The n e w e ng l a n d j o u r na l of
clinical therapeutics
From the Department of Neurology,
­University of Pittsburgh Medical School,
Pittsburgh. Address reprint requests to
Dr. Wechsler at the Department of Neu-
rology, 811 Lillian Kaufmann Bldg., 3471
Fifth Ave., Pittsburgh, PA 15213, or at
wechslerlr@upmc.edu.
N Engl J Med 2011;364:2138-46.
Copyright © 2011 Massachusetts Medical Society.
2138
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m e dic i n e
Intravenous Thrombolytic Therapy
for Acute Ischemic Stroke
Lawrence R. Wechsler, M.D.
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the author’s clinical recommendations.
An 81-year-old man arrived at the emergency department at 9:15 a.m. with speech
difficulty and weakness on the right side. He had awakened that morning without
symptoms. During breakfast at 8 a.m. his wife saw him slump over and fall from the
chair to the floor. He was unable to speak and could not move his right arm or leg.
She called 911, and he was transported to the emergency department. He made a few
attempts to speak, but his speech was unintelligible. He could move his right arm
and leg but could not lift either limb off the bed. Computed tomography (CT) of the
brain showed no hemorrhage and no early ischemic changes. Blood pressure was
160/90 mm Hg. His platelet count, glucose level, and prothrombin time were all nor-
mal. After the patient returned from imaging at 10 a.m., a neurologist was consulted,
who confirmed the presumptive diagnosis of acute ischemic stroke and recommended
immediate initiation of intravenous thrombolytic therapy.
The Cl inic a l Probl em
Stroke is the leading cause of disability among adults in the United States. Despite
advances in preventive strategies and initial therapy for stroke, nearly 800,000
strokes occur per year in the United States,1 and 87% of all strokes worldwide are
ischemic in origin (caused by in situ thrombosis, embolism, or systemic hypoperfu-
sion).1 The risk of stroke is higher among men than among women, among blacks
than among whites, and in older than in younger age groups.
In 2007, stroke accounted for 1 of every 18 deaths in the United States.1 Ac-
cording to one report, the 30-day mortality for ischemic stroke was 8 to 12% for
people 45 to 64 years of age.2 In the Framingham Heart Study, among survivors of
an ischemic stroke who were 65 years of age or older and were evaluated 6 months
after the event, 50% had some evidence of hemiparesis, 30% were unable to walk
without assistance, 19% had aphasia, and 26% were institu­tionalized.3 The esti-
mated direct medical cost of stroke in the United States was $25 billion in 2007.1
Pathoph ysiol o gy a nd Effec t of Ther a py
Ischemic stroke results from vascular occlusion that reduces cerebral blood flow
to the area of brain perfused by the occluded artery. In either thrombotic or em-
bolic stroke, such occlusion is caused by obstruction of the artery by thrombus.
If the reduction in blood flow is sufficiently severe, a series of events occurs at
the cellular level that leads to infarction. The release of excitatory amino acid
neurotransmitters, the influx of calcium, the generation of oxygen free radicals,
membrane depolarization, and eventually, the loss of membrane integrity are all
n engl j med 364;22  nejm.org  june 2, 2011
The New England Journal of Medicine
 clinical Ther apeutics

