Emma Svennberg

Mass Screening for Untreated Atrial Fibrillation The STROKESTOP Study

Background— The aims of the present study were to define the prevalence of untreated atrial fibrillation (AF) in a systematic screening program using intermittent ECG recordings among 75- to 76-year-old individuals and to study the feasibility of initiating protective oral anticoagulant (OAC) treatment. Methods and Results— Half of the 75- to 76-year-old population in 2 Swedish regions were invited to a screening program for AF. Participants without a previous diagnosis of AF underwent intermittent ECG recordings over 2 weeks. If AF was detected, participants were offered OAC. During the 28-month inclusion period, 13 331 inhabitants were invited. Of these, 7173 (53.8%) participated. Of the participants, 218 (3.0%; 95% confidence interval [CI], 2.7–3.5) were found to have previously unknown AF, and of these, AF was found in 37 (0.5% of the screened population) on their first ECG. The use of intermittent ECGs increased new AF detection 4-fold. A previous diagnosis of AF was known in 9.3% (n=666; 95% CI, 8.6–10.0). Total AF prevalence in the screened population was 12.3%. Of participants with known AF, 149 (2.1%; 95% CI, 1.8–2.4) had no OAC treatment. In total, 5.1% (95% CI, 4.6–5.7) of the screened population had untreated AF; screening resulted in initiation of OAC treatment in 3.7% (95% CI, 3.3–4.2) of the screened population. More than 90% of the participants with previously undiagnosed AF accepted initiation of OAC treatment. Conclusions— Mass screening for AF in a 75- to 76-year-old population identifies a significant proportion of participants with untreated AF. Initiation of stroke prophylactic treatment was highly successful in individuals with newly diagnosed AF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01593553.

Population screening of 75- and 76-year-old men and women for silent atrial fibrillation (STROKESTOP)

Atrial fibrillation (AF) is important because it is common and is a major cause of stroke unless treated with oral anticoagulant. The prevalence of AF increases with age as does the risk of stroke. At 75 years the risk from age alone is so high that current guidelines recommend anticoagulation even in the absence of other risk factors. Atrial fibrillation is often asymptomatic and only discovered by chance or when a stroke already has occurred. We have launched a major screening study for silent AF in which 25,000 Swedes aged 75 and 76 years are randomized to either participate in a screening programme using ambulant intermittent electrocardiogram (ECG) recording to detect silent AF, or act as a control group. Patients in whom AF is detected are offered cardiological examination and anticoagulant treatment according to current guidelines. The cohort and the controls will be followed prospectively for 5 years after the inclusion of the first participant. An interim analysis will be made after 3 years. Our hypothesis is that screening for AF will reduce stroke incidence in the screened population, and that this screening will prove to be cost effective. Secondary endpoints are: any thromboembolic event, intracranial bleeding, other major bleeding, first ever diagnosis of dementia, death from any cause, and a composite of these endpoints.

Cost-effectiveness of mass screening for untreated atrial fibrillation using intermittent ECG recording

AIMS The aim of this study was to estimate the cost-effectiveness of 2 weeks of intermittent screening for asymptomatic atrial fibrillation (AF) in 75/76-year-old individuals. METHODS AND RESULTS The cost-effectiveness analysis of screening in 75-year-old individuals was based on a lifelong decision analytic Markov model. In this model, 1000 hypothetical individuals, who matched the population of the STROKESTOP study, were simulated. The population was analysed for different parameters such as prevalence, AF status, treatment with oral anticoagulation, stroke risk, utility, and costs. In the base-case scenario, screening of 1000 individuals resulted in 263 fewer patient-years with undetected AF. This implies eight fewer strokes, 11 more life-years, and 12 more quality-adjusted life years (QALYs) per 1000 screened individuals. The screening implies an incremental cost of €50 012, resulting in a cost of €4313 per gained QALY and €6583 per avoided stroke. CONCLUSIONS With the use of a decision analytic simulation model, it has been shown that screening for asymptomatic AF in 75/76-year-old individuals is cost-effective.

