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Paroxysmal tachycardias - Cardiac event recorder implantation after cryptogenic stroke – First in a series

An article from the e-journal of the ESC Council for Cardiology Practice

Atrial fibrillation (AF) is a common risk factor for ischemic stroke. The causal source in approximately 25-30 % of ischemic stroke cannot be detected despite intensive diagnostic workup. In this case the stroke is labelled as cryptogenic stroke. The EMBRACE and CRYSTAL-AF trials have shown that in up to one third of such patients, AF can be detected with extended cardiac monitoring and might be the cause of stroke.

Stroke


Background

Ischemic stroke causes disability, and can lead to death (1). Atrial fibrillation (AF) is a treatable condition that can lead to ischemic stroke (2) and is known to be associated with the highest severity of stroke (3). However, AF, frequently paroxysmal and asymptomatic also often remains undetected in patients with ischemic stroke, especially when conventional monitoring methods - i.e. 12-lead electrocardiography (ECG), 24-hour Holter ECG, or 24-hour continuous telemetry monitoring - are used (4-6). Patients with ischemic stroke caused by AF are moreover under increased risk of recurrent stroke (7). Therefore, current guidelines suggest initiating anticoagulant therapy after ischemic stroke in documented AF (8). It seems obvious that strategies which improve the diagnosis of atrial fibrillation will reduce reoccurrence of stroke. Indeed, several observational studies have shown that there is an increased rate of detection of AF by serial or prolonged (ECG) monitoring in patients with ischemic stroke (5, 9).
Based on this data, two new randomised controlled trials (RCTs) sought to determine the benefit of long term heart rhythm monitoring compared to conventional diagnostic methods (10, 11). The EMBRACE study (30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event; set in Canada) investigated a noninvasive 30 day event-triggered loop recorder from Braemar (ER910AF Cardiac Event Monitor) (11), while  CRYSTAL-AF (CRYptogenic STroke And underLying AF Trial; conducted in Europe, Canada, and the US) used an insertable cardiac monitor (ICM) from Medtronic (REVEAL XT).

 

I - Cryptogenic Stroke and detection of AF

Atherosclerosis, small vessel occlusion, and cardioembolism are the main causes of ischemic stroke. Less commonly, toxins, hypercoagulable disorders, and vasospasm can induce ischemic stroke. Each source carries its own risk of recurrence and prognosis (3, 12). The ASCO (atherosclerosis, small vessel disease, cardiac causes, other uncommon causes) (13) or the TOAST (Trial of ORG 10172 in acute stroke treatment) classification (14) and its enhancement the Causative Classification System for Ischemic Stroke (CCS) (15, 16) (available free for academic use at http://ccs.mgh.harvard.edu) were tools designed for subtyping ischemic stroke. If however, despite intensive diagnostic workup, the source cannot be determined, the stroke is labelled cryptogenic or etiologically undefined. Approximately 25-30 % of all ischemic strokes fall into this category (4, 10, 17).
The AF detection rate with 12-lead ECG ranges between 2 and 5% after ischemic stroke or transient ischemic stroke (TIA) (18), and between 2 and 6% if a 24-hour Holter device is used (19, 20). However, ECG is suspected to have limited sensitivity and limited negative predictive value for AF (6, 21).


2 - CRYSTAL-AF and EMBRACE

A) Similarities

Rationale: Both CRYSTAL-AF and EMBRACE hypothesised that prolonged monitoring of patients with unexplained TIA or stroke increases the detection rate of AF and prescription of anticoagulant therapy on the promise from previous observational studies that ischemic stroke patients had shown an increased detected rate of AF by serial or prolonged ECG monitoring than conventional 24 hour ECG.
Trial design: Both trials are RCTs.
Randomisation: Both RCTs enrolled around 500 patients (447 in CRYSTAL-AF and 572 in EMBRACE) with cryptogenic stroke whose diagnosis was made by exclusion after intensive diagnostic work up. They were randomised in a 1:1 fashion into an intervention and a control group. In the intervention groups AF was mainly asymptomatic at the time of the first diagnosis.
Results (Table I): In both trials, detection rate of AF was significantly higher in the intervention group – whether using the implanted device or the belt.

