Original Contribution Atrial Premature Beats Predict Atrial Fibrillation in Cryptogenic Stroke Results From the EMBRACE Trial David J. Gladstone, MD, PhD; Paul Dorian, MD; Melanie Spring, MD; Val Panzov, MD; Muhammad Mamdani, PharmD, MPH; Jeff S. Healey, MD; Kevin E. Thorpe, MMath; for the EMBRACE Steering Committee and Investigators* Background and Purpose—Many ischemic strokes or transient ischemic attacks are labeled cryptogenic but may have undetected atrial fibrillation (AF). We sought to identify those most likely to have subclinical AF. Methods—We prospectively studied patients with cryptogenic stroke or transient ischemic attack aged ≥55 years in sinus rhythm, without known AF, enrolled in the intervention arm of the 30 Day Event Monitoring Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event (EMBRACE) trial. Participants underwent baseline 24-hour Holter ECG poststroke; if AF was not detected, they were randomly assigned to 30-day ECG monitoring with an AF auto-detect external loop recorder. Multivariable logistic regression assessed the association between baseline variables (Holter-detected atrial premature beats [APBs], runs of atrial tachycardia, age, and left atrial enlargement) and subsequent AF detection. Results—Among 237 participants, the median baseline Holter APB count/24 h was 629 (interquartile range, 142–1973) among those who subsequently had AF detected versus 45 (interquartile range, 14–250) in those without AF (P720/24 h, which is potentially clinically important based on the above literature.15 However, as the aforementioned studies did not use any sensitive long-term monitoring for AF, it is unclear whether the increased stroke or death risks were because of subsequent development of AF. Two cohort studies in pacemaker patients demonstrated that subclinical AF as brief as
Table. Predicted Probability of Atrial Fibrillation for a Given Number of Atrial Premature Beats in Patients With Cryptogenic Stroke or Transient Ischemic Attack No. of APBs/24 h on Baseline Holter Monitor
Probability of AF, %*
Lower CI, %
Upper CI, %
0
6.6
3.6
11.6
25
7.2
4.1
12.3
50
7.9
4.6
13.0
75
8.6
5.2
13.7
100
9.3
5.8
14.5
150
10.9
7.2
16.2
200
12.6
8.5
18.1
250
14.4
10.0
20.2
300
16.2
11.3
22.6
350
18.1
12.7
25.1
400
19.9
13.9
27.7
450
21.8
15.1
30.4
500
23.6
16.2
33.1
550
25.4
17.2
35.7
600
27.1
18.2
38.3
650
28.6
19.0
40.7
700
30.1
19.8
42.9
750
31.5
20.6
45.0
800
32.8
21.2
46.9
850
33.9
21.8
48.5
900
35.0
22.4
50.0
950
35.9
22.9
51.3
1000
36.7
23.3
52.5
1100
38.0
24.1
54.2
1200
38.9
24.6
55.4
1300
39.6
25.1
56.1
1400
39.9
25.4
56.5
1500
40.2
25.6
56.7
1600
40.3
25.8
56.7
1700
40.4
26.0
56.6
1800
40.5
26.2
56.6
1900
40.5
26.3
56.6
2000
40.6
26.5
56.5
AF indicates atrial fibrillation; APB, atrial premature beat; and CI, confidence interval. *Defined as ≥1 episodes of AF ≥30 s detected by 30-day ECG monitoring or by any means within 90 days after randomization.
