Urban-rural inequalities in IV thrombolysis for acute ischemic stroke: A nationwide study.

INTRODUCTION: Rural residency has been associated with lower reperfusion treatment rates for acute ischemic stroke in many countries. We aimed to explore urban-rural differences in IV thrombolysis rates in a small country with universal health care, and short transport times to stroke units. PATIENTS AND METHODS: In this nationwide cohort study, adult ischemic stroke patients registered in the Danish Stroke Registry (DSR) between 2015 and 2020 were included. The exposure was defined by residence rurality. Data from the DSR, Statistics Denmark, and the Danish Health Data Authority, were linked on the individual level using the Civil Registration Number. Adjusted treatment rates were calculated by balancing baseline characteristics using inverse probability of treatment weights. RESULTS: Among the included 56,175 patients, prehospital delays were shortest for patients residing in capital municipalities (median 4.7 h), and longest for large town residents (median 7.1 h). Large town residents were predominantly admitted directly to a comprehensive stroke center (98.5%), whereas 30.9% of capital residents were admitted to a hospital with no reperfusion therapy available (non-RT unit). Treatment rates were similar among all non-rural residents (18.5%-18.7%), but slightly lower among rural residents (17.2% [95% CI 16.5-17.8]). After adjusting for age, sex, immigrant status, and educational attainment, rural residents reached treatment rates comparable to capital and large town residents at 18.5% (95% CI 17.7-19.4). DISCUSSION AND CONCLUSION: While treatment rates varied minimally by urban-rural residency, substantial differences in median prehospital delay and admission to non-RT units underscored marked urban-rural differences in potential obstacles to reperfusion therapies.

Temporal trends in lifetime risks of atrial fibrillation and its complications between 2000 and 2022: Danish, nationwide, population based cohort study.

OBJECTIVES: To examine how the lifetime risks of atrial fibrillation and of complications after atrial fibrillation changed over time. DESIGN: Danish, nationwide, population based cohort study. SETTING: Population of Denmark from 1 January 2000 to 31 December 2022. PARTICIPANTS: 3.5 million individuals (51.7% women and 48.3% men) who did not have atrial fibrillation at 45 years of age or older were followed up until incident atrial fibrillation, migration, death, or end of follow-up, whichever came first. All 362 721 individuals with incident atrial fibrillation (46.4% women and 53.6% men), but with no prevalent complication, were further followed up until incident heart failure, stroke, or myocardial infarction. MAIN OUTCOME MEASURES: Lifetime risk of atrial fibrillation and lifetime risks of complications after atrial fibrillation over two prespecified periods (2000-10 v 2011-22). RESULTS: The lifetime risk of atrial fibrillation increased from 24.2% in 2000-10 to 30.9% in 2011-22 (difference 6.7% (95% confidence interval 6.5% to 6.8%)). After atrial fibrillation, the most frequent complication was heart failure with a lifetime risk of 42.9% in 2000-10 and 42.1% in 2011-22 (-0.8% (-3.8% to 2.2%)). Individuals with atrial fibrillation lost 14.4 years with no heart failure. The lifetime risks of stroke and of myocardial infarction after atrial fibrillation decreased slightly between the two periods, from 22.4% to 19.9% for stroke (-2.5% (-4.2% to -0.7%)) and from 13.7% to 9.8% for myocardial infarction (-3.9% (-5.3% to -2.4%). No evidence was reported of a differential decrease between men and women. CONCLUSION: Lifetime risk of atrial fibrillation increased over two decades of follow-up. In individuals with atrial fibrillation, about two in five developed heart failure and one in five had a stroke over their remaining lifetime after atrial fibrillation diagnosis, with no or only small improvement over time. Stroke risks and heart failure prevention strategies are needed for people with atrial fibrillation.

Birth cohort effects on diagnosed atrial fibrillation incidence: nationwide cohort study from 1980 to 2018.