 

  EMBRACECRYSTAL-AF
Patients enrolled - n  572  447
Mean age in years ±SD  72.5 ± 8.5  61.5 ± 11.3
Median CHADS2Score of all patients  3  3
Hypertension in intervention group - n/n total IG(%)  204/286 (71.3%)  144/221 (65.2%)
Diabetes mellitus in intervention group - n/n total IG(%)  55/286 (19.2%)  34/221 (15.4%)
Monitoring device in intervention group  30 day event-triggered loop recorder from Braemar (ER910AF Cardiac Event Monitor)  insertable cardiac monitor from Medtronic (REVEAL XT)
Invasive insertion of device required  No  Yes
Primary endpoint  newly detected AF lasting >30s within 90 days after randomisation time to first detection of AF (lasting >30s) within 6 months

 

  EMBRACECRYSTAL-AFCRYSTAL-AFCRYSTAL-AF
Follow up - months 3 mth 6 mth 12 mth 36 mth
AF Detection rate        
Intervention group - n/n total IG* 45/280 (16.1%)$ 19/221 (8.9%) § 29/221 (12.4%)# 42/221 (30.0%)&
Control group - n/n total CG * 9/277 (3.2%) 3/220 (1.4%) 4/220 (2.0%) 5/220 (3.0%)
Number needed to screen~ - n 8 14 10 4

Table I. Main similarities and differences concerning patients methods, and results of EMBRACE and CRYSTAL-AF.

Legend:
*Consisting only of patients included in primary analyses.
$ AF detection was significantly increased compared to the EMBRACE control group p<0.001; CI 8.0 – 17.6).
§ AF detection was significantly increased compared to the CRYSTAL-AF control group (p<0.001; HR 6.4; 95% CI 1.9 – 21.7).
# AF detection was significantly increased compared to the CRYSTAL-AF control group (p<0.001; HR 7.3; 95% CI 2.6 – 20.8).
& AF detection was significantly increased compared to the CRYSTAL-AF control group (p<0.001; HR 8.8; 95% CI 3.5 – 22.2).
~Number of patients needed to be evaluated with prolonged monitoring to detect a first episode of AF.
AF: Atrial fibrillation; HR: hazard ratio; CI: confidence interval; IG; intervention group; CG: control group.
YSTAL-AF.


Atrial fibrillation detection rates (primary endpoint) for

  • CRYSTAL-AF groups: implanted device: 8.9% after 6 months, months. Control: 1.4% after 6 months;
  • EMBRACE groups: belt: 16 % after 3 months. Control: 3.2% after 3 months.


Anticoagulant therapy: The mean CHADS2 Score was 3 (5.9% annual stroke risk) in both study populations. Patients in the intervention arms received oral anticoagulant therapy more often than in the conventional monitoring group.

  • CRYSTAL-AF groups: implanted device: 10.1% after 6 months and 14.7% after 12 months. Control: 4.6% after 6 months and 6.0% after 12 months.
  • EMBRACE groups: belt: 18.6% after 3 months. Control: 11.1% after 3 months.

 


B) Differences and limitations

Patient characteristics: mean age and number of patients with hypertension or diabetes in EMBRACE compared to CRYSTAL-AF was higher (71.3% vs. 65.2%; and 19.2% vs. 15.4%; 72.5±8.5 years versus 61.5±11.3 years).

Primary Endpoint: CRYSTAL-AF: time to first detection of AF at 6 months follow up whereas in EMBRACE it was set as newly detected AF or atrial flutter lasting 30 seconds or longer within 90 days after randomisation.

Complications: Of the 208 ICMs implanted in the CRYSTAL-AF population 5 ICMs had to be removed due to infection at the insertion site or pocket erosion.

 

3 - Patient characteristics challenge apparent superiority of non- invasive monitoring in detecting AF

Overall results: By increasing the detection rate of AF in patients with cryptogenic stroke by up to one third, CRYSTAL-AF and EMBRACE showed that long term heart rhythm monitoring is superior to conventional diagnostic methods that include 24 h ECG. These results confirm the findings of observational studies that had demonstrated a high rate of undetected AF in patients after cryptogenic stroke.

