Atrial Fibrillation in Cryptogenic Stroke
Look Harder, Look Longer, But Just Keep Looking
Yee Cheng Lau, MRCP;
Deirdre A. Lane, PhD; Gregory Y.H. Lip, MD
D
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espite atrial fibrillation (AF) being the most common
cardiac arrhythmia, its asymptomatic (and sometimes,
paroxysmal) nature makes subsequent detection and diagnosis
challenging. Ischemic stroke as a result of AF is usually more
severe and results in greater functional loss, and patients with
undetected AF will undoubtedly by at greater risk of recurrent
stroke. The failure to diagnose AF after stroke also relegates
this particularly vulnerable group to using antiplatelet agents,
which are known to be only minimally effective in established
AF, while placing them at similar risk of hemorrhagic complications as with oral anticoagulation therapy.
Current guidelines (both European and American) recommend the use of short-term (usually 24 hours) cardiac monitoring among stroke and patients with transient ischemic attack
for whom occult AF or paroxysmal AF is suspected, and no
other causes for stroke are found.1,2 However, even in selected
high-risk patient group (such as the elderly, cryptogenic stroke
patients, etc), the use of 24-hour ECGs only improve new AF
detection rates to just >10%,3 whereas extended monitoring (>24 hours) with external loop recorder or implantable
device can further increase detection rates to >14%. This
would suggest that longer cardiac monitoring among patients
with cryptogenic stroke is indicated and would have important therapeutic and clinical implications. Therefore, current
guidelines and strategies for AF detection may need to be
reviewed.
Until recently, the evidence-base for protracted cardiac
monitoring among such patients relied on relatively small
cohort studies that lacked a control group and, therefore, it
was not possible to conclude whether extended monitoring
would actually improve AF diagnosis over current practice.
However, 2 randomized controlled trials recently published
in the New England Journal of Medicine have provided compelling evidence in favor of longer ECG monitoring among
patients with cryptogenic stroke.
The first of these, the Cryptogenic Stroke and Underlying
Atrial Fibrillation (CRYSTAL AF) trial,4 included 441 patients
newly diagnosed with cryptogenic stroke, half of whom were
subsequently provided with an implantable cardiac monitor
for continuous monitoring for ≥6 months; the others received
usual care. The second study, the 30-Day Cardiac Event
Monitor Belt for Recording Atrial Fibrillation After a Cerebral
Ischemic Event (EMBRACE) trial,5 involved 572 patients
with cryptogenic stroke and subsequently randomized them to
receive a 30-day event trigger cardiac monitor or 24-hour cardiac monitor. In both trials, patients were extensively investigated before a diagnosis of cryptogenic stroke was made, and
before enrollment and randomization all patients underwent
initial 24-hour ECG monitoring to detect the presence of AF.
In the CRYSTAL AF trial, by the sixth month, new AF was
detected in 8.9% of patients with implantable cardiac monitor
when compared with 1.4% among those receiving standard
follow-up, increasing further to 12.4% by 12 months (versus 2.0% in controls).5 A similar trend was observed in the
EMBRACE trial, in which new AF was detected in 16.1% of
patients who received with 30-day event recorder, versus only
3.2% by 24-hour monitor.
Further analysis of data from CRYSTAL AF trial shows that
the majority of patients (≤79%) who subsequently developed
AF were asymptomatic, and ≤92% of patients had a maximum
of 1-day duration of AF lasting >6 minutes. Extrapolating
from these results, <10 patients would need to be screened
by extended cardiac monitoring to detect 1 new diagnosis of
AF among those with cryptogenic stroke (number needed to
treat=8 in EMBRACE trial), and even more protracted monitoring over time equates to improve detection rate (as shown by
the 6-month versus 12-month results in CRYSTAL AF). Such
detection of AF allows greater numbers of patients to benefit
from oral anticoagulation therapy, with a potential reduction in
recurrent strokes and a reduced morbidity and mortality.
In short, both the CRYSTAL AF and EMBRACE trials
demonstrate the effectiveness of extended cardiac monitoring over contemporary practice of a single 24-hour ECG in
post-ischaemic stroke patients. The rate of AF detections by
implantable cardiac monitor and external cardiac monitor is
in accordance with results from previous studies.3,6 The higher
new AF detection rate in EMBRACE trial may be explained
by the older patient group (>70 years) when compared with
younger patients (age ≈60s) in CRYSTAL AF.
