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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).

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

M
ild stroke is the most commonly cited reason for
nonuse of intravenous alteplase among patients Key Points
with ischemic stroke who present to the hospital
Question Does intravenous alteplase benefit patients with
within the guideline-based eligible treatment window of 4.5 ischemic stroke presenting with minor neurologic deficits that are
hours. 1 Yet prospective data suggest that 30% of such judged not clearly disabling?
patients have functional disability at 90 days after stroke.2,3
Findings In this randomized clinical trial that included 313 of a
Reasons for the development of disability might include
planned 948 patients with acute ischemic stroke, there was no
underappreciated deficits, stroke progression, or medical significant difference in the adjusted percentage with favorable
comorbidities leading to additional medical events, including functional outcome at 90 days for those treated with alteplase vs
recurrent stroke. Vessel reperfusion may avert disability aspirin (78% vs 81%).
because of the first 2 of these reasons. Clinical use of
Meaning Although the study did not demonstrate a significant
alteplase for ischemic stroke with low National Institutes of benefit of alteplase for patients with minor nondisabling acute
Health Stroke Scale (NIHSS) scores has increased in recent ischemic stroke, the very early study termination precludes any
years, presumably based on concern for this substantial post- definitive conclusions.
stroke disability.4,5
Although alteplase is the standard of care for patients Patient Selection and Randomization
with ischemic stroke and disabling deficits regardless Inclusion criteria included clinical diagnosis of acute ische-
of severity judged by NIHSS scores,6,7 the optimal manage- mic stroke, age 18 years or older, NIHSS score of 0 to 5, and
ment of patients with not clearly disabling deficits is unclear. deficits judged to not be clearly disabling at presentation.
Most major trials of alteplase (NINDS Parts 1 and 2; ECASS 1, A clearly disabling deficit was operationally defined as a defi-
2, and 3; Atlantis Parts A and B; and EPITHET) explicitly cit that, if unchanged, would prevent the patient from per-
excluded varying subsets of patients with the mildest defi- forming basic activities of daily living (ie, bathing, ambulat-
cits (see eTable 1 in Supplement 1 for exclusion criteria). ing, toileting, hygiene, and eating) or returning to work. Local
The IST 3 trial permitted enrollment of patients with minor clinicians made this determination in consultation with
deficits, but only when the local enrolling physician had patients and available family. Intensive study efforts to facili-
personal equipoise regarding benefit and without collecting tate uniform application of enrollment criteria, including
data to distinguish which enrolled patients had disabling web-based and smartphone-based patient selection tools,
vs nondisabling deficits at presentation.8 In the absence of pocket laminated cards, and tutorials, were implemented.
definitive evidence, current US clinical guidelines indicate Local investigators were also advised to ensure that patients
uncertainty regarding use of alteplase in patients with low could walk unassisted. Exclusion criteria included prestroke
NIHSS scores and nondisabling deficits (strength of recom- disability (modified Rankin Scale score of 2-6), dysphagia,
mendation class IIb [weak]; quality of evidence level C-LD intracranial hemorrhage on acute neuroimaging, and
[limited data]).7 other standard contraindications to intravenous alteplase
The purpose of this study was to test the efficacy and as reflected in the clinical guidelines that were current dur-
safety of alteplase administered within 3 hours of onset of ing the trial.10
ischemic stroke symptoms among patients presenting with Participants were randomized in a 1:1 ratio stratified by site.
minor deficits (NIHSS score of 0-5) judged not clearly dis- A step-forward randomization procedure was used to ensure
abling at presentation. 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
Methods
response system. Balance within site was controlled via the urn
Trial Design method, which drew the first treatment assignment from
The study was approved by institutional review boards for a metaphorical active urn containing a complete block of treat-
all study sites, and all enrolled patients provided written ment assignments and then placed it into an inactive urn; a
informed consent. The protocol, protocol amendment, and minimally balanced set of assignments was returned to facili-
statistical analysis plan are provided in Supplement 2, tate balance.12 The overall allocation was balanced using a bi-
Supplement 3, and Supplement 4, and detailed methods ased coin method in which treatments were allocated with un-
have been published.9 equal but not deterministic probability when imbalance
The Potential of rtPA for Ischemic Strokes With Mild achieved preset criteria.13 A patient was considered enrolled
Symptoms (PRISMS) trial was designed as a phase 3b, ran- when the study treatment bolus was administered.
domized, double-blind clinical trial testing the safety and
efficacy of intravenous alteplase administered within 3 hours Study Intervention
of symptom onset (time from witnessed onset or time from Participants were randomized to receive either intravenous al-
last known well time if unwitnessed). The time window of 3 teplase at standard dosing for ischemic stroke (0.9 mg/kg) with
hours was chosen to harmonize with the US Food and Drug a placebo oral aspirin or oral aspirin, 325 mg, with placebo in-
Administration–labeled time window for use of alteplase in travenous alteplase. The placebos were identical in appear-
patients with disabling ischemic stroke. ance to active study drugs to maintain treatment blinding of