5 or 6 minutes in duration is associated with an increased risk of stroke.24,25 However, many strokes in the pacemaker studies occurred without the development of longer-lasting AF episodes or lacked a temporal association with the AF episodes.26,27 Such observations suggest that brief atrial arrhythmias or frequent APBs may be a stroke risk marker independent of causal mechanisms, such as the development of long-lasting AF. This research has practice implications for secondary stroke prevention. The findings are clinically relevant because 1 in every 4 ischemic stroke patients (and half of TIA patients) are labeled as cryptogenic28 yet a substantial proportion will have undetected and untreated AF.1–3 Prolonged ambulatory
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4 Stroke April 2015 ECG monitoring significantly improves AF detection compared with the usual practice of short-term ECG monitoring, enabling initiation of anticoagulant therapy aimed at preventing recurrent disabling or fatal strokes. New practice guidelines now call for prolonged ECG monitoring to evaluate patients with cryptogenic stroke or TIA, yet the recommended duration of monitoring varies across different guidelines, ranging from ≥1 weeks2 to ≈30 days8 or additional ambulatory monitoring of unspecified duration.7 Because prolonged monitoring can be costly, difficult to access in some regions, and burdensome for some patients, appropriate selection of patients and monitoring strategy is needed. Both noninvasive and minimally invasive monitoring technologies for AF detection are available, and our data suggest that any approach will be most effective, and cost-effective, when applied to patients with frequent APBs. Our findings may be particularly pertinent to patient selection for costly implantable ECG monitors or repeated noninvasive monitoring over time. Patients with excessive APB who do not have AF detected in the short term may benefit from longer-term surveillance for AF. In light of our study results, we propose a tiered approach for detecting subclinical AF in patients being investigated after an embolic stroke or TIA (Figure 2). We suggest 24-hour Holter ECG as an initial screen. If AF is not detected and the patient meets criteria for an embolic stroke of undetermined source28 and is considered an appropriate candidate for additional monitoring and potential anticoagulation (and is not being anticoagulated empirically or randomized in an anticoagulant trial), then we suggest additional noninvasive ECG monitoring using a device capable of continuous recording (mobile outpatient telemetry) or an AF auto-detect loop recorder (note that traditional patient-triggered event recorders that only capture symptomatic episodes will miss subclinical AF). In terms of the target monitoring duration, we suggest 4 weeks of monitoring for patients with frequent APBs; 2 weeks may be reasonable for patients with infrequent APBs given the present analysis and the fact that most AF cases in the EMBRACE trial were detected within the first 2 weeks of monitoring.4 A threshold of >500 APBs/24 h seems to be
a reasonable pragmatic definition for frequent APBs in this population based on the data from this study. For patients with excessive APBs (eg, >1000 APBs/24 h), if AF is not documented after 4 weeks of monitoring then we would consider further monitoring. The role of empiric anticoagulant therapy for patients with frequent APBs, but without documented AF, is currently unknown; randomized trials of anticoagulation for cryptogenic stroke are currently underway and hopefully will evaluate subgroups with frequent APBs.29,30 This study has several limitations. The sample size could not support the evaluation of additional predictor variables, such as neuroimaging features. Our results reflect detection of AF based on 30-day monitoring in an older, predominantly white, Canadian population. Longer monitoring would have yielded more AF and our 2-year AF rate, therefore, is probably an underestimate.5 Most of the study monitor-detected AF was brief and subclinical, and may or may not have been causally related to the index stroke, but nevertheless represents a potentially treatable risk factor for recurrent stroke.7,24,31,32 Increasing age is known to be associated with a greater likelihood of both clinical and subclinical AF,4,33 but we found that age was not a significant predictor when APB count is included in the model. However, we did not study patients aged 1000 APBs/24h)
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Gladstone et al Predicting AF in Cryptogenic Stroke 5 study affirms its value as a prognostic tool for those in sinus rhythm and suggests that it may have value as a triage tool to identify higher-risk patients who may benefit from additional monitoring. Beyond the secondary stroke prevention population, this work also has research implications for predicting AF and targeting AF screening in primary care or special populations (after ablation, cardiac surgery, or apparent transient postoperative AF).36
Appendix Members of EMBRACE Steering Committee or Operations Committee R. Aviv, K. Boyle, J. Blakely, R. Cote, P. Dorian, D.J. Gladstone (Chair), J. Hall, M.K. Kapral, N. Kozlowski, A. Laupacis, M. Mamdani, M. O’Donnell, V. Panzov, K. Sabihuddin, M. Sharma, A. Shuaib, M. Spring, K. Thorpe, H. Vaid.
ECG Adjudication Committee P. Dorian, M. Spring, A. Pinter.
