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Europace
Europace
europace
Europace
1099-5129
1532-2092
Oxford University Press UK

39298681
10.1093/europace/euae234
euae234
Trial Design
AcademicSubjects/MED00200
Eurheartj/23
Eurheartj/24
Eurheartj/1
Eurheartj/3
Increasing the reach: optimizing screening for atrial fibrillation—the STROKESTOP III study
https://orcid.org/0000-0003-1615-5173
Khan Mashroor Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Stockholm, Sweden

Ingre Michael Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Stockholm, Sweden

Carlstedt Fredrik Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden

Eriksson Anders Department of Clinical Physiology, Region Värmland, Karlstad, Sweden

https://orcid.org/0000-0002-6360-1167
Skröder Sofia Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden
Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden

Star Tenn Johanna Department of Clinical Physiology, Region Värmland, Karlstad, Sweden

https://orcid.org/0000-0003-3337-9259
Rosenqvist Mårten Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Danderyd, Sweden

https://orcid.org/0000-0002-6413-0870
Svennberg Emma Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Stockholm, Sweden

Corresponding author. Tel: +46 73 987 67 76. E-mail address: mashroor.khan@regionstockholm.se
9 2024
20 9 2024
20 9 2024
26 9 euae23409 7 2024
03 9 2024
20 9 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
2024
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Abstract

Aims

Atrial fibrillation (AF) is the most common type of cardiac arrythmia and is an important risk factor for ischaemic stroke. Many cases of AF remain undiagnosed due to its paroxysmal, intermittent, and often asymptomatic nature. Early detection of AF through screening and initiation of treatment with oral anticoagulants can prevent stroke, increase life expectancy, and decrease the cost of healthcare for the society. However, participation has been low in previous AF screening studies employing population screening. The aim of this study is to determine whether opportunistic screening is a superior method to increase participation in comparison to population screening. We hypothesize that opportunistic screening will significantly increase participation.

Methods and results

In our study, STROKESTOP III, a randomized prospective cohort study, we compare two different methods of AF screening in high-risk individuals: population screening vs. opportunistic screening. Sixteen different primary clinics in Värmland, Sweden, serving 75–76-year-old individuals (n = 2954), will be randomized to either population screening or opportunistic screening. The individuals will be instructed to record electrocardiogram (ECG) for 30 s, 3 times daily for 2 weeks, using a handheld one-lead ECG device. Patients with detected AF will be referred to their primary healthcare physician and offered treatment. The main objective of the study is to determine the rate of participation in opportunistic screening in comparison to population screening.

Conclusions

The STROKESTOP III study will provide valuable information on which screening method to use for improved participation in atrial fibrillation screening.

Graphical Abstract

Graphical Abstract

Atrial fibrillation
Screening
Prevention
Stroke
Swedish Heart-Lung Foundation 10.13039/501100003793 2022-03484 2022-01466 Stockholm County Council 10.13039/501100011727
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pmcWhat’s new?

Opportunistic screening will be compared to population screening to determine the optimal atrial fibrillation (AF) screening method to maximize participation.

An artificial intelligence (AI) algorithm for predicting atrial fibrillation from a normal one-lead electrocardiogram during sinus rhythm will be prospectively tested.

Introduction

Atrial fibrillation (AF) is the most common type of cardiac arrythmia and is an important risk factor for ischaemic stroke.1 Approximately one out of five ischaemic strokes are associated with AF, commonly associated with more severe clinical outcomes.2,3 Although treatment with oral anticoagulants (OAC) have shown to significantly reduce the incidence of ischaemic stroke and reduce mortality, asymptomatic and intermittent AF remain undiagnosed and untreated.4,5

Early identification of AF through population screening could enable early initiation of treatment and thereby avoiding consequences including stroke and premature death.6

In our previous population screening studies, STROKESTOP I and II, we observed that most patients who were screened for AF, initiated and were able to maintain their OAC regimen continuously throughout the entire study.6,7 In a sub-study of the STROKESTOP I trial, it was shown that 11 additional life years could be added by screening 1000 high-risk patients, making AF screening economically effective.8 However, results from other studies show conflicting results regarding treatment of screening-detected AF, indicating that not all patients with screening-detected AF need OAC, particularly those with a short duration.9,10

Participation was modest in both STROKESTOP I and STROKESTOP II; only 50% of the participants who were invited to the studies chose to participate. Non-participants generally had a lower socio-economic status and more risk factors for AF and stroke.6 These patients would probably benefit more from screening.

