Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous Tissue-Type Plasminogen Activator for Treatment of Acute StrokeThe Standard Treatment with Alteplase to Reverse Stroke (STARS) Study. JAMA. 2000;283(9):1145-1150. doi:10.1001/jama.283.9.1145
Author Affiliations: Stanford Stroke Center, Stanford University Medical Center, Palo Alto, Calif (Dr Albers); Dent Neurological Institute, Millard Fillmore Hospital, Buffalo, NY (Dr Bates); Oregon Stroke Center, Oregon Health Sciences Center, Portland, (Dr Clark); Thomas Jefferson University, Philadelphia, Pa (Dr Bell); Seton Hall University, Edison, NJ (Dr Verro); and Genentech Inc, San Francisco, Calif (Dr Hamilton).
Context Tissue-type plasminogen activator (tPA) is the only therapy for acute
ischemic stroke approved by the Food and Drug Administration.
Objective To assess the safety profile and to document clinical outcomes and adverse
events in patients treated with intravenous tPA for acute stroke in clinical
Design and Setting Prospective, multicenter study of consecutive patients enrolled between
February 1997 and December 1998 at 57 medical centers in the United States
(24 academic and 33 community).
Intervention Intravenous tPA (recombinant alteplase).
Patients Three hundred eighty-nine patients with a mean age of 69 years (range,
28-100 years); 55% were men.
Main Outcome Measures Time intervals between stroke symptom onset, hospital arrival, and treatment
with tPA; pretreatment computed tomographic scan results, intracerebral hemorrhage,
and major systemic bleeding. The modified Rankin Scale score was used to assess
clinical outcomes at 30 days.
Results Median time from stroke onset to treatment was 2 hours 44 minutes, and
the median baseline National Institutes of Health Stroke Scale score was 13.
The 30-day mortality rate was 13%. At 30 days after treatment, 35% of patients
had very favorable outcomes (modified Rankin score, 0-1) and 43% were functionally
independent (modified Rankin score, 0-2). Thirteen patients (3.3%) experienced
symptomatic intracerebral hemorrhage, including 7 who died. Twenty-eight patients
(8.2%) had asymptomatic intracerebral hemorrhage within 3 days of treatment
with tPA. Protocol violations were reported for 127 patients (32.6%), and
included treatment with tPA more than 3 hours after symptom onset in 13.4%,
treatment with anticoagulants within 24 hours of tPA administration in 9.3%,
and tPA administration despite systolic blood pressure exceeding 185 mm Hg
in 6.7%. A multivariate analysis found predictors of favorable outcome to
be a less severe baseline National Institutes of Health Stroke Scale score,
absence of specific abnormalities (effacement or hypodensity of >33% of the
middle cerebral artery territory or a hyperdense middle cerebral artery) on
the baseline computed tomographic scan, an age of 85 years or younger, and
a lower mean arterial pressure at baseline.
Conclusions This study, conducted at multiple institutions throughout the United
States, suggests that favorable clinical outcomes and low rates of symptomatic
intracerebral hemorrhage can be achieved using tPA for stroke treatment.
Tissue-Type plasminogen activator (tPA) is the only medication approved
for treatment of acute ischemic stroke. This therapy was approved by the Food
and Drug Administration in June 1996 for selected patients who can be treated
within 3 hours of stroke onset. The approval was based on the results of a
clinical trial sponsored by the National Institute of Neurological Disorders
and Stroke (NINDS) that randomized a total of 624 patients to treatment with
intravenous tPA (0.9 mg/kg, maximum of 90 mg) vs placebo within 3 hours of
stroke onset.1,2 This study demonstrated
substantial and statistically significant benefits in neurologic outcomes
at 3 and 12 months, despite a 6.4% rate of symptomatic intracerebral hemorrhage
(ICH) within 36 hours of tPA treatment.
Use of intravenous tPA for appropriately selected patients with acute
ischemic stroke has been strongly endorsed (Grade A recommendations) by the
American Academy of Neurology, the American Heart Association, and the American
College of Chest Physicians.3- 5
Despite these endorsements, only a small fraction of eligible stroke patients
currently receive tPA therapy.6,7
One of the greatest concerns regarding the use of tPA for stroke treatment
is the belief that the risk of symptomatic ICH may be higher in routine clinical
use than it was in the NINDS-sponsored research study.8
Standard Treatment with Alteplase to Reverse Stroke (STARS) was a large
phase 4 study, mandated by the Food and Drug Administration, and designed
to assess the safety profile and clinical outcomes obtained following intravenous
tPA therapy for acute stroke patients in clinical practice. This prospective,
monitored, multicenter study followed the clinical course of nearly 400 patients
with acute ischemic stroke consecutively treated at 57 medical centers in
the United States.