EMBRACE Participating Sites, Site Investigators and Coordinators (sites listed according to patient enrollment; names listed alphabetically) London Health Sciences Centre; London, Ontario: S. Abootalebi, R. Chan, S. Crann, L. Fleming, C. Frank, V. Hachinski, K. Hesser, B.S. Kumar, P. Soros, M. Wright. Sunnybrook Health Sciences Centre; Toronto, Ontario: V. Basile, K. Boyle, D. Gladstone, J. Hopyan, Y. Rajmohan, R. Swartz, H. Vaid, G. Valencia. J. Ween. Foothills Hospital; Calgary, Alberta: H. Aram, P.A. Barber, S. Coutts, A.M. Demchuk, K. Fischer, M.D. Hill, G. Klein, C. Kenney, B. Menon, M. McClelland, A. Russell, K. Ryckborst. P. Stys, E.E. Smith, T.W. Watson. Hamilton Health Sciences Centre; Hamilton, Ontario: S. Chacko, D. Sahlas, J. Sancan. Montreal General Hospital; Montreal, Québec: R. Côté, L. Durcan, E. Ehrensperger, J. Minuk, T. Wein, L. Wadup. Vancouver Hospital and Health Sciences Centre; Vancouver, British Columbia: N. Asdaghi, J. Beckman, N. Esplana, P. Masigan, C. Murphy, E. Tang, P. Teal, K. Villaluna, A. Woolfenden, S. Yip. The Ottawa Hospital; Ottawa, Ontario: M. Bussière, D. Dowlatshahi, M. Sharma, G. Stotts, S. Robert. Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute; London, Ontario: K. Ford, D. Hackam, L. Miners, T. Mabb, J. D. Spence. Grey Nuns Hospital; Edmonton Alberta: B. Buck, T. Griffin-Stead, R. Jassal, M. Siddiqui. Centre Hospitalier Affilié Universitaire de Québec: Hôpital de l’Enfant-Jesus; Québec, Québec: A. Hache, C. Lessard, F. Lebel, A. Mackey, S. Verreault. University Health Network; Toronto, Ontario: C. Astorga, LK Casaubon, M. del Campo, C. Jaigobin, L. Kalman, FL Silver. Vancouver Island Health Authority; Victoria, British Columbia: L. Atkins, K. Coles, A. Penn, R. Sargent, C. Walter. Mackenzie Health Sciences Centre; Edmonton, Alberta: Y. Gable, N. Kadribasic, B. Schwindt, A. Shuaib. St. Michael’s Hospital; Toronto, Ontario: P. Kostyrko, D. Selchen, G. Saposnik. Kingston General Hospital; Kingston, Ontario: P. Christie, A. Jin. Thunder Bay Regional Health Sciences Centre; Thunder
Bay, Ontario: D. Hicklin, D. Howse, E. Edwards, S. Jaspers, F. Sher, S. Stoger. Community neurologists who referred patients for study participation: D. Crisp, A. Dhanani, V. John, M. Levitan, M. Mehdiratta, D. Wong.
Sources of Funding The EMBRACE trial was funded by peer-reviewed operating grants from the Canadian Stroke Network and coordinated at the Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, and Sunnybrook Research Institute, University of Toronto. Dr Gladstone was supported by a Clinician-Scientist Award from the Heart and Stroke Foundation of Ontario, the Bastable-Potts Chair in Stroke Research at Sunnybrook Health Sciences Centre, the Sam Sorbara Charitable Foundation, the Department of Medicine, University of Toronto and the Eaton Scholar Award, the Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, the Bril Chair in Neurology at the University of Toronto, and the Department of Medicine and Hurvitz Brain Sciences Program at Sunnybrook Health Sciences Centre, Toronto.
Disclosures Dr Gladstone is principal investigator of the SCREEN-AF trial, a Canadian Institutes of Health Research (CIHR)-funded Canadian Stroke Prevention Intervention Network project; coprincipal investigator of a peer-reviewed Ontario Centres of Excellence provincial government grant; and reports receiving lecture fees and honoraria for ad hoc consulting or advisory board participation from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer and an advisory board honorarium from Daiichi Sankyo; Dr Dorian, consulting fees from Servier, lecture fees from Bristol-Myers Squibb, Bayer, Pfizer, and Boehringer Ingelheim, and grant support through his institution from Bristol-Myers Squibb, Bayer, Pfizer, Boehringer Ingelheim, and Servier. Dr Healey is principal investigator of the ASSERT-II trial funded by St. Jude Medical and the ARTESiA trial funded by Medtronic. Dr Mamdani reports fees for participating on advisory boards from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Roche, Novartis, Novo Nordisk, and Pfizer. The other authors report no conflicts.
