Opinion Editorial

ARTICLE INFORMATION smokers: 5-year results of the MILD trial. Eur J
Author Affiliations: Department of Medicine,
Division of Cardiology, University of California,
San Francisco; Editor, JAMA Internal Medicine.
Corresponding Author: Rita F. Redberg, MD, MSc,
Department of Medicine, Division of Cardiology,
University of California San Francisco, 505
Parnassus, M1180, San Francisco, CA 94143
(rita.redberg@ucsf.edu).
Published Online: August 13, 2018.
doi:10.1001/jamainternmed.2018.3527
Conflict of Interest Disclosures: Dr Redberg
chaired the April 2014 Medicare Evidence
Development & Coverage Advisory Committee
meeting on lung cancer screening.
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4, 2018]. JAMA. doi:10.1001/jama.2018.6617

Screening for Atrial Fibrillation Comes With Many Snags

John Mandrola, MD; Andrew Foy, MD; Gerald Naccarelli, MD

The association of atrial fibrillation (AF) with an increased risk

of stroke and heart failure makes it a serious health condi-
tion. Many people have AF and do not know it, and its preva-
lence continues to rise in parallel with the growing numbers
of people living with obesity and cardiac risk factors.1,2
These elements, along with the proliferation of devices ca-
pable of monitoring the heart rhythm, have led many physi-
cians to promote screening for AF.3 The hypothesis is that early
detection would allow treatment with anticoagulation, which
would then deliver a net clini-
Box 1. Sample Calculation of NNS for AF With ECG
to Prevent 1 Strokea
• New AF found on initial ECG in 0.5% of screened population
• NNS to diagnose 1 new case of AF, 1/0.005 = 200 people
• Estimated absolute risk reduction from anticoagulation, 2%
• Number needed to treat to prevent 1 stroke, 1/0.02 = 50 people
• NNS to prevent 1 stroke, 200 × 50 = 10 000 people
Abbreviations: AF, atrial fibrillation; ECG, electrocardiography; NNS, number
needed to screen.

cal benefit. Screening, how- a

Related articles at jama.com ever, is not a sure win. Two
pioneers of public health, Drs
Wilson and Jungner, wrote a
half-century ago: “in theory…screening is an admirable method
of combating disease,…but in practice, there are snags.”4(p7)
A systematic review for the US Preventive Services Task
Force (USPSTF) published in the current issue of JAMA,5
conducted in support of the USPSTF Recommendation State-
ment published in the same issue,6 found the current evi-
dence insufficient to assess the balance of benefits and harms
of screening for AF with electrocardiography (ECG) (I state-
ment). We concur with this conclusion and expand on many
of the “snags” of AF screening.
Lack of Efficacy
An AF screening program must do more than pick up the ar-
rhythmia or increase use of anticoagulant drugs; it must de-
liver more benefit than harm in the screened group. Since there
All data are from the STROKESTOP study.7
are no trials that assess clinical outcomes from AF screening
programs, we can only estimate efficacy—by multiplying the
number needed to test to diagnose 1 new case of AF by the
number needed to treat with anticoagulation to prevent 1
stroke.
We used data from STROKESTOP,7 a study of AF screen-
ing using intermittent ECG recordings among individuals aged
75 to 76 years in 2 Swedish regions. In this older-aged cohort,
the number needed to screen (NNS) to prevent 1 stroke equaled
10 000 (Box 1). For comparison, the NNS for abdominal aortic
aneurysm to save 1 disease-specific death is 250; for fecal oc-
cult blood testing screening, the NNS is 625.8 The prevalence
of AF increases with age; thus, the NNS to prevent 1 stroke
would be higher in people younger than 75 years.
A cost analysis is sobering. If an ECG costs $100, society
would pay $1 million (100 × 10 000 NNS) to prevent 1 stroke