thought to contribute to the detrimental effectstreatment of acute ischemic stroke after the Na-
of ischemia.4 tional Institute of Neurological Disorders and
A newer concept of ischemic injury considersStroke Recombinant Tissue Plasminogen Activa-
neurons, astrocytes, and vascular structures andtor (NINDS rt-PA) Stroke Study was completed.11
their interactions to be a neurovascular unit.5 Dis-
In part 1 of this study, 291 patients with acute
turbance of the complex signaling and interactions
ischemic stroke were randomly assigned, within
between components of the neurovascular unit 3 hours after the onset of the stroke, to either
probably plays an important role in ischemic brain
intravenous rt-PA or placebo. The primary end
injury. Matrix metalloproteinase 9 is up-regulated
point was the rate at 24 hours of either complete
during ischemia and may contribute to the break-neurologic recovery or neurologic improvement, as
down of the blood–brain barrier and hemorrhagic indicated by an improvement of at least 4 points
transformation.6 Similarly, oxidative stress and in-
above baseline values on the National Institutes
flammation are triggered by ischemia and contrib-
of Health Stroke Scale (NIHSS) (a 42-point scale
ute to the process of cellular injury and infarction.5
that quantifies neurologic deficits in 11 categories,
In experimental models of stroke, both the with higher scores indicating more severe deficits).
duration and the severity of ischemia determine In this part of the trial, no significant difference
the threshold for irreversible damage.7 Magneticwas seen in the primary end point between pa-
resonance imaging (MRI) and CT perfusion stud- tients receiving rt-PA and those receiving place-
ies in patients with acute stroke suggest that the
bo (51% and 46%, respectively; relative risk with
ischemic areas of the brain may in some cases rt-PA, 1.1; 95% confidence interval [CI], 0.8 to 1.6;
remain viable for as long as 24 hours, with the P = 0.56).
potential for the restoration of normal function In part 2 of this study, an additional 333 pa-
after reperfusion (Fig. 1).8 However, the benefit
tients were enrolled and randomly assigned to the
of extending the treatment window for patients same two groups. The primary end point was the
rate of complete or nearly complete recovery at
selected on the basis of the results of perfusion
90 days, as indicated by a combined assessment of
imaging has not been validated by clinical studies.
four separate neurologic-outcome scales. In this
Tissue plasminogen activator (t-PA) is a serine
protease that acts by enhancing the conversion part of the trial, the rate of a favorable outcome was
of inactive plasminogen to active plasmin. Plas-significantly greater with intravenous rt-PA than
with placebo (odds ratio, 1.7; 95% CI, 1.2 to 2.6;
min acts on fibrin clots, causing dissolution and
P = 0.008). This benefit was sustained at 6 months
lysis. The activity of t-PA is greatly enhanced in
the presence of fibrin, increasing fibrinolysis and at 1 year.12
specifically at the site of thrombosis.9 In vivo, Three additional randomized trials showed no
t-PA is released by endothelial cells; in contrast,
benefit of intravenous rt-PA as compared with pla-
exogenously administered t-PA is derived from cebo. These trials included the European Coopera-
the application of recombinant DNA technology tive Acute Stroke Study (ECASS),13 ECASS II,14 and
and is thus designated recombinant t-PA (rt-PA).the Alteplase Thrombolysis for Acute Noninterven-
Unlike first-generation plasminogen activators tional Therapy in Ischemic Stroke (ATLANTIS)
trial.15 These trials differed from the NINDS study
such as streptokinase and urokinase, rt-PA is fi-
in several important respects. Most notably, pa-
brin-selective and preferentially activates fibrin-
bound plasminogen. Although rt-PA is inhibited tients could be enrolled up to 6 hours after the
onset of stroke, and only 14% of patients were
by plasminogen activator inhibitor type 1 (PAI-1)
treated within 3 hours after the event.16 In con-
in plasma, the capacity of PAI-1 to bind rt-PA is
rapidly exceeded when the drug is administered trast, in the NINDS trial, almost all patients were
systemically, thus increasing the risk of bleed-treated within 3 hours and 48% within 90 minutes
ing.10 The half-life of rt-PA in the circulation is
after stroke onset.
about 4 minutes, but the physiological effect may In the subsequent ECASS III, 821 patients who
last longer as a consequence of fibrin binding. presented between 3 and 4.5 hours after the onset
of stroke were randomly assigned to intravenous
Cl inic a l E v idence rt-PA or placebo.17 The primary outcome was dis-
ability at 90 days, dichotomized as either a favor-
In 1996, the Food and Drug Administration (FDA) able outcome (a score of 0 or 1) or an unfavorable
approved the use of intravenous rt-PA for the outcome (a score of 2 to 6) according to the