References 1. Kishore A, Vail A, Majid A, Dawson J, Lees KR, Tyrrell PJ, et al. Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Stroke. 2014;45:520–526. doi: 10.1161/STROKEAHA.113.003433. 2. Culebras A, Messé SR, Chaturvedi S, Kase CS, Gronseth G. Summary of evidence-based guideline update: prevention of stroke in nonvalvular atrial fibrillation: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82:716–724. doi: 10.1212/WNL.0000000000000145. 3. Seet RC, Friedman PA, Rabinstein AA. Prolonged rhythm monitoring for the detection of occult paroxysmal atrial fibrillation in ischemic stroke of unknown cause. Circulation. 2011;124:477–486. doi: 10.1161/ CIRCULATIONAHA.111.029801. 4. Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, et al; for the EMBRACE Investigators and Coordinators. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014;370:2467–2477. doi: 10.1056/NEJMoa1311376. 5. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, et al; CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:2478–2486. doi: 10.1056/ NEJMoa1313600. 6. Higgins P, MacFarlane PW, Dawson J, McInnes GT, Langhorne P, Lees KR. Noninvasive cardiac event monitoring to detect atrial fibrillation after ischemic stroke: a randomized, controlled trial. Stroke. 2013;44:2525–2531. doi: 10.1161/STROKEAHA.113.001927. 7. Verma A, Cairns JA, Mitchell LB, Macle L, Stiell IG, Gladstone D, et al; CCS Atrial Fibrillation Guidelines Committee. 2014 focused update of the Canadian Cardiovascular Society Guidelines for the management
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6 Stroke April 2015 of atrial fibrillation. Can J Cardiol. 2014;30:1114–1130. doi: 10.1016/j. cjca.2014.08.001. 8. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160–2236. doi: 10.1161/STR.0000000000000024. 9. Wallmann D, Tüller D, Kucher N, Fuhrer J, Arnold M, Delacretaz E. Frequent atrial premature contractions as a surrogate marker for paroxysmal atrial fibrillation in patients with acute ischaemic stroke. Heart. 2003;89:1247–1248. 10. Wallmann D, Tüller D, Wustmann K, Meier P, Isenegger J, Arnold M, et al. Frequent atrial premature beats predict paroxysmal atrial fibrillation in stroke patients: an opportunity for a new diagnostic strategy. Stroke. 2007;38:2292–2294. doi: 10.1161/STROKEAHA.107.485110. 11. Gaillard N, Deltour S, Vilotijevic B, Hornych A, Crozier S, Leger A, et al. Detection of paroxysmal atrial fibrillation with transtelephonic EKG in TIA or stroke patients. Neurology. 2010;74:1666–1670. doi: 10.1212/ WNL.0b013e3181e0427e. 12. Weber-Krüger M, Gröschel K, Mende M, Seegers J, Lahno R, Haase B, et al. Excessive supraventricular ectopic activity is indicative of paroxysmal atrial fibrillation in patients with cerebral ischemia. PLoS One. 2013;8:e67602. doi: 10.1371/journal.pone.0067602. 13. Kochhäuser S, Dechering DG, Dittrich R, Reinke F, Ritter MA, Ramtin S, et al. Supraventricular premature beats and short atrial runs predict atrial fibrillation in continuously monitored patients with cryptogenic stroke. Stroke. 2014;45:884–886. doi: 10.1161/STROKEAHA.113.003788. 14. Engström G, Hedblad B, Juul-Möller S, Tydén P, Janzon L. Cardiac arrhythmias and stroke: increased risk in men with high frequency of atrial ectopic beats. Stroke. 2000;31:2925–2929. 15. Binici Z, Intzilakis T, Nielsen OW, Køber L, Sajadieh A. Excessive supraventricular ectopic activity and increased risk of atrial fibrillation and stroke. Circulation. 2010;121:1904–1911. doi: 10.1161/ CIRCULATIONAHA.109.874982. 16. Chong BH, Pong V, Lam KF, Liu S, Zuo ML, Lau YF, et al. Frequent premature atrial complexes predict new occurrence of atrial fibrillation and adverse cardiovascular events. Europace. 2012;14:942–947. doi: 10.1093/europace/eur389. 17. Suzuki S, Sagara K, Otsuka T, Kano H, Matsuno S, Takai H, et al. Usefulness of frequent supraventricular extrasystoles and a high CHADS2 score to predict first-time appearance of atrial fibrillation. Am J Cardiol. 2013;111:1602–1607. doi: 10.1016/j.amjcard.2013.01.335. 18. Dewland TA, Vittinghoff E, Mandyam MC, Heckbert SR, Siscovick DS, Stein PK, et al. Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study. Ann Intern Med. 2013;159:721–728. doi: 10.7326/0003-4819-159-11-201312030-00004. 19. Inohara T, Kohsaka S, Okamura T, Watanabe M, Nakamura Y, Higashiyama A, et al; NIPPON DATA 80/90 Research Group. Long-term outcome of healthy participants with atrial premature complex: a 15-year follow-up of the NIPPON DATA 90 cohort. PLoS One. 2013;8:e80853. doi: 10.1371/journal.pone.0080853. 20. Murakoshi N, Xu D, Sairenchi T, Igarashi M, Irie F, Tomizawa T, et al. Prognostic impact of supraventricular premature complexes in community-based health checkups: the Ibaraki Prefectural Health Study [published online ahead of print October 29, 2014]. Eur Heart J. http:// eurheartj.oxfordjournals.org/content/early/2014/10/29/eurheartj.ehu407. Accessed January 9, 2015.
21. Conen D, Adam M, Roche F, Barthelemy JC, Felber Dietrich D, Imboden M, et al. Premature atrial contractions in the general population: frequency and risk factors. Circulation. 2012;126:2302–2308. doi: 10.1161/CIRCULATIONAHA.112.112300. 22. John RM, Stevenson WG. Predicting atrial fibrillation: can we shape the future? Eur Heart J. 2015;36:145–147. doi: 10.1093/eurheartj/ehu432. 23. Kramer DB, Zimetbaum PJ. Ectopy and expectations: can we predict atrial fibrillation, and should we try? Ann Intern Med. 2013;159:787– 788. doi: 10.7326/0003-4819-159-11-201312030-00014. 24. Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, et al; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120–129. doi: 10.1056/ NEJMoa1105575. 25. Glotzer TV, Hellkamp AS, Zimmerman J, Sweeney MO, Yee R, Marinchak R. Atrial high rate episodes detected by pacemaker diagnostics predict death and stroke: report of the atrial diagnostics ancillary study of the mode selection trial (MOST). Circulation. 2003;107:1614– 1619. doi: 10.1161/01.CIR.0000057981.70380.45. 26. Daoud EG, Glotzer TV, Wyse DG, Ezekowitz MD, Hilker C, Koehler J, et al; TRENDS Investigators. Temporal relationship of atrial tachyarrhythmias, cerebrovascular events, and systemic emboli based on stored device data: a subgroup analysis of TRENDS. Heart Rhythm. 2011;8:1416–1423. doi: 10.1016/j.hrthm.2011.04.022. 27. Brambatti M, Connolly SJ, Gold MR, Morillo CA, Capucci A, Muto C, et al; ASSERT Investigators. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation. 2014;129:2094–2099. doi: 10.1161/CIRCULATIONAHA.113.007825. 28. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al; Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13:429–438. doi: 10.1016/S1474-4422(13)70310-7. 29. Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients with Recent Embolic Stroke of Undetermined Source (NAVIGATE-ESUS). https://clinicaltrials.gov/ct2/show/NCT02313909. Accessed January 9, 2015. 30. Dabigatran Etexilate for Secondary Stroke Prevention in Patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS). https:// clinicaltrials.gov/ct2/show/NCT02239120. Accessed January 9, 2015. 31. Martinez C, Katholing A, Freedman SB. Adverse prognosis of incidentally detected ambulatory atrial fibrillation. A cohort study. Thromb Haemost. 2014;112:276–286. doi: 10.1160/TH4-04-0383. 32. Glotzer TV, Ziegler PD. Silent atrial fibrillation as a stroke risk factor and anticoagulation indication. Can J Cardiol. 2013;29:S14–S23. doi: 10.1016/j.cjca.2013.03.023. 33. Wachter R, Weber-Krüger M, Seegers J, Edelmann F, Wohlfahrt J, Wasser K, et al. Age-dependent yield of screening for undetected atrial fibrillation in stroke patients: the Find-AF study. J Neurol. 2013;260:2042– 2045. doi: 10.1007/s00415-013-6935-x. 34. Tsang TS, Barnes ME, Bailey KR, Leibson CL, Montgomery SC, Takemoto Y. Left atrial volume: important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc. 2001;76:467–475. doi: 10.4065/76.5.467. 35. Hoit BD. Left atrial size and function: role in prognosis. J Am Coll Cardiol. 2014;63:493–505. doi: 10.1016/j.jacc.2013.10.055. 36. Gialdini G, Nearing K, Bhave PD, Bonuccelli U, Iadecola C, Healey JS, et al. Perioperative atrial fibrillation and the long-term risk of ischemic stroke. JAMA. 2014;312:616–622. doi: 10.1001/jama.2014.9143.