NT-proBNP is a powerful predictor for incident atrial fibrillation — Validation of a multimarker approach

BACKGROUND Biomarkers may be of value to identify individuals at risk of developing atrial fibrillation (AF). Using a multimarker approach, this study investigated if the biomarkers; NT-proBNP, high-sensitivity cardiac troponin (hs-cTn), growth differentiation factor-15 (GDF-15), cystatin C and high-sensitivity C-reactive protein (CRP) are independent predictors for incident AF. METHODS Blood samples were collected from 883 individuals in the Uppsala Longitudinal Study of Adult Men (ULSAM) and 978 individuals in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Participants were followed for 10-13years with n=113 incident AF cases in ULSAM and n=148 in PIVUS. The associations between biomarkers and incident AF were analysed in Cox proportional hazards regression models. RESULTS The hazard ratio (HR) for incident AF was significant for all five biomarkers in unadjusted analyses in both cohorts. Only NT-proBNP remained significant when adjusting for cardiovascular risk factors and the other biomarkers (HR (1SD) 2.05 (1.62-2.59) (ULSAM) and 1.56 (1.30-1.86) (PIVUS), both p<0.001). The C-index improved from 0.64 to 0.69 in ULSAM and from 0.62 to 0.68 in PIVUS, by adding NT-proBNP to cardiovascular risk factors (both p<0.001). The C-index of the CHARGE-AF risk score increased from 0.62 to 0.68 (ULSAM) and 0.60 to 0.66 (PIVUS) by addition of NT-proBNP (p<0.001). CONCLUSIONS Using a multimarker approach NT-proBNP was the strongest predictor of incident AF in two cohorts, and improved risk prediction when added to traditional risk factors. NT-proBNP significantly improved the predictive ability of the novel CHARGE-AF risk score, although the predictive value remained modest.

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.

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.

Geographic and socio-demographic differences in uptake of population-based screening for atrial fibrillation: The STROKESTOP I study

BACKGROUND The rationale behind screening for atrial fibrillation (AF) is to prevent ischemic stroke. Socio-demographic differences are expected to affect screening uptake. Geographic differences may provide further insights leading to targeted interventions for improved uptake. The objective of this study was to evaluate geographic and socio-demographic differences in uptake of AF screening in the population-based study STROKESTOP I. METHODS STROKESTOP was carried out in two Swedish counties with a total population of 2.3 million inhabitants. Half of the residents aged 75-76years were randomized to the screening arm: invitation to clinical examination followed by ambulant ECG recording. Information on each invited persons residential parish (n=157) was used. On parish-level, aggregated data for the participants and non-participants, respectively, were obtained with respect to socioeconomic variables: educational level, disposable income, immigrant and marital status. Geo-maps displaying participation ratios were estimated by hierarchical Bayes methods. RESULTS The overall participation rate was similar in men and women but lower in Stockholm, 47.6% (5665/11,903) than in Halland, 61.2% (1495/2443). Participation was clearly associated with the socioeconomic variables. Participation not taking into account socioeconomy varied more markedly across the parishes in the Stockholm county (range: 0.65-1.26) than in the Halland county (0.94-1.27). After adjustment for socioeconomic variables, a geographic variation remained in Stockholm, but not in Halland. CONCLUSION Participation in AF screening varied according to socioeconomic conditions. Geographic variation in participation was marked in the Stockholm county, with only one screening clinic. Geo-mapping of participation yielded useful information needed to intervene for improved screening uptake.

N-terminal pro B-type natriuretic peptide in systematic screening for atrial fibrillation