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A CT Perfusion before Intravenous rt-PA

CT MTT CBV CBF

A A A A

R R R R

B CT Perfusion after Intravenous rt-PA

CT MTT CBV CBF

A A A A

R R R R

Figure 1. CT Perfusion Imaging in a Patient with Stroke, before and after Thrombolysis with Recombinant Tissue
Plasminogen Activator (rt-PA).
Standard CT images without contrast material (left two images) and CT perfusion images obtained during the first
pass of an intravenous bolus of iodinated contrast material (right six images) are shown. Images were obtained be-
fore (Panel A) and after (Panel B) thrombolysis with rt-PA. Mathematical algorithms are used to create, from the
perfusion data, maps of the mean transit time (MTT) (the difference in time between arterial inflow and venous
outflow), cerebral blood volume (CBV), and cerebral blood flow (CBF). The CT scan without contrast material that
was obtained before thrombolysis shows hypodensity in the area of the left caudate nucleus (arrow), with loss of
definition between gray matter and white matter. The scan obtained after thrombolysis shows a central area of hy-
perdensity in the area of the left caudate nucleus, which is consistent with hemorrhage within the infarct zone, sur-
rounded by an area of hypodensity (arrow), which is consistent with infarction. The CT perfusion maps in Panel A,
obtained before thrombolysis, show prolonged MTT (arrow), decreased CBV (arrow), and decreased CBF (arrow) in
the left hemisphere. There is some degree of mismatch between the CBV map (which emphasizes irreversible injury,
primarily in the area of the left caudate nucleus) and the CBF map (which shows an extensive area of abnormality
throughout the left hemisphere, indicating tissue at risk). The CT perfusion maps in Panel B, obtained after throm-
bolysis, show some improvement in MTT, CBV, and CBF in most areas, although the focus of hypoperfusion in the
area of the left caudate nucleus persists (arrows), which is consistent with the area of infarction shown on the CT
scan obtained without contrast material. In these images, the color spectrum indicates the spectrum of values for
each quantity. On the MTT map, the areas of fastest transit time appear red and those of slowest transit time ap-
pear blue. On the CBV and CBF maps, the area of greatest blood volume or blood flow appear red and those of least
blood volume or blood flow appear blue. Although quantitative values can be assigned to these data, CT perfusion
images are usually interpreted qualitatively by comparing areas of normal with areas of abnormal perfusion. Areas
without detectable perfusion are black. A denotes anterior, and R right.

modified Rankin scale (which ranges from 0 to
6, with 0 indicating no symptoms and 6 indicat-
ing death). In ECASS III, patients were excluded
if they were older than 80 years of age, had had
a severe stroke (defined as an NIHSS score >25 or
hypodensity of more than one third of the mid-
dle-cerebral-artery territory on CT scanning), had
received prior treatment with anticoagulants, re-
gardless of the international normalized ratio
(INR), or had a history of both stroke and dia-
betes. At 90 days, significantly more patients
treated with rt-PA had favorable outcomes, as com-