Consecutive patients who presented with an acute ischemic stroke and
who received intravenous tPA were eligible for participation in the study.
Patients treated with tPA at the participating centers were approached just
prior to, or immediately following, tPA therapy and asked to participate in
this study. Investigators were instructed to attempt to enroll every patient
they treated with intravenous tPA for acute stroke at each participating center.
Data regarding the number of potentially eligible patients who refused tPA
therapy were not collected. The protocol was approved by the human subjects
committee at each participating center. Informed consent was obtained from
the patient (or the responsible family member if the patient was not capable
of understanding the study).
Information regarding patient demographics, associated medical problems,
time intervals between stroke symptom onset, hospital arrival, and treatment
with tPA was collected. A cranial computed tomographic (CT) scan was performed
prior to tPA treatment in all patients; the initial CT interpretation was
performed by the investigator or a radiologist, or both, or a neuroradiologist.
The patients' clinical course was followed closely by the investigators during
hospitalization. If significant neurologic deterioration occurred, an urgent
CT scan was obtained to assess the presence of ICH. Any major systemic bleeding
or requirement for a blood transfusion was recorded. At the time of treatment,
the baseline National Institutes of Health Stroke Scale (NIHSS) score9 was obtained. Information regarding the findings on
the baseline CT scan was collected based both on the investigator's reading
of the study and the final radiology report.
Patient follow-up (either by telephone or in person) occurred 30 days
after therapy. The patient or caregiver provided information regarding any
significant adverse effects following the acute hospitalization and a modified
Rankin Scale score10 was obtained to assess
functional outcome. For patients who died, the cause of death was determined.
In addition, if any clinically significant neurologic deterioration occurred
following the acute hospitalization, an attempt was made to determine the
cause based on review of the medical record. All follow-up data were collected
by one of the principal investigators or study coordinators; these individuals
were all trained in the administration of both the NIHSS and the modified
All 83 active centers that were participating in an ongoing randomized
clinical trial (the Alteplase ThromboLysis for Acute Noninterventional Therapy
in Ischemic Stroke [ATLANTIS] study),11 which
was evaluating the benefits of intravenous tPA therapy administered between
3 and 5 hours after stroke symptom onset, were invited to participate in the
STARS study. Fifty-seven medical centers (24 academic and 33 community) agreed
to participate (listed at the end of this article). Nearly all of the principal
investigators were neurologists who had previous experience treating patients
with stroke with tPA or placebo in the setting of a clinical trial. Patients
were enrolled between February 1997 and December 1998.
A preplanned multivariate analysis was carried out to assess predictors
of recovery (modified Rankin Scale score, ≤1) and independence (modified
Rankin Scale score, ≤2). Potential predictors of favorable outcome were
identified in advance by members of the STARS publication committee. It was
specified in advance that any variable with more than 10% missing values would
not be used in this analysis.
Data in this study were collected on standardized case report forms
that were audited by study monitors at onsite visits. Data were double-entered
and checked for consistency at a centralized data management center (Genentech
Inc, San Francisco, Calif). Errors and inconsistencies were resolved by contacting
study site personnel.
Violations of the protocol for tPA administration used for the NINDS
tPA Stroke Trial were assessed. The following were considered to be protocol
violations: dose of tPA administered of more than 10% the calculated dose
requirement, treatment initiated more than 3 hours after symptom onset, evidence
of ICH on the baseline CT scan, blood pressure higher than 185/110 mm Hg at
the time of tPA treatment, baseline international normalized ratio of more
than 1.7, elevation of the baseline partial thromboplastin time, treatment
with antiplatelet agents or anticoagulants within 24 hours of tPA administration,
and prior medical history contraindication (known bleeding diathesis, intracerebral
neoplasm, arteriovenous malformation, or cerebral aneurysm).
Three hundred eighty-nine consecutive patients were enrolled at 57 medical
centers. The median number of patients enrolled per center was 5 (range, 1-24).
Demographic characteristics of the patient population are shown in Table 1. The median time from stroke onset
to tPA treatment was 2 hours 44 minutes (25th-75th percentiles, 2 hours 14
minutes–2 hours 56 minutes). The median time from presentation to the
emergency department (ED) and tPA treatment was 1 hour and 36 minutes (25th-75th
percentiles, 1 hour 15 minutes–2 hours 4 minutes). Most patients (82.3%)
were treated with tPA between 91 and 180 minutes after stroke onset, 4.1%
were treated within 90 minutes, and 13.4% were treated after 180 minutes.