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

patients and investigators. Intravenous study treatment was consider the generalizability of the results. All adverse events,
to be administered within 3 hours of stroke onset. The same regardless of relationship to study treatment, were reported
was encouraged for the oral study treatment; however, it could until 30 days after study treatment administration. After 30 days,
be administered up to 24 hours after symptom onset at insti- only data on serious adverse events, nonserious adverse events
tutions that required formal swallow evaluation. Clinical man- of special interest (consisting of sICH events not otherwise re-
agement after study treatment administration was to be in ac- ported, stroke recurrence, or suspected transmission of an in-
cordance with institutional protocols and clinical guidelines fectious agent via a medicinal product), and adverse events re-
for care after alteplase administration. The study mandated sulting in withdrawal from the study were collected.
follow-up neuroimaging (computed tomography or magnetic Concomitant medication use was recorded at all visits.
resonance imaging per institutional standard of care) within Study monitors performed ongoing source data verifica-
22 to 36 hours after intravenous study treatment bolus. tion. An independent data monitoring committee, composed
of 1 stroke neurologist, 1 emergency physician, 1 neuroradi-
Study Outcomes ologist, and 1 statistician, provided ongoing review of accu-
The primary outcome end point was a modified Rankin Scale mulating adverse events. The independent data monitoring
(mRS) score of 0 or 1 (total range, 0 [symptom free] to 6 [dead]), committee was also charged with conducting the interim fu-
reflecting favorable functional outcome, evaluated at 90 days tility analysis, planned to take place after 50% of participants
after enrollment and adjusted for age, time from symptom on- had completed follow-up. Two independent, blinded neuro-
set to treatment, and baseline NIHSS score. radiologists at the central imaging core interpreted relevant
Secondary outcome measures of efficacy, also assessed at imaging data.
90 days, consisted of level of disability (assessed by the 6-level Determination of presenting events as either ischemic
ordinal mRS score, collapsing levels 5 and 6) and global favor- cerebral events (stroke or transient ischemic attack) or neuro-
able recovery, which was defined as an mRS score of 0 or 1, vascular mimic was carried out by site investigators. For
NIHSS score of 0 or 1, Barthel Index of 95 or 100 (total range, patients with neuroimaging evidence of new infarction,
0 [totally dependent] to 100 [patient performs self-care and site investigators’ diagnoses of ischemic stroke were ac-
mobility without assistance]), and Glasgow Outcome Scale cepted without further review. For patients without neuroim-
score of 1 (total range, 1 [good recovery] to 5 [death]). aging evidence of new infarction, central review was per-
Exploratory outcome measures of efficacy included formed by steering committee neurologists (P.K. and J.G.R.)
ambulatory speed (10-Meter Walk Test), which assesses com- prior to database lock and without unblinding, indepen-
fortable walking speed over 6 m; stroke-related quality of life dently rendering diagnoses of ischemic cerebral event or
(Stroke Impact Scale 16) score, which ranges from 0 to 100, neurovascular-mimicking condition. When assessments were
with higher scores indicating better physical performance discordant, discussions were held between the site investiga-
(strength, hand function, physical and instrumental activities tor and central reviewer to ensure that all relevant data were
of daily living, and mobility); and general health-related considered in the final determination. The site principal
quality of life (EuroQoL Group EQ-5D) score, which ranges investigators then made a final diagnostic determination.
from 0 (death) to 1 (perfect health) at 90 days. Cognitive out-
comes and a brief depression assessment were also assessed Statistical Analysis
(results not presented in this article). The trial was designed to detect a 9% absolute difference in
The primary safety end point was symptomatic intracra- the proportion of participants with favorable outcome with
nial hemorrhage (sICH), defined as any neurologic decline 80% power, using a 1-sided type I error rate of .025 to test the
within 36 hours attributed to ICH by local investigators; this superiority hypothesis, under the assumption that 65% of par-
definition was modified from the NINDS-tPA trials’ defini- ticipants randomized to receive aspirin would experience a fa-
tion requiring only a temporal association of decline with ICH.14 vorable outcome, and allowing for 1 interim futility analysis.
Other safety measures included an alternate definition of sICH The sample size calculation was 1-sided to reflect the objec-
(a deterioration in NIHSS score of ≥4 with a radiological pa- tive of establishing the superiority of alteplase over standard
renchymal hemorrhage type 2),15 any radiologic ICH within 36 medical care. Accounting for these assumptions, the neces-
hours, all-cause mortality within 90 days, stroke-related and sary sample size was calculated to be 856 participants. The
neurologic deaths within 90 days, and the severity and spec- sample size was adjusted to 948 participants to account for di-
trum of all adverse events. lution of the treatment effect associated with nonadherence
parameters (loss to follow-up, treatment crossovers, and neu-
Data Collection and Monitoring rovascular mimics [stroke and transient ischemic attack]). The
Key clinical and radiological data were collected, including planned 9% effect size was derived from a previously pub-
(1) baseline neuroimaging and NIHSS score; (2) 22- to 36-hour lished post hoc analysis of the IST-3 trial subset of patients that
repeat neuroimaging and NIHSS score; (3) 5-day (or dis- met the PRISMS trial’s eligibility criteria (with the exception
charge if sooner) NIHSS score, stroke etiology, and discharge lo- that qualifying deficits could not be ascertained as not clearly
cation; (4) 30-day mRS score by telephone follow-up; and disabling).16 The steering committee expected that treat-
(5) final 90-day mRS score, along with secondary and explor- ment effects of less than 9% were still likely to be clinically
atory outcomes, assessed in person when possible. Ethnicity and meaningful. It was anticipated that a higher rate of favorable
race were self-reported (fixed categories) and were collected to outcome in participants randomized to aspirin and a lower rate

