Research

JAMA | Original Investigation

Effect of Alteplase vs Aspirin on Functional Outcome

for Patients With Acute Ischemic Stroke
and Minor Nondisabling Neurologic Deficits
The PRISMS Randomized Clinical Trial
Pooja Khatri, MD, MSc; Dawn O. Kleindorfer, MD; Thomas Devlin, MD; Robert N. Sawyer Jr, MD; Matthew Starr, MD; Jennifer Mejilla, DO;
Joseph Broderick, MD; Anjan Chatterjee, MD; Edward C. Jauch, MD, MS; Steven R. Levine, MD; Jose G. Romano, MD; Jeffrey L. Saver, MD;
Achala Vagal, MD, MS; Barbara Purdon, PhD; Jenny Devenport, PhD; Andrey Pavlov, PhD; Sharon D. Yeatts, PhD; for the PRISMS Investigators

Visual Abstract
IMPORTANCE More than half of patients with acute ischemic stroke have minor neurologic Editorial page 141
deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation.
Although prior major trials of alteplase included patients with low NIHSS scores, few without Supplemental content

clearly disabling deficits were enrolled. Related article at

jamaneurology.com
OBJECTIVE To evaluate the efficacy and safety of alteplase in patients with NIHSS scores
of 0 to 5 whose deficits are not clearly disabling.

DESIGN, SETTING, AND PARTICIPANTS The PRISMS trial was designed as a 948-patient,
phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase
compared with aspirin for emergent stroke at 75 stroke hospital networks in the United
States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS
and judged not clearly disabling and in whom study treatment could be initiated within 3
hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with
final follow-up on March 22, 2017.

INTERVENTIONS Participants were randomized to receive intravenous alteplase at the

standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with
intravenous placebo (n = 157).

MAIN OUTCOMES AND MEASURES The primary outcome was the difference in favorable
functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via
Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from
onset to treatment. Because of early termination of the trial, prior to unblinding or interim
analyses, the plan was revised to examine the risk difference of the primary outcome by a
linear model adjusted for the same factors. The primary safety end point was symptomatic
intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment.

RESULTS Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years;
144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to
treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients
(78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable
outcome (adjusted risk difference, −1.1%; 95% CI, −9.4% to 7.3%). Five alteplase-treated
patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI,
0.8%-7.4%). Author Affiliations: Author
affiliations are listed at the end of this
article.
CONCLUSIONS AND RELEVANCE Among patients with minor nondisabling acute ischemic
stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable Group Information: The PRISMS
Investigators are listed at the end of
functional outcome at 90 days. However, the very early study termination precludes any this article.
definitive conclusions, and additional research may be warranted. Corresponding Author: Pooja
Khatri, MD, MSc, Department of
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02072226 Neurology, University of Cincinnati,
260 Stetson St, ML 0525, Cincinnati,
JAMA. 2018;320(2):156-166. doi:10.1001/jama.2018.8496 OH 45208 (pooja.khatri@uc.edu).

156 (Reprinted) jama.com

© 2018 American Medical Association. All rights reserved.

Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018

 Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits
M
ild stroke is the most commonly cited reason for
nonuse of intravenous alteplase among patients
with ischemic stroke who present to the hospital
within the guideline-based eligible treatment window of 4.5
hours. 1 Yet prospective data suggest that 30% of such
patients have functional disability at 90 days after stroke.2,3
Reasons for the development of disability might include
underappreciated deficits, stroke progression, or medical
comorbidities leading to additional medical events, including
recurrent stroke. Vessel reperfusion may avert disability
because of the first 2 of these reasons. Clinical use of
alteplase for ischemic stroke with low National Institutes of
Health Stroke Scale (NIHSS) scores has increased in recent
years, presumably based on concern for this substantial post-
stroke disability.4,5
Although alteplase is the standard of care for patients
with ischemic stroke and disabling deficits regardless
of severity judged by NIHSS scores,6,7 the optimal manage-
ment of patients with not clearly disabling deficits is unclear.
Most major trials of alteplase (NINDS Parts 1 and 2; ECASS 1,
2, and 3; Atlantis Parts A and B; and EPITHET) explicitly
excluded varying subsets of patients with the mildest defi-
cits (see eTable 1 in Supplement 1 for exclusion criteria).
The IST 3 trial permitted enrollment of patients with minor
deficits, but only when the local enrolling physician had
personal equipoise regarding benefit and without collecting
data to distinguish which enrolled patients had disabling
vs nondisabling deficits at presentation.8 In the absence of
definitive evidence, current US clinical guidelines indicate
uncertainty regarding use of alteplase in patients with low
NIHSS scores and nondisabling deficits (strength of recom-
mendation class IIb [weak]; quality of evidence level C-LD
[limited data]).7
The purpose of this study was to test the efficacy and
safety of alteplase administered within 3 hours of onset of
ischemic stroke symptoms among patients presenting with
minor deficits (NIHSS score of 0-5) judged not clearly dis-
abling at presentation.
Methods
Trial Design
The study was approved by institutional review boards for
all study sites, and all enrolled patients provided written
informed consent. The protocol, protocol amendment, and
statistical analysis plan are provided in Supplement 2,
Supplement 3, and Supplement 4, and detailed methods
have been published.9
The Potential of rtPA for Ischemic Strokes With Mild
Symptoms (PRISMS) trial was designed as a phase 3b, ran-
domized, double-blind clinical trial testing the safety and
efficacy of intravenous alteplase administered within 3 hours
of symptom onset (time from witnessed onset or time from
last known well time if unwitnessed). The time window of 3
hours was chosen to harmonize with the US Food and Drug
Administration–labeled time window for use of alteplase in
patients with disabling ischemic stroke.
jama.com
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018
Original Investigation Research
Key Points
Question Does intravenous alteplase benefit patients with
ischemic stroke presenting with minor neurologic deficits that are
judged not clearly disabling?
Findings In this randomized clinical trial that included 313 of a
planned 948 patients with acute ischemic stroke, there was no
significant difference in the adjusted percentage with favorable
functional outcome at 90 days for those treated with alteplase vs
aspirin (78% vs 81%).
Meaning Although the study did not demonstrate a significant
benefit of alteplase for patients with minor nondisabling acute
ischemic stroke, the very early study termination precludes any
definitive conclusions.
Patient Selection and Randomization
Inclusion criteria included clinical diagnosis of acute ische-
mic stroke, age 18 years or older, NIHSS score of 0 to 5, and
deficits judged to not be clearly disabling at presentation.
A clearly disabling deficit was operationally defined as a defi-
cit that, if unchanged, would prevent the patient from per-
forming basic activities of daily living (ie, bathing, ambulat-
ing, toileting, hygiene, and eating) or returning to work. Local
clinicians made this determination in consultation with
patients and available family. Intensive study efforts to facili-
tate uniform application of enrollment criteria, including
web-based and smartphone-based patient selection tools,
pocket laminated cards, and tutorials, were implemented.
Local investigators were also advised to ensure that patients
could walk unassisted. Exclusion criteria included prestroke
disability (modified Rankin Scale score of 2-6), dysphagia,
intracranial hemorrhage on acute neuroimaging, and
other standard contraindications to intravenous alteplase
as reflected in the clinical guidelines that were current dur-
ing the trial.10
Participants were randomized in a 1:1 ratio stratified by site.
A step-forward randomization procedure was used to ensure
that the treatment assignment was available prior to the ar-
rival of each eligible patient, allowing for rapid initiation of
study treatment.11 A “use next” drug kit was assigned by a dy-
namic randomization algorithm managed by an interactive web
response system. Balance within site was controlled via the urn
method, which drew the first treatment assignment from
a metaphorical active urn containing a complete block of treat-
ment assignments and then placed it into an inactive urn; a
minimally balanced set of assignments was returned to facili-
tate balance.12 The overall allocation was balanced using a bi-
ased coin method in which treatments were allocated with un-
equal but not deterministic probability when imbalance
achieved preset criteria.13 A patient was considered enrolled
when the study treatment bolus was administered.
Study Intervention
Participants were randomized to receive either intravenous al-
teplase at standard dosing for ischemic stroke (0.9 mg/kg) with
a placebo oral aspirin or oral aspirin, 325 mg, with placebo in-
travenous alteplase. The placebos were identical in appear-
ance to active study drugs to maintain treatment blinding of
(Reprinted) JAMA July 10, 2018 Volume 320, Number 2 157
 Research Original Investigation Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits
patients and investigators. Intravenous study treatment was
to be administered within 3 hours of stroke onset. The same
was encouraged for the oral study treatment; however, it could
be administered up to 24 hours after symptom onset at insti-
tutions that required formal swallow evaluation. Clinical man-
agement after study treatment administration was to be in ac-
cordance with institutional protocols and clinical guidelines
for care after alteplase administration. The study mandated
follow-up neuroimaging (computed tomography or magnetic
resonance imaging per institutional standard of care) within
22 to 36 hours after intravenous study treatment bolus.
Study Outcomes
The primary outcome end point was a modified Rankin Scale
(mRS) score of 0 or 1 (total range, 0 [symptom free] to 6 [dead]),
reflecting favorable functional outcome, evaluated at 90 days
after enrollment and adjusted for age, time from symptom on-
set to treatment, and baseline NIHSS score.
Secondary outcome measures of efficacy, also assessed at
90 days, consisted of level of disability (assessed by the 6-level
ordinal mRS score, collapsing levels 5 and 6) and global favor-
able recovery, which was defined as an mRS score of 0 or 1,
NIHSS score of 0 or 1, Barthel Index of 95 or 100 (total range,
0 [totally dependent] to 100 [patient performs self-care and
mobility without assistance]), and Glasgow Outcome Scale
score of 1 (total range, 1 [good recovery] to 5 [death]).
Exploratory outcome measures of efficacy included
ambulatory speed (10-Meter Walk Test), which assesses com-
fortable walking speed over 6 m; stroke-related quality of life
(Stroke Impact Scale 16) score, which ranges from 0 to 100,
with higher scores indicating better physical performance
(strength, hand function, physical and instrumental activities
of daily living, and mobility); and general health-related
quality of life (EuroQoL Group EQ-5D) score, which ranges
from 0 (death) to 1 (perfect health) at 90 days. Cognitive out-
comes and a brief depression assessment were also assessed
(results not presented in this article).
The primary safety end point was symptomatic intracra-
nial hemorrhage (sICH), defined as any neurologic decline
within 36 hours attributed to ICH by local investigators; this
definition was modified from the NINDS-tPA trials’ defini-
tion requiring only a temporal association of decline with ICH.14
Other safety measures included an alternate definition of sICH
(a deterioration in NIHSS score of ≥4 with a radiological pa-
renchymal hemorrhage type 2),15 any radiologic ICH within 36
hours, all-cause mortality within 90 days, stroke-related and
neurologic deaths within 90 days, and the severity and spec-
trum of all adverse events.
Data Collection and Monitoring
Key clinical and radiological data were collected, including
(1) baseline neuroimaging and NIHSS score; (2) 22- to 36-hour
repeat neuroimaging and NIHSS score; (3) 5-day (or dis-
charge if sooner) NIHSS score, stroke etiology, and discharge lo-
cation; (4) 30-day mRS score by telephone follow-up; and
(5) final 90-day mRS score, along with secondary and explor-
atory outcomes, assessed in person when possible. Ethnicity and
race were self-reported (fixed categories) and were collected to
158 JAMA July 10, 2018 Volume 320, Number 2 (Reprinted)
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018
consider the generalizability of the results. All adverse events,
regardless of relationship to study treatment, were reported
until 30 days after study treatment administration. After 30 days,
only data on serious adverse events, nonserious adverse events
of special interest (consisting of sICH events not otherwise re-
ported, stroke recurrence, or suspected transmission of an in-
fectious agent via a medicinal product), and adverse events re-
sulting in withdrawal from the study were collected.
Concomitant medication use was recorded at all visits.
Study monitors performed ongoing source data verifica-
tion. An independent data monitoring committee, composed
of 1 stroke neurologist, 1 emergency physician, 1 neuroradi-
ologist, and 1 statistician, provided ongoing review of accu-
mulating adverse events. The independent data monitoring
committee was also charged with conducting the interim fu-
tility analysis, planned to take place after 50% of participants
had completed follow-up. Two independent, blinded neuro-
radiologists at the central imaging core interpreted relevant
imaging data.
Determination of presenting events as either ischemic
cerebral events (stroke or transient ischemic attack) or neuro-
vascular mimic was carried out by site investigators. For
patients with neuroimaging evidence of new infarction,
site investigators’ diagnoses of ischemic stroke were ac-
cepted without further review. For patients without neuroim-
aging evidence of new infarction, central review was per-
formed by steering committee neurologists (P.K. and J.G.R.)
prior to database lock and without unblinding, indepen-
dently rendering diagnoses of ischemic cerebral event or
neurovascular-mimicking condition. When assessments were
discordant, discussions were held between the site investiga-
tor and central reviewer to ensure that all relevant data were
considered in the final determination. The site principal
investigators then made a final diagnostic determination.
Statistical Analysis
The trial was designed to detect a 9% absolute difference in
the proportion of participants with favorable outcome with
80% power, using a 1-sided type I error rate of .025 to test the
superiority hypothesis, under the assumption that 65% of par-
ticipants randomized to receive aspirin would experience a fa-
vorable outcome, and allowing for 1 interim futility analysis.
The sample size calculation was 1-sided to reflect the objec-
tive of establishing the superiority of alteplase over standard
medical care. Accounting for these assumptions, the neces-
sary sample size was calculated to be 856 participants. The
sample size was adjusted to 948 participants to account for di-
lution of the treatment effect associated with nonadherence
parameters (loss to follow-up, treatment crossovers, and neu-
rovascular mimics [stroke and transient ischemic attack]). The
planned 9% effect size was derived from a previously pub-
lished post hoc analysis of the IST-3 trial subset of patients that
met the PRISMS trial’s eligibility criteria (with the exception
that qualifying deficits could not be ascertained as not clearly
disabling).16 The steering committee expected that treat-
ment effects of less than 9% were still likely to be clinically
meaningful. It was anticipated that a higher rate of favorable
outcome in participants randomized to aspirin and a lower rate
jama.com
 Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits
of nonadherence parameters would allow detection of a lower
absolute treatment effect with the same 80% power.
The trial initially intended to test the primary end point
via a Cochran-Mantel-Haenszel hypothesis test, stratified by
age (<65 vs ≥65 years), time from symptom onset to treat-
ment (0-2 vs >2 hours), and pretreatment NIHSS score (0-2 vs
3-5). Because the trial was terminated early by the sponsor
for enrollment below target, it was recognized that the study
would be underpowered to formally test the hypothesis.
Therefore, the statistical analysis plan was finalized, prior to
database lock and unblinding, to evaluate the size of an effect
(and its associated uncertainty). The updated plan was to
evaluate the hypothesis by examining the adjusted risk dif-
ference (point values and 95% CIs) in the rate of the primary
outcome (mRS score of 0 or 1) using a linear model, which
included treatment assignment, age, time from symptom
onset to study treatment, and baseline NIHSS score as con-
tinuous covariates.
A sensitivity analysis confined to patients with final
diagnoses of acute cerebral ischemia was also planned. Addi-
tional exploratory analyses of the primary outcome were pre-
specified to test the consistency of the findings: (1) unad-
justed risk difference; (2) logistic regression, adjusting for
pretreatment NIHSS score, age, and time to treatment;
(3) risk difference adjusted for additional potential covariate
imbalances using a propensity score; and (4) repeated-
measures model (in which mRS score outcomes at day 30 and
day 90 were modeled jointly by a logistic regression).
Missing primary outcome data (90-day mRS scores) were
prespecified for imputation with the 30-day mRS score re-
sult, when available, and otherwise imputed via hot-deck
method, which randomly selected the outcome value from a
pool of patients with observed mRS scores matched by treat-
ment group, age, pretreatment NIHSS score, and time of symp-
tom onset.
The secondary outcome of ordinal analysis was achieved
by fitting a proportional odds model with mRS score at day 90
as the dependent variable and treatment group, pretreat-
ment NIHSS score, age, and time from symptom onset to treat-
ment as the continuous predictors. Quadratic terms for the con-
tinuous covariates would be added to the model, if the Wald
P value for the quadratic term was less than 0.1. The propor-
tional odds assumption was tested by the score test.
The secondary outcome of global favorable recovery
was derived from a generalized linear model with logit-link
function, computed with generalized estimating equations.
This global statistic simultaneously evaluated the effect in
all 4 outcome measures (mRS score of 0 or 1, NIHSS score of
0 or 1, Barthel Index of 95 or 100, and Glasgow Outcome
Scale score of 1).
Analyses for heterogeneity of treatment effect for the pri-
mary outcome were prespecified for subgroups of age, base-
line NIHSS score, and time from symptom onset to treat-
ment. Odds ratios (ORs) were estimated using multivariable
logistic regressions. P values were estimated by adding the in-
teraction of each subgroup and treatment variable to the lo-
gistic regression model. A possible interaction was prespeci-
fied as P < .10.
jama.com
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018
Original Investigation Research
A post hoc analysis evaluated the likelihood of alteplase
benefit, given study findings, for clinical interpretation and fu-
ture trial planning purposes. Using an uninformative prior on
the treatment-specific unadjusted outcome proportions, the
posterior distribution of the risk difference was constructed via
simulation to calculate the probability of alteplase benefit.
This uninformative prior β[1, 1] reflects a uniform distribution
on the interval [0, 1]; this prior was used to construct the pos-
terior distribution of the risk difference via simulation to cal-
culate the probability of alteplase benefit. The analysis was not
adjusted for differences in age, time to treatment, or baseline
NIHSS score, as with the primary outcome. The trial steering
committee clinicians were surveyed in December 2015 (prior
to study termination and without unblinding) to propose ef-
fect sizes that would change clinical practice toward treat-
ment in the context of various associated sICH risk rates of al-
teplase. They suggested that an alteplase effect size as low as
6% might still change clinical practice toward treatment in the
context of a 3% increased sICH risk. Therefore, the post hoc
analysis considered the likelihood of (1) any benefit of al-
teplase and (2) an absolute benefit of alteplase of more than 6%.
For statistical analyses, SAS version 9.2 or higher (SAS In-
stitute Inc) was executed on the SunOS version 5.10 (SUN 64)
platform. The post hoc Bayesian analysis was executed
using WinBUGS14.
Early Study Termination
Study enrollment was terminated on December 20, 2016, by
the sponsor, prior to database lock and without unblinding,
because of patient recruitment below target. This was a
financial decision based on the fact that the trial could not be
completed within the allotted funds in the specified time
frame. The interim futility analysis was not completed for
consideration of this decision because less than 50% of
patients had completed follow-up. Neither the sponsor, the
independent data monitoring committee, nor the steering
committee evaluated study data as part of the decision to ter-
minate the trial. The academic members of the steering com-
mittee recommended against termination but accepted this
financial decision by the sponsor. The sponsor assured that
the accrued data would be fully analyzed and disseminated
to maximize the contributions of the enrolled patients and
thereby maintain ethical responsibilities. The independent
data monitoring committee had 2 reviews of aggregate data
and recruitment rates but did not participate in the decision
to terminate enrollment; the committee was informed of the
decision after it was made. After enrollment was halted, all
enrolled patients were to complete protocol-specified proce-
dures through 90-day follow-up. As a result of the early ter-
mination of the study, the plan for analysis of the primary
outcome was revised as detailed above.
Results
Study Population
From May 1, 2014, to December 20, 2016, 313 patients were en-
rolled, with a mean age of 62 years (SD, 13 years), 144 (46%)
(Reprinted) JAMA July 10, 2018 Volume 320, Number 2 159
 Research Original Investigation Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits

Figure 1. Flow of Patients Through the PRISMS Trial

356 Study treatment

kits randomizeda

43 Excluded
39 Study drug premixed but patients
determined to be ineligible
3 Randomization for “use next” kit
done erroneously
1 Kit opened but patient subsequently
determined to be ineligible

313 Patients enrolled

156 Randomized to receive intravenous 157 Randomized to receive intravenous

alteplase + oral placebo placebo + oral aspirin
154 Received intervention as randomized 153 Received intervention as randomized
2 Did not receive intervention as 4 Did not receive intervention as
randomizedb randomizedc

15 Missing 90-d primary outcome datad
13 Lost to follow-up
1 Withdrew consent
1 Inadequate source documentation
17 Missing 90-d primary outcome datae
10 Lost to follow-up
5 mRS score not assessed within 90-d
window
2 Inadequate source documentation

156 Included in primary analysis 157 Included in primary analysis

a c
The total number of patients assessed for eligibility is not available because
screening log data were not available. The total number randomized does not
reflect the enrolled population because in step-forward randomization, a “use
next” drug kit was assigned prior to a potential trial candidate’s arrival at an
emergency department. Many patients who arrived at an emergency
department after a kit was designated were not eligible and were not enrolled
in the trial. A patient was considered enrolled when the study treatment bolus
was administered.
b
These 2 patients received intravenous placebo instead of intravenous
alteplase because of pharmacy error.
Two patients received oral placebo instead of oral aspirin because of pharmacy
error; 1 patient was determined to have an aspirin allergy after enrollment; and
1 patient had neurologic worsening and became eligible for intravenous
alteplase treatment as standard of care.
d
Missing data were imputed using the 30-day modified Rankin Scale (mRS)
score for 12 patients and hot-deck imputation for 3 patients.
e
Missing data were imputed using the 30-day mRS score for 13 patients and
hot-deck imputation for 4 patients.

women, a median NIHSS score of 2 (interquartile range, 1-3), Primary Outcome

and a median time from symptom onset to start of study
treatment of 2.7 hours (interquartile range, 2.1-2.9). Of the
313 enrolled patients, 281 (89.8%) completed the trial’s pri-
mary outcome assessment and data for the remainder were
imputed as prespecified. Study randomization, enrollment,
and follow-up are shown in Figure 1 and patient characteris-
tics in Table 1. Study groups were generally well balanced,
with the most common medical risk factors being hyperten-
sion (80.1%) and hyperlipidemia (72.3%), and atrial fibrilla-
tion in only 12.8%. The most prevalent neurologic deficits at
enrollment were sensory (46%), facial palsy (39%), and dys-
arthria (28%), as shown in the context of associated deficits
in eFigure 1 in Supplement 1.
Features of the presenting event are shown in Table 2. Final
diagnosis was acute cerebral ischemia in 87.0% of patients and
neurovascular mimic in 13.0%. Among patients with acute ce-
rebral ischemia, the most common stroke mechanisms were
small vessel disease (36.6%) and undetermined mechanism
(31.5%), with cardioembolism (13.6%) and large artery athero-
sclerosis (11.0%) less frequent.
In the primary analysis, 122 patients (78.2%) randomized to
alteplase had favorable outcomes at 90 days compared with
128 patients (81.5%) randomized to aspirin (adjusted abso-
lute risk difference, −1.1%; 95% CI, −9.4% to 7.3%). The full dis-
tribution of levels of disability on the mRS score at 90 days are
shown in Figure 2 and eTable 2 in Supplement 1, and distri-
butions without missing data imputation are shown in eFig-
ure 2 in Supplement 1.
Secondary Outcomes
Secondary outcomes, including the ordinal analysis of mRS
scores (OR, 0.81; 95% CI, 0.5-1.2) and global favorable recov-
ery (OR, 0.86; 95% CI, 0.5-1.4), did not significantly favor either
group (Table 3).
Adverse Events
Adverse event results are shown in Table 4. The primary ad-
verse event, sICH within 36 hours, occurred in 5 patients, all
treated with alteplase (3.2% vs 0; absolute risk difference, 3.3%;
95% CI, 0.8%-7.4%) (eFigure 3 in Supplement 1). Four sICH

160 JAMA July 10, 2018 Volume 320, Number 2 (Reprinted) jama.com

© 2018 American Medical Association. All rights reserved.

Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018

 Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits Original Investigation Research

Table 1. Baseline Patient Characteristics

Intravenous Alteplase + Intravenous Placebo +
Characteristics Oral Placebo (n=156) Oral Aspirin (n = 157)
Age, mean (SD), y 62 (14) 61 (13)
Male sex, No. (%) 77 (49) 92 (59)
Race, No. (%)a
White 117 (75.0) 126 (80.3)
Black/African American 35 (22.4) 27 (17.2)
American Indian or Alaska Native 1 (0.6) 3 (1.9)
Asian 0 1 (0.6)
≥2 races 1 (0.6) 0
Unknown 2 (1.3) 0
Hispanic or Latino ethnicity, No. (%)a 14 (9.0) 18 (11.5)
Medical history, No. (%)
Hypertension 126 (81.3) 124 (79.0)
Hyperlipidemia 114 (73.1) 114 (72.6)
Diabetes mellitus 57 (36.5) 44 (28.0)
Previous stroke 28 (17.9) 24 (15.3)
Atrial fibrillation 23 (14.7) 17 (10.8)
Medications prior to onset, No. (%)
Antiplatelet agents 64 (41.0) 59 (37.6)
Anticoagulant agents 1 (0.6) 1 (0.6)
Time from symptom onset to intravenous Abbreviation: IQR, interquartile
study treatment bolus, h range.
No. (%)
SI conversion: To convert glucose to
0 to 2 25 (16.0) 36 (22.9) mmol/L, multiply by 0.0555.
a
>2 to 3 126 (80.8) 119 (75.8) Race and ethnicity were
>3 b
5 (3.2) 2 (1.3) self-reported as categories of
Hispanic/Latino (yes/no) and either
Median (IQR) 2.7 (2.2-2.9) 2.6 (2.1-2.9) American Indian or Alaska Native,
Time from onset to oral study treatment, 2.9 (2.5-3.1) 2.8 (2.4-3.1) Asian, black or African American,
median (IQR), h Native Hawaiian or other Pacific
Baseline NIHSS scorec Islander, white, or other.
b
No. (%) Six of the 7 patients received the
0 7 (4.5) 7 (4.5) study bolus within 3 hours
and 15 minutes.
1 38 (24.4) 50 (31.8) c
The National Institutes of Health
2 52 (33.3) 50 (31.8) Stroke Scale (NIHSS) score classifies
3 32 (20.5) 30 (19.1) neurologic deficit from 0 (no deficit)
to 42 (most severe).
4 21 (13.5) 16 (10.2)
d
Alberta Stroke Program Early
5 6 (3.8) 4 (2.5)
Computed Tomography Score
Mean (SD) 2.3 (1.2) 2.0 (1.2) (ASPECTS) semiquantitatively
Glucose level, mean (SD), mg/dL 141.2 (72.9) 132.1 (61.8) measures the extent of acute early
ischemic changes in the middle
Systolic blood pressure >140 mm Hg, No. (%) 83 (53.2) 112 (71.3)
cerebral artery distribution on a
Diastolic blood pressure >90 mm Hg, No. (%) 31 (19.9) 44 (28.0) computed tomography scan, with a
Baseline international normalized ratio >1.1, No. (%) 42 (26.9) 52 (33.1) score range of 0 (maximum
changes) to 10 (no ischemic
Baseline ASPECTS, median (range)d 10 (7-10) 10 (7-10)
changes).

events were parenchymal hematoma type 2 (hematomas ex-
ceeding 30% of the infarction area with significant space-
occupying effect) and 1 was a remote parenchymal hematoma
type 1 (small petechial hemorrhage outside of the infarction
bed). Symptomatic ICH volumes in each of the 5 patients were
0.4, 10, 18, 29, and 70 cm3; mRS scores at 90 days were 1, 2, 2,
3, and 4; and none of the patients with sICH died. Serious
adverse events occurred in 40 patients (26.0%) treated with
alteplase compared with 20 (13.1%) treated with aspirin; all
adverse events are summarized in eTable 3 in Supplement 1.
One patient who was treated with alteplase died at 90 days of
volvulus, adjudicated as related to a history of bowel obstruc-
tion and resection and unrelated to study treatment.
Exploratory Outcomes and Analyses
All prespecified exploratory outcomes and sensitivity analy-
ses for the primary outcome showed no statistically signifi-
cant differences between groups (Table 3). Changes in NIHSS
scores over time are shown in eFigure 4 in Supplement 1.
Heterogeneity of treatment effect was not observed for

jama.com (Reprinted) JAMA July 10, 2018 Volume 320, Number 2 161

© 2018 American Medical Association. All rights reserved.

Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018

 Research Original Investigation Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits

mative prior, the posterior probability that alteplase therapy

Table 2. Presenting Event Characteristics
would improve favorable outcomes (mRS score of 0 or 1 at 90
No. (%) days) to any degree was 23%, and the probability that al-
Intravenous Alteplase + Intravenous Placebo + teplase therapy would improve favorable outcomes by more
Characteristics Oral Placebo (n = 156) Oral Aspirin (n = 157)
Rapid improvement 8 (5.1) 7 (4.5)
than an absolute 6% was 1.9%. The 95% credible interval of
of symptoms prior the unadjusted risk difference was −12.2% to 5.5%.
to study treatment
administration
Localization of
presenting deficita
Right hemisphere 75 (48.1) 67 (42.7) Discussion
Left hemisphere 59 (37.8) 62 (39.5) Among patients with minor, nondisabling acute ischemic
Unknown 19 (12.2) 21 (13.4) stroke, treatment with alteplase compared with aspirin did not
Brainstem/cerebellum 9 (5.8) 18 (11.5) increase the likelihood of favorable functional outcome at 90
Final diagnosis days. Treatment benefit with alteplase was also not demon-
Acute cerebral ischemia 136 (88.3) 131 (85.6) strated for secondary and exploratory end points at 90 days.
Neurovascular mimicb 18 (11.7) 22 (14.4) The study results raise the hypothesis that even a 6% treat-
Ischemic cerebral event n=138 n=135 ment effect might be unlikely. However, the very early study
etiologyc termination precludes any definitive conclusions.
Small vessel disease 48 (34.8) 52 (38.5) The trial tested alteplase in a unique ischemic stroke sub-
Undetermined etiology 40 (29.0) 46 (34.1) population. The operational definition of not clearly dis-
Cardioembolism 20 (14.5) 17 (12.6) abling deficits at presentation was intended to capture pa-
Large artery 20 (14.5) 10 (7.4) tients for whom treatment evidence was lacking and
atherosclerosis
community equipoise for treatment benefit was present.
Other determined 10 (7.2) 10 (7.4)
etiologyd Single-center clinical data without this type of explicit opera-
a
Localization of presenting deficits was assigned by the local investigator at the tionalization has suggested that 30% of these types of pa-
time of hospital discharge based on clinical examination and/or neuroimaging. tients would have disability (mRS score of 2-6) at 90 days,2,3
A single patient may have had a stroke in more than 1 location. higher than the observed 19% rate. Better outcomes may have
b
Leading etiologies of neurovascular mimics were seizure and/or postictal been observed in the current study because of the formal defi-
(without concurrent stroke): alteplase, n = 1, aspirin, n = 2; psychogenic:
nition of the population and other trial entry criteria select-
alteplase, n = 3, aspirin, n = 7; complicated migraine: alteplase, n = 5, aspirin,
n = 6; recrudescence of prior stroke: alteplase, n = 2, aspirin, n = 0; and other ing for healthier patients. The functional outcomes of pa-
reasons: alteplase, n = 7, aspirin, n = 7. tients enrolled in the trial may have been improved by earlier
c
Assigned by the treating physician. administration of aspirin (75% within 3.1 hours of onset) com-
d
Precise other etiologies not available. pared with general practice recommendations (within 24-48
hours).8 Additionally, prior observational cohorts not under-
going thrombolysis may have included more severely af-
Figure 2. Modified Rankin Scale Score Distributions at 90 Days
by Treatment Group fected patients, given recent trends toward increased use of
alteplase for patients with minor stroke in clinical practice.4,5
Modified Rankin Scale score An increase in sICH was associated with alteplase in this
0 1 2 3 4 5-6 population (risk difference, 3.3%; 95% CI, 0.8%-7.4%) with-
out an associated increase in mortality. In a nationwide US reg-
Intravenous alteplase + istry, among 5910 patients with NIHSS scores of 0 to 5 treated
oral placebo (n = 156)
with alteplase in routine practice, a 1.8% (95% CI, 1.5%-2.2%)
absolute risk of sICH was observed.17 The sICH risk associ-
Intravenous placebo +
oral aspirin (n = 157) ated with alteplase was anticipated to be even lower in the cur-
rent trial, which consisted of patients who had both low NIHSS
0 20 40 60 80 100 scores and deficits judged to not be clearly disabling. The point
Patients, % estimate for the absolute risk of sICH of 3.2% in the current
trial was higher than this 1.8% rate but lower than the 5% to
These distributions, which were used for the primary outcome analysis,
6% risk of sICH associated with alteplase in patients with higher
included imputation for missing 90-day scores.
NIHSS scores; however, wide confidence intervals included
both of these comparators.14,18 The sICH events in this trial had
subgroups based on age (P = .92 for interaction), baseline NIHSS no associated mortality compared with the sICH events in the
score (P = .10 for interaction), or time from symptom onset to NINDS trials associated with 75% mortality.19
treatment (P = .70 for interaction) (eFigure 5 in Supplement 1). The findings from the current trial cannot be extrapolated
to all patients with lower stroke severity based on an NIHSS score
Post Hoc Analysis of 0 to 5. Those with disabling deficits, such as isolated leg
In a post hoc Bayesian analysis, when the primary efficacy end weakness causing inability to walk and isolated aphasia pre-
point results of the current study were added to an uninfor- venting communication, were excluded from the current study.

