Estimated stroke risk, yield, and number needed to screen for atrial fibrillation detected through single time screening: a multicountry patient-level meta-analysis of 141,220 screened individuals

English version

Autoři: Nicole Lowres ^aff001; Jake Olivier ^aff002; Tze-Fan Chao ^aff003; Shih-Ann Chen ^aff003; Yi Chen ^aff005; Axel Diederichsen ^aff007; David A. Fitzmaurice ^aff006; Juan Jose Gomez-Doblas ^aff009; Joseph Harbison ^aff011; Jeff S. Healey ^aff013; F. D. Richard Hobbs ^aff014; Femke Kaasenbrood ^aff015; William Keen ^aff016; Vivian W. Lee ^aff017; Jes S. Lindholt ^aff018; Gregory Y. H. Lip ^aff019; Georges H. Mairesse ^aff021; Jonathan Mant ^aff022; Julie W. Martin ^aff016; Enrique Martín-Rioboó ^aff023; David D. McManus ^aff025; Javier Muñiz ^aff027; Thomas Münzel ^aff029; Juliet Nakamya ^aff013; Lis Neubeck ^aff032; Jessica J. Orchard ^aff001; Luis Ángel Pérula de Torres ^aff033; Marco Proietti ^aff019; F. Russell Quinn ^aff037; Andrea K. Roalfe ^aff014; Roopinder K. Sandhu ^aff038; Renate B. Schnabel ^aff039; Breda Smyth ^aff041; Apurv Soni ^aff042; Robert Tieleman ^aff043; Jiguang Wang ^aff005; Philipp S. Wild ^aff031; Bryan P. Yan ^aff049; Ben Freedman ^aff001
Působiště autorů: Heart Research Institute, Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia ^aff001; School of Mathematics and Statistics, University of New South Wales, Sydney, Australia ^aff002; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan ^aff003; Institute of Clinical Medicine and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan ^aff004; The Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai, China ^aff005; Shanghai Jiaotong University School of Medicine, Shanghai, China ^aff006; Department of Cardiology and Centre of Individualized Medicine of Arterial Disease, Odense University Hospital, Odense, Denmark ^aff007; Warwick Medical School, University of Warwick, Coventry, United Kingdom ^aff008; Servicio de Cardiologia, Hospital Universitario Virgen de la Victoria, Malaga, Spain ^aff009; CIBERCV, Malaga, Spain ^aff010; Discipline of Medical Gerontology, Trinity College Dublin, Dublin, Ireland ^aff011; The Irish Longitudinal Study of Ageing, Dublin, Ireland ^aff012; Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada ^aff013; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom ^aff014; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands ^aff015; Kaiser Permanente San Diego, San Diego, United States of America ^aff016; School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong ^aff017; Department of Vascular Surgery, Odense University Hospital, Odense, Denmark ^aff018; Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom ^aff019; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark ^aff020; Department of Cardiology, Cliniques du Sud Luxembourg, Vivalia, Arlon, Belgium ^aff021; Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom ^aff022; University of Córdoba, Reina Sofia University Hospital, Unit of Family and Community Medicine of Córdoba, UGC Poniente, Córdoba and Guadalquivir Sanitary District, Córdoba, Spain ^aff023; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain ^aff024; Division of Cardiology, Department of Medicine, University of Massachusetts Medical School, Worcester, United States of America ^aff025; UMass Memorial Medical Center, Worcester, United States of America ^aff026; Universidade da Coruña, A Coruña, Spain ^aff027; Instituto Universitario de Ciencias de la Salud e Instituto de Investigación Biomédica de A Coruña, CIBERCV, A Coruña, Spain ^aff028; Center of Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany ^aff029; Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany ^aff030; DZHK (German Center for Cardiovascular Research), partner site RhineMain, Mainz, Germany ^aff031; School of Health and Social Care, Edinburgh Napier University, Edinburgh, Scotland ^aff032; Teaching Unit of Family and Community Medicine of Córdoba, Córdoba and Guadalquivir Sanitary District. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain ^aff033; Reina Sofía University Hospital, University of Córdoba, Córdoba, Spain ^aff034; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy ^aff035; Geriatric Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy ^aff036; Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada ^aff037; Cardiac Electrophysiology, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada ^aff038; University Heart Center Hamburg, Hamburg, Germany ^aff039; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany ^aff040; Department of Public Health Medicine, HSE West, Galway, Ireland ^aff041; Clinical and Population Health Research, Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, United States of America ^aff042; Department of Cardiology, Martini Hospital Groningen, Groningen, the Netherlands ^aff043; Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands ^aff044; Preventive Cardiology and Preventive Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany ^aff045; Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany ^aff046; Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany ^aff047; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany ^aff048; Division of Cardiology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China ^aff049; Prince of Wales Hospital, Hong Kong SAR, China ^aff050
Vyšlo v časopise: Estimated stroke risk, yield, and number needed to screen for atrial fibrillation detected through single time screening: a multicountry patient-level meta-analysis of 141,220 screened individuals. PLoS Med 16(9): e32767. doi:10.1371/journal.pmed.1002903
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1002903

