Long-term cause-specific mortality in adolescent and young adult Hodgkin lymphoma patients treated with contemporary regimens-A nationwide Danish cohort study.

The documented treatment-induced excess mortality in Hodgkin lymphoma (HL) has spurred important treatment changes over recent decades. This study aimed to examine mortality among young HL patients treated with contemporary strategies, including historical data comparison. This nationwide study included 1348 HL patients, diagnosed in 1995-2015 and aged 15-40 at diagnosis. Among the patients, 66.5% had Ann Arbor stage I-II and 33.5% had stage III-IV disease. With a median follow-up of 14.76 years, 139 deaths occurred, yielding a 5-year overall survival of 94.6%. Older age, advanced disease, earlier treatment periods and extensive regimens were associated with higher overall mortality risk. The cumulative risk of HL-related death showed an initial sharp rise, with a plateau at 5.3% 10-year post-diagnosis. Deaths due to cardiovascular or pulmonary diseases and second cancers initially had minimal risk, gradually reaching 1.2% and 2.0% at the 20-year mark respectively. HL cases had a 7.5-fold higher mortality hazard than the background population. This study suggests that contemporary HL treatment still poses excess mortality risk, but recent changes have notably reduced overall and cause-specific mortality compared to earlier eras. Balancing treatment efficacy and toxicity remains crucial, but our findings highlight improved outcomes with modern treatment approaches.

Effect of early cryoballoon ablation on atrial fibrillation recurrence-A Danish nationwide register study.

INTRODUCTION: Cryoballoon ablation is a safe and efficient rhythm control strategy in atrial fibrillation (AF) patients. The impact of time from diagnosis to ablation is unclear. The aim of this study was to examine the impact of timing of first-time cryoballoon ablation on AF recurrence in a nationwide cohort of AF patients. METHODS AND RESULTS: From nationwide registers, all AF patients ≥18 years of age who underwent first-time AF cryoballoon ablation in Denmark from 2012 to 2018 were included. The AF patients were stratified by ablation timing: Early group (≤1 year after AF diagnosis), intermediate group (1-3 years after AF diagnosis), and late group (≥3 years after AF diagnosis). By adjusted Cox regression models, the effect of timing on AF recurrence was examined. This study included 1064 AF patients with a median age of 63 years. Most patients were male (66%) and had paroxysmal AF (67%). The 1-year risk of AF recurrence increased from 31% in the early group to 41% and 44% in the intermediate and late group. The hazard ratios (95% confidence intervals) were 1.28 (0.95, 1.74) in the intermediate group and 1.42 (1.09, 1.86) in the late group when compared to the early group. Continuous diagnosis-to-ablation time seemed to have the greatest impact on AF recurrence within the first 2 years. CONCLUSION: In AF patients undergoing cryoballoon ablation, late timing of ablation was associated with a significantly higher AF recurrence rate when compared to early timing of ablation. These findings support early cryoballoon ablation to improve the outcomes after ablation.

Patient Characteristics, Microbiology, and Mortality of Infective Endocarditis After Transcatheter Aortic Valve Implantation.

BACKGROUND: Infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) is associated with high mortality and surgery is rarely performed. Thus, to inform on preventive measures and treatment strategies, we investigated patient characteristics and microbiology of IE after TAVI. METHODS: Using Danish nationwide registries, we identified patients with IE after TAVI, IE after non-TAVI prosthetic valve (nTPV), and native valve IE. Patient characteristics; overall, early (≤12 m), and late IE (>12 m) microbiology; and unadjusted and adjusted mortality were compared. RESULTS: We identified 273, 1022, and 5376 cases of IE after TAVI, IE after nTPV, and native valve IE. Age and frailty were highest among TAVI IE (4.8%; median age: 82 y; 61.9% frail). Enterococcus spp. were common for IE after TAVI (27.1%) and IE after nTPV (21.2%) compared with native valve IE (11.4%). Blood culture-negative IE was rare in IE after TAVI (5.5%) compared with IE after nTPV (15.2%) and native valve IE (13.5%). The unadjusted 90-day mortality was comparable, but the 5-year mortality was highest for IE after TAVI (75.2% vs 57.2% vs 53.6%). In Cox models adjusted for patient characteristics and bacterial etiology for 1-90 days and 91-365 days, there was no significant difference in mortality rates. CONCLUSIONS: Patients with IE after TAVI are older and frailer, enterococci and streptococci are often the etiologic agents, and are rarely blood culture negative compared with other IE patients. Future studies regarding antibiotic prophylaxis strategies covering enterococci should be considered in this setting.

