Wayne M. Clark, Stanley Wissman, Gregory W. Albers, Jack H. Jhamandas, Kenneth P. Madden, Scott Hamilton, for the ATLANTIS Study Investigators. Recombinant Tissue-Type Plasminogen Activator (Alteplase) for Ischemic Stroke 3 to 5 Hours After Symptom OnsetThe ATLANTIS Study: A Randomized Controlled Trial. JAMA. 1999;282(21):2019–2026. doi:10.1001/jama.282.21.2019
Author Affiliations: Oregon Stroke Center, Portland (Dr Clark); Stucky Research Center, Fort Wayne, Ind (Dr Wissman); Stanford Stroke Center, Stanford University, Palo Alto, Calif (Dr Albers); Department of Neurology, University of Alberta, Edmonton (Dr Jhamandas); Marshfield Clinic, Marshfield, Wis (Dr Madden); and Genentech Inc, South San Francisco, Calif (Dr Hamilton). Dr Wissman is deceased.
Context Recombinant tissue-type plasminogen activator (rt-PA) improves outcomes
for patients with acute ischemic stroke, but current approved use is limited
to within 3 hours of symptom onset. This restricts the number of patients
who can be treated, since most stroke patients present more than 3 hours after
Objective To test the efficacy and safety of rt-PA in patients with acute ischemic
stroke when administered between 3 and 5 hours after symptom onset.
Design The Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic
Stroke (ATLANTIS) study is a phase 3, placebo-controlled, double-blind randomized
study conducted between December 1993 and July 1998, with up to 90 days of
Setting One hundred forty university and community hospitals in North America.
Patients An intent-to-treat population of 613 acute ischemic stroke patients
was enrolled, with 547 of these treated as assigned within 3 to 5 hours of
symptom onset. A total of 39 others were treated within 3 hours of symptom
onset, 24 were treated more than 5 hours after symptom onset, and 3 never
received any study drug.
Intervention Administration of 0.9 mg/kg of rt-PA (n = 272) or placebo (n = 275)
intravenously over 1 hour.
Main Outcome Measures Primary efficacy was an excellent neurologic recovery at day 90 (National
Institutes of Health Stroke Scale [NIHSS] score of ≤1); secondary end points
included excellent recovery on functional outcome measures (Barthel index,
modified Rankin scale, and Glasgow Outcome Scale) at days 30 and 90. Serious
adverse events were also assessed.
Results In the target population, 32% of the placebo and 34% of rt-PA patients
had an excellent recovery at 90 days (P = .65). There
were no differences on any of the secondary functional outcome measures. In
the first 10 days treatment with rt-PA significantly increased the rate of
symptomatic intracerebral hemorrhage (ICH) (1.1% vs 7.0% [P<.001]), a symptomatic ICH (4.7% vs 11.4% [P = .004]), and fatal ICH (0.3% vs 3.0% [P<.001]).
Mortality at 90 days was 6.9% with placebo and 11.0% with rt-PA (P = .09). Results in the intent-to-treat population were similar.
Conclusions This study found no significant rt-PA benefit on the 90-day efficacy
end points in patients treated between 3 and 5 hours. The risk of symptomatic
ICH increased with rt-PA treatment. These results do not support the use of
intravenous rt-PA for stroke treatment beyond 3 hours.
The Food and Drug Administration (FDA) approval in June 1996 of intravenous
recombinant tissue-type plasminogen activator (rt-PA) for patients with acute
ischemic stroke treated within 3 hours of symptom onset marked a historic
first step in treating this devastating disease. This approval was primarily
based on the results of the National Institute of Neurologic Disorders (NINDS)
trials (1 and 2).1 In the NINDS trials, patients
with ischemic stroke were treated within 3 hours of symptom onset with either
0.9 mg/kg of rt-PA (alteplase) (maximum dose <90 mg) or placebo. A significant
11% to 15% absolute benefit was found favoring rt-PA despite a significant
increase in the symptomatic intracerebral hemorrhage (ICH) rate (6.4% vs 0.6%; P<.001) at 36 hours. The current approved use of rt-PA
is limited to otherwise eligible patients in whom treatment can be initiated
within 3 hours after the onset of stroke symptoms. This greatly restricts
the number of patients who could potentially be treated, because most stroke
patients present more than 3 hours after symptom onset.2
This time limitation is reflected in the finding that, since approval, less
than 5% of all stroke patients are receiving rt-PA.3- 5
This raises the question of whether intravenous rt-PA is still relatively
safe and effective if given beyond 3 hours after stroke. This question is
particularly important in light of a recent phase 4 trial in North America
finding that more than 15% of patients receiving rt-PA are actually being
treated after 3 hours from symptom onset even at experienced stroke centers.6
The objective of this phase 3 study, Alteplase ThromboLysis for Acute
Noninterventional Therapy in Ischemic Stroke (ATLANTIS), was to assess the
efficacy, as measured by improved clinical outcome, and relative safety of
0.9 mg/kg of rt-PA vs placebo in acute ischemic stroke patients treated between
3 and 5 hours of stroke onset.
