Editorial Opinion

13. Casaclang-Verzosa G, Gersh BJ, Tsang TS. stroke in adults with paroxysmal atrial fibrillation: and the Heart Rhythm Society. Circulation. 2014;
Structural and functional remodeling of the KP-RHYTHM Study [published online 130(23):e199-e267. doi:10.1161/CIR
the left atrium: clinical and therapeutic May 16, 2018]. JAMA Cardiol. .0000000000000041
implications for atrial fibrillation. J Am Coll 15. January CT, Wann LS, Alpert JS, et al; 16. Lopes RD, Alings M, Connolly SJ, et al. Rationale
Cardiol. 2008;51(1):1-11. doi:10.1016/j.jacc ACC/AHA Task Force Members. 2014 and design of the Apixaban for the Reduction of
.2007.09.026 AHA/ACC/HRS guideline for the management of Thrombo-Embolism in Patients With
14. Go AS, Reynolds K, Yang J, et al. Association of patients with atrial fibrillation: a report of the Device-Detected Sub-Clinical Atrial Fibrillation
burden of atrial fibrillation with risk of ischemic American College of Cardiology/American Heart (ARTESiA) trial. Am Heart J. 2017;189:137-145.
Association Task Force on practice guidelines doi:10.1016/j.ahj.2017.04.008

Intravenous Alteplase for Mild Nondisabling

Acute Ischemic Stroke
A Bridge Too Far?
William J. Powers, MD

Treatment of patients with stroke has changed substantially
during the past 25 years. In 1995, the NINDS rt-PA trial
showed among selected patients with acute ischemic stroke
who were treated with intra-
venous alteplase within 3
Related article page 156 hours of known stroke onset
or last known well time had
reduced disability at 3 months.1 In 2008, the ECASS III trial
demonstrated benefit of intravenous alteplase among
selected patients treated up to 4.5 hours after known stroke
onset or last known well time.2 Benefit from alteplase treat-
ment occurred despite higher rates of symptomatic intracra-
nial hemorrhage compared with placebo (6.4% vs 0.6% in
the NINDS rt-PA trial; 2.4% vs 0.3% in ECASS III).1,2 More
recently, thrombectomy has been shown to substantially
reduce morbidity in selected patients with ischemic stroke.3
Experience with intravenous alteplase in acute ischemic
stroke has defined many clinical situations in which the
overall benefit of reducing disability with treatment out-
weighs the risk of hemorrhage.4 However, situations remain
for which data are insufficient. One involves acute ischemic
stroke with initially mild neurologic deficits. Many of these
patients who are not treated with alteplase do well, but up
to 15% may experience early worsening of signs and symp-
toms and approximately 30% have some degree of disability
at 3 months.5,6 For such patients who are treated with intra-
venous alteplase, the risk of symptomatic intracranial hem-
orrhage is still 2% to 3%.7 A meta-analysis of 9 trials of intra-
venous alteplase in acute ischemic stroke showed a
significant reduction in functional disability at 3 months for
patients with mild stroke.8 These patients were not further
categorized by whether their acute neurologic deficits were
disabling. Current guidelines from the American Heart
Association/American Stroke Association (AHA/ASA) recom-
mend intravenous alteplase administration within 3 hours
for patients with mild but disabling stroke symptoms but
are indecisive about those with nondisabling symptoms.4
It is this latter group of patients that has posed a persistent
therapeutic dilemma: treat because they might get worse
or do not treat because of the risk of symptomatic intracra-
nial hemorrhage?
In this issue of JAMA, Khatri and colleagues report the
results of the PRISMS trial of intravenous alteplase vs aspirin
administered within 3 hours of known stroke onset or last
known well time for patients with acute ischemic stroke and
initially mild, nondisabling deficits.9 A National Institutes of
Health Stroke Scale (NIHSS) score of 5 or lower was used to
define mild stroke. The NIHSS is an 11-item scale with scores
ranging from 0 to 42 and higher scores indicating worse neu-
rologic deficits.10 Patients can achieve a score of 5 or lower
with different neurologic deficits and constitute a heteroge-
neous group. For example, the following deficits would all
score 5 or lower: complete paralysis of 1 leg (score of 4), com-
plete aphasia (score of 3), mild arm weakness with mild sen-
sory loss (score of 2), mild dysarthria (score of 1), and double
vision (score of 0). Thus, PRISMS eligibility also required that
deficits be judged “not clearly disabling”; ie, that they would
not prevent a patient from performing basic activities of daily
living (bathing, ambulating, toileting, hygiene, and eating)
or returning to work. The primary end point was favorable
functional outcome—a modified Rankin Scale (mRS) score of
0 or 1—at 90 days. An mRS score of 0 indicates no symptoms;
an mRS score of 1 indicates no significant disability despite
symptoms and that a patient is able to carry out all usual
duties and activities.11
PRISMS was designed to detect a 9% absolute difference
in the proportion of participants with favorable outcome with
80% power. The study was terminated early by the sponsor
without unblinding because of poor recruitment when one-
third of the projected 948 study participants had been en-
rolled. Among the 313 patients in PRISMS, 78% who received
alteplase vs 81% who received aspirin achieved an mRS score
of 0 or 1 at 90 days (adjusted risk difference, −1.1%; 95% CI,
−9.4% to 7.3%).9
These numerically similar outcomes between the 2 groups
are quite a departure from the 10% difference observed in