Population screening was employed in STROKESTOP I and II. Population screening is a systematic screening approach that involves identifying high-risk individuals for a disease and inviting them to screening.6,7 Opportunistic screening, in contrast, approaches potential screening participants at the time of a healthcare visit, irrespective of diagnosis. A prior, small observational study showed that opportunistic screening could increase participation to 70%.11 Results from the SAFE study, published in 2005, also suggests that opportunistic screening is a more cost-effective AF screening method.12

Aim

The aim of this study is to determine whether population screening or opportunistic screening is more effective in increasing participation rate for AF screening among 75–76-year-olds.

Hypothesis

Opportunistic screening will significantly improve participation rate to ∼70% in compared to a participation rate of 50% in population-based screening approach.

Study design

Randomized, prospective cohort study.

Ethics

The study was approved by the Swedish National Ethics Committee, Dnr: 2023-04659-01. The study will be conducted in compliance with the Declaration of Helsinki. All participants will receive written information and sign consent before inclusion.

Methods

Study population

Individuals born 1948–1949 (75–76 years old) and served by healthcare facilities from five different primary healthcare areas in the Region of Värmland (in total: 2954 participants) are eligible to be included in the study. Individuals aged 75–76 have been selected because these individuals have a strong indication for treatment with OAC upon AF detection. The same age range was also used in the STROKESTOP I study, which resulted in a small net benefit from screening.6 Participants with known AF, ongoing OAC medication, contraindications for treatment of AF or unable to give informed consent will be excluded.

Randomization and study setting

In total, 16 different healthcare facilities, in Värmland, will be clustered to either opportunistic screening or population screening (Figure 1). The allocation will consider the size of the facilities as well as socio-economic factors. A multivariate distance is calculated between all healthcare facilities based on their size and care need index.13 The facilities are then matched in blocks of two based on the smallest multivariate distance between unassigned facilities, repeatedly, until all facilities have been assigned to a block. For each block, one facility is randomized to opportunistic screening and the other to population screening. Matching and randomization is performed with the block Tools package (version 0.6.4) in R statistical software (version 4.4.0; R Foundation for Statistical Computing, Vienna, Austria).

Figure 1 Graph showing overview of the STROKESTOP III study, including the predicted participation rate. The clinics will be randomized to either population screening or opportunistic screening. OAC, oral anti-coagulation; ECG, Electrocardiogram.

Opportunistic screening procedure

Over the course of a year, it is estimated that more than 90% of individuals living in Värmland aged 75–76 years old will visit their primary clinic at least once. During their routine visit to the primary clinic, individuals who do not meet any exclusion criteria will be offered screening for AF regardless of the cause of the visit. In cases where the visit does not allow enough time, the participants will later be contacted by phone and informed about the screening procedure. Interested individuals will receive written information regarding the study and asked to provide written consent. Consenting individuals will receive a handheld Zenicor One ECG recording device (Zenicor Medical systems AB). All participants will provide information regarding co-morbidities, symptoms of palpitations, and ongoing medication.

Population screening procedure

Individuals born 1948–1949 living in the uptake area of a primary clinic assigned to population screening will receive an invitation by letter with an offer for screening of AF. Participants who do not meet the exclusion criteria will receive handheld ECG recording device and written instructions to their home. A contact phone number will be provided in case of difficulties registering ECGs or other study related questions. Written consent, information regarding co-morbidities, and ongoing medication will be sent by the participant in a return envelope.

Electrocardiogram monitoring and follow-up

The participants will be instructed to perform at least three ECG recordings daily using the Zenicor One handheld device for a total of 2 weeks. The participants will make additional ECG recordings when they experience symptoms of irregular heartbeat. The Zenicor handheld device records a single-lead ECG in lead I and automatically transmits the recording to a database (Zenicor View). The recording device by Zenicor has been validated and used in previous AF screening studies.6,14–17 The criteria for AF will be at least one episode of irregular heartbeat lasting 30 s without P-waves. The Zenicor handheld device is able to detect atrial fibrillation with a sensitivity of 98% and specificity of 88%.18 The initial screening of the single-lead ECG will be done by technicians and, in case of positive findings, be reviewed by a physician. The final diagnosis will be made by a specially trained physician. In case of uncertainty, a long-term ECG registration using a different lead, or multiple leads, will be provided to the participant prior to determine the diagnosis. Participants whose ECG recordings fulfil the criteria for AF will be referred to their primary care physician for follow-up and initiation of treatment with OAC.

Inclusion period

Participants will be included from the first quarter of 2024 to the second quarter of 2025.

Primary outcome

The rate of participation in opportunistic screening in comparison to population screening.

Secondary outcome

The number of participants detected with AF in opportunistic screening in comparison to population screening.

The number of participants with newly diagnosed AF who have an OAC prescription within 30 days of AF detection.

Compliance to OAC medication at 1-year follow-up.

Health–economic assessment of costs accrued in the systematic screening group compared to the opportunistic screening group.