Monitoring device: The results of CRYSTAL-AF clearly showed a correlation between the duration of monitoring and an increased detection rate of AF for a period of up to 36 months. The detection rate of first episodes of AF increased from 8.9% after 6 months to 12.4% after 12 months up to 30.0% after 36 months in the intervention group. This seems to underline the need for a monitoring longer than the 3 months investigated in EMBRACE. Concerning extended monitoring a major advantage of an implanted device (CRYSTAL) compared to a noninvasive monitoring by belt (EMBRACE) is the straightforward possibility of extended monitoring without any extra inconvenience for the patient.

Apparent superiority: The trial results would seem to demonstrate superiority of the noninvasive method in detecting AF: In EMBRACE detection of first diagnosed AF was 16.1% within 3 months after randomisation by using a 30-day event-triggered recorder. Detection in the intervention group of CRYSTAL-AF was 8.9% after 6 months.
However, the mean age and the number of patients with hypertension or diabetes in EMBRACE was higher than in CRYSTAL-AF, which might explain lower detection in the intervention group of CRYSTAL-AF compared to that of EMBRACE. This is underpinned by the finding that the detection rates of AF in the control groups are also lower in the population of CRYSTAL-AF than in the population of EMBRACE (1.4% vs. 3.2%).

 

4 - Advantages of ICM

A study comparing noninvasive versus invasive monitoring would be needed to determine superiority of one method over the other. Treating physicians for the time being need to weigh the patient’s individual needs to determine the appropriate monitoring device. Advantages of ICM are that there is a) No need for patient compliance after ICM insertion, and b) Monitoring for several months is easily possible. The greatest disadvantage however is that implantation bears a risk of infection, pocket erosion and wound healing problems. Conversely, this is currently the only advantage of a noninvasive method.

 

5 - Anticoagulation during monitoring

Expert opinion is controversial when it comes to patients with increased risk factors but unproven AF (22, 23). On one hand, without effective anticoagulation these patients are at increased risk of recurrent ischemic stroke. However, effective anticoagulation in patients without yet detected AF may place the patient under an unnecessary increased risk of bleeding. An intense view into each patient’s medical history and especially in terms of history of bleeding and potential risk of bleeding is suggested. If the treating physician decides that early anticoagulation is required, anticoagulation only in combination with long term monitoring with an implantable device along - with prompt interruption of anticoagulation should AF remain undetected - is strongly recommended. This way potential overuse of anticoagulation is limited. However, it has to be mentioned that, if the patient is compliant a noninvasive monitoring system might be a potentially less invasive method.

 

6 - Embolic stroke of undetermined source (ESUS)

To overcome the uncertainty between antiplatelet and anticoagulant medication in the initial phase after the diagnosis of cryptogenic stroke, a new recent construct called embolic stroke of undetermined source (ESUS) has been offered for use (17). Patients with ESUS are a subgroup of patients with cryptogenic stroke. ESUS refers to patients with cryptogenic stroke who have undergone sufficient diagnostic assessment to rule out major risk cardioembolic sources, occlusive atherosclerosis, and lacunar stroke. The idea is that ESUS patients have a causal mechanism that is mostly embolism of unestablished source (17). Based on the ESUS construct a RCT comparing rivaroxaban and acetylsalicylic acid was initiated in December ‘14. This new trial may provide the physicians with the evidence based results necessary for determining whether anticoagulation is necessary in these patients or not.

 

7 - Anticoagulation after prolonged monitoring

In case of non-cardioembolic stroke, the current joint guidelines for the early management of patients with acute ischemic stroke of the American Heart Association (AHA) and the American Stroke Association (ASA) recommended antiplatelet therapy (2). In case of documented AF as plausible cause of ischemic stroke, the risk of recurrence of ischemic stroke is high (24). Furthermore, the stroke risk was found to be similarly high independently of whether AF was paroxysmal or sustained (25, 26). Additionally, investigating pacemaker patients have revealed that subclinical atrial fibrillation predicts the onset of clinically evident AF and recurrence of stroke (4, 27). Current guidelines therefore recommend initiating anticoagulant therapy after ischemic stroke when AF is documented.