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

of nonadherence parameters would allow detection of a lower A post hoc analysis evaluated the likelihood of alteplase
absolute treatment effect with the same 80% power. benefit, given study findings, for clinical interpretation and fu-
The trial initially intended to test the primary end point ture trial planning purposes. Using an uninformative prior on
via a Cochran-Mantel-Haenszel hypothesis test, stratified by the treatment-specific unadjusted outcome proportions, the
age (<65 vs ≥65 years), time from symptom onset to treat- posterior distribution of the risk difference was constructed via
ment (0-2 vs >2 hours), and pretreatment NIHSS score (0-2 vs simulation to calculate the probability of alteplase benefit.
3-5). Because the trial was terminated early by the sponsor This uninformative prior β[1, 1] reflects a uniform distribution
for enrollment below target, it was recognized that the study on the interval [0, 1]; this prior was used to construct the pos-
would be underpowered to formally test the hypothesis. terior distribution of the risk difference via simulation to cal-
Therefore, the statistical analysis plan was finalized, prior to culate the probability of alteplase benefit. The analysis was not
database lock and unblinding, to evaluate the size of an effect adjusted for differences in age, time to treatment, or baseline
(and its associated uncertainty). The updated plan was to NIHSS score, as with the primary outcome. The trial steering
evaluate the hypothesis by examining the adjusted risk dif- committee clinicians were surveyed in December 2015 (prior
ference (point values and 95% CIs) in the rate of the primary to study termination and without unblinding) to propose ef-
outcome (mRS score of 0 or 1) using a linear model, which fect sizes that would change clinical practice toward treat-
included treatment assignment, age, time from symptom ment in the context of various associated sICH risk rates of al-
onset to study treatment, and baseline NIHSS score as con- teplase. They suggested that an alteplase effect size as low as
tinuous covariates. 6% might still change clinical practice toward treatment in the
A sensitivity analysis confined to patients with final context of a 3% increased sICH risk. Therefore, the post hoc
diagnoses of acute cerebral ischemia was also planned. Addi- analysis considered the likelihood of (1) any benefit of al-
tional exploratory analyses of the primary outcome were pre- teplase and (2) an absolute benefit of alteplase of more than 6%.
specified to test the consistency of the findings: (1) unad- For statistical analyses, SAS version 9.2 or higher (SAS In-
justed risk difference; (2) logistic regression, adjusting for stitute Inc) was executed on the SunOS version 5.10 (SUN 64)
pretreatment NIHSS score, age, and time to treatment; platform. The post hoc Bayesian analysis was executed
(3) risk difference adjusted for additional potential covariate using WinBUGS14.
imbalances using a propensity score; and (4) repeated-
measures model (in which mRS score outcomes at day 30 and Early Study Termination
day 90 were modeled jointly by a logistic regression). Study enrollment was terminated on December 20, 2016, by
Missing primary outcome data (90-day mRS scores) were the sponsor, prior to database lock and without unblinding,
prespecified for imputation with the 30-day mRS score re- because of patient recruitment below target. This was a
sult, when available, and otherwise imputed via hot-deck financial decision based on the fact that the trial could not be
method, which randomly selected the outcome value from a completed within the allotted funds in the specified time
pool of patients with observed mRS scores matched by treat- frame. The interim futility analysis was not completed for