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Atrial Premature Beats Predict Atrial Fibrillation in Cryptogenic Stroke: Results From the EMBRACE Trial David J. Gladstone, Paul Dorian, Melanie Spring, Val Panzov, Muhammad Mamdani, Jeff S. Healey and Kevin E. Thorpe for the EMBRACE Steering Committee and Investigators Stroke. published online February 19, 2015; Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/early/2015/02/19/STROKEAHA.115.008714
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Table. Predicted Probability of Atrial Fibrillation for a Given Number of Atrial Premature Beats in Patients With Cryptogenic Stroke or Transient Ischemic Attack No. of APBs/24 h on Baseline Holter Monitor
Probability of AF, %*
Lower CI, %
Upper CI, %
0
6.6
3.6
11.6
25
7.2
4.1
12.3
50
7.9
4.6
13.0
75
8.6
5.2
13.7
100
9.3
5.8
14.5
150
10.9
7.2
16.2
200
12.6
8.5
18.1
250
14.4
10.0
20.2
300
16.2
11.3
22.6
350
18.1
12.7
25.1
400
19.9
13.9
27.7
450
21.8
15.1
30.4
500
23.6
16.2
33.1
550
25.4
17.2
35.7
600
27.1
18.2
38.3
650
28.6
19.0
40.7
700
30.1
19.8
42.9
750
31.5
20.6
45.0
800
32.8
21.2
46.9
850
33.9
21.8
48.5
900
35.0
22.4
50.0
950
35.9
22.9
51.3
1000
36.7
23.3
52.5
1100
38.0
24.1
54.2
1200
38.9
24.6
55.4
1300
39.6
25.1
56.1
1400
39.9
25.4
56.5
1500
40.2
25.6
56.7
1600
40.3
25.8
56.7
1700
40.4
26.0
56.6
1800
40.5
26.2
56.6
1900
40.5
26.3
56.6
2000
40.6
26.5
56.5
AF indicates atrial fibrillation; APB, atrial premature beat; and CI, confidence interval. *Defined as ≥1 episodes of AF ≥30 s detected by 30-day ECG monitoring or by any means within 90 days after randomization.