Sodium-glucose cotransporter-2 inhibitors compared with glucagon-like-peptide-1 receptor agonists and out-of-hospital cardiac arrest in type 2 diabetes: a nationwide nested case-control study.

AIMS: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have beneficial direct effects on the myocardium by impacting cardiac ion channels and exchangers that control cardiac electrophysiology. We investigated the relationship between SGLT-2is in comparison to glucagon-like peptide-1 receptor agonists (GLP-1as) and out-of-hospital cardiac arrest (OHCA) in individuals with type 2 diabetes. METHODS: Using data from Danish registries, we conducted a nationwide nested case-control study in a cohort of individuals with type 2 diabetes between 2013 and 2019. Cases were defined as OHCA victims from presumed cardiac causes and each case was randomly matched with five controls without OHCA based on age, sex, and index-date (OHCA date). Conditional logistic regression models were used to estimate the adjusted odds ratios (ORs) with 95% confidence interval (95% CI) of OHCA comparing SGLT-2i use with GLP-1as (reference). RESULTS: The study population consisted of 3618 OHCA cases and 18 090 matched controls. SGLT-2i was used by 91 cases and 593 controls, and was associated with reduced odds of OHCA compared with use of GLP-1a after controlling for the relevant confounders (adjusted OR 0.76 [95% CI:0.58-0.99]). The adjusted OR of OHCA associated with SGLT-2i use did not vary significantly by sex (P-value interaction: 0.461), pre-existing cardiac disease (P-value interaction: 0.762), heart failure (P-value interaction: 0.891), diabetes duration (P-value interaction: 0.101), and chronic kidney disease (P-value interaction: 0.894). CONCLUSION: Use of SGLT-2i is associated with a reduced risk of OHCA compared with use of GLP-1a in type 2 diabetes.

Use of methylphenidate is associated with increased risk of out-of-hospital cardiac arrest in the general population: a nationwide nested case-control study.

AIM: Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity disorder (ADHD), is associated with cardiovascular events, but few studies have explored the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether methylphenidate use is associated with OHCA in the general population. METHODS AND RESULTS: Using Danish nationwide registries, we conducted a nested case-control study with OHCA cases of presumed cardiac causes and age/sex/OHCA-date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the odds ratio (OR) of OHCA by comparing methylphenidate use with no use of methylphenidate.The study population consisted of 46 578 OHCA cases [median: 72 years (interquartile range: 62-81), 68.8% men] and 232 890 matched controls. Methylphenidate was used by 80 cases and 166 controls, and was associated with an increased OR of OHCA compared with non-users {OR: 1.78 [95% confidence interval (CI): 1.32-2.40]}. The OR was highest in recent starters (OR≤180 days: 2.59, 95% CI: 1.28-5.23). The OR of OHCA associated with methylphenidate use did not vary significantly by age (P-value interaction: 0.37), sex (P-value interaction: 0.94), and pre-existing cardiovascular disease (P-value interaction: 0.27). Furthermore, the ORs remained elevated when we repeated the analyses in individuals without registered hospital-based ADHD (OR: 1.85, 95% CI: 1.34-2.55), without severe psychiatric disorders (OR: 1.98, 95% CI: 1.46-2.67), without depression (OR: 1.93, 95% CI: 1.40-2.65), or in non-users of QT-prolonging drugs (OR: 1.79, 95% CI: 1.27-2.54). CONCLUSION: Methylphenidate use is associated with an increased risk of OHCA in the general population. This increased risk applies to both sexes and is independent of age and the presence of cardiovascular disease.

Risk of out-of-hospital cardiac arrest in patients with sarcoidosis: a Danish nationwide nested case-control study.