BACKGROUND: The incidence of atrial fibrillation (AF) shows substantial temporal trends, but the contribution of birth cohort effects is unknown. These effects refer to the relationship between birth year and the likelihood of developing AF. We aimed to assess trends in cumulative incidence of diagnosed AF across birth cohorts and to disentangle the effects of age, birth cohort and calendar period by using age-period-cohort analyses. METHODS: In a Danish nationwide population-based cohort study, 4.7 million individuals were selected at a given index age (45, 55, 65 and 75 years) free of AF and followed up for diagnosed AF. For each index age, we assessed trends in 10-year cumulative incidence of AF across six 5-year birth cohorts. An age-period-cohort model was estimated using Poisson regression with constrained spline functions collapsing data into 1-year intervals across ages and calendar years. RESULTS: Cumulative incidence of AF diagnosis increased across birth cohorts for all index ages (ptrend<0.001). Compared with the first birth cohort, the diagnosed AF incidence rate ratio in the last birth cohort was 3.0 (95% CI 2.9 to 3.2) for index age 45 years, 2.9 (2.8 to 3.0) for 55 years, 2.8 (2.7 to 2.8) for 65 years and 2.7 (2.6 to 2.7) for 75 years. Age-period-cohort analyses showed substantial birth cohort effects independent of age, with no clear period effect. Compared with individuals born in 1930, the diagnosed AF incidence rate was 0.125 smaller among individuals born in 1885 and was four times larger among individuals born in 1975. CONCLUSION: Substantial birth cohort effects, independent of age and calendar period, influence trends in diagnosed AF incidence.

Geographical Variation in the Use of Oral Anticoagulation and Clinical Outcomes among Patients with Atrial Fibrillation in Denmark, Sweden, and Finland.

Background Geographical mapping of variations in the treatment and outcomes of a disease is a valuable tool for identifying inequity. We examined international and intranational variations in initiating oral anticoagulation (OAC) therapy and clinical outcomes among patients with atrial fibrillation (AF) in Nordic countries. We also tracked real-world trends in initiating OAC and the clinical outcomes. Methods We conducted a registry-based multinational cohort study of OAC-naive patients with an incident hospital diagnosis of AF in Denmark ( N = 61,345), Sweden ( N = 124,120), and Finland ( N = 59,855) and a CHA 2 DS 2 -VASc score of ≥1 in men and ≥2 in women between 2012 and 2017. Initiation of OAC therapy was defined as dispensing at least one prescription between 90 days before and 90 days after the AF diagnosis. Clinical outcomes included ischemic stroke, intracerebral hemorrhage, intracranial bleeding, other major bleeding, and all-cause mortality. Results The proportion of patients initiating OAC therapy ranged from 67.7% (95% CI: 67.5-68.0) in Sweden to 69.6% (95% CI: 69.2-70.0) in Finland, with intranational variation. The 1-year risk of stroke varied from 1.9% (95% CI: 1.8-2.0) in Sweden and Finland to 2.3% (95% CI: 2.2-2.4) in Denmark, with intranational variation. The initiation of OAC therapy increased with a preference for direct oral anticoagulants over warfarin. The risk of ischemic stroke decreased with no increase in intracranial and intracerebral bleeding. Conclusion We documented inter- and intranational variation in initiating OAC therapy and clinical outcomes across Nordic countries. Adherence to structured care of patients with AF could reduce future variation.

Socioeconomic Inequalities in Functional Outcome After Reperfusion-Treated Ischemic Stroke.

BACKGROUND: We aimed to investigate whether socioeconomic status (SES) was associated with functional outcome in patients with ischemic stroke treated with reperfusion therapy (intravenous thrombolysis and/or thrombectomy). METHODS: This nationwide cohort study included reperfusion-treated patients with ischemic stroke ≥18 years registered in the Danish Stroke Registry between 2015 and 2018. Functional outcome was determined by the modified Rankin Scale score 90 days after stroke. SES was defined by educational attainment, family income, and employment status before stroke. SES data were available from Statistics Denmark and linked on the individual level with data from the Danish Stroke Registry. Uni- and multivariable ordinal logistic regression was performed for each socioeconomic parameter individually (education, income, and employment) to estimate the common odds ratios (cORs) for lower 90-day modified Rankin Scale scores. RESULTS: A total of 5666 patients were included. Mean age was 68.7 years (95% CI, 68.3-69.0), and 38.4% were female. Low SES was associated with lower odds for achieving lower 90-day modified Rankin Scale score: Low versus high education, cOR, 0.69 (95% CI, 0.61-0.79), low versus high income, cOR, 0.59 (95% CI, 0.53-0.67), and unemployed versus employed, cOR, 0.70 (95% CI, 0.58-0.83). Inequalities were reduced after adjusting for age, sex, and immigrant status, except for unemployed versus employed patients, adjusted cOR, 0.66 (95% CI, 0.54-0.80). No statistically significant differences remained after adjusting for potentially mediating variables (eg, stroke severity, prestroke modified Rankin Scale, and smoking). CONCLUSIONS: Socioeconomic inequalities were observed in functional outcome after reperfusion treated ischemic stroke. In particular, prestroke unemployment was negatively associated with good functional outcome. A more adverse prognostic profile among patients with low SES appeared to explain the majority of these inequalities.

