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AimsThyroid dysfunction is considered the most frequent complication to amiodarone treatment, but data on its occurrence outside clinical trials are sparse. The present study aimed to examine the incidence of thyroid dysfunction following initiation of amiodarone treatment in a nationwide cohort of patients with and without heart failure (HF).Methods and resultsIn Danish registries, we identified all patients with first-time amiodarone treatment during the period 2000–18, without prior thyroid disease or medication. The primary outcome was a composite of thyroid diagnoses and initiation of thyroid drugs. Outcomes were assessed at 1-year follow-up, and for patients free of events in the first year, in a landmark analysis for the subsequent 5 years. We included 43 724 patients with first-time amiodarone treatment, of whom 16 939 (38%) had HF. At 1-year follow-up, the cumulative incidence and adjusted hazard ratio (HR) of the primary outcome were 5.3% and 1.37 (95% confidence interval 1.25–1.50) in patients with a history of HF and 4.2% in those without HF (reference). In the 1-year landmark analysis, the subsequent 5-year cumulative incidences and adjusted HRs of the primary outcome were 5.3% (reference) in patients with 1-year accumulated dose 63.88 g (ADD >175 mg).ConclusionAmong patients who initiated amiodarone treatment, around 5% had thyroid dysfunction at 1-year follow-up, with a slightly higher incidence in those with HF. A dose–response relationship was observed between the 1-year accumulated amiodarone dose and the subsequent 5-year cumulative incidence of thyroid dysfunction.

Aim: Treatment with certain drugs can augment the risk of developing malignant arrhythmias (e.g. torsades de pointes [TdP]). Hence, we examined the overall TdP risk drug use before out-of-hospital cardiac arrest (OHCA) and possible association with shockable rhythm and return of spontaneous circulation (ROSC). Methods: Patients ≥18 years with an OHCA of cardiac origin from the Danish Cardiac Arrest Registry (2001–2014) and TdP risk drug use according to www.CredibleMeds.org were identified. Factors associated with TdP risk drug use and secondly how use may affect shockable rhythm and ROSC were determined by multivariable logistic regression. Results: We identified 27,481 patients with an OHCA of cardiac origin (median age: 72 years [interquartile range 62.0, 80.0 years]). A total of 37% were in treatment with TdP risk drugs 0–30 days before OHCA compared with 33% 61–90 days before OHCA (p < 0.001). Most commonly used TdP risk drugs were citalopram (36.1%) and roxithromycin (10.7%). Patients in TdP risk drug treatment were older (75 vs 70 years) and more comorbid compared with those not in treatment. Subsequently, TdP risk drug use was associated with less likelihood of the presenting rhythm being shockable (odds ratio [OR] = 0.63, 95% confidence interval [CI]:0.58–0.69) and ROSC (OR = 0.73, 95% CI:0.66–0.80). Conclusion: TdP risk drug use increased in the time leading up to OHCA and was associated with reduced likelihood of presenting with a shockable rhythm and ROSC in an all-comer OHCA setting. However, patients in TdP risk drug treatment were older and more comorbid than patients not in treatment.

Aims The aim of this study was to examine contemporary data on the 1-year prognosis of patients surviving acute coronary syndrome (ACS) and concomitant first-time detected atrial fibrillation (AF). Methods and results Using Danish nationwide registries, we identified all patients surviving a first-time admission with ACS from 2000 to 2018 and grouped them into (i) those without AF prior to or during ACS; (ii) those with a history of AF; and (iii) those with first-time detected AF during admission with ACS. With 1 year of follow-up, rates of ischaemic stroke, death, and bleeding were compared between study groups using multivariable adjusted Cox proportional hazards analysis. We included 161 266 ACS survivors: 135 878 (84.2%) without AF, 18 961 (11.8%) with history of AF, and 6427 (4.0%) with first-time detected AF at admission with ACS. Compared to those without AF, the adjusted 1-year rates of outcomes were as follows: ischaemic stroke [hazard ratio (HR) 1.38 (95% CI 1.22–1.56) for patients with history of AF and HR 1.67 (95% CI 1.38–2.01) for patients with first-time detected AF]; mortality [HR 1.25 (95% CI 1.21–1.31) for patients with history of AF and HR 1.52 (95% CI 1.43–1.62) for patients with first-time detected AF]; and bleeding [HR 1.22 (95% CI 1.14–1.30) for patients with history of AF and HR 1.28 (95% CI 1.15–1.43) for patients with first-time detected AF]. Conclusion In patients with ACS, first-time detected AF appeared to be at least as strongly associated with the 1-year rates of ischaemic stroke, mortality, and bleeding as compared with patients with a history of AF.

