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Protocol for a Systematic Review and Individual Participant Data Meta-Analysis of Randomized Trials of Screening for Atrial Fibrillation to Prevent StrokeFunding This work is funded by a grant from the Horizons-2020 program of the European Union N°847770, and with funds from the Canadian Stroke Prevention Intervention Network, which is funded by the Canadian Institutes of Health Research.
Introduction Atrial fibrillation (AF) is a common cause of stroke. Timely diagnosis of AF and treatment with oral anticoagulation (OAC) can prevent up to two-thirds of AF-related strokes. Ambulatory electrocardiographic (ECG) monitoring can identify undiagnosed AF in at-risk individuals, but the impact of population-based ECG screening on stroke is uncertain, as ongoing and published randomized controlled trials (RCTs) have generally been underpowered for stroke.
Methods and analysis The AF-SCREEN Collaboration, with support from AFFECT-EU, have begun a systematic review and individual participant data meta-analysis of RCTs evaluating ECG screening for AF. The primary outcome is stroke. Secondary outcomes include AF detection, OAC prescription, hospitalization, mortality, and bleeding.
After developing a common data dictionary, anonymized data will be collated from individual trials into a central database. We will assess risk of bias using the Cochrane Collaboration tool, and overall quality of evidence with the Grading of Recommendations Assessment, Development and Evaluation approach.
We will pool data using random effects models. Prespecified subgroup and multilevel meta-regression analyses will explore heterogeneity. We will perform prespecified trial sequential meta-analyses of published trials to determine when the optimal information size has been reached, and account for unpublished trials using the SAMURAI approach.
Impact and Dissemination Individual participant data meta-analysis will generate adequate power to assess the risks and benefits of AF screening. Meta-regression will permit exploration of the specific patient, screening methodology, and health system factors that influence outcomes.
Trial registration number PROSPERO CRD42022310308.
The protocol for this individual participant data meta-analysis has been registered with PROSPERO, the international prospective register of systematic reviews (PROSPERO CRD42022310308).
Strengths and Limitations of this Study
• Rigorous search strategy including gray literature and nonindexed trials.
• Broad range of screening approaches, populations, and health care settings with prespecified measures to explore heterogeneity.
• Individual participant data meta-analysis.
• Quality of evidence assessment using the GRADE framework.
• Sensitivity analysis considering unpublished registered trials.
• Ongoing analysis of OIS with publication of new trials.
Dr. Bowman reports research grants from Novartis, The Medicines Company, UK Medical Research Council, British Heart Foundation, NIHR. Dr. Brandes reports personal fees (honoraria) from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, travel grants from Biotronik, and research grants from Theravance outside the submitted work. Dr. Buck reports receiving research funding from Alberta Innovates Health Solutions. Dr. Casadei reports in-kind support for clinical studies from iRhythm and Roche Diagnostics. Dr. Chen Reports NIH Grants. Dr. S. Diederichsen reports personal consulting fees from Bristol-Myers Squibb Pfizer, Vital Beats, and Acesion Pharma, personal speaker fees from Bristol-Myers Squibb Pfizer, and institutional travel grants from Abott and Medtronic. Dr. Engdahl reports consultancy or lecture fees from Pfizer, Roche Diagnostics, Philips, Boehringer Ingelheim, and Bristol-Myers Squibb. Dr. Freedman reports grants to the Institution for investigator-initiated studies from the BMS-Pfizer Alliance, the Medical Research Future Fund (Federal government), and NSW State Health, consulting fees from the BMS-Pfizer Alliance, and loan of hand-held ECG devices from Alivecor for investigator-initiated studies. Dr. Gibson reports research support from Johnson & Johnson. He receives consulting support from Astra-Zenca, Johnson & Johnson, Janssen & Bayer. Dr. Haeusler reports speaker's honoraria, consulting fees, lecture honoraria, and/or study grants from Abbott, Amarin, Alexion, AstraZeneca, Bayer Healthcare, Sanofi, Biotronik, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medronic, Pfizer, Portola, SUN