Geographical variation in persistence to oral anticoagulation therapy and clinical outcomes among patients with atrial fibrillation initiating therapy in Denmark, Sweden, Norway and Finland.

AIM: To examine inter-national and regional variations in persistence of oral anticoagulation (OAC) therapy and incidence of clinical outcomes and mortality, among patients with incident atrial fibrillation (AF) in the Nordic countries. METHODS: We conducted a registry-based multinational cohort study of OAC-naïve patients diagnosed with AF that redeemed at least one prescription of OAC after AF in Denmark (N = 25 585), Sweden (N = 59 455), Norway (N = 40 046) and Finland (N = 22 415). Persistence was dispensing at least one prescription of OAC from Day 365 after the first prescription and 90 days forward. RESULTS: Persistence was 73.6% (95% confidence interval 73.0-74.1) in Denmark, 71.1% (70.7-71.4) in Sweden, 89.3% (88.2-90.1) in Norway and 68.6% (68.0-69.3) in Finland. One-year risk of ischemic stroke varied between 2.0% (1.8-2.1) in Norway and 1.5% (1.4-1.6) in Sweden and 1.5% (1.3-1.6) in Finland. One-year risk of major bleeding other than intracranial bleeding varied between 2.1% (1.9-2.2) in Norway and 5.9% (5.6-6.2) in Denmark. One-year mortality risk varied between 9.3% (8.9-9.6) in Denmark and 4.2% (4.0-4.4) in Norway. CONCLUSION: In OAC-naïve patients with incident AF, persistence of OAC therapy and clinical outcomes vary across Denmark, Sweden, Norway and Finland. Initiation of real-time efforts are warranted to ensure uniform high-quality care across nations and regions.

Development and validation of prediction models for incident atrial fibrillation in heart failure.

OBJECTIVES: Accurate prediction of heart failure (HF) patients at high risk of atrial fibrillation (AF) represents a potentially valuable tool to inform shared decision making. No validated prediction model for AF in HF is currently available. The objective was to develop clinical prediction models for 1-year risk of AF. METHODS: Using the Danish Heart Failure Registry, we conducted a nationwide registry-based cohort study of all incident HF patients diagnosed from 2008 to 2018 and without history of AF. Administrative data sources provided the predictors. We used a cause-specific Cox regression model framework to predict 1-year risk of AF. Internal validity was examined using temporal validation. RESULTS: The population included 27 947 HF patients (mean age 69 years; 34% female). Clinical experts preselected sex, age at HF, NewYork Heart Association (NYHA) class, hypertension, diabetes mellitus, chronic kidney disease, obstructive sleep apnoea, chronic obstructive pulmonary disease and myocardial infarction. Among patients aged 70 years at HF, the predicted 1-year risk was 9.3% (95% CI 7.1% to 11.8%) for males and 6.4% (95% CI 4.9% to 8.3%) for females given all risk factors and NYHA III/IV, and 7.5% (95% CI 6.7% to 8.4%) and 5.1% (95% CI 4.5% to 5.8%), respectively, given absence of risk factors and NYHA class I. The area under the curve was 65.7% (95% CI 63.9% to 67.5%) and Brier score 7.0% (95% CI 5.2% to 8.9%). CONCLUSION: We developed a prediction model for the 1-year risk of AF. Application of the model in routine clinical settings is necessary to determine the possibility of predicting AF risk among patients with HF more accurately and if so, to quantify the clinical effects of implementing the model in practice.

Life-Years Lost After Newly Diagnosed Atrial Fibrillation in Patients with Heart Failure.

Objective: Prior work estimated excess death rates associated with atrial fibrillation (AF) in heart failure (HF) with hazard ratios (HR). The aim was to estimate the life-years lost after newly diagnosed AF in HF patients. Methods: Among patients diagnosed with HF in 2008-2018 in the nationwide Danish Heart Failure Registry, we compared patients with incident AF to referents matched on age, sex, and time since HF. We estimated the marginal hazard ratio (HR) for death and marginal difference in restricted mean survival times (RMST) between AF cases and referents at 10 years after AF diagnosis. We adjusted for sex, age at AF diagnosis, clinical and lifestyle risk factors, and medications. Results: Among 4463 AF cases and 17,792 referents (mean age 73.7 years, 29% women), the HR was 1.41 (95% CI 1.38; 1.44) but there was evidence of non-proportional hazards. The difference in RMST was -18.2 months (95% CI -16.8; -19.6) at 10 years after AF diagnosis. There were differences in life-years lost between patients diagnosed with AF >1 year and ≤1 year after HF (-25.7 months, 95% CI -23.7; -27.7 vs -10.4 months, 95% CI -8.2; -12.5, p < 0.001), women and men (-20.3 months, 95% CI -17.7; -21.9 vs -17.2 months, 95% CI -15.5; -19.0, p = 0.05), patients with low, medium, and high CHA2DS2-VASc (10.3 months, 95% CI -4.6; -16.1 vs -18.5 months, 95% CI -16.7; -20.4 vs 22.1, 95% CI -18.8; -22.3, p = 0.002). Conclusion: HF patients with incident AF lost on average 1.5 life-years over 10 years after AF. Life-years lost were larger among patients diagnosed with AF >1 year after HF, women, and patients with higher CHA2DS2-VASc.

Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke.

BACKGROUND: Reperfusion therapies (thrombolysis and thrombectomy) are of paramount importance for the recovery after ischemic stroke. We aimed to investigate if socioeconomic status (SES) was associated with the chance of receiving reperfusion therapy for ischemic stroke in a country with tax-funded health care. METHODS: This nationwide register-based cohort study included patients with ischemic stroke registered in the Danish Stroke Registry between 2015 and 2018. SES was determined by prestroke educational attainment, income level, and employment status. Data on SES was obtained from Statistics Denmark and linked on an individual level with data from the Danish Stroke Registry. Risk ratios (RR) for receiving reperfusion therapies were calculated using univariate and multivariable Poisson regression with robust variance. RESULTS: A total of 37 187 ischemic stroke patients were included. Low SES, as defined by education, income and employment status, was associated with lower treatment rates. The socioeconomic gradient was most pronounced according to employment status, with intravenous thrombolysis rates of 23.7% versus 15.8%, and thrombectomy rates of 5.1% versus 2.8% for employed versus unemployed patients. When the analyses were restricted to patients with timely hospital arrival, and adjusted for age, sex and immigrant status, low SES according to income and employment remained unfavorable for the likelihood of receiving intravenous thrombolysis: adjusted RR, 0.90 (95% CI, 0.86-0.95) for low versus high income, and adjusted RR, 0.77 (95% CI, 0.71-0.84) for unemployed versus employed patients. Similarly, low SES according to income and employment status remained unfavorable for the likelihood of receiving thrombectomy: adjusted RR, 0.83 (95% CI, 0.72-0.95) for low versus high income and adjusted RR, 0.68 (95% CI, 0.53-0.88) for unemployed versus employed patients. CONCLUSIONS: Socioeconomic inequalities in reperfusion treatment rates among ischemic stroke patients prevail, even in a country with tax-funded universal health care.

Trends in the incidence and mortality of intracerebral hemorrhage, and the associated risk factors, in Denmark from 2004 to 2017.

BACKGROUND AND PURPOSE: The distribution of the major modifiable risk factors for intracerebral hemorrhage (ICH) changes rapidly. These changes call for contemporary data from large-scale population-based studies. The aim of the present study was to examine trends in incidence, risk factors, and mortality in ICH patients from 2004 to 2017. METHODS: In a population-based cohort study, we calculated age- and sex-standardized incidence rates (SIRs), incidence rates (IRs) stratified by age and sex per 100,000 person-years, and trends in risk profiles. We estimated absolute mortality risk, and the Cox proportional hazards regression multivariable-adjusted hazard ratios for 30-day and 1-year mortality. RESULTS: We included 16,902 patients (53% men; median age 75 years) from 2004 to 2017. The SIR of ICH decreased from 33 (95% confidence interval [CI] 32-34) in 2004/2005 to 28 (95% CI 27-29) in 2016/2017. Among patients aged ≥70 years, the IR decreased from 137 (95% CI 130-144) in 2004/2005 to 112 (95% CI 106-117) in 2016/2017. The IR in patients aged <70 years was unchanged. From 2004 to 2017, the proportion of patients with hypertension increased from 49% to 66%, the use of oral anticoagulants increased from 7% to 18%, and the use of platelet inhibitors decreased from 40% to 28%. The adjusted hazard ratio for 30-day mortality in 2016/2017 was 0.94 (95% CI 0.89-1.01) and 1-year mortality was 0.98 (95% CI 0.93-1.04) compared with 2004/2005. CONCLUSION: The incidence of spontaneous ICH decreased from 2004 to 2017, with no clear trend in mortality. The risk profile of ICH patients changed substantially, with increasing proportions of hypertension and anticoagulant treatment. Given the high mortality rate of ICH, further advances in prevention and treatment are urgently needed.