 

Conclusions

Current AHA and ASA guidelines recommend performing an ECG in patients with cryptogenic stroke for 24 hours (or more – with no further detail). EMBRACE and CRYSTAL-AF showed that extended monitoring increased the detection rate of AF in patients with cryptogenic stroke by up to one third. We recommend considering cardiac event recorder implantation to ensure straightforward, objective cardiac monitoring for several months independently of patients compliance and motivation, or at least considering the use of a prolonged noninvasive monitoring method in patients with cryptogenic stroke, especially in patients who are known to be at increased risk of AF.




References


  1. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=24352519 Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Circulation. 2014;129(3):e28-e292.
  2. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. http://stroke.ahajournals.org/cgi/pmidlookup?view=long&pmid=23370205 Jauch EC, Saver JL, Adams HP, Jr., Bruno A, Connors JJ, Demaerschalk BM, et al. Stroke. 2013;44(3):870-947.
  3. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. http://stroke.ahajournals.org/cgi/pmidlookup?view=long&pmid=11692017 Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, et al. Stroke. 2001;32(11):2559-66.
  4. Subclinical atrial fibrillation and the risk of stroke. http://www.nejm.org/doi/full/10.1056/NEJMoa1105575 Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, et al. N Engl J Med. 2012;366(2):120-9.
  5. Prolonged rhythm monitoring for the detection of occult paroxysmal atrial fibrillation in ischemic stroke of unknown cause. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=21788600 Seet RC, Friedman PA, Rabinstein AA. Circulation. 2011;124(4):477-86.
  6. Comparison of continuous versus intermittent monitoring of atrial arrhythmias. http://www.ncbi.nlm.nih.gov/pubmed/17161787 Ziegler PD, Koehler JL, Mehra R. Heart Rhythm. 2006;3(12):1445-52.
  7. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. http://www.ncbi.nlm.nih.gov/pubmed/17679673 Neurology. 2007;69(6):546-54.
  8. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. http://www.escardio.org/GUIDELINES-SURVEYS/ESC-GUIDELINES/Pages/atrial-fibrillation.aspx Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. Eur Heart J. 2012;33(21):2719-47.
  9. Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. http://stroke.ahajournals.org/cgi/pmidlookup?view=long&pmid=24385275 Kishore A, Vail A, Majid A, Dawson J, Lees KR, Tyrrell PJ, et al. Stroke. 2014;45(2):520-6.
  10. Cryptogenic stroke and underlying atrial fibrillation. http://www.nejm.org/doi/full/10.1056/NEJMoa1313600 Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, et al. N Engl J Med. 2014;370(26):2478-86.
  11. Atrial fibrillation in patients with cryptogenic stroke. http://www.nejm.org/doi/full/10.1056/NEJMoa1311376 Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, et al. N Engl J Med. 2014;370(26):2467-77.
  12. Cryptogenic stroke-the appropriate diagnostic evaluation. http://www.ncbi.nlm.nih.gov/pubmed/24352977 Amin H, Greer DM. Curr Treat Options Cardiovasc Med. 2014;16(1):280.
  13. Comparison of the new ASCO classification with the TOAST classification in a population with acute ischemic stroke. http://www.ncbi.nlm.nih.gov/pubmed/22146904  Wolf ME, Sauer T, Alonso A, Hennerici MG. J Neurol. 2012;259(7):1284-9.
  14. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. http://stroke.ahajournals.org/content/24/1/35.long  Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Stroke. 1993;24(1):35-41.
  15. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. http://stroke.ahajournals.org/content/38/11/2979 .long Ay H, Benner T, Arsava EM, Furie KL, Singhal AB, Jensen MB, et al. Stroke. 2007;38(11):2979-84.
