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Canadian Journal of General Internal Medicine
16 Volume 13, Special Issue 1, 2018
About the Author
Jeff Healey is with the Population Health Research Institute, McMaster University, Hamilton, Ontario Canada.
Corresponding Author: Jeff.Healey@phri.ca
How Much Atrial Fibrillation is Enough to
Warrant Oral Anticoagulation: Management of
Subclinical Atrial Fibrillation?
Jeff S. Healey
DOI: 10.22374/cjgim.v13iSP1.314
ABSTRACT
Stroke due to atrial fibrillation (AF) is common, the cause of significant morbidity and
mortality, but is highly preventable with the appropriate use of oral anticoagulants. Recent
advances in implantable and wearable electrocardiographic (ECG) technologies now allow
continuous monitoring of a patients heart rhythm for months or years at a time. Cohort
studies have shown that using such methods, it is very common to find asymptomatic,
short-lasting episodes of subclinical AF. Subclinical AF is also associated with an increased
risk of stroke; however, the risk is lower than with traditional, ECG-detected AF and the
absolute risk appears to depend on the overall burden of AF. There is currently great
uncertainty as to what duration of AF should trigger the use of oral anticoagulation in
specific patient groups. Large randomized trials are underway to help clarify this issue;
however, in the meantime, researchers and guideline committees have proposed some
guidance to assist clinicians.
Atrial Fibrillation Special Issue
Background
The use of oral anticoagulants in patients with atrial fibrillation
(AF) is one of the most effective strategies to prevent stroke.
1,2
As our population ages, the risks of both AF and stroke are
increasing.
3
However; with the advent of safe, and easy-to-use
direct oral anticoagulants,
2
clinicians are increasingly motivated to
detect and treat AF. There is optimism in the medical community
that screening for AF may be an effective way to reduce the rate
of stroke at the population level.
4
Over the last two decades, there has been substantial
development in the tools available to detect AF.
4–6
In addition to
the standard 12-lead electrocardiogram (ECG) Holter monitor
and event recorder, there are now a number of devices ranging
from handheld or smartphone-based tools to intermittently
record a single-lead ECG,
5
to wearable monitors and patches that
can continuously record cardiac activity for several weeks at a
time.
7,8
There are also implantable cardiac monitors, pacemakers
and defibrillators that can automatically detect and record AF
continuously for many years (Figure 1).
6,9,10
The use of specific
technologies does not yet follow any specific algorithm; however,
a more aggressive search for underlying AF using longer-term,
continuous monitoring is often employed in high-risk individuals,
such as patients who have suffered an embolic stroke.
8,9
Although
there is often a strong clinical desire to treat such individuals with
an anticoagulant, it is unclear how much AF must be present to
require such therapy.
Canadian Journal of General Internal Medicine
Volume 13, Special Issue 1, 2018 17
Atrial Fibrillation Defined and Quantified
Atrial fibrillation can be defined as an abnormal heart rhythm
characterized by rapid and irregular beating of the atrium, without
electrocardiographic evidence of organized atrial activity and
with a duration of at least 30 seconds. The last criterion is similar
to that used to distinguish between sustained and non-sustained
ventricular tachycardia, and operationally helps to distinguish
between AF and non-sustained atrial tachycardia. The latter
arrhythmia is extremely common,
10,11
as even 3-consecutive
premature atrial contractions would be considered an atrial
tachycardia. The 30-second minimum duration to define
AF thus eliminates any uncertainty around the classification
of common, short-lasting, irregular atrial arrhythmia. It has
therefore been used as a definition in clinical research to define
the presence of AF.
8
However, it should be recognized that runs
of atrial tachycardia lasting only a few seconds, and even frequent
premature atrial contractions are associated with an increased
risk of stroke; however, this risk is lower than observed for
ECG-detected AF and these transient arrhythmias may simply
be a marker for longer-lasting AF.
12,13
It remains unclear if a
single, 30-second run of AF detected via long-term monitoring
is sufficient to justify lifelong anticoagulation, thus the term
subclinical” AF has been developed to highlight the treatment
uncertainty for brief episodes of AF detected in this fashion.
