Cost-effectiveness of population screening for atrial fibrillation: the STROKESTOP study.

AIMS: Previous studies on the cost-effectiveness of screening for atrial fibrillation (AF) are based on assumptions of long-term clinical effects. The STROKESTOP study, which randomised 27 975 persons aged 75/76 years into a screening invitation group and a control group, has a median follow-up time of 6.9 years. The aim of this study was to estimate the cost-effectiveness of population-based screening for AF using clinical outcomes. METHODS AND RESULTS: The analysis is based on a Markov cohort model. The prevalence of AF, the use of oral anticoagulation, clinical event data, and all-cause mortality were taken from the STROKESTOP study. The cost for clinical events, age-specific utilities, utility decrement due to stroke, and stroke death was taken from the literature. Uncertainty in the model was considered in a probabilistic sensitivity analysis. Per 1000 individuals invited to the screening, there were 77 gained life years and 65 gained quality-adjusted life years. The incremental cost was €1.77 million lower in the screening invitation group. Gained quality-adjusted life years to a lower cost means that the screening strategy was dominant. The result from 10 000 Monte Carlo simulations showed that the AF screening strategy was cost-effective in 99.2% and cost-saving in 92.7% of the simulations. In the base-case scenario, screening of 1000 individuals resulted in 10.6 [95% confidence interval (CI): -22.5 to 1.4] fewer strokes (8.4 ischaemic and 2.2 haemorrhagic strokes), 1.0 (95% CI: -1.9 to 4.1) more cases of systemic embolism, and 2.9 (95% CI: -18.2 to 13.1) fewer bleedings associated with hospitalization. CONCLUSION: Based on the STROKESTOP study, this analysis shows that a broad AF screening strategy in an elderly population is cost-effective. Efforts should be made to increase screening participation.

Atrial Fibrillation and Dementia: A Report From the AF-SCREEN International Collaboration.

Growing evidence suggests a consistent association between atrial fibrillation (AF) and cognitive impairment and dementia that is independent of clinical stroke. This report from the AF-SCREEN International Collaboration summarizes the evidence linking AF to cognitive impairment and dementia. It provides guidance on the investigation and management of dementia in patients with AF on the basis of best available evidence. The document also addresses suspected pathophysiologic mechanisms and identifies knowledge gaps for future research. Whereas AF and dementia share numerous risk factors, the association appears to be independent of these variables. Nevertheless, the evidence remains inconclusive regarding a direct causal effect. Several pathophysiologic mechanisms have been proposed, some of which are potentially amenable to early intervention, including cerebral microinfarction, AF-related cerebral hypoperfusion, inflammation, microhemorrhage, brain atrophy, and systemic atherosclerotic vascular disease. The mitigating role of oral anticoagulation in specific subgroups (eg, low stroke risk, short duration or silent AF, after successful AF ablation, or atrial cardiopathy) and the effect of rhythm versus rate control strategies remain unknown. Likewise, screening for AF (in cognitively normal or cognitively impaired patients) and screening for cognitive impairment in patients with AF are debated. The pathophysiology of dementia and therapeutic strategies to reduce cognitive impairment warrant further investigation in individuals with AF. Cognition should be evaluated in future AF studies and integrated with patient-specific outcome priorities and patient preferences. Further large-scale prospective studies and randomized trials are needed to establish whether AF is a risk factor for cognitive impairment, to investigate strategies to prevent dementia, and to determine whether screening for unknown AF followed by targeted therapy might prevent or reduce cognitive impairment and dementia.

Prognostic implication of premature ventricular contractions in patients without structural heart disease.