Objective Screening for atrial fibrillation (AF) in individuals aged 65 and above is recommended by the European Society of Cardiology. Increased levels of the biomarker N-terminal pro B-type natriuretic peptide (NT-proBNP) has in cohort studies been associated with incident AF. The aim of this study was to assess whether NT-proBNP could be useful for AF detection in systematic screening. Methods The Strokestop study entailed 7173 Swedish residents aged 75/76 that were screened for AF using twice daily intermittent ECG recordings during 2 weeks. In a substudy of 886 participants, the last 815 consecutive participants and 71 individuals with newly detected AF, levels of NT-proBNP were determined. Results Participants with newly detected AF (n=96) had a median NT-proBNP of 330 ng/L (IQR 121;634). In individuals without AF (n=742), median NT-proBNP was 171 ng/L (IQR 95;283), p<0.001. The CHA2DS2-VASc parameters did not differ significantly between individuals with newly detected AF and without AF nor between newly detected AF in the NT-proBNP cohort compared with the cohort where NT-proBNP was not assessed. Using an NT-proBNP cut-off of ≥125 ng/L in a non-acute setting yielded a negative predictive value of 92%, meaning that 35% fewer participants would need to be screened when applied to systematic AF screening. Adding weight to NT-proBNP further reduced participants needed to be screened with a preserved sensitivity. Conclusions NT-proBNP was increased in individuals with newly detected AF. Prospective studies could clarify if NT-proBNP can be used to correctly select individuals that benefit most from AF screening. Clinical trials ClinicalTrials.gov. Identifier: NCT01593553.

Usefulness of Short-Lasting Episodes of Supraventricular Arrhythmia (Micro-Atrial Fibrillation) as a Risk Factor for Atrial Fibrillation

According to the present European Society of Cardiologys guidelines for atrial fibrillation (AF), the definition of AF contains a 30-second time criterion, based on consensus. The aim of this cohort study is to evaluate whether very short-lasting episodes of AF, micro-AF, are risk factors for developing AF and to compare AF detection between continuous and intermittent ECG recordings applied in parallel. All participants, n = 102, were identified from the STROKESTOP study, a Swedish mass-screening study for AF. Participants were divided into 2 groups depending on results in the STROKESTOP study: a micro-AF group (with abrupt onset episodes of ≥4 consecutive supraventricular beats, irregular rate-to-rate intervals, absence of regular p waves, lasting for <30 seconds), n = 54, and a control group, n = 48. After a follow-up period participants who were clinically free of AF were invited to undergo repeat AF screening during a 2-week period, using continuous ECG recording and 30 seconds intermittent recordings simultaneously. After 2.3years of follow-up, significantly more participants in the micro-AF group had developed AF, 27 of 54 (50%), compared with the control group, 5 of 48 (10%), p < 0.001. Among the 94 participants not already diagnosed with AF who underwent AF-screening, 25 of 25 (100%) AF cases were detected with help of continuous monitoring whereas 10 of 25 (40%) AF cases were found with intermittent ECGs. In conclusion, micro-AF seems to be an important risk factor for the development of AF in an elderly population. The detection of AF was significantly higher using 2 weeks of continuous ECG monitoring compared with intermittent 30-second ECG recordings twice daily for 2 weeks.

Why should we screen for atrial fibrillation

Atrial fibrillation (AF) constitutes an increasing challenge to the medical community and healthcare providers. With a prevalence of almost 3% in the adult Swedish population1 and a forecasted twofold or threefold increase by 2050 in the USA, we are facing a diagnosis with epidemic proportions. Apart from increased mortality, AF also increases the risk of heart failure, hospitalisations and ischaemic stroke.2 Of these complications, ischaemic stroke gives a particularly heavy burden on patients, their family and society. Ischaemic stroke is the most common reason for permanent neurological disability in the adult Western population, and stroke in connection to AF and cardiac emboli results in worse neurological outcome and higher mortality in relation to other subtypes of stroke.3 In patients with AF and stroke risk factors, oral anticoagulation (OAC) therapy reduces the risk of ischaemic stroke and systemic emboli by 60–70%. Unfortunately, there is still widespread undertreatment with OAC in patients with AF and risk factors. AF is often present with no or very subtle symptoms, both in paroxysmal form and in permanent form. The absence of symptoms reduces the chance of recognition and diagnosis, in particular in paroxysmal cases, since patients will not seek medical attention for their arrhythmia. The prevalence of so-called silent AF is only partly known since yield in screening studies varies with ECG recording duration. There are, however, no data supporting that silent AF have better outcomes in comparison with AF with typical presentation.4 …