ObjectiveSarcoidosis is over-represented among victims of cardiac arrest. We aimed to establish whether sarcoidosis is associated with out-of-hospital cardiac arrest (OHCA) in the general population.MethodsWe conducted a nested case-control study in a nationwide cohort of individuals between 1 June 2001 and 31 December 2015 in Denmark. OHCA cases from presumed cardiac causes were matched 1:10 by sex and age on OHCA date with non-OHCA controls from the general population. The association between sarcoidosis and OHCA was assessed using Cox regression by calculating HR and 95% CIs. Models were adjusted for cardiovascular disease. Finally, stratified analyses were performed according to sex, heart failure and ischaemic heart disease. RESULTS: We identified 35 195 OHCA cases and 351 950 matched controls without OHCA (median age 72 years and 66.8% male). Patients with sarcoidosis had higher rate of OHCA compared with the general population after adjustments for common OHCA risk factors (HR 1.51, 95% CI 1.19 to 1.92). This increased OHCA rate occurred in women (HR 2.11, 95% CI 1.42 to 3.12) but not in men (HR 1.27, 95% CI 0.93 to 1.72; p value interaction=0.033), and was larger in patients with than without heart failure (HRheart failure: 2.59, 95% CI 1.42 to 4.73; HRno heart failure: 1.33, 95% CI 1.01 to 1.74; p value interaction: 0.007). The HR associated with sarcoidosis did not vary by the presence of ischaemic heart disease. CONCLUSION: Patients with sarcoidosis have a higher OHCA rate than the general population. This increased OHCA rate occurred in women but not in men, and was larger in patients with than without heart failure.

Risk and timing of venous thromboembolism in patients with gastrointestinal cancer: a nationwide Danish cohort study.

AIMS: Cancer is a well-known risk factor of venous thromboembolism (VTE). Some cancers are believed to be more thrombogenic. The purpose of this study was to investigate the characteristics of patients with incident gastrointestinal cancers (GI) and their associated 1-year risk and timing of venous thromboembolic events and the 1-year mortality. METHODS: This study was a retrospective cohort study. Through Danish nationwide registries, all patients with first-time GI cancer diagnosis from 2008 to 2018 were identified. Incident VTE events were identified within a 1-year follow-up after GI cancer diagnosis using the Aalen-Johansen estimator. Cox proportional-hazard models were applied to investigate risk factors for VTE events and the impact of VTE on mortality. RESULTS: A total of 87 069 patients were included and stratified by cancer types: liver (5.8%), pancreatic (12.0%), gastric (6.9%), small intestinal (1.9%), colorectal (61.8%), oesophageal (7.3%) and gallbladder (3%). Most VTE events happened close to onset of the cancer diagnosis with declining events by time. The 1-year cumulative incidence of VTE differed according to cancer type with pancreatic cancer being most thrombogenic (7.8%), and colorectal and liver cancer being the least (3.6%). Prior VTE, heart failure, chronic obstructive pulmonary disease (COPD), liver disease, chronic kidney disease (CKD) and diabetes increased the VTE risk. Overall, the patients with GI cancer had high 1-year mortality of 33.3% with patients with pancreatic cancer having the highest mortality (70.3%). CONCLUSION: We found that most VTE events happen close to onset of the GI cancer diagnosis and thrombogenicity differed by type of GI cancer, ranging from 7.8% in patients with pancreatic cancer to 3.6% in colorectal and patients with liver cancer. Prior VTE, heart failure, COPD, liver disease, CKD and DM were associated with increased risk of VTE.

Blood-brain barrier permeable ß-blockers linked to lower risk of Alzheimer's disease in hypertension.