Souhrn

Background

The precise age distribution and calculated stroke risk of screen-detected atrial fibrillation (AF) is not known. Therefore, it is not possible to determine the number needed to screen (NNS) to identify one treatable new AF case (NNS-Rx) (i.e., Class-1 oral anticoagulation [OAC] treatment recommendation) in each age stratum. If the NNS-Rx is known for each age stratum, precise cost-effectiveness and sensitivity simulations can be performed based on the age distribution of the population/region to be screened. Such calculations are required by national authorities and organisations responsible for health system budgets to determine the best age cutoffs for screening programs and decide whether programs of screening should be funded. Therefore, we aimed to determine the exact yield and calculated stroke-risk profile of screen-detected AF and NNS-Rx in 5-year age strata.

Methods and findings

A systematic review of Medline, Pubmed, and Embase was performed (January 2007 to February 2018), and AF-SCREEN international collaboration members were contacted to identify additional studies. Twenty-four eligible studies were identified that performed a single time point screen for AF in a general ambulant population, including people ≥65 years. Authors from eligible studies were invited to collaborate and share patient-level data. Statistical analysis was performed using random effects logistic regression for AF detection rate, and Poisson regression modelling for CHA₂DS₂-VASc scores. Nineteen studies (14 countries from a mix of low- to middle- and high-income countries) collaborated, with 141,220 participants screened and 1,539 new AF cases. Pooled yield of screening was greater in males across all age strata. The age/sex-adjusted detection rate for screen-detected AF in ≥65-year-olds was 1.44% (95% CI, 1.13%–1.82%) and 0.41% (95% CI, 0.31%–0.53%) for <65-year-olds. New AF detection rate increased progressively with age from 0.34% (<60 years) to 2.73% (≥85 years). Neither the choice of screening methodology or device, the geographical region, nor the screening setting influenced the detection rate of AF. Mean CHA₂DS₂-VASc scores (n = 1,369) increased with age from 1.1 (<60 years) to 3.9 (≥85 years); 72% of ≥65 years had ≥1 additional stroke risk factor other than age/sex. All new AF ≥75 years and 66% between 65 and 74 years had a Class-1 OAC recommendation. The NNS-Rx is 83 for ≥65 years, 926 for 60–64 years; and 1,089 for <60 years. The main limitation of this study is there are insufficient data on sociodemographic variables of the populations and possible ascertainment biases to explain the variance in the samples.

Conclusions

People with screen-detected AF are at elevated calculated stroke risk: above age 65, the majority have a Class-1 OAC recommendation for stroke prevention, and >70% have ≥1 additional stroke risk factor other than age/sex. Our data, based on the largest number of screen-detected AF collected to date, show the precise relationship between yield and estimated stroke risk profile with age, and strong dependence for NNS-RX on the age distribution of the population to be screened: essential information for precise cost-effectiveness calculations.