Objectives: The ability to remain in employment addresses an important consequence of stroke beyond the usual clinical parameters. However, data on the association between time to intravenous thrombolysis and workforce attachment in patients with acute ischemic stroke are sparse. Materials and methods: In this nationwide cohort study, stroke patients of working age (18-60 years) treated with thrombolysis (2011-2016) who were part of the workforce prior to admission and alive at discharge were identified using the Danish Stroke Registry. The association between time to thrombolysis and workforce attachment one year later was examined with multivariable logistic regression. Results: The study population comprised 1,329 patients (median age 51 years [25th-75th percentile 45-56], 67.3% men). The median National Institutes of Health Stroke Scale score at presentation was 4 (25th-75th percentile 2-8), and the median time from symptom-onset to initiation of thrombolysis was 140min (25th-75th percentile 104-196min). The proportion of patients who were part of the workforce at one-year follow-up was 64.6%, 64.3%, 64.9%, and 60.0% in patients receiving thrombolysis within 90min, between 91-180min, between 181-270min, and after 270min, respectively. In adjusted analysis, time to thrombolysis between 91-180min, 181-270min, and >270min was not significantly associated with workforce attachment compared with thrombolysis received ≤90min of symptom-onset (ORs 0.89 [95%CI 0.60-1.31], 0.93 [0.66-1.31], and 0.80 [0.43-1.52], respectively). Conclusions: In patients of working age admitted with stroke and treated with thrombolysis, two out of three were part of the workforce one year after discharge. There was no graded relationship between time to thrombolysis and the likelihood of workforce attachment.

Aims In atrial fibrillation (AF) patients 150 mg b.i.d. dabigatran is the standard dose, yet guidelines recommend 110 mg b.i.d. when bleeding risk is high. It is unknown to which extend these recommendations are followed in patients switching from vitamin K antagonist (VKA) to dabigatran. The aim of this study was to investigate if AF patients are switched from VKA to the appropriate dose of dabigatran. Methods and results Using nationwide registries (22 August 2011 to 31 December 2012), we identified VKA-experienced AF patients with available creatinine values who switched to dabigatran. European guidelines criteria 2012 on dabigatran dosing were examined: age ≥80 years, HAS-BLED ≥3, estimated glomerular filtration rate (eGFR) Conclusion Among VKA-experienced AF patients one in four were switched to a dabigatran dose contrary to guideline recommendations.

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 [25th–75th percentile 60–78 years], 60% men). The median follow-up was 2.5 years (25th–75th percentile 1.2–4.1 years). The median time to thrombolysis was 138 minutes (25th–75th percentile 101–185 minutes), and the median National Institutes of Health Stroke Scale score at presentation was 5 (25th–75th percentile 3–10). 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 (91–180 minute: adjusted hazard ratio, 1.25 [95% CI, 1.06–1.48]; 181–270 minutes: adjusted hazard ratio, 1.35 [95% CI, 1.12–1.61]). 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.

Background The incidence and mortality of ischaemic heart disease have been declining over many years. The development with ischaemic stroke is less well studied, and with an increasing elderly population, there is a need for large-scale studies. Recent changes in stroke prevention and treatments may have affected the incidence and mortality of ischaemic stroke. Purpose To examine time trends and sex and age differences in the incidence and mortality of first-time ischaemic stroke in Denmark between 1996–2016. Methods In this observational cohort study, we used Danish nationwide registries to identify all individuals >18 years of age admitted with a first-time diagnosis of ischaemic stroke between 1996–2016. We calculated age- and sex-stratified annual incidence rates and absolute 30-day and 1-year mortality risks. Further, we calculated annual incidence rate ratios using multivariable Poisson regression, odds ratios for 30-day mortality using multivariable logistic regression, and hazard ratios for 1-year mortality using multivariable Cox regression. Results The study population consisted of 224,617 individuals >18 years of age with first-time ischaemic stroke between 1996–2016. The figure displays the unadjusted incidence rates and 1-year mortality risks of ischaemic stroke by calendar year. The overall unadjusted incidence rates of ischaemic stroke per 1,000 person-years increased from 1996 (2.43 [95% confidence interval [CI], 2.38–2.47]) to 2002 (2.91 [95% CI, 2.86–2.96]) and then gradually decreased to below the initial level until 2016 (1.99 [95% CI, 1.95–2.03]). Men had higher incidence rates than women in all age groups except in patients between 18–30 years and >85 years. The absolute mortality risk decreased between 1996–2016 (30-day mortality from 17.1% to 7.6% and 1-year mortality from 30.9% to 17.3%). Women had higher mortality than men in the age groups 55–64 years and >85 years. Similar trends were observed for all analyses after multivariable adjustment. Conclusions The overall incidence of first-time hospitalization for ischaemic stroke increased from 1996–2002 and then gradually decreased to below the initial level until 2016. The absolute 30-day and 1-year mortality risk decreased between 1996–2016. These findings correspond to the increased awareness of stroke prevention and introduction of new treatment options during the study period. Trends in stroke incidence and mortality Funding Acknowledgement Type of funding source: None