Alzheimer's disease is a neurodegenerative disorder in which the pathological accumulation of amyloid-ß and tau begins years before symptom onset. Emerging evidence suggests that ß-blockers (ß-adrenergic antagonists) increase brain clearance of these metabolites by enhancing CSF flow. Our objective was to determine whether ß-blocker treatments that easily cross the blood-brain barrier reduce the risk of Alzheimer's disease compared to less permeable ß-blockers. Data from the Danish national registers were used to identify a retrospective cohort of individuals with hypertension, and those treated with ß-blockers were included in the analysis. People with indications for ß-blocker use other than hypertension (e.g. heart failure) were only retained in a sensitivity analysis. ß-blockers were divided into three permeability groups: low, moderate and high. We used multivariable cause-specific Cox regression to model the effect of ß-blocker blood-brain barrier permeability on time to dementia outcomes, adjusting for baseline comorbidities, demographics and socioeconomic variables. Death was modelled as a competing risk. The 10-year standardized absolute risk was estimated as the averaged person-specific risks per treatment. In a cohort of 69 081 (median age = 64.4 years, 64.8% female) people treated with ß-blockers for hypertension, highly blood-brain barrier-permeable ß-blockers were associated with reduced risk of Alzheimer's disease versus low permeability ß-blockers (-0.45%, P < 0.036). This effect was specific to Alzheimer's diagnoses and did not extend to dementia in general. Propensity score analysis matching high and low blood-brain barrier-permeable patients also detected a decreased Alzheimer's risk (-0.92%, P < 0.001) in the high permeability group compared to the low, as did a 1-year landmark analysis (-0.57%, P < 0.029) in which events within the first year of follow-up were ignored as likely unrelated to treatment. Our results suggest that amongst people taking ß-blockers for hypertension, treatment with highly blood-brain barrier permeable ß-blockers reduces the risk of Alzheimer's disease compared to low permeability drugs. Our findings support the hypothesis that highly permeable ß-blockers protect against Alzheimer's disease by promoting waste brain metabolite clearance.

Coronary CT and timing of invasive coronary angiography in patients ≥75 years old with non-ST segment elevation acute coronary syndromes.

BACKGROUND: The ability of coronary CT angiography (cCTA) to rule out significant coronary artery disease (CAD) in older patients with non-ST segment elevation acute coronary syndromes (NSTEACS) is unclear since valid cCTA analysis may be limited by extensive coronary artery calcification. In addition, the effect of very early invasive coronary angiography (ICA) with possible revascularisation is debated. METHODS: This is a posthoc analysis of patients ≥75 years included in the Very Early vs Standard Care Invasive Examination and Treatment of Patients with Non-ST-Segment Elevation Acute Coronary Syndrome Trial. cCTA was performed prior to the ICA. The diagnostic accuracy of cCTA was investigated. Presence of a coronary artery stenosis ≥50% by subsequent ICA was used as reference. Patients were randomised to a very early (within 12 hours of diagnosis) or a standard ICA (within 48-72 hours of diagnosis). The primary composite endpoint was 5-year all-cause mortality, non-fatal recurrent myocardial infarction or hospital admission for refractory myocardial ischaemia or heart failure. RESULTS: Of 452 (21%) patients ≥75 years, 161 (35.6%) underwent cCTA. 19% of cCTAs excluded significant CAD. The negative predictive value (NPV) of cCTA was 94% (95% CI 79 to 99) and the sensitivity 98% (95% CI 94 to 100). No significant differences in the frequency of primary endpoints were seen in patients randomised to very early ICA (at 5-year follow-up, n=100 (46.9%) vs 122 (51.0%), log-rank p=0.357). CONCLUSION: In patients ≥75 years with NSTEACS, cCTA before ICA showed a high NPV. A very early ICA <12 hours of diagnosis did not significantly improve long-term clinical outcomes.

Treatment patterns for oral anticoagulants in older patients with atrial fibrillation: a retrospective, cross-sectional, nationwide study from Denmark.

OBJECTIVES: Atrial fibrillation (AF) is a predominant risk factor of ischaemic stroke and treatment with oral anticoagulants (OACs) is recommended in all patients with risk factors. This study sought to examine treatment patterns of OACs in older patients with AF. DESIGN: Retrospective, cross-sectional study. SETTING: Danish nationwide administrative and clinical registers and databases. PARTICIPANTS: A total of 40 027 patients, >75 years of age, after their first hospital contact due to AF between 2010 and 2018. PRIMARY AND SECONDARY OUTCOMES MEASURES: The primary event of interest was claimed prescriptions for OACs within 180 days after first hospital contact due to AF. Proportions of patients treated with OACs were estimated and clinical factors associated with the probability of receiving OAC treatment were identified using adjusted logistic regression models. RESULTS: A total of 40 027 patients were included with a slight majority of women (54%). The median age was 81 years (IQR 78-86). We found that an overall 32 235 patients (81%) were prescribed an OAC after their first hospital contact due to AF with a marked increase in the proportion of patients treated from 2010 to 2018. Factors related to a decreased probability of receiving treatment were bleeding risk factors such as a history of haemorrhagic stroke (OR 0.21, 95% CI 0.16 to 0.27), any bleeding (OR 0.58, 95% CI 0.53 to 0.62) as well as markers of frailty such as osteoporosis (OR 0.78, 95% CI 0.71 to 0.85). CONCLUSION: In this large nationwide study, we found that in older patients with AF, the overall rates of OAC prescription were generally high (~80%) and increasing during the last decade. Factors associated with not receiving guideline recommended OAC treatment were generally related to bleeding risk factors or frailty.