Klíčová slova:

Age groups – Ischemic stroke – Screening guidelines – Health screening – Cost-effectiveness analysis – Electrocardiography – Age distribution – Atrial fibrillation

Zdroje

1. Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibrillation. Lancet. 2016;388(10046):806–17. doi: 10.1016/S0140-6736(16)31257-0 27560276

2. Freedman B. Major progress in anticoagulant uptake for atrial fibrillation at last: does it translate into stroke prevention? Eur Heart J. 2018;39(32):2984–6. doi: 10.1093/eurheartj/ehy487 30107395

3. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893–962. doi: 10.1093/eurheartj/ehw210 27567408

4. Mairesse GH, Moran P, Gelder ICV, Elsner C, Rosenqvist M, Mant J, et al. Screening for atrial fibrillation: a European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLAECE). Europace. 2017;19(10):1589–623. doi: 10.1093/europace/eux177 29048522

5. Stott DJ, Dewar RI, Garratt CJ, Griffith KE, Harding NJ, James MA, et al. RCPE UK consensus conference on 'approaching the comprehensive management of atrial fibrillation: evolution or revolution?'. J R Coll Physicians Edinb. 2012;42(Suppl 18):3–4.

6. Freedman B, Camm J, Calkins H, Healey JS, Rosenqvist M, Wang J, et al. Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration. Circulation. 2017;135(19):1851–67. doi: 10.1161/CIRCULATIONAHA.116.026693 28483832

7. Brieger D, Amerena J, Attia J, Bajorek B, Chan KH, Connell C, et al. National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018. Heart Lung Circ. 2018;27(10):1209–66. doi: 10.1016/j.hlc.2018.06.1043 30077228

8. Hobbs FD, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study. Health Technol Assess. 2005;9(40):iii–iv, ix-x, 1–74. 16202350

9. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–34. doi: 10.1016/j.jclinepi.2009.06.006 19631507

10. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12. doi: 10.1001/jama.283.15.2008 10789670

11. Schnabel RB, Wilde S, Wild PS, Munzel T, Blankenberg S. Atrial fibrillation: its prevalence and risk factor profile in the German general population. Dtsch Arztebl Int. 2012;109(16):293–9. doi: 10.3238/arztebl.2012.0293 22577476

12. Yan B, Lee V. Hong Kong outpatient atrial fibrillation screening using single-lead ECG device. U.S. National library of medicine: Clinical trials registry https://clinicaltrials.gov/ct2/show/NCT02409654?term=NCT02409654&rank=1. 2017.

13. Gomez-Doblas JJ, Muniz J, Martin JJ, Rodriguez-Roca G, Lobos JM, Awamleh P, et al. Prevalence of atrial fibrillation in Spain. OFRECE study results. Rev Esp Cardiol (Engl Ed). 2014;67(4):259–69.

14. Deif B, Lowres N, Freedman SB. Screening for atrial fibrillation above age 65 detects an asymptomatic subset at high risk of stroke. Int J Cardiol. 2013;164(3):371–2. doi: 10.1016/j.ijcard.2012.08.002 22964080

15. Soni A, Karna S, Patel H, Fahey N, Raithatha S, Handorf A, et al. Study protocol for Smartphone Monitoring for Atrial fibrillation in Real-Time in India (SMART-India): a community-based screening and referral programme. BMJ Open. 2017;7(12):e017668. doi: 10.1136/bmjopen-2017-017668 29247089

16. Proietti M, Mairesse GH, Goethals P, Scavee C, Vijgen J, Blankoff I, et al. A population screening programme for atrial fibrillation: a report from the Belgian Heart Rhythm Week screening programme. Europace. 2016;18(12):1779–86. doi: 10.1093/europace/euw069 27170000

17. Li LH, Sheng CS, Hu BC, Huang QF, Zeng WF, Li GL, et al. The prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population: a prospective study. BMC Cardiovasc Disord. 2015;15:31. doi: 10.1186/s12872-015-0023-3 25953603

18. Smyth B, Marsden P, Corcoran R, Walsh R, Brennan C, McSharry K, et al. Opportunistic screening for atrial fibrillation in a rural area. QJM. 2016;109(8):539–43. doi: 10.1093/qjmed/hcw011 26819299

19. Chao TF, Chen SA. P1693The results of screen of atrial fibrillation event in Taiwan: the SAFE-Taiwan study. EP Europace. 2017;19(suppl_3):iii363–iii.

20. Kvist TV, Lindholt JS, Rasmussen LM, Søgaard R, Lambrechtsen J, Steffensen FH, et al. The DanCavas pilot study of multifaceted screening for subclinical cardiovascular disease in men and women aged 65–74 years. Eur J Vasc Endovas Surg. 2017;53(1):123–31.