Quality of care and risk of incident atrial fibrillation in patients with newly diagnosed heart failure: a nationwide cohort study.

AIMS: Incident atrial fibrillation (AF) is an adverse prognostic indicator in heart failure (HF); identifying modifiable targets may be relevant to reduce the incidence and morbidity of AF. Therefore, we examined the association between quality of HF care and risk of AF. METHODS AND RESULTS: Using the Danish Heart Failure Registry, we conducted a nationwide registry-based cohort study of all incident HF patients diagnosed between 2008 and 2018 and without history of AF. Quality of HF care was assessed by seven process performance measures, including echocardiographic examination, New York Heart Association classification, treatment with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta-blockers, and mineralocorticoid antagonists, physical training, and patient education. In the main analysis, we examined adherence with all measures in a cohort of 25 100 patients (mean age 68.5 ± 13.2 years; 33.6% women). The median follow-up was 3.1 years. Cox proportional hazard regressions estimated the hazard ratios (HRs) with 95% confidence intervals (95% CIs) between the number of fulfilled measures and incident AF. In a multivariable-adjusted analysis with 0 fulfilled performance measures as reference, the HRs (95% CIs) were 1: 0.78 (0.61-1.00), 2: 0.63 (0.49-0.80), 3: 0.53 (0.36-0.80), 4: 0.64 (0.44-0.94), 5: 0.56 (0.39-0.82), 6: 0.51 (0.35-0.74), and 7: 0.49 (0.33-0.73), with a significant decreasing linear trend (P < 0.001). CONCLUSION: In patients with incident HF, fulfilment of guideline-based process performance measures was associated with decreased long-term risk of AF. This study supports initiatives to improve the quality of care for patients with HF to prevent incident AF.

Newly diagnosed atrial fibrillation and hospital utilization in heart failure: a nationwide cohort study.

AIMS: Atrial fibrillation (AF) constitutes a major burden to health services, but the importance of incident AF in patients with heart failure (HF) is unclear. We examined the associations between incident AF and hospital utilization in patients with HF. METHODS AND RESULTS: In a nationwide matched-cohort study of HF patients, we identified patients diagnosed with incident AF between 2008 and 2018 in the Danish Heart Failure Registry (N = 4463), and we compared them to matched referents without AF (N = 17 802). Incident AF was associated with a multivariable-adjusted 4.8-fold increase (95% CI 4.1-5.6) and 4.3-fold increase (95% CI 3.9-4.8) in the cumulative incidence of inpatient and outpatient contacts within 30 days, respectively. At 1 year, the cumulative incidence ratios were 1.8 (95% CI 1.7-1.9) and 1.4 (95% CI 1.4-1.5). Incident AF was also associated with increases in the total numbers of inpatient and outpatient hospital contacts within 30 days (multivariable-adjusted rate ratio 1.4, 95% CI 1.4-1.5, and 1.6, 95% CI 1.6-1.7, respectively). At 1 year, the ratios were 2.2 (95% CI 2.1-2.3) and 2.0 (95% CI 1.9-2.1). The multivariable-adjusted proportion of bed-day use among HF patients with incident AF was 10.9-fold (95% CI 9.3-12.9) higher at 30 days and 5.3-fold (95% CI 4.3-6.4) higher at 1 year compared with AF-free referents. CONCLUSIONS: Incident AF in HF is associated with earlier hospital contact, more hospital contacts, and more hospital bed-days. More evidence on interventions that may prevent the risk and subsequent burden of AF in HF is urgently needed.

A monomer-trimer model supports intermittent glucagon fibril growth.

We investigate in vitro fibrillation kinetics of the hormone peptide glucagon at various concentrations using confocal microscopy and determine the glucagon fibril persistence length 60µm. At all concentrations we observe that periods of individual fibril growth are interrupted by periods of stasis. The growth probability is large at high and low concentrations and is reduced for intermediate glucagon concentrations. To explain this behavior we propose a simple model, where fibrils come in two forms, one built entirely from glucagon monomers and one entirely from glucagon trimers. The opposite building blocks act as fibril growth blockers, and this generic model reproduces experimental behavior well.

Ecological oscillations induced by a shared predator and the "Winner peaks first" rule.

We investigate the dynamics of an ecological system made up of one predator feeding on two different prey species. In a large range of parameter space, the system displays oscillating solutions. We show that, in the regime in which the two preys coexist, the better fit prey consistently peaks first. Further, we classify the possible oscillations of the network by a symbolic dynamics method. Our findings show that the symbolic orbits of an ecological system contain information about which of two preys is the better fit, and when one is bound to extinction.