Ethnic disparities in out-of-hospital cardiac arrest: A population-based cohort study among adult Danish immigrants.

Background: Ethnicity might impact out-of-hospital cardiac arrest (OHCA) risk, but it has scarcely been studied in Europe. We aimed to assess whether ethnicity influenced the risk of OHCA of cardiac cause in Danish immigrants and its interplay with risk factors for OHCA and socioeconomic status. Methods: This nationwide study included all immigrants between 18 and 80 years present in Denmark at some point between 2001 and 2020. Regions of origin were defined as Africa, Arabic countries, Asia, Eastern Europe, Latin America, and Western countries. OHCAs with presumed cardiac cause were identified from the Danish Cardiac Arrest Registry. Findings: Overall, among 1,011,565 immigrants, a total of 1,801 (0.2%) OHCAs (median age 64 (Q1-Q3 53-72) years, 72% males) occurred. The age- and sex- standardized (reference: Western countries) incidence of OHCA (/1,00,000 person-years) was 34.6 (27.8-43.4) in African, 34.1 (30.4-38.4) in Arabic, 33.5 (29.3-38.2) in Asian, 35.6 (31.9-39.6) in Eastern European, and 16.2 (9.0-27.2) in Latin American immigrants. When selecting Western origin as a reference, and after adjusting on OHCA risk factors, Arabic (HR 1.18, 95%CI 1.04-1.35; P=0.01), Eastern European (HR 1.28, 95%CI 1.13-1.46; P<0.001), and African origin (HR 1.34, 95%CI 1.10-1.63; P<0.01) were associated with higher risk of OHCA, whereas Latin American origin (HR 0.58, 95%CI 0.35-0.0.96; P=0.03) was associated with lower risk of OHCA. Comparable results were observed when adjusting on education level and economic status. Interpretation: This study emphasizes that ethnicity is associated with OHCA risk, even when considering traditional cardiac arrest risk factors. Funding: R Garcia received a grant from the Fédération Française de Cardiologie for his post-doctoral fellowship and this work was supported by the Novo Nordisk Foundation Tandem Programme 2022 (grant# 31364).

Nationwide study of mortality and sudden cardiac death in young persons diagnosed with chronic kidney disease.

AIMS: The aim of this study was to compare short- and long-term risk of sudden cardiac death (SCD) among persons aged 18-49 years with and without chronic kidney disease (CKD). METHODS AND RESULTS: Using Danish nationwide health registries, all persons aged 18-49 years diagnosed with earlier stages of CKD or chronic kidney failure from 1 July 1995 through 2009 were identified. Non-exposed subjects matched on sex and birth-year were identified. All SCD in the Danish population aged 18-49 years in 2000-2009 have previously been identified using information from the Danish nationwide health registries, death certificates, and autopsy reports. In total, 9308 incident cases of earlier stage CKD and 1233 incident cases of chronic kidney failure were included. Among patients with earlier stage CKD, the absolute risk of SCD 1, 5, and 10 years after diagnosis was 0.14%, 0.37%, and 0.68%, respectively. Compared with age- and sex-matched subjects the corresponding relative risk (RR) was 20.3 [95% confidence interval (CI) 8.4-48.8], 7.1 (95% CI 4.2-12.0), and 6.1 (95% CI 3.8-9.7), respectively. Among patients with chronic kidney failure, the absolute 1-, 5-, and 10-year risk of SCD was 0.17%, 0.56%, and 2.07%, respectively. The corresponding RR was 12.5 (95% CI 1.4-111.6), 7.9 (95% CI 2.3-27.0), and 10.1 (95% CI 4.5-22.6). CONCLUSION: Persons with earlier stage CKD and chronic kidney failure had increased risk of SCD compared with the background population with a 6- to 20-fold increased risk of SCD. These findings underline the importance of early cardiovascular risk monitoring and assessment in persons with CKD.

Geographical inequalities in the decreasing 28-day mortality following incident acute myocardial infarction: a Danish register-based cohort study, 1987-2016.