AIMS: Premature ventricular contractions (PVCs) are a common form of arrhythmia associated with an unfavourable prognosis in patients with structural heart disease. However, the prognostic significance in absence of heart disease is debated. With this study, we aim to investigate whether subjects with PVC, without structural heart disease, have a worse prognosis than the general population. METHODS AND RESULTS: Patients evaluated for PVC at a secondary care centre in Stockholm County from January 2010 to December 2016 were identified. We included patients without history of previous heart disease who had undergone echocardiography and exercise test with normal findings. Based on sex and age, we matched the PVC cohort to a four times bigger control group from the general population and compared the outcome in terms of mortality and cardiovascular morbidity during a median follow-up time of 5.2 years. We included 820 patients and 3,264 controls. Based on a non-inferiority analysis, the PVC group did not have a higher mortality than the control group (0.44, CI 0.27-0.72). Sensitivity analysis with propensity score matching confirmed this result. CONCLUSIONS: PVC patients, who after thorough evaluation showed no signs of structural heart disease, did not have a worse prognosis when compared to an age- and sex- control group based on the general population.

Clinical outcomes in systematic screening for atrial fibrillation (STROKESTOP): a multicentre, parallel group, unmasked, randomised controlled trial.

BACKGROUND: Atrial fibrillation is a leading cause of ischaemic stroke. Early detection of atrial fibrillation can enable anticoagulant therapy to reduce ischaemic stroke and mortality. In this randomised study in an older population, we aimed to assess whether systematic screening for atrial fibrillation could reduce mortality and morbidity compared with no screening. METHODS: STROKESTOP was a multicentre, parallel group, unmasked, randomised controlled trial done in Halland and Stockholm in Sweden. All 75-76-year-olds residing in these two regions were randomly assigned (1:1) to be invited to screening for atrial fibrillation or to a control group. Participants attended local screening centres and those without a history of atrial fibrillation were asked to register intermittent electrocardiograms (ECGs) for 14 days. Treatment with oral anticoagulants was offered if atrial fibrillation was detected or untreated. All randomly assigned individuals were followed up in the intention-to-treat analysis for a minimum of 5 years for the primary combined endpoint of ischaemic or haemorrhagic stroke, systemic embolism, bleeding leading to hospitalisation, and all-cause death. This trial is registered with ClinicalTrials.gov, NCT01593553. FINDINGS: From March 1, 2012, to May 28, 2014, 28 768 individuals were assessed for eligibility and randomly assigned to be invited to screening (n=14 387) or the control group (n=14 381). 408 individuals were excluded from the intervention group and 385 were excluded from the control group due to death or migration before invitation. There was no loss to follow-up. Of those invited to screening, 7165 (51·3%) of 13 979 participated. After a median follow-up of 6·9 years (IQR 6·5-7·2), significantly fewer primary endpoint events occurred in the intervention group (4456 [31·9%] of 13 979; 5·45 events per 100 years [95% CI 5·52-5·61]) than in the control group (4616 [33·0%] of 13 996; 5·68 events per 100 years [5·52-5·85]; hazard ratio 0·96 [95% CI 0·92-1·00]; p=0·045). INTERPRETATION: Screening for atrial fibrillation showed a small net benefit compared with standard of care, indicating that screening is safe and beneficial in older populations. FUNDING: Stockholm County Council, the Swedish Heart & Lung Foundation, King Gustav V and Queen Victoria's Freemasons' Foundation, the Klebergska Foundation, the Tornspiran Foundation, the Scientific Council of Halland Region, the Southern Regional Healthcare Committee, the Swedish Stroke Fund, Carl Bennet AB, Boehringer Ingelheim, Bayer, and Bristol Myers Squibb-Pfizer.

Impaired fasting glucose: a risk factor for atrial fibrillation and heart failure.