The ATLANTIS study first began in August 1991 and was initially designed
to assess the efficacy and safety of intravenous rt-PA in patients with acute
ischemic stroke administered from 0 to 6 hours after symptom onset. This company-sponsored
trial (Genentech Inc, South San Francisco, Calif) was designed to run concurrently
with the NINDS trials in an effort to obtain more information on the use of
rt-PA in stroke treatment. In December 1993, enrollment was halted and the
time window was changed because of safety committee (data monitoring safety
board) concerns in the 5- to 6-hour group. It was decided to restart the trial
as "part B," reflecting a new time window (0-5 hours after symptom onset)
and new study end points, with patients enrolled in "part A" to be considered
a separate trial for analysis and reporting purposes. The company and investigators
remained blinded to results from patients in part A. Data from part A will
be reported in a separate publication.7 The
ATLANTIS part B study was further modified in February 1996 to a 3- to 5-hour
window after stroke onset in light of the results of the NINDS rt-PA study.
At that time, 100 new study sites were added. Thirty-one patients were enrolled
within 0 to 3 hours of stroke onset per protocol in part B of the trial before
the change was made to the 3- to 5-hour window. Although data for all part
B intent-to-treat (ITT) patients are presented here, this article focuses
primarily on the patients enrolled in the 3- to 5-hour window who are the
target population for the ATLANTIS part B trial.
This was a randomized, double-blind, multicenter, placebo-controlled
clinical trial. Enrollment was based on clinical and computed tomography (CT)
criteria; angiography was not required. The study was conducted at 140 centers
in North America. All investigators were required to be certified in the National
Institutes of Health Stroke Scale (NIHSS)8
according to National Institutes of Health (NIH) guidelines by means of a
standard training videotape.9 Patients were
randomized (1:1) and treated with either rt-PA (0.9 mg/kg) or matched placebo.
All patients or their legal representatives signed an informed consent approved
by the institutional review board of each study site.
The target population for part B of the study was defined as patients
aged 18 through 79 years who presented with a clinical diagnosis of ischemic
stroke causing a measurable neurologic deficit and received the study drug
within 3 to 5 hours of definite symptom onset (Table 1). A CT scan excluding ICH was required before randomization.
In addition, patients were excluded if signs of cerebral ischemia were seen
in more than one third of the territory of the middle cerebral artery. This
criterion was included in the February 1996 protocol amendment following the
results of the European Cooperative Acute Stroke Study (ECASS) I trial10 that suggested that the risk of ICH is higher in
this subgroup of patients. Copies of all CT scans were sent to a central neuroradiologist
who was blinded to the patients' treatment group.
Primary exclusion criteria for this study are shown in Table 1. Simple measures (eg, use of nitropaste) were allowed to
lower blood pressure to less than 185/110 mm Hg prior to treatment but aggressive
treatment (eg, nitropresside intravenous infusion) was not. Patients taking
coumadin were allowed only if their prothrombin time was normal. Patients
taking antiplatelet agents were allowed.