ment group, age, pretreatment NIHSS score, and time of symp- consideration of this decision because less than 50% of
tom onset. patients had completed follow-up. Neither the sponsor, the
The secondary outcome of ordinal analysis was achieved independent data monitoring committee, nor the steering
by fitting a proportional odds model with mRS score at day 90 committee evaluated study data as part of the decision to ter-
as the dependent variable and treatment group, pretreat- minate the trial. The academic members of the steering com-
ment NIHSS score, age, and time from symptom onset to treat- mittee recommended against termination but accepted this
ment as the continuous predictors. Quadratic terms for the con- financial decision by the sponsor. The sponsor assured that
tinuous covariates would be added to the model, if the Wald the accrued data would be fully analyzed and disseminated
P value for the quadratic term was less than 0.1. The propor- to maximize the contributions of the enrolled patients and
tional odds assumption was tested by the score test. thereby maintain ethical responsibilities. The independent
The secondary outcome of global favorable recovery data monitoring committee had 2 reviews of aggregate data
was derived from a generalized linear model with logit-link and recruitment rates but did not participate in the decision
function, computed with generalized estimating equations. to terminate enrollment; the committee was informed of the
This global statistic simultaneously evaluated the effect in decision after it was made. After enrollment was halted, all
all 4 outcome measures (mRS score of 0 or 1, NIHSS score of enrolled patients were to complete protocol-specified proce-
0 or 1, Barthel Index of 95 or 100, and Glasgow Outcome dures through 90-day follow-up. As a result of the early ter-
Scale score of 1). mination of the study, the plan for analysis of the primary
Analyses for heterogeneity of treatment effect for the pri- outcome was revised as detailed above.
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-
Results
teraction of each subgroup and treatment variable to the lo- Study Population
gistic regression model. A possible interaction was prespeci- From May 1, 2014, to December 20, 2016, 313 patients were en-
fied as P < .10. rolled, with a mean age of 62 years (SD, 13 years), 144 (46%)

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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 17 Missing 90-d primary outcome datae
13 Lost to follow-up 10 Lost to follow-up
1 Withdrew consent 5 mRS score not assessed within 90-d
1 Inadequate source documentation 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 Two patients received oral placebo instead of oral aspirin because of pharmacy
screening log data were not available. The total number randomized does not error; 1 patient was determined to have an aspirin allergy after enrollment; and
reflect the enrolled population because in step-forward randomization, a “use 1 patient had neurologic worsening and became eligible for intravenous
next” drug kit was assigned prior to a potential trial candidate’s arrival at an alteplase treatment as standard of care.
emergency department. Many patients who arrived at an emergency d
Missing data were imputed using the 30-day modified Rankin Scale (mRS)
department after a kit was designated were not eligible and were not enrolled score for 12 patients and hot-deck imputation for 3 patients.
in the trial. A patient was considered enrolled when the study treatment bolus e
Missing data were imputed using the 30-day mRS score for 13 patients and
was administered.
hot-deck imputation for 4 patients.
b
These 2 patients received intravenous placebo instead of intravenous
alteplase because of pharmacy error.