Patients who arrived at the ED soon after stroke onset typically had
longer delays between ED arrival and tPA treatment (Figure 1). On average, every 30-minute delay between stroke onset
and ED arrival was associated with a 15-minute decrease in the time between
arrival and initiation of tPA therapy (regression coefficient, −0.56; P<.001). The median NIHSS score at baseline was 13 (mean,
14 [range, 1-38]). Stroke severity ranged from mild (NIHSS score, ≤4) in
8% to severe (NIHSS score, >20) in 19% (Table 1). All 389 patients had a baseline CT scan prior to tPA treatment
(Table 1). Three hundred forty-two
patients (88%) had a follow-up head CT scan during their hospitalization.
Symptomatic ICH occurred within 3 days of treatment in 13 patients (3.3%
[95% confidence interval, 1.8%-5.6%]). Seven (54%) of the 13 patients with
symptomatic ICH died. Two (29%) of the 7 patients who had hypodensity involving
greater than one third of the middle cerebral artery (MCA) territory on the
baseline CT scan had a symptomatic ICH compared with 11 (3%) of the 382 patients
who had no hypodensity or hypodensity in less than one third of the MCA territory
(P = .02). Asymptomatic ICH within 3 days of treatment
occurred in 28 patients (8.2% [95% confidence interval, 5.2%-11.1%]). Major
systemic bleeding occurred in 6 patients (1.5% [95% confidence interval, 0.3%-2.8%]).
Protocol violations occurred in 127 patients (32.6%) (Table 2). Symptomatic ICH occurred in 3.9% of the patients with
protocol violations (time-to-treatment >3 hours [n = 3]; blood pressure >185/110
mm Hg at time of treatment [n = 1]; >10% overdose of tPA [n = 1]) compared
with a rate of 3.1% in patients without protocol violations (P = .70).
Thirty-day follow-up data were available for 382 (98%) of the 389 enrolled
patients. The 30-day mortality rate was 13%: 51 patients died. A total of
132 patients (35%) had a very favorable clinical outcome (modified Rankin
Scale score, ≤1) and 165 (43%) were functionally independent (modified
Rankin Scale score, ≤2). Moderate disability (modified Rankin Scale score,
3) was present in 47 (12%), and 119 (31%) had moderate-to-severe or severe
disability (modified Rankin score, 4-5).
Because of the low incidence of symptomatic ICH, it was not possible
to perform a multiple logistic regression to assess predictors of ICH. The
results of the multiple regression model to determine predictors of recovery
(Rankin score, 0-1) or independence (Rankin score, 0-2) at 30 days are shown
in Table 3. Predictors of favorable
clinical outcome were a baseline NIHSS score of 10 or less, absence of specific
abnormalities (hyperdense MCA, hypodensity, or effacement of >one third of
the MCA territory) on the baseline CT scan, age 85 years and younger, and
lower mean arterial pressure at baseline.
For every 5-point increase in baseline NIHSS score, patients had a 22%
decrease in the odds of recovery (P = .16), and patients
with baseline NIHSS scores greater than 10 had a 75% decrease in the odds
of recovery. Patients with a hyperdense MCA sign or hypodensity or effacement
of more than 33% of the MCA territory on the baseline CT scan had an 87% decrease
in odds of recovery. Only 5% of the patients with these early CT signs recovered
compared with 38% of those who did not have these findings. Every 10-point
increase in baseline mean arterial pressure decreased the odds of recovery
The results of the multivariate model to predict independence were similar
to those of the model developed to predict recovery (Table 3). The only significant differences were that age of 85 years
and younger was a predictor of independence and baseline mean arterial pressure
The STARS study is the largest prospective, monitored, postapproval
trial with intravenous tPA for treatment of acute ischemic stroke. The most
important difference between STARS and the NINDS clinical trial is that STARS
did not include a control group to allow an assessment of the efficacy of
tPA therapy. In addition, clinical outcomes were assessed 30 days after treatment
in STARS, and at 90 days in the NINDS study. Furthermore, the methods for
assessment of ICHs differed slightly between the 2 studies. These differences
significantly limit any direct comparison of the results of these 2 studies.
Despite these limitations, the STARS results provide compelling evidence that
the NINDS protocol can be applied safely by physicians at a wide variety of
medical centers throughout the United States.
The most important finding of this study is that the symptomatic ICH
rate was 3.3% at 3 days, which is lower than the rate (6.4%) observed in the
NINDS tPA Stroke Trial.1 This finding demonstrates
that use of tPA for treatment of acute ischemic stroke in clinical practice
by properly trained physicians can be as safe as it was in the NINDS-sponsored
This low rate of symptomatic hemorrhage is unlikely to be explained
by major differences between the patient populations enrolled in STARS and
the NINDS study. Independent predictors of symptomatic ICH in the NINDS study
were baseline stroke severity and the presence of brain edema on the baseline
CT.12 The median NIHSS score was only slightly
lower in the STARS study than the NINDS trial (13 vs 14), while the number
of patients with very severe strokes (NIHSS score, >20), 19% in STARS and
20% in NINDS, was similar. Cerebral edema on the baseline CT scan was reported
in 4% of the NINDS study patients and 6% of the STARS patients.