BACKGROUND: Mortality following acute myocardial infarction (AMI) has decreased in western countries for decades; however, it remains unknown whether the decrease is distributed equally across the population independently of residential location. This study investigated whether the observed decreasing 28-day mortality following an incident AMI in Denmark from 1987 to 2016 varied geographically at municipality level after accounting for sociodemographic characteristics. METHODS: A register-based cohort study design was used to investigate 28-day mortality among individuals with an incident AMI. Global spatial autocorrelation (within sub-periods) was analysed at municipality level using Moran's I. Analysis of spatio-temporal autocorrelation before and after adjusting for sociodemographic characteristics was performed using logistic regression and conditional autoregressive models with inference in a Bayesian setting. RESULTS: In total, 368,839 individuals with incident AMI were registered between 1987 and 2016 in Denmark; 128,957 incident AMIs were fatal. The 28-day mortality decreased over time at national level with an odds ratio of 0.788 (95% credible interval (0.784, 0.792)) per 5-year period after adjusting for sociodemographic characteristics. The decrease in the 28-day mortality was geographically unequally distributed across the country and in a geographical region in northern Jutland, the 28-day mortality decreased significantly slower (4-12%) than at national level. CONCLUSIONS: During the period from 1987 to 2016, the 28-day mortality following an incident AMI decreased substantially in Denmark. However, in a local geographical region, the 28-day mortality decreased significantly slower than in the rest of the country both before and after adjusting for sociodemographic differences. Efforts should be made to keep geographical trend inequalities in the 28-day mortality to a minimum.

Treatment of older patients with atrial fibrillation by morbidity burden.

AIMS: Older patients with atrial fibrillation (AF) are at risk of adverse outcomes, which is accentuated by comorbidities. We sought to examine the association between morbidity burden and the treatment of older AF patients. METHODS AND RESULTS: Using Danish nationwide registers we included patients ≥70 years of age between 2010 and 2017 at their first hospitalization due to AF. Using multiple logistic regression models we examined the association between morbidity burden and the odds of receiving oral anticoagulants (OACs), anti-arrhythmic drugs (AADs), and rhythm-control procedures (direct current cardioversions and catheter ablations). A total of 48 995 patients were included with a majority of women (54%), with a median age of 80 years [interquartile range (IQR) 75-85], and a median morbidity burden of 2 comorbidities (IQR 1-3). Increasing morbidity burden was associated with decreasing odds of OAC treatment with patients having >5 comorbidities having the lowest odds [odds ratio (OR) 0.38, 95% confidence interval (CI) 0.35-0.42] compared to patients with low morbidity burden (0-1 comorbidities). Having >5 comorbidities were associated with increased odds of AAD treatment (OR 1.90, 95% CI 1.64-2.21) and decreased odds of AF procedures (OR 0.39, 95% CI 0.31-0.48), compared to patients with a low morbidity burden (0-1 comorbidities). Examining morbidity burden continuously revealed similar results. CONCLUSIONS: In older AF patients, multimorbidity was associated with lower odds of receiving OACs and rhythm-control procedures but increased odds of AADs. This presents a clinical conundrum as multimorbid patients potentially benefit the most from treatment with OACs.

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

AIMS: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer. METHODS AND RESULTS: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively. CONCLUSION: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

Electrical cardioversion of atrial fibrillation and the risk of brady-arrhythmic events.

BACKGROUND: Electrical cardioversion (ECV) is a common procedure for terminating atrial fibrillation (AF). ECV is associated with brady-arrhythmic events, however, the age-specific risks of clinically significant brady-arrhythmic events are unknown. METHODS: Using Danish nationwide registers, we identified patients with AF at their first non-emergent ECV between 2005 and 2018 and estimated their 30-day risk of brady-arrhythmic events. Moreover, factors associated with increased risks of brady-arrhythmias were identified. Absolute risks were estimated using logistic regression models fitted with natural splines as well as standardization (G-formula). RESULTS: We identified 20,725 eligible patients with a median age of 66 years (IQR 60-72) and most males (73%). The 30-day risks of brady-arrhythmic events after ECV were highly dependent on age with estimated risks ranging from 0.5% (95% CI 0.2-1.7) and 1.2% (95% CI 0.99-1.5) to 2.7% (95% CI 2.1-3.3) and 5.1% (95% CI 2.6-9.7) in patients aged 40, 65, 80, and 90 years, respectively. Factors associated with brady-arrhythmias were generally related to cardiovascular disease (eg, ischemic heart disease, heart failure, valvular AF) or a history of syncope. We found no indications that pre-treatment with anti-arrhythmic drugs conferred increased risks of brady-arrhythmic events (standardized absolute risk difference -0.25% [95% CI -0.67 to 0.17]). CONCLUSIONS: ECV conferred clinically relevant 30-day risks of brady-arrhythmic events, especially in older patients. Anti-arrhythmic drug treatment was not found to increase the risk of brady-arrhythmias. Given the widespread use of ECV, these data should provide insights regarding the potential risks of brady-arrhythmic events.