The patients were randomized following a central code using a blocked
randomization, stratified by clinical center. The study used an interactive
voice system for randomization and drug supply management. No one at the local
site was aware of patient group assignment. The study drug consisted of white
lyophilized powder, indistinguishable between groups, that was reconstituted
with sterile water. The reconstituted study drug, 0.9 mg/kg (no more than
90 mg total), was given as a 10% (of total dose) intravenous bolus over 1
to 2 minutes through a dedicated line, followed immediately by a 60-minute
infusion of the remaining dose. Administration of heparin, oral anticoagulants,
antiplatelet agents, or other hemorrheologic agents was prohibited during
the initial 24 hours after completion of the infusion. After 24 hours, the
use of intravenous heparin or other antithrombotic agents was at the local
The sample size estimate for part B using an NIHSS score of 0 or 1 as
the primary end point was based on a 2-sided χ2 test. The placebo
group was assumed to have a 35% primary end point rate. Based on this assumption,
968 patients would be required to detect a primary end point rate of 44% or
higher in the rt-PA group with an α level of .05 and power of 80%. The
trial was stopped prematurely in July 1998 based on an interim analysis by
the data monitoring safety board indicating that "treatment was unlikely to
prove beneficial." Although the timing of this interim analysis was preplanned,
the study did not meet any of the prespecified safety criteria for stopping.
Patients were monitored closely for the development of any neurologic
symptoms or bleeding complications. An NIHSS and general physical examination
were completed by certified investigators at baseline; 120 minutes; 24 hours;
and 7, 30, and 90 days following initiation of study drug, while Barthel index,
modified Rankin scale, and Glasgow Outcome Scale assessments were performed
at days 30 and 90. Vital signs were determined hourly for the first 24 hours.
After initiation of study drug, the patient's blood pressure was maintained
at less than 185/110 mm Hg in accordance with a treatment algorithm that included
aggressive measures, if needed. Clinical laboratory tests, including complete
blood cell counts, coagulation tests, and fibrinogen and fibrin degradation
products (study personnel blinded to results), were performed at baseline,
6, and 24 hours. A noncontrast cerebral CT scan was performed at baseline,
18 to 30 hours (or sooner if clinical deterioration occurred), and 23 to 37
days after study drug infusion for assessment of ICH, infarct signs, and infarct
size. To avoid potential unblinding, the clinical examinations at 30 and 90
days were performed by an individual who was not present during study drug
administration and did not see the patient in the first 24 hours.
The sponsor conducted data management and analysis. All personnel at
each study site and at Genentech involved in conducting and monitoring the
trial were blinded to the study drug codes. The primary efficacy outcome variable
was the percentage of patients at 90 days with an excellent neurologic recovery
defined as a score of 0 or 1 on the NIHSS. Secondary end points included excellent
functional recovery at days 30 and 90 on the modified Rankin scale,11 the Barthel index,12
and the Glasgow Outcome Scale.13 A full list
of the outcome variables for the trial is given in Table 2.
Safety parameters included overall mortality, asymptomatic ICH, symptomatic
ICH, fatal ICH, and other serious adverse events in both treatment groups.
An ICH was defined as the presence of any blood seen on a brain CT scan. The
local investigator assessed cause of death. The records of all patients who
died and who had any type of ICH were reviewed by the blinded independent
data safety monitoring board on an ongoing basis.
Data were double entered and verified using the Informix database management
system. Statistical Analysis Software 6.12 (SAS Institute Inc, Cary, NC) was
used to perform the statistical analysis. All tests of significance were 2-sided
and conducted at the P = .05 level of significance.
Analyses on 2 populations were performed: a target population that was treated
within the 3- through 5-hour window and an ITT analysis based on all patients
randomized, including the 39 patients enrolled less than 3 hours after stroke
onset prior to the protocol amendment. For both analyses, results are based
on the last observation carried forward method with death given the worst
outcome score on all of the measures. Differences in baseline characteristics
were determined using t tests for continuous variables
and χ2 tests for categorical variables. Efficacy end points
were tested using a 2-sample binomial test. Differences in ICH and serious
adverse events between groups were compared with the Fisher exact test.