6,14
As will be shown in this review, the minimum duration of AF
necessary to require the use of oral anticoagulation is a subject
of great controversial.
14
Modern recording devices can detect the presence of AF
even if it is completely asymptomatic and lasting only seconds
at a time.
6,10
However; these devices can also characterize the
frequency, duration and overall burden of AF using a variety
of metrics (Figure 2).
6,7,15
Commonly employed metrics
include the duration of the longest AF episode and the total or
average burden of AF (Figure 2). Different studies evaluating
the relationship between subclinical AF and stroke have used
Figure 1. Subclinical atrial fibrillation detected by an implantable pacemaker.
Figure 2. Sample report from a wearable cardiac
monitor (CardioSTAT).
different metrics,
6,15
and it is unclear if any metric is superior
to any other. Both metrics have potential limitations. Long
episodes can be “partitioned” into smaller episodes as a result
of under-sensing.
16
On the other hand, shorter episodes are
more likely to represent false-AF detection,
16
so frequent, short,
falsely-detected AF could increase the average detected burden
of AF. However; such issues would not have a significant effect
on quantification of patients with very long episodes or high
burden of subclinical AF; which are the patients for which the
association of subclinical AF and stroke is the strongest.
15,17
While monitoring devices can characterize the amount of
AF detected during a particular period of monitoring, one must
also consider the implications of the duration of that monitoring
interval. The detection of 30-seconds of AF at the time of a single,
30-second ECG measurement has much different implications
than finding a single, 30-second episode of subclinical AF at the
time of an annual pacemaker interrogation; the former likely
representing a patient with persistent AF, while the latter reflecting
Jeff S. Healey
Canadian Journal of General Internal Medicine
18 Volume 13, Special Issue 1, 2018
a patient with an extremely low burden of AF. Inaddition to
the characteristics of the AF itself, others have proposed the
incorporation of the patients number of clinical stroke risk
factors when assessing the significance of an episode of AF.
18
The logic is that the minimum duration of AF that would require
treatment is shorter for patients with more stroke risk factors.
18
While intuitively appealing and consistent with how clinicians
manage high-risk individuals, such as patients who have suffered
an embolic stroke,
14
none of these methods has been clearly shown
to identify which individuals with short-lasting subclinical AF
require anticoagulation. However; a great deal of analyses has
been conducted to increase our understanding of this issue, and
several large, intervention studies are now underway.
19,20
The association between AF and stroke was established by
large, epidemiological studies, which ascertained AF by conducting
a standard electrocardiogram one or twice per year
21,22
. These
studies found that the risk of stroke was increased 4- to 5-fold in
patients with AF detected in this manner,
21,22
and that the absolute
risk of stroke is greater among patients with additional stroke risk
factors.
13
However, even with ECG-detected AF, recent research
suggests an association between the burden of AF and the risk of
stroke. In a large cohort of patients with established AF who were
receiving only anti-platelet therapy, it was demonstrated that after
correction for other stroke risk factors, patients with permanent
AF, had about double the absolute of stroke as patients with
paroxysmal AF (i.e., not present on all ECGs during the study),
with patients characterized as persistent AF having an intermediate
risk.
23
However, in this population of individuals who all had
additional stroke risk factors, patients with paroxysmal AF still
had an annual risk of stroke well-above the cutoff for using oral
anticoagulation.
14
Thus, although the characterization of clinical
AF type does not impact the decision to anticoagulate, AF type
does have an impact on a patients absolute risk of stroke. This
association between AF burden and stroke risk is even more
apparent in patients with shorter-lasting episodes of subclinical AF.
Subclinical Atrial Fibrillation: Prevalence and
Association with Stroke
In the 1990s, pacemakers were introduced that allowed detection
and characterization of atrial arrhythmias.
24
However, the
detection of subclinical AF typically did not result in a decision
to anticoagulate patients, given the uncertainty regarding the risk
of stroke in patients with only subclinical AF, and the limitations
of warfarin, the only indicated medication at that time.
25
Two
large prospective cohort studies were conducted to address the
former issue: the TRENDS study
15
and the ASSERT study.