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Box 2. Sample Calculation of AF Misdiagnosis at ECG Specificity
of 95%
• ECG specificity, 95%
• Screened population, 1 000 000 people
• AF prevalence, 2%
• Number with AF, 0.2 × 1 000 000 = 20 000 people
• Number without AF, 1 000 000 − 20 000 = 980 000 people
• True negative, 0.95 × 980 000 = 931 000 people reassured
they have no AF
• False positive, 0.05 × 980 000 = 49 000 people falsely
diagnosed with AF
Abbreviations: AF, atrial fibrillation; ECG, electrocardiography.
in persons older than 75 years, and even more in younger per-
sons. Yet the financial burden of AF screening extends well be-
yond the mere cost of the ECG. The costs of medical care
associated with true- and false-positive diagnoses of AF as
well as incidental ECG findings, such as premature ventricu-
lar contractions, nonspecific ST-T wave changes, and brady-
cardia, would surely be substantial.
Harms From AF Screening
Tests for AF, whether by pulse palpation, ECGs, smartphone,
or watch recordings, are burdened by low specificity. Given the
low prevalence of AF in the populations screened, the ability
to correctly identify healthy patients without AF is critical.
In the Screening for AF in the Elderly (SAFE) study, the
specificity of ECG findings from general practitioners or nurses
was approximately 90%.9 False-positive rates of AF detec-
tion in this range or greater have been confirmed with 12-lead
ECGs, 10,11 the iPhone ECG, 12 and artificial intelligence–
enhanced smart-watch detection of AF.13
A test with a specificity of 90% may seem reasonable, but
its 10% rate of false positives can lead to large numbers of false
diagnoses when used to search for a condition with low preva-
lence. Even if screening had a generous 95% specificity, for ev-
ery 1 million people screened, 49 000 people would be wrongly
told they had AF (Box 2). If half of these people are started on
anticoagulation therapy, and the absolute risk increase of ma-
jor bleeding is 1%, then 250 people will experience unneces-
sary iatrogenic bleeding.
In addition to bleeding, other harms from AF screening
include the anxiety of receiving a misdiagnosis of heart dis-
ease, the risks of complications from the resulting additional
diagnostic and therapeutic testing, and treatments related to
incidental findings on ECGs and misdiagnosed AF.
We Do Not Understand AF Well Enough to Screen for It
The second screening criterion of Wilson and Jungner calls for
a solid understanding of the natural history of the condition.4
Atrial fibrillation is neither simple nor well understood.
We partially understand the relationship between AF and
stroke: multiple cohort studies find an association between AF
ARTICLE INFORMATION University College of Medicine, Hershey,
Author Affiliations: Baptist Health Louisville, Pennsylvania (Foy, Naccarelli).
Louisville, Kentucky (Mandrola); Penn State
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Editorial Opinion
and higher stroke risk, and stasis of blood in the atrium dur-
ing AF provides biologic plausibility of a causal relationship.
But as Kamel et al14 have described, AF fails to fulfill many of
the Hill criteria15 for judging causality.
Atrial fibrillation does not fit the temporality criteria of cau-
sation. In the TRENDS study, the majority of patients who ex-
perienced stroke had no AF episodes within the 30 days prior
to their event.16 Atrial fibrillation also fails for specificity, in
that many strokes occurring in patients with AF are caused by
either small- or large-vessel atherosclerosis, not cardiac
emboli.17,18 Atrial fibrillation may not comport with the bio-
logical gradient or dose-response curve; eg, there should be
greater stroke risk from permanent AF than paroxysmal AF.
Some studies show a gradient of risk based on AF type19,20;
others do not.21,22 And if AF caused stroke, the Hill accor-
dance with experimental evidence criteria15 would hold that
rhythm-control medicines that reduce AF should also reduce
stroke risk. They do not.
Finally, and perhaps most importantly, is the false belief that
we know the risk of stroke in patients with untreated AF. A sys-
tematic review of 34 cohort studies and randomized clinical
trials enrolling patients not treated with anticoagulation found
that stroke rates ranged from 0.45% to 9.28% per year.23 This
variability was likely not due to baseline differences in co-
horts: the authors noted manifold variation of stroke rates across
any given CHA2DS2-VASc score. Provocatively, this review also
found that the Danish National Patient Registry, which is cited
in AF treatment guidelines, had the second highest stroke rate,
significantly higher than all but 1 of the other cohorts.
Patients With Screen-Detected AF May Not Benefit From
Anticoagulation as Symptomatic Patients in Older Trials Did
There are no studies of patients treated for screening-detected
AF. In the 1990s, anticoagulation vs no therapy or aspirin for AF
was shown to provide a net clinical benefit in clinical trials that
enrolled patients mostly referred from physician offices.24 Thirty
years later, however, the milieu has changed: stroke rates have
fallen,25,26 acute stroke therapy has improved; and the rise of
AF detection devices has led to much more aggressive search
for AF. Whether the net benefit of anticoagulation in patients
with screen-detected AF remains as it was in the 1990s is a ques-
tion that can only be answered with clinical trials.
Conclusions
If AF screening is adopted in the absence of any outcomes data,
hundreds of thousands, perhaps millions, of people will rightly
and wrongly gain the diagnosis of a cardiac disorder. Before
turning this many people into patients, there should be com-
pelling evidence that the benefits of this label exceed the
harms, and that these benefits can be achieved at an accept-
able cost. We propose and strongly encourage randomized
clinical trials of AF screening before adopting this practice.
Experience tells us how hard it is to stop even a dangerous or
ineffective practice.
Corresponding Author: John Mandrola, MD,
Baptist Health Louisville, 3900 Kresge Way,
Louisville, KY 40207 (john.mandrola@gmail.com).
(Reprinted) JAMA Internal Medicine October 2018 Volume 178, Number 10 1297
 Opinion Editorial
Published Online: August 7, 2018.
doi:10.1001/jamainternmed.2018.4038
Conflict of Interest Disclosures: Dr Naccarelli has
served as consultant/advisory board member for
Janssen, Daiichi Sankyo, GlaxoSmithKline, and Astra
Zeneca and has received research support from
Janssen. No other disclosures are reported.
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