BACKGROUND: Dysglycaemia is associated with overall cardiovascular disease even at prediabetes levels. The aim of this study was to explore the association between glucose levels and future risk of developing atrial fibrillation and heart failure, respectively. METHODS: In this prospective cohort study subjects from the Swedish AMORIS-cohort with fasting glucose from health examinations 1985-1996 without previous cardiovascular disease (N = 294,057) were followed to 31 December 2011 for incident atrial fibrillation or heart failure. Cox proportional hazard models with attained age as timescale and adjustments for sex, cholesterol, triglycerides, and socioeconomic status were used to estimate hazard ratios by glucose categorized groups (normal glucose 3.9-6.0 mmol/L, impaired fasting glucose; 6.1-6.9 mmol/L, undiagnosed diabetes ≥ 7.0 mmol/L, and diagnosed diabetes). RESULTS: During a mean follow-up time of 19.1 years 28,233 individuals developed atrial fibrillation and 25,604 developed heart failure. The HR for atrial fibrillation was 1.19 (95% confidence interval 1.13-1.26) for impaired fasting glucose, 1.23 (1.15-1.32) for undiagnosed diabetes and 1.30 (1.21-1.41) for diagnosed diabetes. Corresponding figures for heart failure were; 1.40 (1.33-1.48), 2.11 (1.99-2.23), 2.22 (2.08-2.36) respectively. In a subset with BMI data (19%), these associations were attenuated and for atrial fibrillation only remained statistically significant among subjects with diagnosed diabetes (HR 1.25; 1.02-1.53). CONCLUSIONS: Fasting glucose at prediabetes levels is associated with development of atrial fibrillation and heart failure. To some extent increased BMI may drive this association.

Searching for Atrial Fibrillation Poststroke: A White Paper of the AF-SCREEN International Collaboration.

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

Net benefit of oral anticoagulants in patients with atrial fibrillation and active cancer: a nationwide cohort study.

AIMS: To estimate the net cerebrovascular benefit of prophylactic treatment with oral anticoagulants (OACs) in patients with atrial fibrillation (AF) and active cancer. METHODS AND RESULTS: We included all Swedish patients who had been diagnosed with AF in a hospital or in a hospital-associated outpatient unit between 1 July 2005 and 1 October 2017. Patients with active cancer (n = 22 596) and without cancer (n = 440 848) were propensity score matched for the likelihood of receiving OACs at baseline. At baseline, 38.3% of cancer patients with AF and high stroke risk according to CHA2DS2-VASc score received OACs. There was a net benefit of OACs, assessed by the composite outcome of ischaemic stroke, extracranial arterial thromboembolism, all major bleedings, and death, both among patients with active cancer [hazard ratio (HR): 0.81, confidence interval (CI): 0.78-0.85] and among patients without cancer (HR: 0.81, CI: 0.80-0.82). When limiting follow-up to 1 year to minimize the effects of possible treatment cross-over and additionally accounting for death as a competing risk in cancer patients, a net cerebrovascular benefit regarding ischaemic stroke or intracranial bleeding was observed for OACs [subhazard ratio (sHR): 0.67, CI: 0.55-0.83]. A net cerebrovascular benefit was also seen for non-vitamin K antagonist OACs over warfarin after competing risk analyses in cancer patients (sHR: 0.65, CI: 0.48-0.88). CONCLUSION: Patients with AF and active cancer benefit from OAC treatment.

Stepwise mass screening for atrial fibrillation using N-terminal B-type natriuretic peptide: the STROKESTOP II study.

AIMS: To study the prevalence of unknown atrial fibrillation (AF) in a high-risk, 75/76-year-old, population using N-terminal B-type natriuretic peptide (NT-proBNP) and handheld electrocardiogram (ECG) recordings in a stepwise screening procedure. METHODS AND RESULTS: The STROKESTOP II study is a population-based cohort study in which all 75/76-year-old in the Stockholm region (n = 28 712) were randomized 1:1 to be invited to an AF screening programme or to serve as the control group. Participants without known AF had NT-proBNP analysed and were stratified into low-risk (NT-proBNP <125 ng/L) and high-risk (NT-proBNP ≥125 ng/L) groups. The high-risk group was offered extended ECG-screening, whereas the low-risk group performed only one single-lead ECG recording. In total, 6868 individuals accepted the screening invitation of which 6315 (91.9%) did not have previously known AF. New AF was detected in 2.6% [95% confidence interval (CI) 2.2-3.0] of all participants without previous AF. In the high-risk group (n = 3766/6315, 59.6%), AF was diagnosed in 4.4% (95% CI 3.7-5.1) of the participants. Out of these, 18% had AF on their index-ECG. In the low-risk group, one participant was diagnosed with AF on index-ECG. The screening procedure resulted in an increase in known prevalence from 8.1% to 10.5% among participants. Oral anticoagulant treatment was initiated in 94.5% of the participants with newly diagnosed AF. CONCLUSION: N-terminal B-type natriuretic peptide-stratified systematic screening for AF identified 4.4% of the high-risk participants with new AF. Oral anticoagulant treatment initiation was well accepted in the group diagnosed with new AF.