Background It is well-established that the short-term benefits of intravenous thrombolytic therapy are reduced with increasing treatment delay in patients with acute ischaemic stroke. However, there is a paucity of contemporary data on the association between time from symptom onset to initiation of thrombolysis and long-term outcomes. With improving post-stroke survival in the Western world, data on time to thrombolysis and subsequent long-term outcomes are warranted in order to provide further insight into the importance of time to treatment. Purpose To examine the long-term risk of adverse outcomes according to time from symptom onset to intravenous thrombolytic therapy in patients with acute ischaemic stroke. Methods In this observational cohort study, we identified all patients with first-time ischaemic stroke treated with intravenous thrombolysis between 2011–2015 and alive at discharge through the Danish National Stroke Registry. Patients who received thrombolysis after >270 min were excluded. Using multivariable Cox regression, we examined associations between time from symptom onset to thrombolysis and risks of the composite of death, recurrent ischaemic stroke, and dementia, as well as each of these components separately. Patients were followed until the outcome of interest, emigration, or December 31, 2017. Results Of the 4,313 patients with first-time ischaemic stroke treated with intravenous thrombolysis, 4,119 were alive at discharge (median age 69 years [25th-75th percentile 59–78 years], 60% males). The median follow-up was 3.3 years (25th-75th percentile 2.3–4.7 years). The median time from symptom onset to initiation of thrombolytic therapy was 140 min (25th-75th percentile 106–187 min), and the median National Institutes of Health Stroke Scale score at presentation was 5 (25th-75th percentile 3–10). The unadjusted absolute 3-year risks of the composite outcome, death, recurrent ischaemic stroke, and dementia according to time to thrombolysis are displayed in the figure. Compared with thrombolysis within 90 min, time to thrombolysis >90 min was associated with a higher relative risk of the composite outcome (91–180 min: adjusted hazard ratio [HR] 1.37 [95% confidence interval [CI], 1.13–1.68]; 181–270 min: adjusted HR 1.42 [95% CI 1.15–1.76]). The risks of each component of the composite outcome according to time to thrombolysis were similar to results for the composite endpoint, as illustrated in the figure. Conclusions In this nationwide cohort of patients with acute ischaemic stroke treated with thrombolysis, increasing time from symptom onset to initiation of intravenous thrombolytic therapy was associated with higher long-term risks of the composite of death, recurrent ischaemic stroke, and dementia, as well as all three outcomes separately. These data indicate that long-term outcomes of patients with ischaemic stroke treated with intravenous thrombolysis can be greatly improved by reducing treatment delay. Time to thrombolysis and outcomes Funding Acknowledgement Type of funding source: None

