjusted RR of 14.0 (95% confidence interval [CI]: 10.2, 19.0) for BM, 4.4 (CI: 3.9, 5.0) for all-cause mortality, and RR of 4.8 (CI: 4.3, 5.4) for the inverse of BMFS. PSA-DT ≤6 months was associated with an adjusted RR of 7.6 (95% CI: 6.1, 9.5) for BM, RR of 5.9 (CI: 5.2, 6.6) for all-cause mortality, and RR 6.6 (CI: 5.9, 7.4) for the inverse of BMFS., Conclusions: PSA ≥8 ng/mL and PSA-DT ≤6 months are strong predictors of mortality and bone metastasis. The poor prognosis observed in this study may reflect inclusion of patients with severe prostate cancer by requiring repeated PSA measurements., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Human papillomavirus' (HPV's) role in skin cancer is controversial. To examine whether an individual is prone to develop a chronic oncogenic infection, we conducted a nationwide population-based cohort study of the risk of skin cancer after another HPV-related neoplasia-that is, cervical high-grade dysplasia or carcinoma-using cervical conization as a surrogate marker., Methods: Using Danish registries, we identified all women who underwent conization from 1978 to 2011 (n = 87,164) and followed them until first-time skin cancer diagnosis, death, emigration, or 31 December 2011, whichever came first. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma (MM) according to national incidence rates., Results: The 1-year absolute risks were 0.0012%, 0.045%, and 0.029% for SCC, BCC, and MM, respectively. Conization was clearly associated with increased incidence of SCC (SIR = 1.37; 95% CI: 1.13-1.65), but not MM (SIR = 1.00; 95% CI: 0.91-1.11). BCC risk was slightly increased (SIR = 1.08; 95% CI: 1.02-1.13)., Conclusions: The association between conization and cutaneous SCC provides evidence for conization as a marker of underlying general susceptibility to oncogenic HPV., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Recently, it has become apparent that superficial vein thrombosis (SVT) can have serious complications. However, the magnitude of the risk of subsequent deep venous and arterial thrombotic events remains unknown. We examined this in a nationwide population-based setting during a period when SVT was not treated routinely with anticoagulants. The Danish National Registry of Patients, covering all Danish hospitals, was used to identify 10 973 patients with a first-time diagnosis of SVT between 1980 and 2012. A comparison cohort of 515 067 subjects, matched by age, gender, and calendar year, was selected from the general Danish population. Outcomes were venous thromboembolism, acute myocardial infarction, ischemic stroke, and death. During median follow-up of 7 years, the incidence rate of venous thromboembolism was 18.0/1000 person-years (95% confidence interval [CI], 17.2-18.9). The highest risk occurred in the first 3 months (3.4%; 95% CI, 3.0-3.7). Compared with the general population, the hazard ratio was 71.4 (95% CI, 60.2-84.7) in this period, steadily decreasing to 5.1 (95% CI 4.6-5.5), 5 years after the SVT. The hazard ratios for acute myocardial infarction, stroke, and death were 1.2 (95% CI, 1.1-1.3), 1.3 (95% CI, 1.2-1.4), and 1.3 (95% CI, 1.2-1.3), respectively, with the highest risk also shortly after SVT. These data indicate the prognostic importance of SVT and may form the basis for clinical decision-making regarding anticoagulation., (© 2015 by The American Society of Hematology.)

Background: As proxies for local and remote ischemic preconditioning, we examined whether preinfarction angina pectoris and intermittent claudication influenced mortality following myocardial infarction., Methods: Using medical registries, we conducted a nationwide population-based cohort study of all first-time myocardial infarction patients in Denmark during 2004-2012 (n=70,458). We computed all-cause and coronary mortality rate ratios (MRRs). We categorized time between angina/claudication presentation and subsequent myocardial infarction as 0-14, 15-30, 31-90, and > 90 days. We adjusted for age, sex, coronary intervention, comorbidities, and medication use., Results: Among all myocardial infarction patients, 18.4% had prior angina and 3.8% had prior intermittent claudication. Compared to patients without prior angina, the adjusted 30-day coronary MRR was 0.85 (95% confidence interval (CI): 0.80-0.92) for stable and 0.68 (95% CI: 0.58-0.79) for unstable angina patients. The mortality reduction increased when angina presented close to myocardial infarction and was higher for unstable than for stable angina. Thus, the 30-day coronary MRR was 0.72 (95% CI: 0.51-1.02) for stable angina and 0.35 (95% CI: 0.17-0.73) for unstable angina presenting within 14 days before MI. The results were robust for all-cause mortality and in numerous subgroups, including women, diabetics, patients treated with PCI, and patients treated with and without cardioprotective drugs. Preinfarction intermittent claudication was associated with higher short- and long-term mortality compared to patients without intermittent claudication., Conclusions: Preinfarction angina reduced 30-day mortality, particularly when unstable angina closely preceded MI. Preinfarction intermittent claudication was associated with increased short- and long-term mortality., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)