The main limitation of both trials lies in the delay between
the index event of ischemic stroke or transient ischemic attack
and the start of extended cardiac monitoring, varying from 38
days in CRYSTAL AF5 to 75 days in EMBRACE.4 This may
have significant impact because sensitivity of detection of
causative arrhythmia decreases over time, and the increases in
subsequent detection of AF may simply reflect the increased
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the University of Birmingham Centre for Cardiovascular
Sciences, City Hospital, Birmingham, United Kingdom (Y.C.L., D.A.L.,
G.Y.H.L.); and Thrombosis Research Unit, Department of Clinical
Medicine, Aalborg University, Aalborg, Denmark (G.Y.H.L.).
Correspondence to Gregory Y.H. Lip, MD, University of Birmingham
Centre for Cardiovascular Sciences, City Hospital, Birmingham, United
Kingdom. E-mail [email protected]
(Stroke. 2014;45:3184-3185.)
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.006862
3184
Lau et al Atrial Fibrillation in Cryptogenic Stroke 3185
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propensity of AF in the at-risk group of patients. Thus, the
association of AF with stroke versus the causation of index
stroke by undetected paroxysmal AF becomes less clear.
Nonetheless, these trials demonstrate the need for extended
cardiac monitoring, be it 30-day external or implantable
devices, to improve detection of new AF. In addition, both trials
also highlight that most patients who subsequently develop AF
are unaware of it, thus making symptom-driven detection of AF
unreliable. Furthermore, a daily burden of AF of ≥6 minutes was
evident in 92% of new AF detected.4,5 This is important given
that the Asymptomatic AF and Stroke Evaluation in Pacemaker
Patients and the AF Reduction Atrial Pacing Trial (ASSERT)
and Mode Selection Trial (MOST) trials have demonstrated
that subclinical atrial arrhythmias of even this duration are independently associated with increased risk of stroke, death, and
development of permanent AF by upward of 2-fold.7,8
In conclusion, we need to look harder and longer to detect
AF, especially in patients with incident (cryptogenic) stroke.
One might argue that cryptogenic stroke is only a diagnosis of
exclusion, after vigorous efforts to exclude AF by (very?) prolonged monitoring—that is, we need to just keep on looking
for AF. Continuous monitoring would result in newly detected
AF in approximately one third of patients with multiple stroke
risk factors during a year’s follow-up,9 and given that many
such patients are asymptomatic, the development of AF in the
context of associated stroke risk factors would lead to the first
presentation of AF with an acute stroke. Beyond detecting episodes of silent AF, another study suggests that quantification
of AF burden can improve the predictive value of clinical risk
stratification scores.10 Overall, better detection of AF would
allow for the identification of poststroke patients who could
benefit from oral anticoagulation therapy, thus allowing for
the best possible reduction of future recurrent cerebral events
and the associated morbidity and mortality.
Disclosures
Dr Lip has served as a consultant for Bayer, Astellas, Merck, Sanofi,
BMS/Pfizer, Daiichi-Sankyo, Biotronik, Medtronic, Portola, and
Boehringer Ingelheim and has been on the speakers bureau for Bayer,
BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic and
Sanofi Aventis. Dr Lane reports an investigator-initiated educational
grant from Boehringer Ingelheim and honoraria from Boehringer
Ingelheim, Bristol-Myers-Squibb/Pfizerand Bayer for lectures at
educational meetings. Dr Lane is also on the Steering Committee of a
Phase IV clinical trial sponsored by Bristol-Myers-Squibb. Y.C. Lau
reports no conflicts.
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Key Words: Editorials ◼ atrial fibrillation ◼ electrocardiography ◼ stroke
Atrial Fibrillation in Cryptogenic Stroke: Look Harder, Look Longer, But Just Keep
Looking
Yee Cheng Lau, Deirdre A. Lane and Gregory Y.H. Lip
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Stroke. 2014;45:3184-3185; originally published online September 9, 2014;
doi: 10.1161/STROKEAHA.114.006862
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