5 or 6 minutes in duration is associated with an increased risk of stroke.24,25 However, many strokes in the pacemaker studies occurred without the development of longer-lasting AF episodes or lacked a temporal association with the AF episodes.26,27 Such observations suggest that brief atrial arrhythmias or frequent APBs may be a stroke risk marker independent of causal mechanisms, such as the development of long-lasting AF. This research has practice implications for secondary stroke prevention. The findings are clinically relevant because 1 in every 4 ischemic stroke patients (and half of TIA patients) are labeled as cryptogenic28 yet a substantial proportion will have undetected and untreated AF.1–3 Prolonged ambulatory
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4 Stroke April 2015 ECG monitoring significantly improves AF detection compared with the usual practice of short-term ECG monitoring, enabling initiation of anticoagulant therapy aimed at preventing recurrent disabling or fatal strokes. New practice guidelines now call for prolonged ECG monitoring to evaluate patients with cryptogenic stroke or TIA, yet the recommended duration of monitoring varies across different guidelines, ranging from ≥1 weeks2 to ≈30 days8 or additional ambulatory monitoring of unspecified duration.7 Because prolonged monitoring can be costly, difficult to access in some regions, and burdensome for some patients, appropriate selection of patients and monitoring strategy is needed. Both noninvasive and minimally invasive monitoring technologies for AF detection are available, and our data suggest that any approach will be most effective, and cost-effective, when applied to patients with frequent APBs. Our findings may be particularly pertinent to patient selection for costly implantable ECG monitors or repeated noninvasive monitoring over time. Patients with excessive APB who do not have AF detected in the short term may benefit from longer-term surveillance for AF. In light of our study results, we propose a tiered approach for detecting subclinical AF in patients being investigated after an embolic stroke or TIA (Figure 2). We suggest 24-hour Holter ECG as an initial screen. If AF is not detected and the patient meets criteria for an embolic stroke of undetermined source28 and is considered an appropriate candidate for additional monitoring and potential anticoagulation (and is not being anticoagulated empirically or randomized in an anticoagulant trial), then we suggest additional noninvasive ECG monitoring using a device capable of continuous recording (mobile outpatient telemetry) or an AF auto-detect loop recorder (note that traditional patient-triggered event recorders that only capture symptomatic episodes will miss subclinical AF). In terms of the target monitoring duration, we suggest 4 weeks of monitoring for patients with frequent APBs; 2 weeks may be reasonable for patients with infrequent APBs given the present analysis and the fact that most AF cases in the EMBRACE trial were detected within the first 2 weeks of monitoring.4 A threshold of >500 APBs/24 h seems to be
a reasonable pragmatic definition for frequent APBs in this population based on the data from this study. For patients with excessive APBs (eg, >1000 APBs/24 h), if AF is not documented after 4 weeks of monitoring then we would consider further monitoring. The role of empiric anticoagulant therapy for patients with frequent APBs, but without documented AF, is currently unknown; randomized trials of anticoagulation for cryptogenic stroke are currently underway and hopefully will evaluate subgroups with frequent APBs.29,30 This study has several limitations. The sample size could not support the evaluation of additional predictor variables, such as neuroimaging features. Our results reflect detection of AF based on 30-day monitoring in an older, predominantly white, Canadian population. Longer monitoring would have yielded more AF and our 2-year AF rate, therefore, is probably an underestimate.5 Most of the study monitor-detected AF was brief and subclinical, and may or may not have been causally related to the index stroke, but nevertheless represents a potentially treatable risk factor for recurrent stroke.7,24,31,32 Increasing age is known to be associated with a greater likelihood of both clinical and subclinical AF,4,33 but we found that age was not a significant predictor when APB count is included in the model. However, we did not study patients aged 1000 APBs/24h)
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Gladstone et al Predicting AF in Cryptogenic Stroke 5 study affirms its value as a prognostic tool for those in sinus rhythm and suggests that it may have value as a triage tool to identify higher-risk patients who may benefit from additional monitoring. Beyond the secondary stroke prevention population, this work also has research implications for predicting AF and targeting AF screening in primary care or special populations (after ablation, cardiac surgery, or apparent transient postoperative AF).36
Appendix Members of EMBRACE Steering Committee or Operations Committee R. Aviv, K. Boyle, J. Blakely, R. Cote, P. Dorian, D.J. Gladstone (Chair), J. Hall, M.K. Kapral, N. Kozlowski, A. Laupacis, M. Mamdani, M. O’Donnell, V. Panzov, K. Sabihuddin, M. Sharma, A. Shuaib, M. Spring, K. Thorpe, H. Vaid.
ECG Adjudication Committee P. Dorian, M. Spring, A. Pinter.