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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 clinical Ther apeutics
pared with those given placebo (52.4% vs. 45.2%;
odds ratio, 1.34; 95% CI, 1.02 to 1.76; P = 0.04).
Cl inic a l Use
Intravenous administration of t-PA within 3 hours
after the onset of stroke increases the probabil-
ity of a favorable outcome. Recommended proto-
cols for selecting patients for treatment with in-
travenous rt-PA are adapted from the inclusion
and exclusion criteria from the NINDS rt-PA trial
(Table 1). On the basis of results of ECASS III,17
some stroke centers now treat patients who pre­
sent from 3 to 4.5 hours after stroke onset; how-
ever, at present, the FDA has approved only rt-PA
treatment delivered within 3 hours after stroke
onset.
The timing of the onset of stroke should be
determined with as much certainty as possible by
obtaining first-hand information. If the onset was
not observed, the time when the patient was last
seen to be neurologically normal should be con-
sidered the time of stroke onset. Although this
recommendation may exclude some eligible pa-
tients, it ensures that those whose stroke occurred
outside the time limit for a favorable risk-to-benefit
ratio will not be treated.
A rapid examination with the use of the NIHSS
will help to quantify the neurologic deficit. Many
protocols exclude patients who have mild deficits,
since their prognosis for recovery is good with-
out thrombolytic therapy.19,20 However, treatment
should be initiated on the basis of the assessment
of a disabling deficit rather than on a defined
lower limit for the NIHSS score. For example, iso-
lated aphasia or hemianopia is a disabling deficit
despite an NIHSS score of 2 or 3.
Rapidly resolving deficits may complicate deci-
sion making. If the residual deficit continues to
be disabling, treatment should be undertaken de-
spite the improvement. Occasionally, rapid recov-
ery is later followed by clinical worsening.21,22
Patients should therefore be observed closely and
reevaluated frequently during the first 24 hours
after the onset of stroke.
Another common concern regarding eligibil-
ity for intravenous thrombolysis is poorly con-
trolled blood pressure. In patients receiving in-
travenous rt-PA, markedly elevated blood pressure
may increase the risk of hemorrhage.23-27 Cur-
rent guidelines recommend treatment to achieve
a systolic blood pressure of 185 mm Hg or lower
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Table 1. Inclusion and Exclusion Criteria for Intravenous t-PA Therapy
in Patients with Acute Ischemic Stroke.*
Inclusion criteria
Diagnosis of ischemic stroke causing measurable neurologic deficit
Onset of symptoms <3 hr before start of treatment (or, in selected cases,
<4.5 hr†)
Age ≥18 yr
Exclusion criteria
Head trauma or prior stroke within the previous 3 mo
Symptoms suggestive of subarachnoid hemorrhage
Arterial puncture at noncompressible site within the previous 7 days
History of intracranial hemorrhage
Elevated blood pressure (systolic, ≥185 mm Hg, or diastolic, ≥110 mm Hg)
that has not responded to antihypertensive treatment
Evidence of active bleeding on examination
Acute bleeding diathesis, including but not limited to the following:
Platelet count ≤100,000/mm3
Heparin received within 48 hours, resulting in aPTT ≥upper limit of normal
Current use of anticoagulant, with INR ≥1.7 or PT ≥15 sec
Blood glucose concentration ≤50 mg/dl (2.7 mmol/liter)
CT evidence of multilobar infarction (hypodensity >one third of the cerebral
hemisphere)
Relative exclusion criteria, depending on risk:benefit ratio‡
Only minor or rapidly improving stroke symptoms (clearing spontaneously)
Seizure at onset with postictal residual neurologic impairments
Major surgery or serious trauma within the previous 14 days
Gastrointestinal or urinary tract hemorrhage within the previous 21 days
Acute myocardial infarction within the previous 3 mo
* Adapted from Jauch et al.18 The abbreviation aPTT denotes activated partial-
thromboplastin time, INR international normalized ratio, PT prothrombin
time, and rt-PA recombinant tissue plasminogen activator.
† This criterion is based on the results of European Cooperative Acute Stroke
Study III,17 in which the onset of symptoms was between 3 and 4.5 hours and
which excluded patients older than 80 years of age, those with severe stroke
(defined by a score >25 on the National Institutes of Health Stroke Scale),
those receiving anticoagulant therapy regardless of the INR, and those with
both diabetes and prior stroke.
‡ Recent experience suggests that under some circumstances, with careful con-
sideration and weighing of the risks versus benefits of rt-PA administration,
patients may receive fibrinolytic therapy despite one or more of the listed rela-
tive contraindications.
and a diastolic blood pressure of 110 mm Hg or
lower before intravenous rt-PA is administered.18,28
One or two doses of labetalol may be used to
bring blood pressure below these limits, but if
