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Information related to short- and long-term risks of children born to kidney-transplanted women remains limited. With the aim of investigating the risk of neonatal complications, and the short- and long-term risk of infections in offspring of kidney-transplanted women, all children born to kidney-transplanted women in Denmark from 1964 to 2016 were identified in a nationwide retrospective matched cohort study. A total of 124 children of kidney-transplanted women were identified and matched on gender, birth year, and number of siblings at birth 1:10 with children born to nontransplanted women identified in the Danish general population. Prevalence of low birth weight (37.9%, risk ratio [RR] = 12.61; 95% confidence interval [CI], 8.5-18.5), premature birth (46.0%, RR = 11.32; 95% CI, 8.1-15.7) and malformations (11.3%, RR = 1.98; 95% CI, 1.2-3.4) was increased in children of kidney-transplanted women compared with controls. Similarly, prevalence of hospitalization due to infection was increased during the first year of life (21.0%, RR = 1.94; 95% CI, 1.3-2.8), from age 1 to 5 (34.2%, RR = 1.89; 95% CI, 1.4-2.5), and overall (41.9%, RR = 1.67; 95% CI, 1.3-2.1). The risk of infection was also higher in children of kidney-transplanted mothers born preterm or with low birth weight compared with similar controls. In conclusion, risk of neonatal complications, malformations, and both early and late infection were increased in children born to kidney-transplanted women.

Aims Reports have suggested an increased risk of aortic and mitral regurgitation associated with oral fluoroquinolones (FQs) resulting in a safety warning published by the European Medicines Agency (EMA). However, these findings have not yet been replicated.Methods and results Using Danish administrative registers, we conducted a nested case-control study in a nationwide cohort of individuals between 2005 and 2018. Cases were defined as the first occurrence of aortic or mitral regurgitation. Exposure of interest was the use of oral FQs. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were obtained by fitting time-dependent Cox regression models, with penicillin V as comparator, to assess the association between FQ use and incident valvular regurgitation. We identified 38 370 cases of valvular regurgitation with 1 115 100 matched controls. FQ exposure was not significantly associated with increased rates of aortic or mitral regurgitation (HR 1.02, 95% CI 0.95-1.09) compared with penicillin V users. Investigating the cumulative defined daily doses (cDDD) of FQs yielded similar results with no significant association between increasing FQ use and valvular regurgitation (e.g. HR 1.08, 95% CI 0.95-1.23 for cDDD >10 compared with cDDD 1-5). These results were consistent across several analyses including a cohort of patients with hypertension and using a case definition based on valvular surgical interventions.Conclusions In a nationwide nested case-control study, FQs were not significantly associated with increased rates of valvular regurgitation. Our findings do not support a possible causal connection between FQ exposure and incident valvular regurgitation.

OBJECTIVE: More knowledge about the development of sudden cardiac death (SCD) in the general population is needed to develop meaningful predictors of SCD. Our aim with this study was to estimate the incidence of SCD in the general population and examine the temporal changes, demographics and clinical characteristics.METHODS: All participants in the Copenhagen City Heart Study were followed from 1993 to 2016. All death certificates, autopsy reports and national registry data were used to identify all cases of SCD.RESULTS: A total of 14 562 subjects were included in this study. There were 8394 deaths with all information available, whereof 1335 were categorised as SCD. The incidence of SCD decreased during the study period by 41% for persons aged 40-90 years, and the standardised incidence rates decreased from 504 per 100 000 person-years (95% CI 447 to 569) to 237 per 100 000 person-years (95% CI 195 to 289). The incidence rate ratio of SCD between men and women ≤75 years was 1.99 (95% CI 1.62 to 2.46). The proportion of SCD of all cardiac deaths decreased during the observation period and decreased with increasing age. Men had more cardiovascular comorbidities (OR 1.34, 95% CI 1.07 to 1.68, p<0. 01), and SCD was the first registered manifestation of cardiac disease in 50% of all cases.CONCLUSION: The incidence of SCD in the general population has declined significantly during the study period but should be further investigated for more recent variations as well as novel risk predictors for persons with low to medium risk of SCD.