162 JAMA July 10, 2018 Volume 320, Number 2 (Reprinted) jama.com

© 2018 American Medical Association. All rights reserved.

Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018

 Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits Original Investigation Research

Table 3. 90-Day Efficacy Results

No. (%) Effect Estimate,

Intravenous Alteplase + Intravenous Placebo + Risk Difference or
Outcomes Oral Placebo (n = 156) Oral Aspirin (n = 157) OR (95% CI)a
Primary Outcome
mRS score of 0 or 1, adjustedb −1.1 (−9.4 to 7.3)
Secondary Outcomes
mRS score distribution at 90 dc OR, 0.81 (0.5 to 1.2)
0 70 (44.9) 79 (50.3)
1 52 (33.3) 49 (31.2)
2 18 (11.5) 18 (11.5)
3 4 (2.6) 5 (3.2)
4 8 (5.1) 4 (2.5)
5-6 4 (2.6) 2 (1.3)
Global favorable recoveryd OR, 0.86 (0.5 to 1.4)
Exploratory Outcomes
mRS score of 0 or 1, unadjustede 122 (78.2) 128 (81.5) −3.3 (−12.2 to 5.6)
mRS score of 0, adjustedb 70 (44.9) 79 (50.3) −3.6 (−14.2 to 7.1)
NIHSS score of 0 or 1, adjustedb 108 (85.7) 98 (81.7) OR, 1.3 (0.65 to 2.6)
NIHSS score, mean (SD) 1.2 (3.75) 0.8 (2.01) 0.4 (−0.4 to 1.1)
Barthel Index of 95 or 100, adjustedb,f 107 (79.3) 118 (88.7) OR, 0.5 (0.3 to 1.1)
Glasgow Outcome Scale score of 1, adjustedb,g 110 (81.5) 113 (85.6) OR, 0.8 (0.4 to 1.6)
Ambulatory performance, mean (SD), m/se,h 0.95 (0.34) 0.98 (0.44) −0.03 (−0.13 to 0.08)
EuroQoL Group EQ-5D quality-of-life score, 0.81 (0.21) 0.83 (0.20) −0.02 (−0.07 to 0.03)
mean (SD)e,i
Stroke Impact Scale 16 score, mean (SD)e,j 85.1 (21.0) 86.3 (21.4) −1.1 (−6.2 to 4.0)
Recurrent ischemic stroke 5 (3.2) 6 (4.0)
Exploratory Analyses for the Primary Outcome
Acute cerebral ischemia cases only 107/138 (77.5) 109/135 (80.7) −1.4 (−10.5 to 7.7)
(mimics excluded)b
mRS score of 0 or 1, nonimputed 110/141 (78.0) 114/140 (81.4) −2.3 (−11.1 to 6.6)
Propensity score–adjusted modelk −2.4 (−11.2 to 6.4)
Logistic regression modell OR, 0.9 (0.5 to 1.7)
Repeated-measures modelm OR, 0.9 (0.5 to 1.4)
g
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; mRS, modified The Glasgow Outcome Scale score ranges from 1 (good recovery) to 5 (death).
Rankin Scale; OR, odds ratio. h
Ambulatory performance assesses comfortable walking speed for 6 meters.
a
Positive values for risk differences and ORs greater than 1 favor alteplase. i
The EuroQoL Group EQ-5D score ranges from 0 (death) to 1 (perfect health).
b
Adjusted risk difference values were calculated from a linear regression with j
The Stroke Impact Scale 16 score ranges from 0 to 100, with higher scores
treatment, age, time from symptom onset to treatment, and baseline NIHSS indicating better physical performance (strength, hand function, physical and
score. Quadratic terms for age and baseline NIHSS score were also added to instrumental activities of daily living, and mobility).
the model if the Wald P value for the quadratic term was P < .10. Modified k
Propensity scores were derived from the logistic regression for treatment
Rankin Scale scores range from 0 (symptom free) to 6 (dead).
group with the following covariates: sex, race, ethnicity, smoking,
c
The proportional odds assumption was met (score test P = .50); therefore, the history of hypertension, history of diabetes, history of atrial fibrillation,
common OR was calculated by fitting a proportional odds model with mRS history of stroke, prior antiplatelet drug use, prior anticoagulant drug use,
scores at day 90 as the dependent variable and treatment group, baseline glucose level, baseline systolic blood pressure, and baseline
pretreatment NIHSS score, age, and time from symptom onset to treatment as international normalized ratio.
the continuous predictors. Quadratic terms for the continuous covariates were l
Adjusted OR was obtained from a logistic regression adjusted for
added to the model if the Wald P value for the quadratic term was less than 0.1.
pretreatment NIHSS score, age, and time from symptom onset to treatment as
d
The global favorable recovery statistic was derived from a generalized linear continuous covariates and quadratic terms for the continuous covariates if the
model with logit-link function computed using generalized estimating Wald P value for the quadratic term was <0.1.
equations. This global statistic simultaneously evaluated the effect in all 4 m
Using all available mRS score responses at both day 30 and day 90. Odds
outcome measures (mRS score of 0 or 1, NIHSS score of 0 or 1, Barthel Index of
ratios are adjusted for age, time from symptom onset to treatment, baseline
95 or 100, and Glasgow Outcome Scale score of 1).
NIHSS score, and quadratic terms for age (logistic) and age and baseline NIHSS
e
Confidence interval was computed using the normal approximation method. score (repeated measures).
f
The Barthel Index ranges from 0 (totally dependent) to 100 (patient performs
self-care and mobility without assistance).