Brief episodes of rapid irregular atrial activity (micro-AF) are a risk marker for atrial fibrillation: a prospective cohort study.

BACKGROUND: Short supraventricular tachycardias with atrial fibrillation (AF) characteristics are associated with an increased risk of developing AF over time. The aim of this study is to determine if presence of very short-lasting episodes of AF-like activity (micro-AF) can also be used as a marker of undiagnosed silent atrial fibrillation. METHODS: In the STROKESTOP II study, a Swedish mass screening study for AF among 75- and 76-year-olds, participants with NT-proBNP ≥125 ng/L performed intermittent ECG recordings 30 s, four times daily for 2 weeks. Participants with micro-AF (sudden onset of irregular tachycardia with episodes of ≥5 consecutive supraventricular beats and total absence of p-waves, lasting less than 30 s) were invited to undergo extended AF screening using continuous event recording for 2 weeks. A control group of individuals without micro-AF was examined using the same ECG modalities. RESULTS: Out of 3763 participants in STROKESTOP II who had elevated NT-proBNP levels and were free of AF, n = 221 (6%) had micro-AF. The majority of participants with micro-AF (n = 196) accepted further investigation with continuous ECG monitoring which showed presence of AF in 26 of them. In the control group (n = 250), continuous monitoring detected 7 new AF cases. Thus, AF was significantly more common in the micro AF group (13%) compared to the control group (3%), p < 0.001. CONCLUSIONS: Presence of short-lasting episodes of AF-like activity (micro-AF) indicates increased likelihood for undetected AF. Continuous screening therefore seems recommendable if a finding of AF would change clinical management. TRAIL REGISTRATION: ClinicalTrials.gov, identifier: NCT02743416, registered April 19, 2016.

Less dementia and stroke in low-risk patients with atrial fibrillation taking oral anticoagulation.

AIMS: To investigate if patients with atrial fibrillation (AF) without clear indication for oral anticoagulant (OAC) due to perceived low stroke risk may benefit from OAC treatment when also dementia and intracerebral bleeding risks are considered. METHODS AND RESULTS: Retrospective study of cross-matched national registries of all individuals in Sweden with a hospital diagnosis of AF between 2006 and 2014 (n = 456 960). Exclusion was made of patients with a baseline CHA2DS2-VASc score >1, not counting female sex, and of patients with previous diagnosis of dementia or intracranial bleeding. After exclusions, 91 254 patients remained in the study of whom 43% used OAC at baseline. Propensity score matching and falsification endpoints were used. Treatment with OAC was associated with lower risk of dementia after adjustment for death as a competing risk [subhazard ratio (sHR) 0.62 with 95% confidence interval (CI) 0.48-0.81]. Regarding the composite brain protection endpoint, OAC treatment was associated with an overall 12% lower risk (sHR 0.88, CI 0.72-1.00). This apparent benefit was restricted to patients aged >65 years, whereas OAC treatment of patients <60 years of age without risk factors appeared to do more harm than good. CONCLUSION: Low-risk AF patients who take OAC have lower risk of dementia than those who do not use OAC. Patients age >65 years appear to benefit from OAC treatment irrespective of stroke risk score.

Sociodemographic factors and choice of oral anticoagulant in patients with non-valvular atrial fibrillation in Sweden: a population-based cross-sectional study using data from national registers.