AIMS: Patients with atrial fibrillation (AF) treated with oral anticoagulants (OAC) have an increased risk of bleeding including hematuria. In the general population gross hematuria is associated with urinary tract cancer. Consequently, we aimed to investigate the potential association between gross hematuria and urinary tract cancer in anticoagulated patients with AF.METHODS AND RESULTS: Using Danish nationwide registers, we included Danish AF patients treated with OACs between 2001 and 2016. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risk of urinary tract cancer in patients with- and without gross hematuria. We included 125,063 AF patients with a median age of 74 years (interquartile range [IQR] 65-80) and a majority of males (57%). The absolute risk of gross hematuria 12 months after treatment initiation increased with age ranging from 0.37% (95% Confidence Interval [CI] 0.31 - 0.42) to 0.85% (95% CI 0.75 - 0.96) in the youngest and oldest age groups of ≤ 70 years and > 80 years of age, respectively. The 1-year risk of urinary tract cancer after hematuria ranged from 4.2% (95% CI 2.6-6.6) to 6.5% (95% CI 4.6-9.0) for patients in age group > 80 years and 71-80 years, respectively. Gross hematuria conferred large risk ratios of urinary tract cancer when comparing patients with- and without hematuria across all age groups.CONCLUSION: Gross hematuria was associated with clinically relevant risks of urinary tract cancer in anticoagulated patients with AF. Thus, underlining the importance of meticulously examining anticoagulated patients with hematuria.

AIMS: We aimed to investigate the long-term cardio-protective effect associated with beta-blocker (BB) treatment in stable, optimally treated myocardial infarction (MI) patients without heart failure (HF).METHODS AND RESULTS: Using nationwide registries, we included patients with first-time MI undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) during admission and treated with both acetyl-salicylic acid and statins post-discharge between 2003 and 2018. Patients with prior history of MI, prior BB use, or any alternative indication or contraindication for BB treatment were excluded. Follow-up began 3 months following discharge in patients alive, free of cardiovascular (CV) events or procedures. Primary outcomes were CV death, recurrent MI, and a composite outcome of CV events. We used adjusted logistic regression and reported standardized absolute risks and differences (ARD) 3 years after MI. Overall, 30 177 stable, optimally treated MI patients were included (58% acute PCI, 26% sub-acute PCI, 16% CAG without intervention). At baseline, 82% of patients were on BB treatment (median age 61 years, 75% male) and 18% were not (median age 62 years, 68% male). BB treatment was associated with a similar risk of CV death, recurrent MI, and the composite outcome of CV events compared with no BB treatment [ARD (95% confidence intervals)] correspondingly; 0.1% (-0.3% to 0.5%), 0.2% (-0.7% to 1.2%), and 1.2% (-0.2% to 2.7%).CONCLUSIONS: In this nationwide cohort study of stable, optimally treated MI patients without HF, we found no long-term effect of BB treatment on CV prognosis following the patients from 3 months to 3 years after MI admission.

BACKGROUND: During the COVID-19 pandemic, decreasing rates of hospitalisations for cardiovascular disease raised concerns for undertreatment, particularly for vulnerable groups. We investigated how the initial COVID-19 public lockdown, impacted the risk of being hospitalised with a major cardiovascular event (MCE: myocardial infarction/stroke/heart failure) according to educational level.METHODS: We grouped all Danish residents according to educational attainment level (low, medium, high) and age (40-59, 60-69, ≥70 years). In each group, we calculated the age-standardised and sex standardised risk of MCE hospitalisation in the initial COVID-19 lockdown-period (13 March 2020-3 May 2020) and in the corresponding calendar period in 2019. We calculated age-standardised and sex-standardised risks to investigate whether the COVID-19 lockdown had a differential effect on MCE incidence according to educational level.RESULTS: In the period in 2019, 2700 Danish residents were hospitalised with MCE, compared with only 2290 during the lockdown. During lockdown, the risk of hospitalisation for MCE decreased among residents aged ≥70 with low education (risk difference (RD) -46.2 (-73.2; -19.2) per 100,000) or medium education (RD -23.2 (-50.8; 4.3) per 100 000), but not among residents with high education (RD 5.1 (-32.3; 42.5), per 100 000). The risk of hospitalisation for MCE did not decrease significantly for the younger age groups.CONCLUSIONS: The COVID-19 lockdown is associated with a reduced incidence for MCE, especially among low educated, elderly residents. This raises concern for undertreatment that without clinical awareness and action may widen the educational gap in cardiovascular morbidity and mortality.