The NINDS trial required a repeat CT scan 24 hours after treatment for
all patients. In STARS, a repeat CT was only required for patients who experienced
clinical deterioration; however, 88% of the patients in STARS had follow-up
CT scans during their hospitalization. The rates of asymptomatic plus symptomatic
ICH (11.5% in STARS and 10.9% in the NINDS study) were similar. It is possible
that some of the hemorrhages considered to be asymptomatic by STARS investigators
might have been rated symptomatic in the NINDS study.
Although 5 of the 13 patients with symptomatic ICH in STARS had protocol
violations, this was not a significant increase when compared with patients
who did not have protocol violations. Several smaller trials have documented
higher rates of symptomatic ICH in patients with violations of the NINDS protocol.13,14 Further study is required to determine
which protocol violations are most closely associated with ICH.
Very favorable clinical outcomes at 30 days (modified Rankin score, ≤1)
occurred in 35% of the STARS patients; 43% were functionally independent (modified
Rankin score, ≤2). These clinical outcomes cannot be directly compared
with the NINDS trial results because 30-day modified Rankin scores were not
obtained in the NINDS trial. At 90 days, 39% of the tPA-treated patients in
part 2 of the NINDS study had a modified Rankin score of 1 or less. A larger
percentage of highly favorable outcomes is typically expected at 90 days compared
with the 30-day rates. For example, among 272 patients treated with intravenous
tPA between 3 to 5 hours after stroke onset in the ATLANTIS trial, 36.5% had
a modified Rankin score of 1 or less at 30 days, whereas 42.3% achieved this
level of recovery at 90 days.11 Therefore,
the percentage of patients with 90-day modified Rankin scores of 1 or less
in STARS is likely comparable with the results obtained in the NINDS study.
Several predictors of favorable outcome were identified in the multiple
regression analysis. Patients who were most likely to achieve favorable outcomes
were younger, had milder baseline stroke severity (NIHSS score, ≤10), were
less likely to have certain abnormalities on their baseline CT scan, and had
lower mean arterial pressure at baseline. These same clinical features were
identified in the NINDS trial as important predictors of clinical outcome.15 However, in the NINDS study, the presence of these
features did not predict a differential clinical response to tPA therapy.
Although older patients with severe baseline neurologic deficits generally
have a poor prognosis, tPA therapy may result in more of these patients having
a mild-to-moderate disability rather than a severe disability.15
Therefore, the presence of these poor prognostic features does not indicate
that tPA should be withheld from these patients. Rather, these patients and
their family members can be informed that very favorable outcomes are unlikely,
however, tPA treatment may result in a lower rate of severe disability.
Evidence on baseline CT scan of acute hypodensity involving greater
than one third of the MCA territory was found to be a predictor of poor response
to intravenous tPA therapy in a post-hoc analysis of a study (European Cooperative
Acute Stroke Study I) that treated patients with a higher dose of tPA (1.1
mg/kg) up to 6 hours after stroke onset.16
Only 2% of the STARS patients had acute hypodensity greater than one third
of the MCA territory, and these patients had an increased rate of symptomatic
ICH. This finding supports current recommendations that tPA therapy should
be withheld in patients with evidence of major early infarction on the baseline
CT scan.3- 5
In the NINDS trial, half of the patients were treated within 90 minutes
of symptom onset. Recently, the NINDS investigators concluded that the benefits
of treatment declined significantly toward the end of the 3-hour treatment
window.17 In the STARS study, the median time
from stroke onset to tPA treatment was 2 hours 44 minutes, indicating that
only half the patients were treated prior to the last 15 minutes of the therapeutic
window. In addition, 13.4% of the patients were treated beyond 3 hours after
stroke onset. The relatively long median time from ED arrival to tPA treatment
(1 hour 36 minutes) suggests that considerably more effort is required to
expedite the emergency evaluation of these patients. The inverse relationship
between the time from symptom onset to ED arrival and treatment delays in
the ED indicates that patients arriving early after symptom onset were not
evaluated as rapidly as patients arriving later after symptom onset. This
discrepancy should be a focus of future educational efforts.
The symptomatic ICH rates and favorable outcome rates in STARS are similar
to those reported in several smaller phase 4 studies.18- 20
We believe the STARS data is reliable and accurate because case report forms
were monitored prospectively during the course of the study, data were checked
and verified, and consecutive patients were enrolled.
In summary, the STARS study is the largest prospective, monitored, postapproval
trial with intravenous tPA for treatment of acute ischemic stroke. The results
of this study suggest that favorable outcomes and low rates of symptomatic
ICH can be achieved in clinical practice at multiple medical centers across
the United States.