From December 1993 through July 1998, a total of 613 patients were enrolled
(ITT) at 140 sites into part B; this includes 31 patients appropriately enrolled
at 0 to 3 hours of stroke onset prior to the protocol modification and 32
protocol violators enrolled after the modification within 3 hours (n = 8)
or after 5 hours (n = 24) of stroke onset. An additional 3 patients were excluded
because they did not receive any study medication. Thus, 547 patients received
study medication between 3 and 5 hours of symptom onset. Because of randomization
errors, 9 patients were assigned rt-PA but actually received placebo and 4
patients were assigned placebo but actually received rt-PA. The final target
population consisted of 547 patients (Figure
1). All randomized patients were included in the ITT analysis (grouped
by assigned randomization). For both populations, the groups were well matched
for baseline age and initial NIHSS score (mean, 11 for both groups). The target
population had a higher percentage of men in the placebo group (Table 3).
In the target population, mean time to treatment was 4 hours, 24 minutes
from symptom onset in the placebo group and 4 hours, 28 minutes in the rt-PA
group. The groups were well matched for history of smoking, hypertension,
cardiac disease, and prior stroke. In the treatment population, the rt-PA
group had a trend toward a higher incidence of diabetes and atrial fibrillation.
Results of the efficacy analysis are shown in Table 4. For the primary end point in the target population, 32%
of placebo patients and 34% of rt-PA patients had an excellent recovery at
90 days (P = .65). No treatment benefits were seen
on any of the secondary functional outcomes, including a composite "global
outcome statistic" modeled after the method used in the NINDS rt-PA study,1 and no global treatment effect was seen even when
adjustments were made for baseline differences in diabetes and atrial fibrillation.
The overall distribution of the NIHSS, modified Rankin scale, Barthel index,
and Glasgow Outcome Scale scores in the target population is shown in Figure 2. There appeared to be no treatment
effect on very early recovery. The mean (SD) NIHSS scores at 2 hours were
9.8 (5.7) in the placebo group vs 10.0 (6.4) in the rt-PA group (P = .91); at 24 hours, 9.0 (6.6) vs 9.0 (8.6) (P = .34); and at 7 days, 8.34 (8.3) vs 8.72 (10.1) (P = .36). However, treatment with rt-PA did produce a significant increase
in the percentage of patients in the target population with major neurologic
recovery, defined as an 11-point improvement or complete recovery on the NIHSS
at days 30 and 90 (day 30: placebo, 31%; rt-PA, 40% [P
= .02]; day 90: placebo, 36%; rt-PA, 45% [P = .03]).
In a post hoc analysis, the percentage of patients with "independent" recovery
defined as a modified Rankin scale score of 0,1, or 2 also showed no treatment
effect (placebo, 56%; rt-PA, 54%; P = .75). For the
primary outcome measure (NIHSS score, 0 or 1), an analysis of variance that
accounted for differences in baseline variables was performed. These parameters
did not affect the results significantly. Finally, in an additional post hoc
analysis using 90-day NIHSS scores of 0 and 1, we found an equal lack of efficacy
in patients treated between 3 and 4 hours of stroke onset (n = 111; placebo,
31%; rt-PA, 28%; P = .84) and patients treated between
4 and 5 hours (n = 436; placebo, 33%; rt-PA, 34%; P
No treatment benefit was seen on day 30; CT scan infarct volumes in
both groups showed large variations (Table
4). A detailed analysis of the CT scan findings in this study will
be addressed in a separate publication. There were no planned pharmacoeconomic
analyses in this study; however, there was no significant difference in the
mean (SD) length of hospital stay between groups: placebo, 13 (22) days; rt-PA,
11 (24) days.
Serious adverse events are shown in Table 5. The occurrence of ICH was determined by CT scan at 18 to
30 hours. Determination of whether the ICH was asymptomatic or symptomatic
was made by the local principal investigator. In the target population, treatment
with rt-PA significantly increased the rate of both asymptomatic and symptomatic
ICH: asymptomatic in comparison with placebo, 4.7% placebo vs 11.4% rt-PA
(P = .004); symptomatic, 1.1% placebo vs 7.0% rt-PA
(P<.001) (fatal symptomatic, 0% vs 3%; P = .005). Safety results for the entire ITT population were similar.
These ICH rates represent the incidence of ICH on any CT scan performed in
the first 10 days. Although for most cases, this only involves the CT scan
at 18 to 30 hours, any cases in which an ICH was observed on a repeat CT scan
in the first 10 days were also included. No significant difference in the
mortality rate at 90 days between groups was found in either population, although
mortality rates tended to be higher with rt-PA (placebo, 6.9%; rt-PA, 11.0%; P = .09) (Table 5).