AIMS: To determine the risk of major cardiovascular events (MACE) and death, associated with an early large and rapid decline in HbA1C following first time initiation of an oral antidiabetic drug (OAD).METHODS AND RESULTS: We included 10,518 primary care patients with T2D, who initiated an OAD for the first time. For each individual, we measured a decline in HbA1C, as the difference between the pre-treatment HbA1C (within 3 months before OAD initiation) and the post-treatment HbA1C (within 1.5-4.5 months after OAD initiation), divided by the time between the two measurements. The decline was reported in mmol/mol change per 3 months in HbA1C and categorized by the median decline into levels of steep (≥ 9 mmol/mol [≥ 0.8%]) and flat decline (< 9 mmol/mol per 3 mo. [< 0.8%]). Pre-treatment HbA1C was categorized by the median, into levels of low (48-62 mmol/mol) and high (> 62 mmol/mol). Multiple Cox regression was used to study the effect of decline (steep vs. flat) on the outcome hazard rates separately for patients with low and high pre-treatment HbA1C. Analyses were adjusted for age, sex, traditional cardiovascular risk factors, severe comorbidities, and concomitant medication treatment. During a median follow-up time of 7.7 years, 1,625 developed MACE and 2,323 died. We found that a steep decline vs. a flat decline was significantly associated with a decreased hazard for MACE, both in individuals with high (HR 0.81; 95% CI 0.69-0.94; P = 0.005) and low pre-treatment HbA1C (HR 0.79; 95% CI 0.66-0.96; P = 0.015). The hazard of MACE was more pronounced on the short-term vs. long-term in individuals with high pre-treatment HbA1C. We found no significant association between combinations of pre-treatment HbA1C and decline categories and hazard of all-cause mortality. However, a combination of a low pre-treatment HbA1C and steep decline was associated with increased 1-year mortality (HR 1.52; 95% CI 1.00-2.29; P = 0.048) and hypoglycemia (HR 1.82; 95% C

Objectives: To identify risk factors and to develop a predictive risk score for pacemaker implantation in patients with atrial fibrillation (AF).Methods: Using Danish nationwide registries, patients with newly diagnosed AF from 2000 to 2014 were identified. Cox proportional-hazards regression computed HRs for risk factors of pacemaker implantation. A logistic regression was used to fit a prediction model for 3-month risk of pacemaker implantation and derived a risk score using 80% of the data and its predictive accuracy estimated using the remaining 20%.Results: Among 155 934 AF patients included, the median age (IQR) was 75 (65-83) and 51.3% were men. During a median follow-up time of 3.4 (1.2-5.0) years, 8348 (5.4%) patients received a pacemaker implantation. Risk factors of pacemaker implantation were (in order of highest risk first) age above 60 years, congenital heart disease, heart failure at age under 60 years, prior syncope, valvular AF, hypertension, ischaemic heart disease, male sex and diabetes mellitus. The derived risk score assigns points ranging from 1 to 14 to each of these risk factors. The 3-month risk of pacemaker implantation increased from 0.4% (95% CI: 0.2 to 0.8) at 1 point to 2.6% (95% CI: 1.9 to 3.6) at 18 points. Area under the receiver operator characteristics curve was 62.9 (95% CI: 60.3 to 65.5).Conclusion: We highlighted risk factors of pacemaker implantation in newly diagnosed AF patients and created a risk score. The clinical utility of the risk score needs further investigation.

Aims: To evaluate the risk of heart failure (HF) in patients with type 2 diabetes (T2D) complicated by development of intercurrent ischaemic heart disease (IHD), end-stage renal disease (ESRD), or both, compared to patients with T2D and no IHD and ESRD. Methods and results: From Danish nationwide registries, we identified all patients with new-onset T2D with no history of HF between 1998 and 2015. Landmark analyses were used to estimate the 5-year absolute risk of HF at several follow-up times, and accounted for the occurrence of IHD and ESRD, identified before HF. The Aalen–Johansen estimator was used to account for censoring and the competing risk of death. A total of 285 024 patients with new-onset T2D were included. During follow-up, 19 960 developed incident HF. Among patients with T2D free of HF 5 years after T2D diagnosis, patients without IHD and ESRD had the lowest 5-year risk of HF [4.02%; 95% confidence interval (CI) 3.90–4.15), those with T2D complicated by IHD [11.51%; relative risk (RR) 2.86; 95% CI 2.72–3.02; P < 0.001] or ESRD (8.11%; RR 2.02; 95% CI 1.39–2.93; P < 0.001) an intermediate risk, and those with both IHD and ESRD (19.76%; RR 4.92; 95% CI 3.43–7.05; P < 0.001) the highest risk. Conclusion: Patients with T2D complicated by development of intercurrent IHD, ESRD, or both, showed a significantly higher risk of HF compared to those who did not develop IHD and ESRD. An effective way to delay or prevent the development of HF in patients with T2D may be to prevent IHD and ESRD.