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


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

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

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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.

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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

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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- robust imputation.24
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
Conclusions
minimize this selection bias. Third, the definition of “not Among patients with minor nondisabling acute ischemic
clearly disabling” was subjective and required interpretation stroke, treatment with alteplase compared with aspirin did
by individual clinicians. Although efforts were made to not increase the likelihood of favorable functional outcome
encourage consistency in assessment of eligible patients, this at 90 days. However, the very early study termination pre-
cannot be confirmed. Fourth, the loss to follow-up at day 90 cludes any definitive conclusions, and additional research
was relatively high. However, mRS scores from day 30 may be warranted.

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

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

Neurology, University of California, Los Angeles and conduct. The University of California, Dr Saver’s Barnabas Health /Shore Neurology: Gerald Ferencz,
(Saver); Genentech, South San Francisco, California institution, has patent rights in retrieval devices for MD*, John Sarris, MD; Valley Baptist Medical
(Purdon, Devenport); Everest Clinical Research, stroke. Dr Vagal reports a grant from Genentech to Center: Ameer Hassan, MD*; University of
Markham, Ontario, Canada (Pavlov). the University of Cincinnati for his role as the Wisconsin: Edward Luke Bradbury, MD*; University
Author Contributions: Dr Khatri had full access to principal investigator of the PRISMS Imaging Core. of Utah: Jana Wold, MD*; Inova Fairfax Hospital:
all of the data in the study and takes responsibility Drs Purdon and Devenport are full-time employees John Cochran, MD*; Alexian Brothers: Vipan Gupta,
for the integrity of the data and the accuracy of the of Genentech. Dr Yeatts reports personal fees from MD*; Jackson Memorial Hospital: Moayd Alkhalifah,
data analysis. Genentech for membership on the steering MD, Negar Asdaghi, MD, Varun Chaubal, MD,
Concept and design: Khatri, Kleindorfer, Broderick, committee of the PRISMS Trial and fees contracted George Dillon, MD, Andrea Escobar, MD, Paul
Chatterjee, Jauch, Saver, Purdon, Yeatts. to the institution from C.R. Bard Inc for serving on Gadient, MD, Sebastian Koch, MD, Avi Landman,
Acquisition, analysis, or interpretation of data: a data monitoring committee. No other disclosures Amer Malik, MD*, Erika Marulanda-Londono, MD,
Khatri, Kleindorfer, Devlin, Sawyer, Starr, Mejilla, were reported. Gustavo Ortiz, MD, Jose Romano, MD, Pankaj
Broderick, Jauch, Levine, Romano, Saver, Vagal, Funding/Support: Genentech Inc funded the trial. Sharma, MD, Clinton Wright, MD; University of
Devenport, Pavlov, Yeatts. Louisville: Wei Liu, MD, PhD, Kerri Remmel, MD,
Role of the Funder/Sponsor: The initial protocol PhD*, Jignesh Shah, MD, Elizabeth Wise, APRN;
Drafting of the manuscript: Khatri, Sawyer, was proposed to Genentech Inc by the academic
Chatterjee, Jauch, Vagal, Devenport. University of South Carolina: Souvic Sen, MD*; St
investigators for consideration. After requested Jude Heritage Medical Group: Johnson Moon, MD*;
Critical revision of the manuscript for important modifications, Genentech Inc sponsored the study
intellectual content: Kleindorfer, Devlin, Sawyer, Parkview Research Center: Fen-Lei Chang, MD,