Echocardiographic predictors of long-term adverse cardiovascular outcomes in participants with and without diabetes mellitus: A follow-up analysis of the Copenhagen City Heart Study.

BACKGROUND: Previous studies have identified several echocardiographic markers of cardiac dysfunction in participants with diabetes mellitus, including E/e'. However, previous studies have been limited by short follow-up duration or low statistical power, and none have assessed whether echocardiographic predictors of adverse cardiovascular outcome differ between individuals with DM and individuals without DM. METHODS: A total of 1997 individuals from the general population without heart disease had an echocardiogram performed in 2001 to 2003. Diabetes was defined as HbA1c ≥6.5% (≥48 mmol/mol), non-fasted blood glucose ≥11.1 mmol/L or the use of glucose lowering medication. The end-point was a composite of heart failure (HF), ischemic heart disease (IHD) and cardiovascular death (CVD). RESULTS: At baseline, a total of 292 participants (15%) had diabetes. Median follow-up time was 12.4 years (interquartile-range: 9.8-12.8 years) and follow-up was 100%. During follow-up, 101 participants (35%) with diabetes and 281 participants without diabetes (16%) reached the composite end-point. The prognostic value of E/e' was significantly modified by diabetes (p for interaction: 0.003). In participants with diabetes, only E/e' remained an independent predictor of outcome in a final multivariable model adjusted for clinical and echocardiographic parameters (HR 1.08, 95% CI 1.00-1.17, p = 0.0041, per 1 increase). In participants without diabetes, left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF) and a' remained independent predictors of outcome when adjusted for clinical and echocardiographic parameters. In individuals with diabetes, only E/e' added incremental prognostic value to risk factors from the SCORE risk chart and the ACC/AHA Pooled Cohort Equation. CONCLUSION: In individuals with diabetes from the general population, E/e' is a stronger predictor of cardiovascular mortality and morbidity than in individuals without diabetes and contributes with incremental prognostic value in addition to established cardiovascular risk factors.

Time to Thrombolysis and Long-Term Outcomes in Patients With Acute Ischemic Stroke: A Nationwide Study.

Background and Purpose: It is well-established that increasing treatment delay reduces the benefits of thrombolysis in patients with acute ischemic stroke. However, most studies focus on short-term outcomes. This study examined long-term outcomes according to time to thrombolysis in patients with first-time ischemic stroke. Methods: In this nationwide cohort study, all Danish patients with first-time ischemic stroke treated with intravenous thrombolysis between 2011 and 2017 and alive at discharge were identified through the Danish Stroke Registry. The association between time from symptom onset to thrombolysis and the long-term rate of the composite of death and recurrent ischemic stroke was examined using multivariable Cox regression and restricted cubic spline analysis. Results: The study population included 6252 patients with first-time ischemic stroke treated with thrombolysis (median age, 69 years [25th­75th percentile 60­78 years], 60% men). The median follow-up was 2.5 years (25th­75th percentile 1.2­4.1 years). The median time to thrombolysis was 138 minutes (25th­75th percentile 101­185 minutes), and the median National Institutes of Health Stroke Scale score at presentation was 5 (25th­75th percentile 3­10). The absolute 3-year risk of the composite outcome was 19.0% (95% CI, 16.4%­21.8%) in the 0 to 90 minute group, 23.3% (21.8%­24.9%) in the 91 to 180 minute group, and 23.8% (21.6%­26.1%) in the 181 to 270 minute group. Compared with thrombolysis within 90 minutes, time to thrombolysis >90 minutes was associated with a higher rate of the composite outcome (91­180 minute: adjusted hazard ratio, 1.25 [95% CI, 1.06­1.48]; 181­270 minutes: adjusted hazard ratio, 1.35 [95% CI, 1.12­1.61]). In restricted cubic spline analysis, the rate of the composite outcome increased with increasing time to thrombolysis and leveled off after 138 minutes. Conclusions: In this nationwide cohort of patients with ischemic stroke, the long-term rate of the composite of death and recurrent ischemic stroke increased with increasing time from symptom onset to initiation of thrombolysis.