Furthermore, clinical guidelines and scientific statements re- tionally, patients with mild deficits who have large vessel occlu-
garding alteplase recommend “no exclusion for patients with sions (a minority in this population) may be more prone to stroke
mild but nonetheless disabling stroke symptoms….”7,20 Addi- progression and thus may require further study.21-23

jama.com (Reprinted) JAMA July 10, 2018 Volume 320, Number 2 163

© 2018 American Medical Association. All rights reserved.

Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018

 Research Original Investigation Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits

Table 4. Adverse Event Results (As-Treated Analysis)

No. (%)
Intravenous Alteplase + Intravenous Placebo + Risk Difference,
Adverse Events Oral Placebo (n = 156) Oral Aspirin (n = 157) % (95% CI)
Primary Adverse Event Assessment
Symptomatic intracranial hemorrhag 5 (3.2) 0 3.3 (0.8 to 7.4)
e within 36 h
Secondary Adverse Event Assessments
Symptomatic intracranial hemorrhage 2 (1.3) 0 1.3 (−1.2 to 4.6)
within 36 h, SITS-MOST definitiona
Any radiologic intracranial hemorrhage 11 (7.1) 5 (3.3) 3.9 (−1.2 to 9.5)
within 36 h by central reader
b
By radiological subtype
Hemorrhagic infarction type 1 2 3
Hemorrhagic infarction type 2 2 1
Parenchymal hematoma type 1 1 0
Parenchymal hematoma type 2 4 0
Remote parenchymal hematoma type 1 2 0
Intraventricular hemorrhage 2c 0
Subarachnoid hemorrhage 3c 1
Mortality within 90 d 1 (0.6) 0
Stroke-related and neurologic deaths 0 0
within 90 d
Patients with serious adverse eventsd 40 (26.0) 20 (13.1) 12.9 (4.1 to 21.7)e
Patients with any adverse events 119 (77.3) 104 (68.0)
Abbreviation: SITS-MOST, Safe Implementation of Thrombolysis in parenchymal hematoma type 1, defined as small or medium-sized blood clots
Stroke–Monitoring Study. located remote from the actual infarction; and remote parenchymal
a
The SITS MOST definition of symptomatic intracranial hemorrhage consisted hematoma type 2, defined as large, confluent, dense blood clots in an area
of a deterioration in NIHSS score of ⱖ4 with a radiological parenchymal remote from the actual infarction (substantial space-occupying effect
hemorrhage type 2 (described in footnote below). may be present).
c
b
Radiological subtypes of intracerebral hemorrhage consisted of hemorrhagic These patients (with intraventricular or subarachnoid hemorrhages) also had
infarction type 1, defined as a small petechial hemorrhage along the intracerebral hemorrhage.
d
margin of infarction; hemorrhagic infarction type 2, defined as more confluent Serious adverse events of increased frequency in the alteplase-treated group
petechial hemorrhage within the infarcted area but without space-occupying that were deemed by the local investigator to be treatment related consisted
effect; parenchymal hematoma type 1, defined as hematomal hemorrhage in of vitreous hemorrhage (n = 1), hemorrhagic transformation of stroke (n = 2),
at least 30% of the infarcted area with some slight space-occupying effect; cerebral hemorrhage (n = 5), and intracranial hemorrhage (n = 3).
and parenchymal hematoma type 2, defined as dense hematomal hemorrhage e
This is a post hoc calculation.
in more than 30% of the infarcted area with substantial space-occupying
effect or any hemorrhagic area outside the infarcted area; remote

Limitations (available for 78% of these patients) are known to permit

This study has several limitations. First, the trial’s early ter-
mination leads to significant uncertainty of all observations.
Second, within the bounds of formal trial entry criteria, some
sites may have selectively recruited patients with even
milder, rather than more severe, deficits despite efforts to
minimize this selection bias. Third, the definition of “not
clearly disabling” was subjective and required interpretation
by individual clinicians. Although efforts were made to
encourage consistency in assessment of eligible patients, this
cannot be confirmed. Fourth, the loss to follow-up at day 90
was relatively high. However, mRS scores from day 30
robust imputation.24
Conclusions
Among patients with minor nondisabling acute ischemic
stroke, treatment with alteplase compared with aspirin did
not increase the likelihood of favorable functional outcome
at 90 days. However, the very early study termination pre-
cludes any definitive conclusions, and additional research
may be warranted.

ARTICLE INFORMATION
Accepted for Publication: May 30, 2018.
Author Affiliations: University of Cincinnati,
Cincinnati, Ohio (Khatri, Kleindorfer, Broderick,
Vagal); University of Tennessee College of
Medicine, Chattanooga (Devlin); University of
Buffalo, Buffalo, New York (Sawyer); University of
Pittsburgh Medical Center, Pittsburgh,
Pennsylvania (Starr); Dayton Medical Center,
Department of Veterans Affairs, Dayton, Ohio
(Mejilla); University of Pennsylvania, Philadelphia
(Chatterjee); Medical University of South Carolina,
Charleston (Jauch, Yeatts); SUNY Downstate
Medical Center, Brooklyn, New York (Levine); Kings
County Hospital Center, Brooklyn, New York
(Levine); University of Miami Miller School of
Medicine, Miami, Florida (Romano);
Comprehensive Stroke Center and Department of

164 JAMA July 10, 2018 Volume 320, Number 2 (Reprinted) jama.com

© 2018 American Medical Association. All rights reserved.

Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018

 Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits
Neurology, University of California, Los Angeles
(Saver); Genentech, South San Francisco, California
(Purdon, Devenport); Everest Clinical Research,
Markham, Ontario, Canada (Pavlov).
Author Contributions: Dr Khatri had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Khatri, Kleindorfer, Broderick,
Chatterjee, Jauch, Saver, Purdon, Yeatts.
Acquisition, analysis, or interpretation of data:
Khatri, Kleindorfer, Devlin, Sawyer, Starr, Mejilla,
Broderick, Jauch, Levine, Romano, Saver, Vagal,
Devenport, Pavlov, Yeatts.
Drafting of the manuscript: Khatri, Sawyer,
Chatterjee, Jauch, Vagal, Devenport.
Critical revision of the manuscript for important
intellectual content: Kleindorfer, Devlin, Sawyer,
Starr, Mejilla, Broderick, Jauch, Levine, Romano,
Saver, Vagal, Purdon, Devenport, Pavlov, Yeatts.
Statistical analysis: Saver, Purdon, Devenport,
Pavlov.
Obtained funding: Khatri, Jauch.
Administrative, technical, or material support:
Kleindorfer, Devlin, Starr, Chatterjee, Jauch, Saver.
Supervision: Khatri, Jauch, Levine, Romano, Saver,
Devenport.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest.
Dr Khatri reports payment to her university
department for research efforts from Genentech
(lead PI of PRISMS), Neurospring (coinvestigator;
CREATE grant), Lumosa (data and safety
monitoring board and consultant), Cerenovus
(investigator-initiated study, ENDO LOW PI) and the
National Institutes of Health/National Institute of
Neurological Disorders and Stroke. Dr Khatri also
reports fees from Biogen (data and safety
monitoring board) and Medpace/Novartis
(coinvestigator). Dr Khatri was an unpaid
consultant to EmstopA and received travel support
from Neuravi (academic workshop). Dr Kleindorfer
reports personal fees from Genentech Speakers
Bureau. Dr Devlin reports research support from
Genentech. Dr Sawyer reports personal fees from
Medtronic. Dr Mejilla reports personal fees from
Medtronic and grants from Genentech/Roche.
Drs Broderick, Chatterjee, and Jauch report fees
from Genentech for membership on the steering
committee of the PRISMS trial. Dr Levine reports
personal fees and nonfinancial support from
Genentech for membership on the steering
committee of the PRISMS Trial and other grants
from Genentech. Dr Romano reports personal fees
from Genentech for membership on the steering
committee of the PRISMS Trial and grants from
Genentech to the University of Miami to support his
role as principal investigator of the Mild and Rapidly
Improving Stroke Study. Dr Saver served as an
unpaid steering committee member advising on the
design and conduct of the PRSIMS trial under
a no-remuneration contract with Genentech.
Dr Saver also served as an unpaid site investigator
in the PRISMS trial, for which the University of
California received payments on the basis of clinical
trial contracts for the number of participants
enrolled. Dr Saver reports receiving contracted
hourly payments and travel reimbursement from
Medtronic, Stryker, and Neuravi, and Boehringer
Ingelheim (prevention only) for service on trial
steering committee(s), making recommendations
regarding best approaches to rigorous trial design
jama.com
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018
and conduct. The University of California, Dr Saver’s
institution, has patent rights in retrieval devices for
stroke. Dr Vagal reports a grant from Genentech to
the University of Cincinnati for his role as the
principal investigator of the PRISMS Imaging Core.
Drs Purdon and Devenport are full-time employees
of Genentech. Dr Yeatts reports personal fees from
Genentech for membership on the steering
committee of the PRISMS Trial and fees contracted
to the institution from C.R. Bard Inc for serving on
a data monitoring committee. No other disclosures
were reported.
Funding/Support: Genentech Inc funded the trial.
Role of the Funder/Sponsor: The initial protocol
was proposed to Genentech Inc by the academic
investigators for consideration. After requested
modifications, Genentech Inc sponsored the study
and participated in the writing, design, and conduct
of the trial, including distribution of the study drug
and oversight of study management. The sponsor
did not have access to or manage the data.
A steering committee composed of academic
investigators and sponsor representatives provided
recommendations throughout the trial. The
sponsor controlled and made the decision to
terminate the trial. The first draft of the manuscript
and its revisions were drafted by the academic lead
principal investigator (Dr Khatri). The sponsor,
along with all coauthors, participated in data
interpretation and critical review of the publication
and reviewed the tables, listings, and graphs to
ensure the accuracy of the data analysis and
interpretation. The decision to submit for
publication was made jointly by the steering
committee and the sponsor. The sponsor did not
have the right to veto the publication or the
planned journal of submission.
PRISMS Investigators (asterisks indicate local
principal investigator): University of Cincinnati
Medical Center: Opeolu Adeoye, MD, Joseph
Broderick, MD, Elisheva Coleman, MD, Stacie
Demel, DO, PhD, Bryan Eckerle, MD, Matthew
Flaherty, MD, Anna Gensic, MD, Sabreena Gillow,
MD, Adam Jasne, MD, Daniel Kanter, MD, Rahul
Karamchandani, MD, Brian Katz, MD, Pooja Khatri,
MD, Brett Kissela, MD, Dawn Kleindorfer, MD*,
Natalie Kreitzer, MD, Julian Macedo, MD, Erin
McDonough, MD, Brian Oloizia, MD, Arthur Pancioli,
MD, Blake Smith, MD, Michael Star, MD, Brian
Stettler, MD, Kyle Walsh, MD, Daniel Woo, MD;
Chattanooga Center for Neurologic Research:
Thomas Devlin, MD, PhD*; Buffalo General Medical
Center: Robert Sawyer, MD*; University of
Pittsburgh Cancer Institute: Maxim Hammer, MD,
Ashutosh Jadhav, MD, PhD, Tudor Jovin, MD,
Cynthia Kenmuir,MD, Marcelo Rocha, MD, Matthew
Starr, MD*, Lawrence Wechsler, MD; Riverside
Methodist Hospital: Brian Katz, MD, Jennifer
Mejilla, DO*; Moses H Cone Memorial Hospital:
Pramodkumar Sethi, MD*; University of Mississippi
Medical Center: Rebecca Sugg, MD*; West Virginia
University Hospital: Amelia Adcock, MD,
Muhammad Alvi, MD, JohnBrick, MD*, Matthew
Smith, MD; Temple University Hospital: Paul Katz,
MD*; Renown Institute for Neurosciences: Jorge
Ivan Lopez, MD*;Northwestern Memorial Hospital:
Shyam Prabhakaran, MD*; Christiana Care Health
System: Valerie Dechant, MD, Jason Nomura, MD*,
Jonathan Raser-Schramm, MD; Wright State
University: Bradley Jacobs, MD*; Poudre Valley
Health System: Gerald McIntosh, MD*; Icahn School
of Medicine at Mount Sinai: Stanley Tuhrim, MD*;
(Reprinted) JAMA July 10, 2018 Volume 320, Number 2
Original Investigation Research
Barnabas Health /Shore Neurology: Gerald Ferencz,
MD*, John Sarris, MD; Valley Baptist Medical
Center: Ameer Hassan, MD*; University of
Wisconsin: Edward Luke Bradbury, MD*; University
of Utah: Jana Wold, MD*; Inova Fairfax Hospital:
John Cochran, MD*; Alexian Brothers: Vipan Gupta,
MD*; Jackson Memorial Hospital: Moayd Alkhalifah,
MD, Negar Asdaghi, MD, Varun Chaubal, MD,
George Dillon, MD, Andrea Escobar, MD, Paul
Gadient, MD, Sebastian Koch, MD, Avi Landman,
Amer Malik, MD*, Erika Marulanda-Londono, MD,
Gustavo Ortiz, MD, Jose Romano, MD, Pankaj
Sharma, MD, Clinton Wright, MD; University of
Louisville: Wei Liu, MD, PhD, Kerri Remmel, MD,
PhD*, Jignesh Shah, MD, Elizabeth Wise, APRN;
University of South Carolina: Souvic Sen, MD*; St
Jude Heritage Medical Group: Johnson Moon, MD*;
Parkview Research Center: Fen-Lei Chang, MD,
PhD*; Colorado Neurological Institute: Judd Jensen,
MD*; Akron General Medical Center: James Gebel,
MD*; Medical University of South Carolina (MUSC):
Christine Holmstedt, DO*; University of California
San Diego: Kunal Agrawal, MD, Maysun Ali, DO,
Ronelyn Chavez, Robert Claycomb, MD, Lovella
Hailey, ANP-BC, Thomas Hemmen MD, PhD, James
Ho, MD, Branko Huisa, MD, Brett Meyer, MD, Dawn
Meyer, PhD, RN, Royya Modir, MD*, Melissa Mortin,
ANP-BC, Rajiv Narula, MD, David Nguyen, DO,