A combined endpoint of the rate of stroke, all-cause death, and severe bleeding leading to hospitalization in the group randomized to systematic screening compared to opportunistic screening after 1 year.

An AI algorithm using a convolutional neural network has previously been developed.19 The AI algorithm predicts paroxysmal AF from a single-lead sinus rhythm ECG. Proportion of new AF detected in the group determined as high risk per AI algorithm compared to the group marked as low risk by the AI algorithm. The algorithm has been further developed (see Supplementary material) and will be prospectively tested to determine if individuals classified as high risk to develop AF by the AI algorithm on their initial ECG have an increased risk of screening-detected AF. The ECG reviewers will be blinded to the result of the AI algorithm. The AI algorithm could potentially be used as a screening tool for AF detection in the future.

FIND-AF stands for Future innovations in Novel Detection for Atrial Fibrillation. The FIND-AF study uses an AI model using electronic health care records in the UK to predict increased risk of Incident AF. We aim to determine how accurate the pre-specified variables from the FIND-AF algorithm (age, gender, presence of valvular disease, chronic pulmonary disease, chronic renal failure, and CHADS-VASc parameters) can predict AF (reported by sensitivity, specificity, and area under the curve.20

Statistical power analysis

Based on the number of potential individuals listed at the different healthcare facilities (n = 93–405) and findings from STROKESTOP I & II, indicating that population screening may recruit 50% of individuals while opportunistic screening could increase the participation rate to 70%, a series of clustered power calculations was performed to find the number of facilities needed to achieve >80% power. The smallest available healthcare facilities were repeatedly added in pairs, one for each group, and assumed that 90% of the patients would be available for recruitment during the study period. The availability of patients is based on data showing that over the course of a year, >90% of 75-year-olds residing in Värmland will visit primary healthcare at least once. Power was calculated to detect a significant (alpha = 0.05) difference between the groups, assuming ICC = 0.03 and participation rates of 55% and 70% in the two groups. Eighty-two per cent power was achieved with 16 healthcare facilities and n = 2656. The calculations were performed with clusterPower21 in R statistical software.

Power was also calculated for a secondary outcome of the study (number 6 on the list); AI algorithm used for predicting paroxysmal AF from normal ECG during sinus rhythm. The proportion of new AF detected in the group determined as high risk per AI algorithm will be compared to the number of new AF in the group marked as low-risk by the AI algorithm. These calculations were based on pilot data indicating a sensitivity of 75% and specificity of 50% for the AI algorithm and assumed 3% AF prevalence in the study population. With these assumptions, ∼0.03 × 0.75 + (1−0.03) × 0.5 ≈ 51% of the screened individuals will be classified as high risk with an AF prevalence of (0.03 × 0.75)/(0.03 × 0.75 + (1−0.03) × 0.5) ≈ 4.43%. The low-risk group is the remaining 49% of patients with an AF prevalence of ∼1.52%. Statistical power was calculated to detect the difference in prevalence using the pwr package (package version 1.3-0) in R statistical software. For the sample size calculated above (n = 2656), power was estimated to be 99.5%.

Clinical impact

Atrial fibrillation impacts a significant portion of the population and is a major risk factor for stroke. Atrial fibrillation has also been linked to other diseases, including heart failure and cognitive impairment.22 Early detection and treatment of AF could potentially extend life expectancy and yield economic benefits by reducing healthcare costs.8,22,23 Low participation rates have been a recurring problem in previous AF screening studies. The aim of this study was to increase the participation rate for AF screening. We believe our study will demonstrate that compared to population screening methods, used in past studies, opportunistic screening has greater potential to achieve a broader patient coverage and should be the preferred screening strategy forward.

Supplementary Material

euae234_Supplementary_Data

Supplementary material

Supplementary material is available at Europace online.

Funding

The study is funded by the Swedish Heart and Lung foundation, CIMED, Vinnova (grant number 2022-03484), and the Swedish Research Council (grant number 2022-01466). E.S. has received additional funding from the Region Stockholm (clinical researcher appointment).

Conflict of interest: E.S. has received institutional fees from Abbott, Astra Zeneca, Bayer, Bristol-Myers Squibb-Pfizer, Boehringer Ingelheim, Johnson & Johnson, and Merck Sharp & Dohme. M.R. has received consultant fees from Zenicor. All remaining authors have declared no conflicts of interest.

Data availability

The data that support the findings of this study are not publicly available due to privacy and ethical concerns, as they contain sensitive patient information. Access to the data is restricted in accordance with patient confidentiality agreements and applicable regulations. Researchers interested in the data for replication or further study may contact the corresponding author, but any access will be subject to appropriate data use agreements and ethical approvals.
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