Pharma, W.L. Gore and Associates, and Edwards Lifesciences. Dr. Healey reports research grants and speaking fees from BMS/Pfizer, Medtronic, Boston Scientific, Consulting from Boston Scientific, and Bayer, speaking fees from Servier. Dr. Hobbs reports part support as Director of the NIHR Applied Research Collaboration (ARC) Oxford Thames Valley, and Theme Lead of the NIHR OUH BRC. F.D.R.H. has also received occasional fees or expenses for speaking or consultancy from AZ, BI, Bayer, BMS/Pfizer, and Novartis. Dr. Lip reports consultant and speaker fees for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are received personally. G.Y.H.L is co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899871. Dr. Lopes reports individual consulting fees from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Glaxo Smith Kline, Medtronic, Merck, Pfizer, Portola, and Sanofi; institution Grant Support from Bristol-Myers Squibb, Daiichi Sankyo, Glaxo Smith Kline, Medtronic, Pfizer, and Sanofi. Dr. Lubitz is a full-time employee of Novartis as of July 18, 2022. Dr. Lubitz previously received research support from NIH grants R01HL139731 and R01HL157635, and American Heart Association 18SFRN34250007. Dr. Lubitz received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. Dr. Mant reports honoraria from BMS/Pfizer. Dr. McIntyre reports speaking fees Bayer and Servier outside the submitted work. Dr. McManus reports honorary, speaking/consulting fees, or grants from Heart Rhythm Society, Flexcon, Rose Consulting, Bristol-Myers Squibb, Pfizer, Boston Biomedical Associates, and Avania. David D. McManus has received honorary, speaking/consulting fees, or grants from Heart Rhythm Society, Flexcon, Rose Consulting, Bristol-Myers Squibb, Pfizer, Boston Biomedical Associates, Avania Consulting, Samsung, Phillips, Mobile Sense, CareEvolution, Flexcon, Boehringer Ingelheim, Biotronik, Otsuka Pharmaceuticals, and Sanofi. Dr. McManus also declares financial support for serving on the Steering Committee for the GUARD-AF study (NCT04126486) and Advisory Committee for the Fitbit Heart Study (NCT04176926). Dr Rosenqvist reports paid consultancy for Zenicor and Medtronic and Pfizer. Dr. Sandhu reports research support from Servier Alberta Innovation in Health Fund and BMS/Pfizer Quality Improvement Grant. Dr. Schnabel reports funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under the grant agreement No 648131, from the European Union's Horizon 2020 research and innovation programme under the grant agreement No 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103 and 81Z0710114); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239), Wolfgang Seefried project funding German Heart Foundation. Dr. Singer reports research support from Bristol Myers Squibb. Dr. Svendsen reports research support from Innovation Fund Denmark, The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation, and Medtronic and speaker's fees from Medtronic. Dr. Svennberg reports research support from Research Position Stockholm County Council, Åke Wiberg Foundation, Swedish Heart Foundation, and consulting fees from Bayer, Bristol-Myers Squibb-Pfizer, Johnson & Johnson, and Merck Sharp & Dohme. Dr. Zink reports research support from START-GRANT, University RWTH Hospital Aachen, and consulting fees from BMS Pfizer. Dr. Wachter reports research support from Boehringer Ingelheim, Medtronic, Bundesministerium für Bildung, and Forschung, Deutsche Forschungsgemeinschaft, Deutsches Zentrum für Herz-Kreislaufforschung, and the European Union and personal fees from Abbott, AstraZenexa, Bayer, Bristol Myers Squibb, CvRx, Daiichi Sankyo, Novartis, Pfizer, Pharmacosmos, Sanofi, Servier, SOBI, Sciarc, and Vifor. Dr Tieleman reports grants from Medtronic and Abbott all outside the submitted work. Dr Tieleman is co-inventor of the MyDiagnostick, not receiving royalties for the past 5 years. Dr Tieleman reports personal fees from Boehringer Ingelheim, Bayer and Pfizer/Bristol Meyer Squibb all outside the submitted work.
Drs. Bangdiwala, Benz, Connolly, A. Diederichsen, Dolovich, Halcox, Lucassen, Quinn, Siu, Smyth and Steinhubl has no disclosures.
* Prepared on behalf of the AF SCREEN and AFFECT-EU Collaborators. The names of the collaborators are present in the supporting Appendix section.
Received: 03 June 2022
Accepted: 28 October 2022
Article published online:
02 March 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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