BACKGROUND: The Swedish healthcare system aims to provide equal access to care to all residents yet evidence suggests that patients with low socioeconomic status are less likely to receive new drugs. Associations between sociodemographics and prescription of non-vitamin K antagonist oral anticoagulants (NOACs) as an alternative to warfarin in Sweden have not been investigated. METHODS: We conducted a cross-sectional study using linked national registers in Sweden. The study population included oral anticoagulant naïve patients aged ≥18 years with non-valvular atrial fibrillation (NVAF) who filled a first prescription for a NOAC or warfarin from 01 December 2011 to 31 December 2014. Multivariable logistic regression was used to identify factors associated with the choice of anticoagulant treatment; adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Among 68,056 patients with NVAF, 27.4% (N = 18,638) started treatment with a NOAC and 72.6% (N = 49,418) started on warfarin. Patients starting treatment with a NOAC were more likely to be highly educated (OR 1.37, 95% CI: 1.30-1.45), in the highest income quartile (OR 1.23, 95% CI: 1.16-1.31) and have a leading professional occupation (OR 1.41, 95% CI: 1.27-1.58). Patients residing in rural areas were half as likely to start treatment with a NOAC as those in urban areas (OR 0.48, 95% CI: 0.45-0.51). CONCLUSION: Among Swedish patients with NVAF, those with high socioeconomic status and urban residence were more likely to start preventative treatment with a NOAC than warfarin. Future research should explore reasons for these inequalities in NOAC treatment.

Short lookback periods causing exaggerated stroke risk estimates in atrial fibrillation may expose patients to unnecessary anticoagulant treatment.

PURPOSE: The purpose was to investigate how different lookback periods in observational registry studies affect estimates of stroke risk in patients with atrial fibrillation and stroke risk score CHA2 DS2 -VASc 1, a level where the appreciated risk is likely to affect decisions about oral anticoagulation. METHODS: All 354 854 individuals in Sweden with a hospital diagnosis of atrial fibrillation during 2010-2016 were included. At least 13 years of observational data prior to inclusion was available for all patients. The prevalence of hypertension, heart failure, diabetes, previous thromboembolism, and vascular disease was estimated from data with different lookback periods. The incident stroke rates at CHA2 DS2 -VASc score 1 was then assessed using data with successively longer lookback periods. RESULTS: Depending on duration of lookback period, the proportion of patients with heart failure varied 2.7 times, thromboembolism 3.7 times, hypertension 4.0 times, and diabetes and vascular disease both approximately 4.5 times. During follow-up, 22 237 patients suffered an ischaemic stroke. The estimated risk without anticoagulant treatment at CHA2 DS2 -VASc score 1 was 51% higher if the scores had been calculated with the shortest lookback period than if all information had been used. CONCLUSIONS: Short lookback periods underestimate comorbidity, cause high-risk patients to be misclassified as low risk, and overestimate stroke risk at CHA2 DS2 -VASc 1. This may lead to unnecessary anticoagulant treatment of true low-risk patients. Transparency regarding lookback periods is essential for interpretation and comparison of registry studies.

Less dementia with oral anticoagulation in atrial fibrillation.

Aims: The association between atrial fibrillation (AF) and dementia is well documented, but it is not clear if oral anticoagulant treatment offers protection. The aim of the study is therefore to compare the incidence of new dementia in patients with AF with and without oral anticoagulants, and to explore if there is a difference between novel anticoagulants and warfarin in this respect. Methods and results: Retrospective registry study of all patients with hospital diagnosis of AF and no previous diagnosis of dementia in Sweden between 2006 and 2014. Propensity score matching, falsification endpoints, and analyses according to intention to treat as well as on-treatment principles were used. The study included 444 106 patients and over 1.5 million years at risk. Patients on anticoagulant treatment at baseline was associated with 29% lower risk of dementia than patients without anticoagulant treatment [hazard ratio (HR) 0.71, 95% confidence intervals (95% CI) 0.68-0.74] and 48% lower risk analysed on treatment (HR 0.52, 95% CI 0.50-055). Direct comparison between new oral anticoagulants and warfarin showed no difference (HR 0.97, 95% CI 0.67-1.40). Conclusion: The risk of dementia is higher without oral anticoagulant treatment in patients with AF. This suggests that early initiation of anticoagulant treatment in patients with AF could be of value in order to preserve cognitive function.