26
The TRENDS study defined patients as having subclinical AF
if AF lasting at least 5 minutes was detected, and demonstrated
a borderline-significant 2.2-fold increase risk of stroke among
patients with subclinical AF, whose maximum average daily
burden in any 30-day periods was over 5.5 hours.
15
This study
did not find any increase in the risk of stroke among patients
with lesser amounts of AF. The ASSERT trial took a different
approach, and characterized patients as having subclinical AF
if any episode lasting 6 or more minutes was detected, and then
categorized patients as having (vs. not having) subclinical AF 3
months after study enrollment. ASSERT detected a statistically
significant increase in stroke risk of 2.5-fold among patients with
subclinical AF. However, the absolute risk of stroke among these
patients was only 1.69% per year; much lower than was predicted
based on patients with clinically detected AF and similar clinical
stroke risk factors.
6
A subsequent, time-dependent analysis of the
ASSERT data was conducted, which demonstrated that most of
the increased risk of stroke among patients with subclinical AF
was concentrated among patients with discrete episodes lasting
at least 24 continuous hours.
17
These patients had about a 5-fold
increase in stroke risk, with absolute stroke risk of approximately
5% per year; quite similar to patients with clinically detected
AF.
13,17
In patients whose longest episode of subclinical AF was
less than 24 hours, no increased risk of stroke was observed
13
.
Thus, although both TRENDS and ASSERT show an association
between subclinical AF as brief as 5-6 minutes in duration and
stroke; both studies also suggest that this risk is confined to
patients with longer episodes or higher burden of AF.
The TRENDS and ASSERT trials also shed light on the precise
temporal relationship between subclinical AF and stroke.
26,27
As
all patients in these studies had continuous ECG monitoring
throughout follow-up, analysis of pacemaker logs could tell how
much AF was present in patients who suffered stroke before the
stroke occurred. The studies had consistent findings that only
15–20% of patients who suffered stroke had any history of AF
in the month prior to the stroke.
26,27
The absence of long-lasting
episodes with close temporal association to stroke is at odds with
the classical teaching that thrombus develops if AF lasts more
than 24 hours and subsequently embolizes to cause stroke. This
raised the possibility that subclinical AF may not only be acting
as a direct causal factor for stroke in these patients, but may also
behave like a vascular risk marker. This observation is in keeping
with the association between frequent PACs and very brief
(20beats) runs of atrial tachycardia and stroke seen in another
cohort study.
12
Finally, a blinded adjudication of all strokes in the
ASSERT trial demonstrated that although embolic-appearing
strokes were more common in patients with subclinical AF, a
similar number of patients suffered lacunar stroke (which is not
felt to be embolic) and smaller numbers suffered stroke from
other mechanisms, such as carotid atherosclerosis.
28
As patients
who develop subclinical AF are older and typically have other
cardiovascular conditions, it should not be surprising that stroke
How Much Atrial Fibrillation is Enough to Warrant Oral Anticoagulation
Canadian Journal of General Internal Medicine
Volume 13, Special Issue 1, 2018 19
may occur due to a variety of mechanism, sometimes in the same
individual. This makes the relationship between subclinical AF and
stroke complex in these individuals, with subclinical AF acting in
a causal way sometimes, and as a vascular risk marker at others.
Prevalence and Implications of Subclinical
AtrialFibrillation
While cohort studies have shown that subclinical AF is present
in 30-50% of patients with pacemakers and defibrillators,
6,15
it is
not was not initially clear if these patients were at a particularly
high risk of subclinical AF, or at a similar risk to other older
patients without pacemakers but with cardiovascular risk factors.
Similarly, long-term monitoring detected subclinical AF in 15–30%
of individuals who suffered cryptogenic stroke.
8,9
As neither of
these landmark studies included a control group, it was unclear if
these patients were at greater risk of subclinical AF, or at similar
risk as individuals of the same age with similar comorbidities.
8,9
Thus, several studies were undertaken (Table 1) to define the
prevalence of subclinical AF in a more general population of older
individuals with cardiovascular conditions.
10,29,30
These studies
were quite consistent in finding a very high background prevalence
of subclinical AF, which was at least as high as in patients with
pacemaker or following cryptogenic stroke, (Table 1).