Global longitudinal strain predicts cardiovascular events after coronary artery bypass grafting.

OBJECTIVE: To determine the prognostic value of global longitudinal strain (GLS) after coronary artery bypass grafting (CABG). METHODS: We performed a retrospective cohort study on patients undergoing CABG between 2006 and 2011 who had an echocardiogram available for strain analysis. The patients were followed up through nationwide registries for development of all-cause mortality, cardiovascular death (CVD) and major adverse cardiovascular events (MACEs) defined as heart failure hospitalisation and/or CVD. Multivariable Cox regression was applied to adjust for the European System for Cardiac Operative Risk Evaluation II (EuroSCORE-II). Additive value was assessed by Net Reclassification Index (NRI) improvement. RESULTS: Of the 709 patients included, 80 died during a median follow-up of 3.8 years. Of these, 45 had CVD, and 72 patients experienced MACE. Mean age was 68 years and 85% were men. Left ventricular ejection fraction (LVEF) was 50% and GLS was -13%.GLS was an independent predictor when adjusted for the EuroSCORE-II (all-cause mortality: HR=1.07 (1.01-1.13), p=0.018; CVD: HR=1.11 (1.03-1.20), p=0.007; MACE: HR=1.12 (1.06-1.19), p<0.001, per 1% absolute decrease). GLS significantly improved the NRI score by 0.30 when added to the EuroSCORE-II for predicting MACE, but not significantly for the other endpoints.LVEF modified the association between GLS and outcomes (p for interaction<0.05 for CVD and MACE). GLS remained an independent predictor of outcomes in patients with preserved LVEF (LVEF≥50%) and improved the NRI score when added to the EuroSCORE-II for predicting CVD and MACE, but not all-cause mortality in these patients. CONCLUSION: GLS is an independent predictor of long-term outcomes after CABG. The predictive value appears strongest among patients with preserved LVEF.

Risk of out-of-hospital cardiac arrest in patients with bipolar disorder or schizophrenia.

OBJECTIVE: Patients with bipolar disorder and schizophrenia are at high cardiovascular risk; yet, the risk of out-of-hospital cardiac arrest (OHCA) compared with the general population remains scarcely investigated. METHODS: We conducted a nested case-control study using Cox regression to assess the association of bipolar disorder and schizophrenia with the HRs of OHCA of presumed cardiac cause (2001-2015). Reported are the HRs with 95% CIs overall and in subgroups defined by established cardiac disease, cardiovascular risk factors and psychotropic drugs. RESULTS: We included 35 017 OHCA cases and 175 085 age-matched and sex-matched controls (median age 72 years and 66.9% male). Patients with bipolar disorder or schizophrenia had overall higher rates of OHCA compared with the general population: HR 2.74 (95% CI 2.41 to 3.13) and 4.49 (95% CI 4.00 to 5.10), respectively. The association persisted in patients with both cardiac disease and cardiovascular risk factors at baseline (bipolar disorder HR 2.14 (95% CI 1.72 to 2.66), schizophrenia 2.84 (95% CI 2.20 to 3.67)) and among patients without known risk factors (bipolar disorder HR 2.14 (95% CI 1.09 to 4.21), schizophrenia HR 5.16 (95% CI 3.17 to 8.39)). The results were confirmed in subanalyses only including OHCAs presenting with shockable rhythm or receiving an autopsy. Antipsychotics-but not antidepressants, lithium or antiepileptics (the last two only tested in bipolar disorder)-increased OHCA hazard compared with no use in both disorders. CONCLUSIONS: Patients with bipolar disorder or schizophrenia have a higher rate of OHCA compared with the general population. Cardiac disease, cardiovascular risk factors and antipsychotics represent important underlying mechanisms.