the response is not rapid, treatment with intra-
venous nicardipine or occasionally sodium nitro-
prusside may be started, with the dose rapidly
adjusted to achieve blood-pressure control.
2141
 The n e w e ng l a n d j o u r na l
A CT scan of the brain should be obtained
before the start of treatment and examined for
hemorrhage or early ischemic changes. If a focal
area of low density is seen that involves more
than one third of the middle-cerebral-artery ter-
ritory, most treatment protocols recommend with-
holding throm­bolytic therapy, because in some
studies this finding (which suggests irreversible
injury) has been predictive of subsequent hem-
orrhagic transformation of the infarct.24,29 Lab-
oratory studies that should be obtained before
the initiation of thrombolytic therapy include,
at a minimum, a platelet count, measurement of
glucose levels, and assessment of the prothrombin
time. The platelet count should be greater than
100,000 per cubic millimeter, the prothrombin
time less than 15 seconds (or the INR <1.7), and
the glucose level greater than 50 mg per deciliter
(2.7 mmol per liter) before rt-PA is administered.
The patient and family members must be in-
formed of the benefits and risks of intravenous
rt-PA therapy before it is initiated. Specifically, they
should be told that the benefits include an abso-
lute increase in the odds of a good outcome of
11 to 13 percentage points and a 6% risk of intra-
cerebral hemorrhage possibly causing neurologic
worsening or death. Some hospitals choose to use
a formal consent form, but at a minimum, the
consent process should be documented in the
medical record.28
The FDA-approved dose of intravenous rt-PA is
0.9 mg per kilogram of body weight, with a maxi-
mum dose of 90 mg. A bolus of 10% of the dose
is given over a period of 1 minute, with the remain-
der infused over a period of 60 minutes. Weight
should be determined as reliably as is possible.
Reports of treatment with a lower dose of rt-PA
(0.6 mg per kilogram) in Japan suggest that it has
similar efficacy but the lower dose has not yet been
assessed in large, randomized trials.30,31
Third-generation plasminogen activators, such
as tenecteplase and desmoteplase, are more fibrin-
specific than rt-PA and cause less activation of
systemic lytic activity.32 These agents have been
tested in early-phase trials, with mixed results.33-37
However, their clinical efficacy has not been es-
tablished, and neither agent should be used in pa-
tients with acute ischemic stroke.
For the first 24 hours after treatment, patients
receiving rt-PA should be closely monitored in a
specialized stroke unit. If a stroke unit is not avail-
able, admission to an intensive care unit is war-
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of m e dic i n e
ranted so that the patient can be evaluated fre-
quently by the nursing staff. Blood pressure should
be checked every 15 minutes for the first 2 hours,
every 30 minutes for the next 6 hours, and then
every hour for 16 hours. Antihypertensive therapy
with labetalol or, if necessary, intravenous nicar-
dipine should be administered to maintain blood
pressure at a level below 180 mm Hg systolic and
105 mm Hg diastolic.18,28 Neurologic examina-
tion with the use of the NIHSS should be per-
formed every 15 minutes for the first 2 hours,
every 30 minutes for the next 6 hours, and then
every hour for 16 hours. If a change in neurologic
status is noted, the rt-PA infusion should be dis-
continued and a CT scan obtained. No anticoagu-
lant or antiplatelet therapy should be given for the
first 24 hours after treatment with intravenous
rt-PA. If a CT scan at 24 hours shows no evidence
of hemorrhage, antithrombotic therapy directed at
secondary stroke prevention and tailored to the
presumed cause of the stroke should be started.
In some stroke centers, a CT angiogram is ob-
tained after intravenous rt-PA has been adminis-
tered in order to examine the intracranial vascula-
ture for persistent arterial occlusions. In patients
with persistent arterial occlusion, one option is an
intraarterial intervention: lytic therapy, mechanical
clot disruption with the use of various endovascu-
lar devices, or both. Although this approach is not
approved by the FDA in the treatment of acute
stroke, a randomized, controlled trial has sug-
gested a potential benefit from intraarterial lytic
therapy.38 However, intraarterial interventions
should be carried out only at experienced stroke
centers.
In one U.S. study,39 the cost of rt-PA was es-
timated to be $2,750. In similar studies, the costs
were £480 in the United Kingdom40 and $1,647
U.S. in Australia.41 Cost-effectiveness analyses in
general suggest that rt-PA therapy is more expen-
sive than standard care for ischemic stroke in the
short term, owing to the cost of the drug and the
need for additional resources, but it is associated
with lower costs in the long term, since it reduces
the risk of subsequent disability.
A dv er se Effec t s
The major complication of thrombolytic therapy
for acute stroke is hemorrhage. Symptomatic