6,9
Finding subclinical AF of at least 5 minutes duration in
25–35% of older individuals with cardiovascular conditions has
implies that this condition is not exceptional, and that upon
detecting such episodes, clinicians should not automatically
assume that anticoagulation is required. This was highlighted with
the recent results of the NAVIGATE-ESUS trial, which evaluated
the routine use of oral anticoagulation in patients following an
embolic stroke of undetermined source.
31
Despite the fact that
one would expect to detect subclinical AF in more than 30%
of such patients,
9
routine treatment with rivaroxaban did not
prevent stroke.31 However, the COMPASS trial demonstrated that
aspirin plus a low dose of rivaroxaban was associated with a 42%
reduction in stroke compared to aspirin alone among individuals
with cardiac disease but without manifest clinical AF.
32
Thus,
it remains unclear if any population with a high prevalence of
subclinical AF benefits from empiric antithrombotic therapy to
prevent stroke, or if monitoring for subclinical AF and treatment
if AF is detected should be the preferred strategy. Randomized
intervention studies are now ongoing to address this question.
20,33
Two large randomized trials are underway in patients with
pacemakers, implanted defibrillators or cardiac monitors. The
ARTESiA trial will enroll patients with subclinical AF of between
6 minutes and 24 hours duration and randomize to apixaban or
aspirin.
34
The NOAH-AFNET-6 will enroll patients with subclinical
AF of at least 6 minutes, and both trials will require that patients
have additional stroke risk factors.
19,20
Both trials are well underway
with enrollment, and should present results in the next 2–4 years.
Both trials will also examine the effect of anticoagulant treatment
for patients with subclinical AF duration or burden above versus
below the median value of the cohort; to evaluate if there is a
differential treatment effect for individuals with longer episodes.
Clinical Implications
Subclinical AF is very common in older individuals with
cardiovascular and stroke risk factors. Although it is associated with
an increased risk of stroke, this risk is lower than with traditional,
clinical AF and may be dependent on the burden of arrhythmia.
Pending the results of ongoing studies, it seems prudent to offer
oral anticoagulation to individuals with subclinical AF of greater
than 24 hours duration that is detected by long-term continuous
monitoring (i.e., pacemaker, defibrillator or implanted cardiac
monitor). For episodes less than 6 minutes duration there is no
clear association with stroke risk, while for episodes of between
6 minutes and 24 hours, this is association is unclear, but may
be present for patients with greater AF burden.
Study Sample Size Inclusion Rate of AF Detection
ASSERT-II
10
250 Age>65, AND
CHADS-VASc≥2, or OSA, or BMI> 30; AND
LA> 58 mL, or NT-ProBNP > 290 pg/mL
≥ 5 min
34.4% at one year
REVEAL-AF
29
450 Age ≥ 18
CHADS≥3, or CKD/COPD/OSA/CAD
29.3% at 18 months
PREDATE-AF
30
245 Age>18, AND
CHADS-VASc≥2
≥ 6 min
22.4% at 451 days
DANISH LOOP
35
6000 Age > 70
One of HTN, DM, HF or stroke
Pending
AF = atrial fibrillation; BMI = body mass index; CAD = coronary artery disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disorder; DM = diabetes
milletus; HF = heart failure; HTN = hypertension.
Table 1. Cohort Studies to Define Prevalence of Subclinical AF
Jeff S. Healey
Canadian Journal of General Internal Medicine
20 Volume 13, Special Issue 1, 2018
For patients undergoing monitoring of shorter duration,
the corresponding amount of AF that should trigger treatment
is unknown, but presumably proportionally shorter. A metric
such as average daily burden of AF might be useful to make such
evaluation. However, most individuals in whom subclinical AF
is detected by a single-time-point, intermittent method (like a
6-second ECG or 30-second handheld recording) should receive
anticoagulation according to practice guidelines.
14
Finally, in certain
high-risk populations, such as those with a recent embolic stroke
of unknown source, it may be reasonable to have a much lower
threshold to treat subclinical AF, even if trial data are lacking.
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How Much Atrial Fibrillation is Enough to Warrant Oral Anticoagulation