and participated in the writing, design, and conduct PhD*; Colorado Neurological Institute: Judd Jensen,
Starr, Mejilla, Broderick, Jauch, Levine, Romano, of the trial, including distribution of the study drug
Saver, Vagal, Purdon, Devenport, Pavlov, Yeatts. MD*; Akron General Medical Center: James Gebel,
and oversight of study management. The sponsor MD*; Medical University of South Carolina (MUSC):
Statistical analysis: Saver, Purdon, Devenport, did not have access to or manage the data.
Pavlov. Christine Holmstedt, DO*; University of California
A steering committee composed of academic San Diego: Kunal Agrawal, MD, Maysun Ali, DO,
Obtained funding: Khatri, Jauch. investigators and sponsor representatives provided
Administrative, technical, or material support: Ronelyn Chavez, Robert Claycomb, MD, Lovella
recommendations throughout the trial. The Hailey, ANP-BC, Thomas Hemmen MD, PhD, James
Kleindorfer, Devlin, Starr, Chatterjee, Jauch, Saver. sponsor controlled and made the decision to
Supervision: Khatri, Jauch, Levine, Romano, Saver, Ho, MD, Branko Huisa, MD, Brett Meyer, MD, Dawn
terminate the trial. The first draft of the manuscript Meyer, PhD, RN, Royya Modir, MD*, Melissa Mortin,
Devenport. and its revisions were drafted by the academic lead ANP-BC, Rajiv Narula, MD, David Nguyen, DO,
Conflict of Interest Disclosures: All authors have principal investigator (Dr Khatri). The sponsor, Mohsen Pirastehfar, MD, Hami Ramani, DO, Karen
completed and submitted the ICMJE Form for along with all coauthors, participated in data Rapp, RN, Kathleen Rickes, Kristin Woods; Swedish
Disclosure of Potential Conflicts of Interest. interpretation and critical review of the publication Medical Center: Aaron Stayman, MD*; Columbia
Dr Khatri reports payment to her university and reviewed the tables, listings, and graphs to University: Joshua Willey, MD*; Sinai Hospital of
department for research efforts from Genentech ensure the accuracy of the data analysis and Baltimore: Adrian Goldszmidt, MD*; Cleveland
(lead PI of PRISMS), Neurospring (coinvestigator; interpretation. The decision to submit for Clinic: Ken Uchino, MD*; University of California Los
CREATE grant), Lumosa (data and safety publication was made jointly by the steering Angeles: Allison Arch, MD, Arun Chhabra, MD,
monitoring board and consultant), Cerenovus committee and the sponsor. The sponsor did not Lindsey Frischmann, DO, Jason Hinman, MD, PhD,
(investigator-initiated study, ENDO LOW PI) and the have the right to veto the publication or the Mersedeh Bahr Hosseini, MD, David Liebeskind,
National Institutes of Health/National Institute of planned journal of submission. MD, Konark Malhotra, MD, Neal Rao, MD, Latisha
Neurological Disorders and Stroke. Dr Khatri also PRISMS Investigators (asterisks indicate local Sharma, MD, Sidney Starkman, MD*, Xander Tang,
reports fees from Biogen (data and safety principal investigator): University of Cincinnati PhD, Anita Tipirneni, MD, Parampreet Walia, MD;
monitoring board) and Medpace/Novartis Medical Center: Opeolu Adeoye, MD, Joseph Houston Methodist Hospital: David Chiu, MD*;
(coinvestigator). Dr Khatri was an unpaid Broderick, MD, Elisheva Coleman, MD, Stacie Detroit Receiving Hospital: Mohammed Ibrahim,
consultant to EmstopA and received travel support Demel, DO, PhD, Bryan Eckerle, MD, Matthew MD*; University of Kentucky: Susanth Aroor, MBBS,
from Neuravi (academic workshop). Dr Kleindorfer Flaherty, MD, Anna Gensic, MD, Sabreena Gillow, Sourabh Lahoti, MBBS, Jessica Lee, MD*, Danny
reports personal fees from Genentech Speakers MD, Adam Jasne, MD, Daniel Kanter, MD, Rahul Rose, MD; Nova Clinical Research: Francisco
Bureau. Dr Devlin reports research support from Karamchandani, MD, Brian Katz, MD, Pooja Khatri, Esparza, MD*; NYU Lutheran Medical Center: Nada