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 Opinion Editorial

the meta-analysis8 and the 9% difference postulated by the
investigators. What might explain this discrepancy? The pre-
mature termination of the trial resulted in a sample size with
approximately 30% power under the original trial assump-
tions. To achieve the postulated 9% benefit, the remaining
635 participants would have to have shown a 15% difference
in favor of alteplase. In a post hoc analysis conducted by the
investigators, the probability that alteplase therapy would
improve favorable outcomes to any degree was 23%, and the
probability that it would improve favorable outcomes by
more than 6% was less than 2%. Based on post hoc analysis,
it is unlikely that the premature termination of the trial
was responsible for the failure to demonstrate a benefit of
alteplase. The symptomatic intracranial hemorrhage rate of
3.2% (5/157) in the alteplase group was similar to previous
data from patients with mild stroke and also was not suffi-
cient to explain a lack of alteplase benefit.7,12
However, the trial design created a situation that made it
very difficult for PRISMS to show treatment benefit. The eli-
gibility criterion of “not clearly disabling” is essentially the
same as the definition of the favorable outcome of an mRS
score of 1. Thus, at enrollment, all patients met the criterion
for success. To show a benefit, alteplase treatment would
have to prevent patients from worsening, not improve recov-
ery. This may have been a bridge too far. In the original
NINDS rt-PA trial, intravenous alteplase did not affect early
worsening of neurologic function, and 3-month outcome was
improved only among patients who did show early
worsening.13 Similar drug effects in the PRISMS trial would
lead to a neutral result.
The PRISMS trial helps define the role of intravenous
alteplase in the management of acute ischemic stroke. Even
with early study termination and resultant wide 95% confi-
dence intervals, the excellent outcome in the aspirin group
and the numerically similar outcomes between the 2 groups
render it unlikely that intravenous alteplase treatment mean-
ingfully improves functional outcome in patients with initial
NIHSS scores of 5 or lower with nondisabling deficits. How-
ever, these conclusions do not apply to all patients with mild
stroke. Post hoc analyses of other studies have suggested that
intravenous alteplase treatment was associated with reduced
disability at 3 to 6 months for subgroups of patients with ini-
tial NIHSS scores of 4 or lower, 5 or lower, and 6 or lower who
were not further categorized by whether their baseline neu-
rologic deficits were disabling.8,14,15 The WAKE-UP trial com-
pared intravenous alteplase with placebo among patients
with unknown time of stroke onset, primarily those whose
stroke was discovered on awakening, who could be treated
within 4.5 hours of symptom recognition, and who also met
certain neuroimaging criteria. Most strokes were mild, with a
median NIHSS score of 6 (interquartile range, 4-9). The pri-
mary end point of an mRS score of 0 or 1 at 90 days was
achieved in 53.3% of the alteplase group and in 41.8% of the
placebo group (P = .02).16 Current AHA/ASA guidelines rec-
ommend intravenous alteplase for otherwise eligible patients
with mild but disabling acute ischemic stroke.4
Until 2015, intravenous alteplase was the only effective
treatment for acute ischemic stroke of any severity. In 2015, 5
randomized clinical trials demonstrated benefit of intra-
arterial mechanical thrombectomy performed within 6 hours
with stent retrievers in patients with acute ischemic stroke
and large vessel occlusions of large intracranial arteries, pri-
marily internal carotid artery and proximal middle cerebral
artery. Mechanical thrombectomy almost doubled the per-
centage of patients who recovered to functional indepen-
dence at 3 months (adjusted rate ratio, 1.73; 95% CI, 1.43-
2.09; P < .0001).17 The role of mechanical thrombectomy for
patients with mild stroke is unclear. Only 2 of the 5 trials
enrolled patients with NIHSS scores lower than 6.4 Large ves-
sel occlusions of the intracranial internal carotid arteries or
proximal middle cerebral arteries occur in only 10% of
patients with NIHSS scores lower than 6.18 Pooled data from
the 5 trials showed no significant benefit for the 177 patients
with NIHSS scores of 10 or lower (common odds ratio, 1.67;
95% CI, 0.80-3.50) but also showed no significant interaction
of baseline NIHSS with treatment effect (P = .45).17
Current AHA/ASA guidelines recommend mechanical
thrombectomy performed within 6 hours of symptom onset
with a stent retriever for patients with causative occlusion of
the internal carotid artery or proximal middle cerebral artery
and NIHSS scores of 6 or higher who meet additional criteria,
but the guidelines note that the benefit for patients with
NIHSS scores lower than 6 is uncertain.4 The findings from
the report by Khatri et al provide more certain, but not defini-
tive, evidence suggesting that intravenous alteplase appears
unlikely to meaningfully improve functional outcome in
patients with mild ischemic stroke with initial NIHSS scores
of 5 or lower and with nondisabling deficits, and that for
these patients, treatment with aspirin along with close moni-
toring may be an appropriate course of action.