Other than ICH, the incidence of serious systemic bleeding was less than 0.2%
in both the placebo and rt-PA groups.
The ATLANTIS part B trial did not find a benefit to intravenous rt-PA
therapy for patients with ischemic stroke when treatment was initiated within
3 to 5 hours of symptom onset. No beneficial effects were seen on the day
90 evaluations in either the target population, those patients strictly enrolled
between 3 and 5 hours of stroke onset, or in the ITT analysis group. The demographic
data show that the groups were well matched. Although there was a larger number
of women in the rt-PA group, this is unlikely to have influenced stroke recovery.
Patients treated with rt-PA were on average 1 year older and although age
does impact recovery, it is unlikely that such a minor difference would affect
the results. In this trial, 31 of the patients were appropriately treated
less than 3 hours after the onset of symptoms before the protocol was modified
to the 3- to 5-hour target window. Despite this, less than 7% of the patients
were actually treated in less than 3 hours from onset of symptoms in the ITT
population. Therefore, even the ITT population was primarily an evaluation
of rt-PA treatment given within 3 to 5 hours of stroke onset. The percentage
of patients who experienced at least an 11-point change in the NIHSS score
was significantly higher at day 30 with rt-PA treatment. However, although
this subgroup of patients with "dramatic responses" on the NIHSS was higher
with rt-PA treatment, this effect did not lead to a difference in excellent
overall recovery between the 2 groups. In addition, since this was the only
positive finding out of 25 efficacy variables, the apparent effect may represent
a chance finding due to the multiple comparisons. All of the other planned
study end points failed to demonstrate any beneficial effect. In addition,
a post hoc analysis evaluating the percentage of patients with independent
recovery at day 90 (modified Rankin scale score, 0-2) also failed to document
any significant treatment effect.
Treatment with rt-PA within 3 to 5 hours of symptom onset did significantly
increase the rate of ICH. However, a comparison of the rate of symptomatic
ICH in our trial, 7%, with that in the NINDS study, 6%, suggests that delaying
therapy with rt-PA did not further increase the rate of ICH over that observed
in the population treated within 3 hours from symptom onset. In this study,
there was no significant difference in mortality between groups, although
the trend toward improved 90-day mortality seen in the NINDS trial was not
seen. Therefore, it appears that although the increased rate of symptomatic
ICH remains when rt-PA therapy is delayed to 3 to 5 hours after symptom onset,
the beneficial clinical effects that outweigh this risk in patients treated
under 3 hours were not observed in this study. Finally, the fact that our
trial involved patients with milder stroke and used different CT scan criteria
may be confounding these results: if we had enrolled patients with more severe
stroke, our symptomatic ICH rate may have been higher.
In the target population in this trial, 80% of patients were enrolled
between 4 and 5 hours of symptom onset. One explanation for this is that patients
who could be treated just after the 3-hour window may have been treated with
rt-PA rather than enrolled in this study. Although the study failed to find
a benefit for rt-PA in patients treated between 3 and 4 hours from symptom
onset, the study is underpowered to evaluate the actual safety and efficacy
for patients enrolled between 3 and 4 hours from symptom onset.
In comparison to the NINDS trials, patients in our trial had milder
strokes with a median NIHSS score of 10 compared with 14. This may explain
why the spontaneous recovery rates in the placebo group of our trial were
higher. That patients in our trial had milder strokes is also a likely explanation
for the lower mortality rate (7%) seen in the placebo group in our study vs
that in the NINDS trials (21%). The stringent cerebral CT scan exclusion criteria
in our study may also have excluded some patients with severe stroke. The
spontaneous recovery rate in our study on the NIHSS primary end point (34%)
was actually very close to the predicted value on which the original 968 sample
size was calculated (35%). However, because of the relatively mild stroke
in this population, if the study had used 1 of the functional end points that
had a 50% spontaneous recovery rate, it would have been difficult for any
therapy to obtain statistically significant effects (type II error) in a sample
size of 900 patients. The conclusion that enrollment criteria should be an
NIHSS score higher than 4 has also been supported by other clinical stroke
The ATLANTIS study is the third large randomized stroke trial evaluating
intravenous rt-PA with the majority of patients being treated more than 3
hours after symptom onset that has failed to find a treatment benefit in the
ITT population. In 1995, ECASS I was published, which evaluated the safety
and effectiveness of 1.1 mg/kg of intravenous rt-PA in patients treated within
6 hours of ischemic stroke.10 More than 80%
of the patients were enrolled after 3 hours, with an average time to treatment
of 4.3 hours, nearly identical to that in the ATLANTIS trial. The ECASS I
study failed to find a significant treatment benefit in the ITT population
for the primary end points, the Barthel index, or the modified Rankin scale
score. The incidence of large intracerebral parenchymal hemorrhages was significantly
more frequent in the rt-PA–treated patients. In the ECASS I study, the
most frequent protocol violation was the inclusion of patients with early
infarct signs of more than one third of the middle cerebral artery territory.