21. Kaasenbrood F, Hollander M, Rutten FH, Gerhards LJ, Hoes AW, Tieleman RG. Yield of screening for atrial fibrillation in primary care with a hand-held, single-lead electrocardiogram device during influenza vaccination. Europace. 2016;18(10):1514–20. doi: 10.1093/europace/euv426 26851813

22. Lowres N, Neubeck L, Salkeld G, Krass I, McLachlan AJ, Redfern J, et al. Feasibility and cost-effectiveness of stroke prevention through community screening for atrial fibrillation using iPhone ECG in pharmacies. The SEARCH-AF study. Thromb Haemost. 2014;111(6):1167–76. doi: 10.1160/TH14-03-0231 24687081

23. Sandhu RK, Dolovich L, Deif B, Barake W, Agarwal G, Grinvalds A, et al. High prevalence of modifiable stroke risk factors identified in a pharmacy-based screening programme. Open Heart. 2016;3(2):e000515. doi: 10.1136/openhrt-2016-000515 28123758

24. Quinn FR, Gladstone DJ, Ivers NM, Sandhu RK, Dolovich L, Ling A, et al. Diagnostic accuracy and yield of screening tests for atrial fibrillation in the family practice setting: a multicentre cohort study. CMAJ Open. 2018;6(3):E308–E15. doi: 10.9778/cmajo.20180001 30072410

25. Gonzalez Blanco V, Perula de Torres LA, Martin Rioboo E, Martinez Adell MA, Parras Rejano JM, Gonzalez Lama J, et al. Opportunistic screening for atrial fibrillation versus detecting symptomatic patients aged 65 years and older: A cluster-controlled clinical trial. Med Clin (Barc). 2017;148(1):8–15.

26. Fitzmaurice DA, Hobbs FD, Jowett S, Mant J, Murray ET, Holder R, et al. Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: cluster randomised controlled trial. BMJ. 2007;335(7616):383. doi: 10.1136/bmj.39280.660567.55 17673732

27. Orchard J, Neubeck L, Freedman B, Li J, Webster R, Zwar N, et al. eHealth Tools to Provide Structured Assistance for Atrial Fibrillation Screening, Management, and Guideline‐Recommended Therapy in Metropolitan General Practice: The AF‐SMART Study. J Am Heart Assoc. 2019;8(1):e010959. doi: 10.1161/JAHA.118.010959 30590964

28. Keen W, Martin J, Lopez C, Pena-Ruiz M, Antons K, Longson S, et al. Abstract 18153: Screening for atrial fibrillation is feasible in US managed care outpatient facilities. Circulation. 2017;136(Suppl 1):A18153.

29. Wang J-G, Chen Y, Huang Q-F, Li Y, Freedman B. Rationale and design of the randomized controlled trial of intensive versus usual ECG screening for atrial fibrillation in elderly chinese by an automated ECG system in community health centers in Shanghai (AF-CATCH). Cardiovasc Innovat Applicat. 2017;2(2):273–7.

30. Simmonds MC, Higgins JP. A general framework for the use of logistic regression models in meta-analysis. Stat Methods Med Res. 2016;25(6):2858–77. doi: 10.1177/0962280214534409 24823642

31. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr., et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2019:25873.

32. Proietti M, Mujovic N, Potpara TS. Optimizing stroke and bleeding risk assessment in patients with atrial fibrillation: A balance of evidence, practicality and precision. Thromb Haemost. 2018;118(12):2014–7. doi: 10.1055/s-0038-1676074 30458556

33. Borre ED, Goode A, Raitz G, Shah B, Lowenstern A, Chatterjee R, et al. Predicting thromboembolic and bleeding event risk in patients with non-valvular atrial fibrillation: A systematic review. Thromb Haemost. 2018;118(12):2171–87. doi: 10.1055/s-0038-1675400 30376678

34. Macle L, Cairns J, Leblanc K, Tsang T, Skanes A, Cox JL, et al. 2016 Focused update of the Canadian cardiovascular society guidelines for the management of atrial fibrillation. Can J Cardiol. 2016;32(10):1170–85. doi: 10.1016/j.cjca.2016.07.591 27609430