BACKGROUND: Heart failure (HF) in patients with type 2 diabetes mellitus (T2D) has received growing attention. We examined the effect of HF development on prognosis compared with other cardiovascular or renal diagnoses in patients with T2D. METHODS AND RESULTS: Patients with new T2D diagnosis patients were identified between 1998 and 2015 through Danish nationwide registers. At yearly landmark timepoints after T2D diagnosis, we estimated the 5-year risks of death, 5-year risk ratios, and decrease in lifespan within 5 years associated with the development of HF, ischemic heart disease, stroke, peripheral artery disease, and chronic kidney disease. A total of 153 403 patients with newly diagnosed T2D were followed for a median of 9.7 years (interquartile range, 5.8-13.9) during which 48 087 patients died. The 5-year risk ratio of death associated with HF development 5 years after T2D diagnosis was 3 times higher (CI, 2.9-3.1) than patients free of diagnoses (CI, 2.9-3.1). Five-year risk ratios were lower for ischemic heart disease (1.3 [1.3-1.4]), stroke (2.2 [2.1-2.2]), chronic kidney disease (1.7 [1.7-1.8]), and peripheral artery disease (2.3 [2.3-2.4]). The corresponding decrease in lifespan within 5 years when compared with patients free of diagnoses (in months) was HF 11.7 (11.6-11.8), ischemic heart disease 1.6 (1.5-1.7), stroke 6.4 (6.3-6.5), chronic kidney disease 4.4 (4.3-4.6), and peripheral artery disease 6.9 (6.8-7.0). HF in combination with any other diagnosis imposed the greatest risk of death and decrease in life span compared with other combinations. Supplemental analysis led to similar results when stratified according to age, sex, and comorbidity status, and inclusion period. CONCLUSIONS: HF development, at any year since T2D diagnosis, was associated with the highest 5-year absolute and relative risk of death, and decrease in lifespan within 5 years, when compared with development of other cardiovascular or renal diagnoses.

Background Potassium disturbances per se increase the risk of ventricular fibrillation (VF). Whether potassium disturbances in the acute phase of ST-segment-elevation myocardial infarction (STEMI) are associated with VF before primary percutaneous coronary intervention (PPCI) is uncertain. Methods and Results All consecutive STEMI patients were identified in the Eastern Danish Heart Registry from 1999 to 2016. Comorbidities and medication use were assessed from Danish nationwide registries. Potassium levels were collected immediately before PPCI start. Multivariate logistic models were performed to determine the association between potassium and VF. The main analysis included 8624 STEMI patients of whom 822 (9.5%) had VF before PPCI. Compared with 6693 (77.6%) patients with normokalemia (3.5-5.0 mmol/L), 1797 (20.8%) patients with hypokalemia (<3.5 mmol/L) were often women with fewer comorbidities, whereas 134 (1.6%) patients with hyperkalemia (>5.0 mmol/L) were older with more comorbidities. After adjustment, patients with hypokalemia and hyperkalemia had a higher risk of VF before PPCI (odds ratio 1.90, 95% CI 1.57-2.30, P<0.001) and (odds ratio 3.36, 95% CI 1.95-5.77, P<0.001) compared with normokalemia, respectively. Since the association may reflect a post-resuscitation phenomenon, a sensitivity analysis was performed including 7929 STEMI patients without VF before PPCI of whom 127 (1.6%) had VF during PPCI. Compared with normokalemia, patients with hypokalemia had a significant association with VF during PPCI (odds ratio 1.68, 95% CI 1.01-2.77, P=0.045) after adjustment. Conclusions Hypokalemia and hyperkalemia are associated with increased risk of VF before PPCI during STEMI. For hypokalemia, the association may be independent of the measurement of potassium before or after VF.