By more effectively excluding these patients, the ECASS investigators hoped
that a repeat study could find significant benefit in the ITT analysis.
The study was therefore repeated as the ECASS II study, with results
reported in 1998.15 This trial enrolled 800
patients in Europe, Australia, and New Zealand, and treated them with rt-PA,
0.9 mg/kg, or placebo within 6 hours of symptom onset. The investigators were
more successful in excluding patients with early infarct signs, with only
4.6% of the patients having significant changes in more than one third of
the middle cerebral artery territory. In this trial, 80% of the patients were
enrolled between 3 and 6 hours of symptom onset. No significant treatment
benefit was seen in the primary end point (a 90-day modified Rankin scale
score of 0-1): 40% of the patients in the rt-PA group had a good outcome compared
with 37% in the placebo group (P = .28). The ECASS
II study also failed to find a significant treatment benefit for any of the
planned secondary end points. However, in a post hoc analysis using independent
recovery (modified Rankin scale scores of 0, 1, or 2), a significant benefit
was seen with 54% of the rt-PA–treated patients vs 46% of placebo-treated
patients being independent at day 90 (P = .02). In
this trial, 8.8% of the rt-PA–treated patients had a symptomatic ICH
vs 3.4% of placebo-treated patients (P<.05).
In the ECASS II Study, treatment benefits may have been undetectable
due to a high rate of spontaneous recovery in the placebo group secondary
to mild baseline stroke severity. A comparison of the ATLANTIS trial with
the ECASS II trial suggests that the 2 trial populations were quite similar.
The median NIHSS score was 10 in the ATLANTIS study vs 11 in the ECASS II
trial. The incidence of excellent spontaneous recovery on the modified Rankin
scale score (0,1) was similar, with approximately 40% of placebo patients
showing an excellent recovery in both trials. However, unlike the ECASS II
trial, the ATLANTIS study did not find a benefit on the outcome of achieving
a modified Rankin scale score of 0, 1, or 2 in our post hoc testing. In addition,
the rate of spontaneous symptomatic ICH in the placebo group of the ECASS
II trial, 3.4%, was much higher than the 1.1% seen in the ATLANTIS study.
This is somewhat puzzling in that the populations seemed to be very similar
in age and initial stroke severity and both used similar CT criteria. The
low spontaneous symptomatic hemorrhage rate seen in ATLANTIS is virtually
identical to that seen in the NINDS trials. However, these are the only reported
large randomized trials that have found placebo group hemorrhage rates this
low; other trials report rates in the 2% to 3% range.10,15
The results of the ATLANTIS trial part B failed to find a treatment
benefit for rt-PA given 3 to 5 hours after symptom onset. Although the risk
of symptomatic ICH did not appear to be higher than in patients treated within
3 hours (NINDS study), the beneficial effects of rt-PA seen in patients treated
within 3 hours of symptom onset were not apparent among patients treated within
3 to 5 hours of symptom onset. These results, along with the results of the
ECASS I and II trials, do not support the use of intravenous rt-PA in a general
population of stroke patients presenting beyond 3 hours after symptom onset.
These negative results apply only to patients treated with rt-PA after 3 hours
of symptom onset. Further investigations using new imaging techniques and
other methods to identify subgroups of patients who may still benefit from
thrombolysis after 3 hours are needed.