Preventing dementia by preventing stroke: The Berlin Manifesto.

The incidence of stroke and dementia are diverging across the world, rising for those in low- and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.

Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration.

Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.

Ventricular arrhythmia and death among atrial fibrillation patients using anti-arrhythmic drugs.

AIM: The aim of the study was to assess and compare the safety of antiarrhythmic drugs (AADs) in an unselected real-world population of patients with atrial fibrillation (AF). METHODS AND RESULTS: This is a study of all patients with diagnosed AF in the Swedish Patient register who filled a prescription for sotalol, amiodarone, dronedarone, flecainide or disopyramide during 2010 to 2015. The main end point consisted of arrhythmic death, successful resuscitation, new diagnosis of sustained ventricular tachycardia, ventricular fibrillation or implantation of ICD. All-cause mortality was a secondary end point. Minimum follow up was 1 year. Falsification end points were used to assess hidden confounding. 44,995 AF patients on AAD and 267,518 AF patients without AAD were studied during a total time at risk of over 1.1 million years. Compared to sotalol, the risk for the main end point was decreased with dronedarone (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.37-0.90), similar with flecainide (HR 0.95, 0.69-1.32) and disopyramide (HR 1.30, CI 0.83-2.05). All-cause mortality was lower with dronedarone (HR 0.44, CI 0.34-0.57) and flecainide (HR 0.55, CI 0.44-0.68) than with sotalol. Hidden confounding prevented reliable assessment of amiodarone. CONCLUSIONS: Dronedarone was the only anti-arrhythmic drug with significantly lower risk for arrhythmic death, sustained ventricular arrhythmia or ICD implantation than sotalol among patients with atrial fibrillation. Both dronedarone and flecainide were associated with lower all-cause mortality than sotalol.

Alcohol-related hospitalization is associated with increased risk of ischaemic stroke among low-risk patients with atrial fibrillation.

Aims: Patients with atrial fibrillation (AF) under the age of 65 and CHA2DS2-VASc risk score of 0 in men or 1 in women are considered to be at low risk for ischaemic stroke, and therefore without benefit of oral anticoagulation therapy. The objective of this study is to assess the incidence and predictors of ischaemic stroke among low-risk patients with AF identified from a National Patient Register. Methods and results: A retrospective study of 25 252 low-risk AF patients (age 18-64) out of total 345 123 AF patients identified from the Swedish Nationwide Patient Register for the period 1 January 2006 to 31 December 2012. During a median follow-up of 5.0 (interquartile range 2.9-6.8) years, ischaemic stroke occurred at an annual rate of 0.34 per 100 patient-years [95% confidence interval (CI) 0.31-0.38]. Significant predictors of stroke were age, hazard ratio (HR) 1.06 (CI 1.05-1.08) per incremental year, and previous alcohol-related hospitalization HR 2.01 (CI 1.45-2.79). Intracerebral bleeding events were rare and not statistically different HR 2.05 (CI 0.76-5.56) between patients with and without alcohol-related hospitalizations. Use of oral anticoagulants was associated with lower risk for ischaemic stroke, HR 0.78 (CI 0.63-0.97). Conclusion: The presence of a previous hospitalization with an alcohol-related disease was associated with a small but significant increase in the risk of stroke among low-risk AF patients. More research about relation between alcohol use and ischaemic stroke in AF patients is warranted.

Stepwise mass screening for atrial fibrillation using N-terminal pro b-type natriuretic peptide: the STROKESTOP II study design.