One of the objectives of personalized medicine is to take treatment decisions based on a biomarker measurement. Therefore, it is often interesting to evaluate how well a biomarker can predict the response to a treatment. To do so, a popular methodology consists of using a regression model and testing for an interaction between treatment assignment and biomarker. However, the existence of an interaction is not sufficient for a biomarker to be predictive. It is only necessary. Hence, the use of the marker-by-treatment predictiveness curve has been recommended. In addition to evaluate how well a single continuous biomarker predicts treatment response, it can further help to define an optimal threshold. This curve displays the risk of a binary outcome as a function of the quantiles of the biomarker, for each treatment group. Methods that assume a binary outcome or rely on a proportional hazard model for a time-to-event outcome have been proposed to estimate this curve. In this work, we propose some extensions for censored data. They rely on a time-dependent logistic model, and we propose to estimate this model via inverse probability of censoring weighting. We present simulations results and three applications to prostate cancer, liver cirrhosis, and lung cancer data. They suggest that a large number of events need to be observed to define a threshold with sufficient accuracy for clinical usefulness. They also illustrate that when the treatment effect varies with the time horizon which defines the outcome, then the optimal threshold also depends on this time horizon.

We show that the widely used concordance index for time to event outcome is not proper when interest is in predicting a $t$-year risk of an event, for example 10-year mortality. In the situation with a fixed prediction horizon, the concordance index can be higher for a misspecified model than for a correctly specified model. Impropriety happens because the concordance index assesses the order of the event times and not the order of the event status at the prediction horizon. The time-dependent area under the receiver operating characteristic curve does not have this problem and is proper in this context.

AIMS: To investigate the risk of stroke/thromboembolism (TE) and major bleeding associated with anaemia among patients with atrial fibrillation (AF). Also, to assess the effects of oral anticoagulation (OAC) and time in therapeutic range (TTR) with vitamin K antagonists according to level of haemoglobin (Hb).METHODS AND RESULTS: Through administrative registry databases, we identified all Danish patients diagnosed with AF from 1997 to 2012. We included 18 734 AF patients with recent available data on Hb. Multiple Cox regression analyses were used to estimate hazard ratios and to compute standardized absolute 1-year risks of stroke/TE and major bleeding. Among included patients, 3796 (20%) had mild anaemia (Hb 6.83-7.45 mmol/L for women and Hb 6.83-8.03 mmol/L for men) and 2562 (14%) had moderate/severe anaemia (Hb <6.83 mmol/L). Moderate/severe anaemia was associated with increased risk of major bleeding and 9.1% lower median TTR compared with no anaemia. Use of OAC was associated with reduced risk of stroke/TE among patients without anaemia [standardized absolute 1-year difference -2.5%, 95% confidence interval (CI) -3.8 to -1.7%] or with mild anaemia (-2.3%, 95% CI -2.8 to -1.8%), but not with moderate/severe anaemia, (0.03%, -1.8 to +2.8%, interaction P = 0.01). Oral anticoagulation was associated with a 5.3% (95% CI 2.1-8.7%) increased standardized absolute risk of major bleeding among AF patients with moderate/severe anaemia.CONCLUSION: Anaemia was common in patients with AF and associated with major bleeding and lower TTR. Oral anticoagulation was associated with more major bleeding, but no reduction in risk of stroke/TE among AF patients with moderate/severe anaemia.

AIMS: Sudden cardiac death in the young (SCDY) accounts for a significant proportion of deaths among the young. The aim of this nationwide study was to examine temporal changes in incidence and causes of SCDY in Denmark in 2000-2009. During this 10-year period, several public and private health initiatives were undertaken to decrease morbidity and mortality in Denmark.METHODS AND RESULTS: All deaths among persons aged 1-35 years in Denmark in 2000-2009 (23.7 million person-years) were included. Death certificates, autopsy reports, discharge summaries, and data from nationwide administrative registries were used to identify SCDY cases. Sudden cardiac death in the young incidence rates were age-adjusted and sex-adjusted using direct standardization. Temporal changes in standardized SCDY incidence rates were reported as average annual percent changes. In the 10-year study period, there were 8756 deaths, of which we identified 635 (7%) SCDY cases. For these SCDY cases, median age at death was 29 years and 68% were men. Standardized incidence of SCDY decreased from 3.1 per 100 000 person-years in 2000 [95% confidence interval (CI) 2.4-3.8] to 2.5 per 100 000 person-years in 2009 (95% CI 1.9-3.2). This corresponds to an average annual percent change of -3.0% (95% CI -5.8 to -0.1). The distribution of major causes of SCDY did not change significantly throughout the study period.CONCLUSION: Incidence of SCDY decreased significantly from 2000 through 2009 in Denmark with an average annual percent change of -3%. Further research is needed to elucidate underlying causes of this development.

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided.Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008).Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.

We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker., SCOPUS: ar.j, info:eu-repo/semantics/published