Genentech. Dr Sawyer reports personal fees from MD, Brett Kissela, MD, Dawn Kleindorfer, MD*, Abou Fayssal, MD*; University of Alabama at
Medtronic. Dr Mejilla reports personal fees from Natalie Kreitzer, MD, Julian Macedo, MD, Erin Birmingham: Michael Lyerly, MD*; Case Western
Medtronic and grants from Genentech/Roche. McDonough, MD, Brian Oloizia, MD, Arthur Pancioli, Reserve University: Jon Schrock, MD*;Cedars Sinai
Drs Broderick, Chatterjee, and Jauch report fees MD, Blake Smith, MD, Michael Star, MD, Brian Medical Center: Shlee Song, MD*; SUNY Downstate
from Genentech for membership on the steering Stettler, MD, Kyle Walsh, MD, Daniel Woo, MD; Medical Center: Yongwoo Kim, MD, Steven Levine,
committee of the PRISMS trial. Dr Levine reports Chattanooga Center for Neurologic Research: MD*, Adrian Marchidann, MD, Diana Rojas-Soto,
personal fees and nonfinancial support from Thomas Devlin, MD, PhD*; Buffalo General Medical MD, Jerome Salvani, MD, Artem Sunik, MD; Banner
Genentech for membership on the steering Center: Robert Sawyer, MD*; University of – University Medical Center Phoenix: Douglas Franz,
committee of the PRISMS Trial and other grants Pittsburgh Cancer Institute: Maxim Hammer, MD, MD*; Rush University Medical Center: Sarah Song,
from Genentech. Dr Romano reports personal fees Ashutosh Jadhav, MD, PhD, Tudor Jovin, MD, MD, MPH*; The Neurology and Pain Clinic:
from Genentech for membership on the steering Cynthia Kenmuir,MD, Marcelo Rocha, MD, Matthew Mahmoud Abu-Ata, MD, Mohammed Alhatou, MD*;
committee of the PRISMS Trial and grants from Starr, MD*, Lawrence Wechsler, MD; Riverside Overlook Hospital: Robert Felberg, MD*;
Genentech to the University of Miami to support his Methodist Hospital: Brian Katz, MD, Jennifer Gunderson Health System: Mouhammed Kubbani,
role as principal investigator of the Mild and Rapidly Mejilla, DO*; Moses H Cone Memorial Hospital: MD*, Michael Leone, MD, Ragasri Kumar, DO;
Improving Stroke Study. Dr Saver served as an Pramodkumar Sethi, MD*; University of Mississippi Washington University: Andria Ford, MD, Laura
unpaid steering committee member advising on the Medical Center: Rebecca Sugg, MD*; West Virginia Heitsch, MD, Jin-Moo Lee, MD, PhD*; University of
design and conduct of the PRSIMS trial under University Hospital: Amelia Adcock, MD, Missouri: Brandi French, MD*; University of Toledo
a no-remuneration contract with Genentech. Muhammad Alvi, MD, JohnBrick, MD*, Matthew Medical Center: Syed Zaidi, MD*.
Dr Saver also served as an unpaid site investigator Smith, MD; Temple University Hospital: Paul Katz, Disclaimer: Dr Saver, an associate editor for JAMA,
in the PRISMS trial, for which the University of MD*; Renown Institute for Neurosciences: Jorge was not involved in the editorial review of or
California received payments on the basis of clinical Ivan Lopez, MD*;Northwestern Memorial Hospital: decision to publish this article.
trial contracts for the number of participants Shyam Prabhakaran, MD*; Christiana Care Health
enrolled. Dr Saver reports receiving contracted Meeting Presentation: Results from this study
System: Valerie Dechant, MD, Jason Nomura, MD*, were presented at the International Stroke
hourly payments and travel reimbursement from Jonathan Raser-Schramm, MD; Wright State
Medtronic, Stryker, and Neuravi, and Boehringer Conference; January 25, 2018; Los Angeles,
University: Bradley Jacobs, MD*; Poudre Valley California.
Ingelheim (prevention only) for service on trial Health System: Gerald McIntosh, MD*; Icahn School
steering committee(s), making recommendations of Medicine at Mount Sinai: Stanley Tuhrim, MD*;
regarding best approaches to rigorous trial design

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

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