ARTICLE INFORMATION REFERENCES quantum leap in stroke systems of care? JAMA.

Author Affiliation: School of Medicine, University 1. National Institute of Neurological Disorders and 2016;316(12):1265-1266. doi:10.1001/jama.2016
of North Carolina at Chapel Hill. Stroke rt-PA Stroke Study Group. Tissue .12266

Corresponding Author: William J. Powers, MD,
Department of Neurology, University of
North Carolina at Chapel Hill, 170 Manning Dr,
Room 2133, PO Box 7025, Chapel Hill, NC 27599
(powersw@neurology.unc.edu).
Conflict of Interest Disclosures: The author has
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
plasminogen activator for acute ischemic stroke.
N Engl J Med. 1995;333(24):1581-1587. doi:10.1056
/NEJM199512143332401
2. Hacke W, Kaste M, Bluhmki E, et al; ECASS
Investigators. Thrombolysis with alteplase 3 to 4.5
hours after acute ischemic stroke. N Engl J Med.
2008;359(13):1317-1329. doi:10.1056
/NEJMoa0804656
3. Warach S, Johnston SC. Endovascular
thrombectomy for ischemic stroke: the second
4. Powers WJ, Rabinstein AA, Ackerson T, et al;
American Heart Association Stroke Council. 2018
guidelines for the early management of patients
with acute ischemic stroke: a guideline for
healthcare professionals from the American Heart
Association/American Stroke Association. Stroke.
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.0000000000000158
5. Smith EE, Abdullah AR, Petkovska I, Rosenthal E,
Koroshetz WJ, Schwamm LH. Poor outcomes in
patients who do not receive intravenous tissue