intracranial hemorrhage occurs in 1.7 to 8.0%
of treated patients.11,17,42-44 Patients with severe
 clinical Ther apeutics
stroke have a greater likelihood of hemorrhage,
but there is no evidence that this subgroup does
not benefit from intravenous rt-PA.45 Symptom-
atic hemorrhage is not increased in the elderly,
but outcomes are worse and mortality is in-
creased.46,47 In addition to age and NIHSS score,
other independent risk factors for symptomatic
intracranial hemorrhage include hypodensity on
CT scanning, elevated serum glucose levels,24,27,48
and persistence of proximal arterial occlusion
for more than 2 hours after administration of the
rt-PA bolus.49 Hemorrhagic transformation of
ischemic infarcts without clinical change (as-
ymptomatic hemorrhage) occurs more frequent-
ly than symptomatic hemorrhage and may be
associated with reperfusion and, in some cases,
clinical improvement.50 Serious systemic (extra-
cranial) hemorrhage has been reported in 0.4 to
1.5% of patients.42,43 Recommendations for the
treatment of intracranial or serious systemic
bleeding after thrombolytic therapy often include
the administration of cryoprecipitate and plate-
lets,51,52 although evidence-based guidelines for
such an approach are lacking.53
Angioedema of the tongue, lips, face, or neck
occurs in 1 to 5% of patients receiving intra­
venous rt-PA.54,55 In most cases, the symptoms are
mild and resolve rapidly. Concomitant use of an-
giotensin-converting–enzyme inhibitors is strong-
ly associated with this complication.55 Treatment
includes glucocorticoids and antihistamines. In
rare cases, edema of the pharynx is sufficiently
severe to compromise breathing, and intubation
may be necessary.54
A r e a s of Uncer ta in t y
More than half the patients with ischemic stroke
who are treated with intravenous rt-PA do not
have complete or near-complete recovery (defined
as a score of 0 or 1 on the modified Rankin
scale).56 Lack of recovery may reflect an absence
of reperfusion of the occluded artery or reperfu-
sion that occurs too late to restore function. Ad-
vanced imaging techniques that involve multi-
modal MRI or CT (Fig. 1) have the potential to
distinguish reversible ischemic injury from irre-
versible infarction and thus to identify patients
who are likely to benefit from thrombolytic ther-
apy.57-60 By identifying extensive areas of estab-
lished infarction, such imaging methods may
also help in selecting patients who are at high
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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
risk for intracranial hemorrhage and should there-
fore not be treated with intravenous rt-PA. How-
ever, whether the additional time needed for ad-
vanced imaging prior to thrombolysis is offset by
improved outcomes must be established in appro-
priately designed clinical trials. At this time, these
imaging methods cannot be recommended for
routine clinical use.60 If a reliable pattern of re-
versibility can be identified, imaging might also
be useful when the interval between the onset of
stroke and presentation is prolonged or the time
of onset is not known.
Transcranial Doppler ultrasonography, which
has been used in some observational studies to
monitor the effect of lytic therapy, was shown
in these studies to be associated with a high rate
of recanalization of the occluded stroke-related
artery.61,62 Transcranial ultrasonography was sub-
sequently evaluated in several small trials and was
shown to enhance the lytic effect of rt-PA,63-65 al-
though some studies have suggested an increased
rate of hemorrhage with transcranial ultrasonog-
raphy.66 This approach, called sonothrombolysis,
has been implemented clinically as an adjunct to
rt-PA administration at some stroke centers.
Guidel ine s
Guidelines for the management of acute stroke is-
sued by the American Heart Association (AHA) and
the European Stroke Organization recommend
treatment with intravenous rt-PA for patients who
meet the stated inclusion criteria, including presen-
tation within 3 hours after the onset of stroke, and
who do not meet any of the stated exclusion crite-
ria.28,67 Both groups have recently updated their
guidelines to extend the treatment window to 4.5
hours. The AHA Science Advisory and Coordinat-
ing Committee also recommends that treatment
within the 3-hour to 4.5-hour time window be lim-
ited to patients who do not meet any of the ECASS
III exclusion criteria.68,69 An American Academy
of Emergency Medicine (AAEM) position statement
adopted in 2002 concluded that intravenous rt-PA
should not be considered the standard of care,
citing the lack of data from trials confirming the
NINDS study findings as well as concerns raised
about the study.70 Physicians were advised to use
their discretion when deciding whether to use rt-PA.
After the results of the ECASS III were published,
an updated clinical practice statement from the
AAEM stated that intravenous rt-PA is a reasonable
2143
 The n e w e ng l a n d j o u r na l of m e dic i n e