ObjectiveTo examine whether the incidence, comorbidity, and mortality of first-time ischemic stroke changed in Denmark between 1996 and 2016 overall and according to age and sex using a nationwide cohort design.MethodsIn this cohort study, 224,617 individuals ≥18 years of age admitted with first-time ischemic stroke between 1996 and 2016 were identified through Danish nationwide registries. We calculated annual age-standardized incidence rates and absolute 30-day and 1-year mortality risks. Furthermore, we calculated annual incidence rate ratios using Poisson regression, odds ratios for 30-day mortality using logistic regression, and hazard ratios for 1-year mortality using Cox regression.ResultsThe overall age-standardized incidence rates of ischemic stroke per 1,000 person-years increased from 1996 (2.70 [95% confidence interval [CI] 2.65–2.76]) to 2002 (3.25 [95% CI 3.20–3.31]) and then gradually decreased to below the initial level until 2016 (1.99 [95% CI 1.95–2.02]). Men had higher incidence rates than women in all age groups except 18 to 34 and ≥85 years. Absolute mortality risk decreased between 1996 and 2016 (30-day mortality from 17.1% to 7.6% and 1-year mortality from 30.9% to 17.3%). Women between 55 and 64 and ≥85 years of age had higher mortality than men. Similar trends were observed for all analyses after multivariable adjustment. The prevalence of atrial fibrillation, hypertension, diabetes mellitus, and use of lipid-lowering medication increased during the study period.ConclusionsThe age-standardized incidence of first-time hospitalization for ischemic stroke increased from 1996 to 2002 and then gradually decreased to below the initial level until 2016. Absolute 30-day and 1-year mortality risks decreased between 1996 and 2016. These findings correspond to increased stroke prevention awareness and introduction of new treatments during the study period.

AimsPostoperative atrial fibrillation (POAF), a common complication following coronary artery bypass graft (CABG) surgery, is associated with increased morbidity and mortality. Inflammation may be an important factor for the pathogenesis of POAF, and increased preoperative levels of C-reactive protein (CRP) are associated with the development of POAF. However, the relationship between postoperative CRP and POAF is less well established.Methods and resultsPatients undergoing first-time isolated CABG surgery (1 January 2000–31 December 2016) were identified using the Eastern Danish Heart Surgery Database and nationwide administrative registries. Patients with no history of atrial fibrillation and with available CRP measurements from postoperative day (POD) 4 were included. The study population was divided into quartiles based on CRP. The association between CRP levels and the odds of developing POAF was investigated using multivariable logistic regression analysis. We included 6711 patients. The CRP intervals on POD 4 for the CRP groups (lowest to highest) were ≤90, >90 to ≤127, >127 to ≤175, and >175 mg/L, respectively. Patients in the highest CRP group were older and more often men compared with patients in the lowest CRP group [median age 67 years (P25–P75: 61–73) and 84.7% men vs. median age 64 years (P25–P75: 56–70) and 77.9% men]. In the lowest and highest CRP groups, 25% and 35% developed POAF, respectively. In adjusted analysis, the highest CRP group, compared with the lowest CRP group, was associated with greater odds of developing POAF (odds ratio 1.31; 95% confidence interval 1.12–1.54).ConclusionIncreased postoperative CRP levels after CABG surgery was associated with the development of POAF.

Objective: Oral anticoagulation with vitamin K antagonists is recommended after mechanical heart valve replacement. However, data regarding the association between the quality of vitamin K antagonist treatment and the risk of complications are sparse. Methods: Patients undergoing mechanical heart valve replacement (1997-2012) with available data on international normalized ratio values were identified in Danish registries. The quality of vitamin K antagonist treatment between discharge after valve replacement and 6 months postdischarge (ie, index) was assessed as time in therapeutic range (TTR) ≥70% or

Background Data on stroke severity and prognosis in patients with AF are lacking and contemporary knowledge thereon could help identify preventive strategies. Purpose To investigate stroke severity among patients with and without AF, and secondly determine in-hospital and 1-year mortality in the two groups. Methods Using the nationwide Danish Stroke Registry we identified patients with first-time stroke (1 January 2005–31 December 2016). Patients with prior or new AF were matched 1:1 by sex, age, and calendar-year with patients with no history of AF. Stroke severity on admission was determined by the Scandinavian Stroke Scale (SSS) (0–29 points indicates very severe to severe stroke, 30–58 points indicates moderate to mild stroke) based on eye movements, paralysis and level of consciousness. The Kaplan-Meier estimator was used to calculate cumulative risk of death in AF patients versus non-AF patients. Risk of 1-year mortality was evaluated in an adjusted multivariable Cox-proportional hazard model. Results We identified 90,042 patients with first-time stroke; 16,186 (18.0%) had prior or new AF, and were included in the study, and matched with patients without AF. The median age was 80 years (p25-p75: 72–86 years) and 52.2% were females. AF patients had a higher comorbidity burden and more severe strokes compared with non-AF patients (median SSS 44 (p25-p75: 25–54) vs. 49 (p25-p75: 36–56), P value Conclusion In a nationwide contemporary stroke registry cohort, AF was associated with adverse stroke severity compared with stroke patients without AF. In-hospital mortality and 1-year mortality was higher among AF patients compared with non-AF patients. Acknowledgement/Funding This study was supported by an internal grant from Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark

Background Postoperative atrial fibrillation (POAF), a common complication following coronary artery bypass graft (CABG) surgery, is associated with increased morbidity and mortality. Inflammation seems to be an important pathogenic factor and elevated preoperative levels of C-reactive protein (CRP) are associated with POAF. However, the association between postoperative CRP and POAF is less established. Purpose To examine the association between postoperative levels of CRP and POAF after CABG. Methods Patients undergoing first-time isolated CABG (Jan 01, 2000 to Dec 31, 2016) were identified using Danish nationwide administrative registries. Patients with CRP measurements from the fourth postoperative day and no history of atrial fibrillation were included. POAF was defined as a postoperative atrial fibrillation rhythm that required medical therapy or cardioversion, with patients being followed for POAF until discharge. The study population was divided into quartiles based on CRP levels. A Cochran-Armitage trend test was used to examine the trend of increased levels of CRP and the associated risk of POAF. The association between CRP levels and POAF was investigated using a multivariable logistic regression analysis adjusted for other patient characteristics. Results The study included 6,711 patients with mean CRP values from the lowest to the highest CRP groups being 66, 109, 150 and 228 mg/L, respectively. Patients in the highest CRP group were older and more likely to be male compared with the lowest CRP group (median age 67 years [P25-P75: 61–73] and 84.7% men vs. median age 64 years [P25-P75: 56–70] and 77.9% men). In the highest CRP group, 35% of patients developed POAF vs. 25% in the lowest CRP group. A dose-response relationship was seen between increasing levels of CRP and the associated risk of POAF (p Conclusion High postoperative CRP levels after CABG were associated with POAF development. Future studies may examine whether CRP also predicts worse outcomes and whether these factors could be modified in the development of POAF. Acknowledgement/Funding Internal grant from Copenhagen University Hospital

Aims: Patients with non-valvular atrial fibrillation (NVAF) receiving vitamin K antagonists (VKAs) with time in therapeutic international normalized ratio (INR) range (TTR) Methods and results: Non-valvular atrial fibrillation patients receiving VKA (1 January 2010 to 31 December 2012) were identified in nationwide registries. Time in therapeutic range was calculated by the Rosendaal method by a minimum of three INR values. Time in therapeutic range of patients continuing VKA (non-switchers) were compared with patients switched from VKA to dabigatran or rivaroxaban (switchers), the only NOACs available at that time. Factors associated with switching were analysed in a multivariable logistic regression model. 7276 patients with NVAF receiving VKA were included; of these, 6437 (88.5%) patients continued VKA [57.9% male, median age 76.7 years (Q1-Q3 68.9-83.5)] and 839 (11.5%) switched to NOAC [54.0% male, median age 76.5 years (Q1-Q3 68.4-83.6)]. No significant differences in CHA2DS2-VASc and HAS-BLED scores were seen between the groups. The mean TTR for non-switchers was 64.0 [standard deviation (SD) 27.8] and 52.9 (SD 28.1) for switchers. Among non-switchers, 51% had a TTR Conclusion: A TTR below 70% was associated with switching from VKA to NOAC, yet by guidelines, most patients were still not switched.

BACKGROUND: Atrial fibrillation (AF) patients on a vitamin K antagonist (VKA) with time in therapeutic range (TTR) ≥70% are not recommended to switch to a direct oral anticoagulant according to guidelines.OBJECTIVES: This study sought to assess future TTR and risk of stroke/thromboembolism and major bleeding among AF patients on VKA with TTR ≥70%.METHODS: The authors used Danish nationwide registries to identify AF patients on VKA from 1997 to 2011 with available international normalized ratio values. Patients were included 6 months after VKA initiation, divided according to TTR, and followed for 12 months after inclusion. Cox proportional hazard models estimated hazard ratios (HRs). TTR was examined both as a baseline variable and as a time-dependent covariate in the Cox models.RESULTS: Of the 4,772 included AF patients still on VKA 6 months after initiation, 1,691 (35.4%) had a TTR ≥70%, and 3,081 (65.6%) had a TTR CONCLUSIONS: Among AF patients on VKA, almost one-half of patients with prior TTR ≥70% had TTR

Background: Patients with non-valvular atrial fibrillation (NVAF) receiving vitamin K antagonists (VKA) with time in therapeutic range (TTR)