35. Lowres N, Neubeck L, Redfern J, Freedman SB. Screening to identify unknown atrial fibrillation. A systematic review. Thromb Haemost. 2013;110(2):213–22. doi: 10.1160/TH13-02-0165 23595785

36. Svennberg E, Engdahl J, Al-Khalili F, Friberg L, Frykman V, Rosenqvist M. Mass Screening for Untreated Atrial Fibrillation: The STROKESTOP Study. Circulation. 2015;131(25):2176–84. doi: 10.1161/CIRCULATIONAHA.114.014343 25910800

37. Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, et al. Subclinical atrial fibrillation and the risk of stroke. New Engl J Med. 2012;366(2):120–9. doi: 10.1056/NEJMoa1105575 22236222

38. Steinhubl SR, Waalen J, Edwards AM, Ariniello LM, Mehta RR, Ebner GS, et al. Effect of a home-based wearable continuous ecg monitoring patch on detection of undiagnosed atrial fibrillation: The mSToPS randomized clinical trial. JAMA. 2018;320(2):146–55. doi: 10.1001/jama.2018.8102 29998336

39. Halcox JPJ, Wareham K, Cardew A, Gilmore M, Barry JP, Phillips C, et al. Assessment of remote heart rhythm sampling using the AliveCor heart monitor to screen for atrial fibrillation: The REHEARSE-AF Study. Circulation. 2017;136(19):1784–94. doi: 10.1161/CIRCULATIONAHA.117.030583 28851729

40. Freedman B, Boriani G, Glotzer TV, Healey JS, Kirchhof P, Potpara TS. Management of atrial high-rate episodes detected by cardiac implanted electronic devices. Nat Rev Cardiol. 2017;14(12):701–14. doi: 10.1038/nrcardio.2017.94 28682320

41. Aronsson M, Svennberg E, Rosenqvist M, Engdahl J, Al-Khalili F, Friberg L, et al. Cost-effectiveness of mass screening for untreated atrial fibrillation using intermittent ECG recording. Europace. 2015;17(7):1023–9. doi: 10.1093/europace/euv083 25868469

42. Sposato LA, Cipriano LE, Saposnik G, Ruiz Vargas E, Riccio PM, Hachinski V. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol. 2015;14(4):377–87. doi: 10.1016/S1474-4422(15)70027-X 25748102

43. Samol A, Masin M, Gellner R, Otte B, Pavenstadt HJ, Ringelstein EB, et al. Prevalence of unknown atrial fibrillation in patients with risk factors. Europace. 2013;15(5):657–62. doi: 10.1093/europace/eus366 23258819

44. Jacobs MS, Kaasenbrood F, Postma MJ, van Hulst M, Tieleman RG. Cost-effectiveness of screening for atrial fibrillation in primary care with a handheld, single-lead electrocardiogram device in the Netherlands. Europace. 2018;20(1):12–8. doi: 10.1093/europace/euw285 27733465

45. Moran PS, Teljeur C, Harrington P, Smith SM, Smyth B, Harbison J, et al. Cost-effectiveness of a national opportunistic screening program for atrial fibrillation in Ireland. Value Health. 2016;19(8):985–95. doi: 10.1016/j.jval.2016.07.007 27987649

46. Tarride JE, Dolovich L, Blackhouse G, Guertin JR, Burke N, Manja V, et al. Screening for atrial fibrillation in Canadian pharmacies: an economic evaluation. CMAJ Open. 2017;5(3):E653–E61. doi: 10.9778/cmajo.20170042 28835370

47. Cowan JC, Wu J, Hall M, Orlowski A, West RM, Gale CP. A 10 year study of hospitalized atrial fibrillation-related stroke in England and its association with uptake of oral anticoagulation. Eur Heart J. 2018;39(32):2975–83. doi: 10.1093/eurheartj/ehy411 29982405

48. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency Hospitalizations for Adverse Drug Events in Older Americans. N Engl J Med. 2011;365(21):2002–12. doi: 10.1056/NEJMsa1103053 22111719

49. Freedman B, Schnabel R, Calkins H. Opportunistic Electrocardiogram Screening for Atrial Fibrillation to Prevent Stroke. JAMA Cardiol. 2018;4(2):91–2.