  16. An evidence-based causative classification system for acute ischemic stroke. http://www.ncbi.nlm.nih.gov/pubmed/16240340  Ay H, Furie KL, Singhal A, Smith WS, Sorensen AG, Koroshetz WJ. Ann Neurol. 2005;58(5):688-97.
  17. Embolic strokes of undetermined source: the case for a new clinical construct. http://www.ncbi.nlm.nih.gov/pubmed/24646875  Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O'Donnell MJ, et al. Lancet Neurol. 2014;13(4):429-38.
  18. Noninvasive cardiac monitoring for detecting paroxysmal atrial fibrillation or flutter after acute ischemic stroke: a systematic review. Liao J, Khalid Z, Scallan C, Morillo C, O'Donnell M. http://stroke.ahajournals.org/cgi/pmidlookup?view=long&pmid=17901394  Stroke. 2007;38(11):2935-40.
  19. Detection of atrial fibrillation with concurrent holter monitoring and continuous cardiac telemetry following ischemic stroke and transient ischemic attack. Lazzaro MA, Krishnan K, Prabhakaran S. http://www.ncbi.nlm.nih.gov/pubmed/20656504  J Stroke Cerebrovasc Dis. 2012;21(2):89-93.
  20. Holter monitoring in the diagnosis of stroke mechanism. http://www.ncbi.nlm.nih.gov/pubmed/15228390  Shafqat S, Kelly PJ, Furie KL. Intern Med J. 2004;34(6):305-9.
  21. Twenty-four-hour holter monitor follow-up does not provide accurate heart rhythm status after surgical atrial fibrillation ablation therapy: up to 12 months experience with a novel permanently implantable heart rhythm monitor device. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=19752365 Hanke T, Charitos EI, Stierle U, Karluss A, Kraatz E, Graf B, et al. Circulation. 2009;120(11 Suppl):S177-84.
  22. Stroke patients with suspected atrial fibrillation should be started on anticoagulation pending the results of long-term cardiac monitoring. http://www.ncbi.nlm.nih.gov/pubmed/23238863 Diener HC. Stroke. 2013;44(1):298-9.
  23. Stroke patients with suspected atrial fibrillation should NOT be started on anticoagulation WHILE AWAITING the results of long-term cardiac monitoring. http://www.ncbi.nlm.nih.gov/pubmed/23238859 Katsnelson M, Sacco RL. Stroke. 2013;44(1):300-1.
  24. Detection of atrial fibrillation after stroke and the risk of recurrent stroke. http://www.ncbi.nlm.nih.gov/pubmed/21546265 Kamel H, Johnson DR, Hegde M, Go AS, Sidney S, Sorel M, et al. J Stroke Cerebrovasc Dis. 2012;21(8):726-31.
  25. Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W Substudy. http://www.ncbi.nlm.nih.gov/pubmed/18036454 Hohnloser SH, Pajitnev D, Pogue J, Healey JS, Pfeffer MA, Yusuf S, et al. J Am Coll Cardiol. 2007;50(22):2156-61.
  26. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. http://www.ncbi.nlm.nih.gov/pubmed/10636278 Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. J Am Coll Cardiol. 2000;35(1):183-7.
  27. Silent atrial fibrillation as a stroke risk factor and anticoagulation indication. http://www.ncbi.nlm.nih.gov/pubmed/23790594 Glotzer TV, Ziegler PD. Can J Cardiol. 2013;29(7 Suppl):S14-23.

 

Notes to editor


Boris Dickmann drafted the manuscript, critically revised the manuscript for important intellectual content, and provided administrative support. Andreas Jähnert and Wolff Schmiegel critically revised the manuscript for important intellectual content, and provided administrative support. All authors reviewed and edited the entire manuscript and approved the final version of the manuscript.

Authors’ disclosures: None declared.

Other resources:
E-journal articles (2013)
Assessing stroke  in patients with atrial fibrillation.
Review (2011) of the ACC/AGA 2011 guidelines on stroke.
Secondary prevention of patients with non-embolic stroke (2014)
Atrial Fibrillation (Management of) 2010 and Focused Update (2012)
A recorded webinar of anticoagulants and invasive approaches in Stroke Prevention in Atrial Fibrillation

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.