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 Editorial Opinion

plasminogen activator because of mild or improving
ischemic stroke. Stroke. 2005;36(11):2497-2499.
doi:10.1161/01.STR.0000185798.78817.f3
6. Khatri P, Conaway MR, Johnston KC; Acute
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7. Whiteley WN, Emberson J, Lees KR, et al; Stroke
Thrombolysis Trialists’ Collaboration. Risk of
intracerebral haemorrhage with alteplase after
acute ischaemic stroke: a secondary analysis of an
individual patient data meta-analysis. Lancet Neurol.
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30076-X
8. Emberson J, Lees KR, Lyden P, et al; Stroke
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of treatment delay, age, and stroke severity on the
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for acute ischaemic stroke: a meta-analysis of
individual patient data from randomised trials. Lancet.
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6736(14)60584-5
9. Khatri P, Kleindorfer DO, Devlin T, et al. Effect of
alteplase vs aspirin on functional outcome for
patients with acute ischemic stroke and minor
nondisabling neurologic deficits: the PRISMS
randomized clinical trial [published July 10, 2018].
JAMA. doi:10.1001/jama.2018.8496
10. Lyden P, Brott T, Tilley B, et al; NINDS TPA
Stroke Study Group. Improved reliability
of the NIH Stroke Scale using video training.
Stroke. 1994;25(11):2220-2226. doi:10.1161/01.STR
.25.11.2220
11. Rankin J. Cerebral vascular accidents in
patients over the age of 60, II: prognosis. Scott Med
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12. Romano JG, Smith EE, Liang L, et al. Outcomes
in mild acute ischemic stroke treated with
intravenous thrombolysis: a retrospective analysis
of the Get With the Guidelines–Stroke Registry.
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13. Grotta JC, Welch KM, Fagan SC, et al. Clinical
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14. Khatri P, Tayama D, Cohen G, et al; PRISMS and
IST-3 Collaborative Groups. Effect of intravenous
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Stroke Trial-3: post hoc analysis. Stroke. 2015;46(8):
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15. You S, Saxena A, Wang X, et al. Efficacy and
safety of intravenous recombinant tissue
plasminogen activator in mild ischaemic stroke:
a meta-analysis. Stroke Vasc Neurol. 2018;3(1):22-27.
doi:10.1136/svn-2017-000106
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time of onset [published online May 16, 2018].
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HERMES Collaborators. Endovascular
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a meta-analysis of individual patient data from five
randomised trials. Lancet. 2016;387(10029):1723-
1731. doi:10.1016/S0140-6736(16)00163-X
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do not reliably identify acute ischemic stroke
patients with large-artery occlusion. Stroke. 2016;
47(6):1466-1472. doi:10.1161/STROKEAHA.116.013144

Ankle-Brachial Index Screening and Improving

Peripheral Artery Disease Detection and Outcomes
Mary M. McDermott, MD; Michael H. Criqui, MD, MPH

Lower extremity peripheral artery disease (PAD) affects an es-
timated 8.5 million adults in the United States and 202 mil-
lion adults worldwide.1,2 PAD consists of atherosclerosis of the
lower extremity arteries, re-
sulting in inadequate oxygen
Related articles pages 177 and
supply to lower extremity
184
muscles during walking activ-
ity. People with PAD typically walk only 1 to 3 blocks before
having to stop and rest because of ischemic leg symptoms. PAD
is also a marker for the presence of atherosclerotic disease in
the coronary and cerebrovascular arteries. Consistent with this
phenomenon, people with PAD have higher rates of acute coro-
nary events, ischemic stroke, and mortality, compared with
people without PAD.
Treatment goals for people with PAD consist of improv-
ing functional performance and preventing coronary events
and stroke.2 Supervised treadmill exercise and some home-
based exercise interventions improve walking performance in
PAD.2,3 In randomized clinical trials, antithrombotic therapy
and statins prevent cardiovascular events in people with symp-
tomatic PAD.2 Diagnosing PAD and implementing effective
therapies has the potential to improve debilitating walking im-
pairment and prevent cardiovascular events in millions of
people with PAD.
Typically, PAD can be diagnosed relatively easily and
noninvasively with the ankle-brachial index (ABI), a ratio of
lower to upper extremity Doppler recorded systolic pres-
sures. In the absence of PAD, arterial pressures increase with
greater distance from the heart, because of increased arterial
impedance as distal arteries taper. Therefore, systolic pres-
sures are normally higher at the ankle than in the brachial
arteries, and people without PAD have an ABI of 1.10 to 1.40.
An ABI less than 0.90 is approximately 72% sensitive and
nearly 99% specific for angiographically significant PAD.4
People with ABI less than 0.90 have significantly higher rates
of cardiovascular events, cardiovascular mortality, and all-
cause mortality compared with those with a normal ABI,
independently of cardiovascular disease risk factors.5 An ABI
less than 0.90 is also associated with greater functional
impairment and higher rates of functional decline compared
with normal ABI values.6,7
Intermittent claudication is the most classic symptom of
PAD and consists of exertional calf pain that does not begin
at rest and that resolves within 10 minutes of rest. Yet many
people with PAD report leg symptoms that are not consis-
tent with classic intermittent claudication.6-8 Others report
no exertional leg symptoms and are considered asymptom-
atic. Among people with an ABI less than 0.90, the preva-
lence of asymptomatic PAD varies from 20% to 60%, with
lower prevalences of asymptomatic PAD in medical center
settings and higher prevalences observed in communities
outside of medical centers.8 Among people with an ABI less

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