EMBRACE Participating Sites, Site Investigators and Coordinators (sites listed according to patient enrollment; names listed alphabetically) London Health Sciences Centre; London, Ontario: S. Abootalebi, R. Chan, S. Crann, L. Fleming, C. Frank, V. Hachinski, K. Hesser, B.S. Kumar, P. Soros, M. Wright. Sunnybrook Health Sciences Centre; Toronto, Ontario: V. Basile, K. Boyle, D. Gladstone, J. Hopyan, Y. Rajmohan, R. Swartz, H. Vaid, G. Valencia. J. Ween. Foothills Hospital; Calgary, Alberta: H. Aram, P.A. Barber, S. Coutts, A.M. Demchuk, K. Fischer, M.D. Hill, G. Klein, C. Kenney, B. Menon, M. McClelland, A. Russell, K. Ryckborst. P. Stys, E.E. Smith, T.W. Watson. Hamilton Health Sciences Centre; Hamilton, Ontario: S. Chacko, D. Sahlas, J. Sancan. Montreal General Hospital; Montreal, Québec: R. Côté, L. Durcan, E. Ehrensperger, J. Minuk, T. Wein, L. Wadup. Vancouver Hospital and Health Sciences Centre; Vancouver, British Columbia: N. Asdaghi, J. Beckman, N. Esplana, P. Masigan, C. Murphy, E. Tang, P. Teal, K. Villaluna, A. Woolfenden, S. Yip. The Ottawa Hospital; Ottawa, Ontario: M. Bussière, D. Dowlatshahi, M. Sharma, G. Stotts, S. Robert. Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute; London, Ontario: K. Ford, D. Hackam, L. Miners, T. Mabb, J. D. Spence. Grey Nuns Hospital; Edmonton Alberta: B. Buck, T. Griffin-Stead, R. Jassal, M. Siddiqui. Centre Hospitalier Affilié Universitaire de Québec: Hôpital de l’Enfant-Jesus; Québec, Québec: A. Hache, C. Lessard, F. Lebel, A. Mackey, S. Verreault. University Health Network; Toronto, Ontario: C. Astorga, LK Casaubon, M. del Campo, C. Jaigobin, L. Kalman, FL Silver. Vancouver Island Health Authority; Victoria, British Columbia: L. Atkins, K. Coles, A. Penn, R. Sargent, C. Walter. Mackenzie Health Sciences Centre; Edmonton, Alberta: Y. Gable, N. Kadribasic, B. Schwindt, A. Shuaib. St. Michael’s Hospital; Toronto, Ontario: P. Kostyrko, D. Selchen, G. Saposnik. Kingston General Hospital; Kingston, Ontario: P. Christie, A. Jin. Thunder Bay Regional Health Sciences Centre; Thunder
Bay, Ontario: D. Hicklin, D. Howse, E. Edwards, S. Jaspers, F. Sher, S. Stoger. Community neurologists who referred patients for study participation: D. Crisp, A. Dhanani, V. John, M. Levitan, M. Mehdiratta, D. Wong.
Sources of Funding The EMBRACE trial was funded by peer-reviewed operating grants from the Canadian Stroke Network and coordinated at the Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, and Sunnybrook Research Institute, University of Toronto. Dr Gladstone was supported by a Clinician-Scientist Award from the Heart and Stroke Foundation of Ontario, the Bastable-Potts Chair in Stroke Research at Sunnybrook Health Sciences Centre, the Sam Sorbara Charitable Foundation, the Department of Medicine, University of Toronto and the Eaton Scholar Award, the Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, the Bril Chair in Neurology at the University of Toronto, and the Department of Medicine and Hurvitz Brain Sciences Program at Sunnybrook Health Sciences Centre, Toronto.
Disclosures Dr Gladstone is principal investigator of the SCREEN-AF trial, a Canadian Institutes of Health Research (CIHR)-funded Canadian Stroke Prevention Intervention Network project; coprincipal investigator of a peer-reviewed Ontario Centres of Excellence provincial government grant; and reports receiving lecture fees and honoraria for ad hoc consulting or advisory board participation from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer and an advisory board honorarium from Daiichi Sankyo; Dr Dorian, consulting fees from Servier, lecture fees from Bristol-Myers Squibb, Bayer, Pfizer, and Boehringer Ingelheim, and grant support through his institution from Bristol-Myers Squibb, Bayer, Pfizer, Boehringer Ingelheim, and Servier. Dr Healey is principal investigator of the ASSERT-II trial funded by St. Jude Medical and the ARTESiA trial funded by Medtronic. Dr Mamdani reports fees for participating on advisory boards from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Roche, Novartis, Novo Nordisk, and Pfizer. The other authors report no conflicts.
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Atrial Premature Beats Predict Atrial Fibrillation in Cryptogenic Stroke: Results From the EMBRACE Trial David J. Gladstone, Paul Dorian, Melanie Spring, Val Panzov, Muhammad Mamdani, Jeff S. Healey and Kevin E. Thorpe for the EMBRACE Steering Committee and Investigators Stroke. published online February 19, 2015; Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
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