AIM: Atrial fibrillation (AF) is the most prevalent clinical arrhythmia and a major risk factor for ischaemic stroke. Treatment with oral anticoagulants (OACs) reduces the risk of stroke by two thirds in AF patients with risk factors. Due to its often paroxysmal and asymptomatic presentation, AF is sometimes challenging to diagnose. So far, AF screening studies have applied opportunistic or systematic screening, most often using a single 12-lead electrocardiogram (ECG) recording or ambulatory ECG. We hypothesise that the biomarker N-terminal pro b-type natriuretic peptide (NT-proBNP) is a valuable adjunct in population based AF screening. METHODS: We are conducting a randomized population-based study on AF screening using ambulatory ECG recording where the decision to use prolonged intermittent ECG recording is directed by NT-proBNP levels, the STROKESTOP II trial. The entire population of inhabitants 75 or 76 years of age (n = 28 712) in the capital region of Sweden will be randomized 1:1 to intervention or control group. In the intervention group NT-proBNP will be analysed in all without previously known AF. Those with NT-proBNP ≤ 125 pg/L will make a single one lead ECG recording, participants with NTproBNP ≥ 125 np/L will be instructed to record ECG for 30 s at least twice daily for 2 weeks with a handheld ambulatory ECG recorder. Participants with newly diagnosed or undertreated AF will be referred to a cardiologist and offered OAC treatment. Primary endpoint is incidence of stroke or systemic embolus, during a 5 year follow-up period in the control group vs the group invited to screening.

Safe automatic one-lead electrocardiogram analysis in screening for atrial fibrillation.

AIMS: Screening for atrial fibrillation (AF) using intermittent electrocardiogram (ECG) recordings can identify individuals at risk of AF-related morbidity in particular stroke. We aimed to validate the performance of an AF screening algorithm compared with manual ECG analysis by specially trained nurses and physicians (gold standard) in 30 s intermittent one-lead ECG recordings. METHODS AND RESULTS: The STROKESTOP study is a mass-screening study for AF using intermittent ECG recordings. All individuals in the study without known AF registered a 30-s ECG recording in Lead I two times daily for 2 weeks, and all ECGs were manually interpreted. A computerized algorithm was used to analyse 80 149 ECG recordings in 3209 individuals. The computerized algorithm annotated 87.1% (n = 69 789) of the recordings as sinus rhythm/minor rhythm disturbances. The manual interpretation (gold standard) was that 69 758 ECGs were normal, making the negative predictive value of the algorithm 99.9%. The number of ECGs requiring manual interpretation in order to find one pathological ECG was reduced from 288 to 35. Atrial fibrillation was diagnosed in 84 patients by manual interpretation, in all of whom the algorithm indicated pathology. On an ECG level, 278 ECGs were manually interpreted as AF, and of these the algorithm annotated 272 ECGs as pathological (sensitivity 97.8%). CONCLUSION: Automatic ECG screening using a computerized algorithm safely identifies normal ECGs in Lead I and reduces the need for manual evaluation of individual ECGs with >85% with 100% sensitivity on an individual basis.

Designing an optimal screening program for unknown atrial fibrillation: a cost-effectiveness analysis.

AIMS: The primary objective of this study was to use computer simulations to suggest an optimal age for initiation of screening for unknown atrial fibrillation and to evaluate if repeated screening will add value. METHODS AND RESULTS: In the absence of relevant clinical studies, this analysis was based on a simulation model. More than two billion different designs of screening programs for unknown atrial fibrillation were simulated and analysed. Data from the published scientific literature and registries were used to construct the model and estimate lifelong effects and costs. Costs and effects generated by 2 147 483 648 different screening designs were calculated and compared. Program designs that implied worse clinical outcome and were less cost-effective compared to other programs were excluded from the analysis. Seven program designs were identified, and considered to be cost effective depending on what the health-care decision makers are ready to pay for gaining a quality-adjusted life-year (QALY). Screening at the age of 75 implied the lowest cost per gained QALY (€4 800/QALY). CONCLUSION: In conclusion, examining the results of more than two billion simulated screening program designs for unknown atrial fibrillation, seven designs were deemed cost-effective depending on how much we are prepared to pay for gaining QALYs. Our results showed that repeated screening for atrial fibrillation implied additional health benefits to a reasonable cost compared to one-off screening.