Mohsen Pirastehfar, MD, Hami Ramani, DO, Karen
Rapp, RN, Kathleen Rickes, Kristin Woods; Swedish
Medical Center: Aaron Stayman, MD*; Columbia
University: Joshua Willey, MD*; Sinai Hospital of
Baltimore: Adrian Goldszmidt, MD*; Cleveland
Clinic: Ken Uchino, MD*; University of California Los
Angeles: Allison Arch, MD, Arun Chhabra, MD,
Lindsey Frischmann, DO, Jason Hinman, MD, PhD,
Mersedeh Bahr Hosseini, MD, David Liebeskind,
MD, Konark Malhotra, MD, Neal Rao, MD, Latisha
Sharma, MD, Sidney Starkman, MD*, Xander Tang,
PhD, Anita Tipirneni, MD, Parampreet Walia, MD;
Houston Methodist Hospital: David Chiu, MD*;
Detroit Receiving Hospital: Mohammed Ibrahim,
MD*; University of Kentucky: Susanth Aroor, MBBS,
Sourabh Lahoti, MBBS, Jessica Lee, MD*, Danny
Rose, MD; Nova Clinical Research: Francisco
Esparza, MD*; NYU Lutheran Medical Center: Nada
Abou Fayssal, MD*; University of Alabama at
Birmingham: Michael Lyerly, MD*; Case Western
Reserve University: Jon Schrock, MD*;Cedars Sinai
Medical Center: Shlee Song, MD*; SUNY Downstate
Medical Center: Yongwoo Kim, MD, Steven Levine,
MD*, Adrian Marchidann, MD, Diana Rojas-Soto,
MD, Jerome Salvani, MD, Artem Sunik, MD; Banner
– University Medical Center Phoenix: Douglas Franz,
MD*; Rush University Medical Center: Sarah Song,
MD, MPH*; The Neurology and Pain Clinic:
Mahmoud Abu-Ata, MD, Mohammed Alhatou, MD*;
Overlook Hospital: Robert Felberg, MD*;
Gunderson Health System: Mouhammed Kubbani,
MD*, Michael Leone, MD, Ragasri Kumar, DO;
Washington University: Andria Ford, MD, Laura
Heitsch, MD, Jin-Moo Lee, MD, PhD*; University of
Missouri: Brandi French, MD*; University of Toledo
Medical Center: Syed Zaidi, MD*.
Disclaimer: Dr Saver, an associate editor for JAMA,
was not involved in the editorial review of or
decision to publish this article.
Meeting Presentation: Results from this study
were presented at the International Stroke
Conference; January 25, 2018; Los Angeles,
California.
165
 Research Original Investigation
REFERENCES
1. Messé SR, Khatri P, Reeves MJ, et al. Why are
acute ischemic stroke patients not receiving IV tPA?
results from a national registry. Neurology. 2016;87
(15):1565-1574. doi:10.1212/WNL
.0000000000003198
2. Fischer U, Baumgartner A, Arnold M, et al. What
is a minor stroke? Stroke. 2010;41(4):661-666.
doi:10.1161/STROKEAHA.109.572883
3. Khatri P, Conaway MR, Johnston KC; Acute
Stroke Accurate Prediction Study Investigators.
Ninety-day outcome rates of a prospective cohort
of consecutive patients with mild ischemic stroke.
Stroke. 2012;43(2):560-562. doi:10.1161/STROKEAHA
.110.593897
4. Schwamm LH, Ali SF, Reeves MJ, et al. Temporal
trends in patient characteristics and treatment with
intravenous thrombolysis among acute ischemic
stroke patients at Get With The Guidelines–Stroke
hospitals. Circ Cardiovasc Qual Outcomes. 2013;6
(5):543-549. doi:10.1161/CIRCOUTCOMES.111.000095
5. Asdaghi N, Wang K, Ciliberti-Vargas MA, et al;
FL-PR CReSD Investigators and Collaborators.
Predictors of thrombolysis administration in mild
stroke: Florida-Puerto Rico Collaboration to Reduce
Stroke Disparities. Stroke. 2018;49(3):638-645.
doi:10.1161/STROKEAHA.117.019341
6. Emberson J, Lees KR, Lyden P, et al; Stroke
Thrombolysis Trialists’ Collaborative Group. Effect
of treatment delay, age, and stroke severity on the
effects of intravenous thrombolysis with alteplase
for acute ischaemic stroke: a meta-analysis of
individual patient data from randomised trials.
Lancet. 2014;384(9958):1929-1935. doi:10.1016
/S0140-6736(14)60584-5
7. 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. 2018;49(3):e46-e110. doi:10.1161/STR
.0000000000000158
8. Sandercock P, Wardlaw JM, Lindley RI, et al;
IST-3 Collaborative Group. The benefits and harms
of intravenous thrombolysis with recombinant
tissue plasminogen activator within 6 h of acute
ischaemic stroke (the Third International Stroke
166 JAMA July 10, 2018 Volume 320, Number 2 (Reprinted)
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a Kaohsiung Med Univ User on 07/10/2018
Alteplase vs Aspirin and Functional Outcome in Ischemic Stroke With Minor Nondisabling Neurologic Deficits
Trial [IST-3]): a randomised controlled trial. Lancet.
2012;379(9834):2352-2363. doi:10.1016/S0140-6736
(12)60768-5
9. Yeatts SD, Broderick JP, Chatterjee A, et al.
Alteplase for the treatment of acute ischemic stroke
in patients with low National Institutes of Health
Stroke Scale and not clearly disabling deficits
(Potential of rtPA for Ischemic Strokes with Mild
Symptoms PRISMS): rationale and design
[published online January 1, 2018]. Int J Stroke.
doi:10.1177/1747493018765269
10. Jauch EC, Saver JL, Adams HP Jr, et al;
American Heart Association Stroke Council; Council
on Cardiovascular Nursing; Council on Peripheral
Vascular Disease; Council on Clinical Cardiology.
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. 2013;44(3):870-947. doi:10.1161/STR
.0b013e318284056a
11. Zhao W, Ciolino J, Palesch Y. Step-forward
randomization in multicenter emergency treatment
clinical trials. Acad Emerg Med. 2010;17(6):659-665.
doi:10.1111/j.1553-2712.2010.00746.x
12. Zhao W, Weng Y. Block urn design—a new
randomization algorithm for sequential trials with
two or more treatments and balanced or
unbalanced allocation. Contemp Clin Trials. 2011;32
(6):953-961. doi:10.1016/j.cct.2011.08.004
13. Wei LJ. The adaptive biased coin design for
sequential experiments. Ann Stat. 1978;6(1):92-100.
doi:10.1214/aos/1176344068
14. National Institute of Neurological Disorders
and Stroke rt-PA Stroke Study Group. Tissue
plasminogen activator for acute ischemic stroke.
N Engl J Med. 1995;333(24):1581-1587. doi:10.1056
/NEJM199512143332401
15. Wahlgren N, Ahmed N, Dávalos A, et al;
SITS-MOST Investigators. Thrombolysis with
alteplase for acute ischaemic stroke in the
Safe Implementation of Thrombolysis in
Stroke–Monitoring Study (SITS-MOST): an
observational study. Lancet. 2007;369(9558):275-
282. doi:10.1016/S0140-6736(07)60149-4
16. Khatri P, Tayama D, Cohen G, et al; PRISMS and
IST-3 Collaborative Groups. Effect of intravenous
recombinant tissue-type plasminogen activator in
patients with mild stroke in the Third International
Stroke Trial-3: post hoc analysis. Stroke. 2015;46(8):
2325-2327. doi:10.1161/STROKEAHA.115.009951
17. 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.
JAMA Neurol. 2015;72(4):423-431. doi:10.1001
/jamaneurol.2014.4354
18. Mehta RH, Cox M, Smith EE, et al; Get With the
Guidelines–Stroke Program. Race/ethnic
differences in the risk of hemorrhagic complications
among patients with ischemic stroke receiving
thrombolytic therapy. Stroke. 2014;45(8):2263-2269.
doi:10.1161/STROKEAHA.114.005019
19. NINDS t-PA Stroke Study Group. Intracerebral
hemorrhage after intravenous t-PA therapy for
ischemic stroke. Stroke. 1997;28(11):2109-2118.
doi:10.1161/01.STR.28.11.2109
20. Demaerschalk BM, Kleindorfer DO, Adeoye
OM, et al; American Heart Association Stroke
Council and Council on Epidemiology and
Prevention. Scientific rationale for the inclusion
and exclusion criteria for intravenous alteplase
in acute ischemic stroke: a statement for
healthcare professionals from the American
Heart Association/American Stroke Association.
Stroke. 2016;47(2):581-641. doi:10.1161/STR
.0000000000000086
21. Rajajee V, Kidwell C, Starkman S, et al. Early MRI
and outcomes of untreated patients with mild or
improving ischemic stroke. Neurology. 2006;67(6):
980-984. doi:10.1212/01.wnl.0000237520.88777.71
22. Nedeltchev K, Schwegler B, Haefeli T, et al.
Outcome of stroke with mild or rapidly improving
symptoms. Stroke. 2007;38(9):2531-2535.
doi:10.1161/STROKEAHA.107.482554
23. Smith EE, Fonarow GC, Reeves MJ, et al.
Outcomes in mild or rapidly improving stroke not
treated with intravenous recombinant tissue-type
plasminogen activator: findings from Get With the
Guidelines–Stroke. Stroke. 2011;42(11):3110-3115.
doi:10.1161/STROKEAHA.111.613208
24. Ovbiagele B, Lyden PD, Saver JL; VISTA
Collaborators. Disability status at 1 month is a
reliable proxy for final ischemic stroke outcome.
Neurology. 2010;75(8):688-692. doi:10.1212/WNL
.0b013e3181eee426
jama.com