treatment option when used in academic centers 2 hours after the onset of the stroke, which is
and primary stroke centers.71 A policy statement within the FDA-approved 3-hour window, and the
approved by the board of directors of the Ameri- probability of recovery is greater the more rapidly
can College of Emergency Physicians in 2002 en- treatment can be administered. Once consent has
dorsed the use of intravenous rt-PA when it is ad- been obtained from his wife, I would elect to pro-
ministered according to the guidelines established ceed with intravenous rt-PA therapy at the stan-
by the NINDS study.72 dard dose of 0.9 mg per kilogram, with 10% giv-
en as a bolus and the remainder infused over a
R ec om mendat ions 60-minute period. After the administration of in-
travenous rt-PA, the patient should be admitted to
The patient described in the case vignette meets all a specialized stroke unit for monitoring and addi-
the inclusion criteria for treatment with intravenous tional workup to determine the cause of the stroke.
rt-PA. Assuming that further history taking reveals
no pertinent findings, he also has no contraindi- Dr. Wechsler reports receiving consulting fees from Abbott
cations to treatment. Evidence from clinical trials Vascular, Lundbeck, and Ferrer and grant support from NMT
does not suggest that persons older than 80 years of Medical and holding stock in NeuroInterventions. No other po-
tential conflict of interest relevant to this article was reported.
age do not benefit from intravenous rt-PA. He com- Disclosure forms provided by the author are available with the
pleted evaluation in the emergency department full text of this article at NEJM.org.

References
1. Roger VL, Go AS, Lloyd-Jones DM, et
al. Heart disease and stroke statistics —
2011 update: a report from the American
Heart Association. Circulation 2011;123
(4):e18-e209. [Erratum, Circulation 2011;
123(6):e240.]
2. Rosamond WD, Folsom AR, Chamb-
less LE, et al. Stroke incidence and sur-
vival among middle-aged adults: 9-year
follow-up of the Atherosclerosis Risk in
Communities (ARIC) cohort. Stroke 1999;
30:736-43.
3. Kelly-Hayes M, Beiser A, Kase CS,
Scaramucci A, D’Agostino RB, Wolf PA.
The influence of gender and age on dis-
ability following ischemic stroke: the
Framingham study. J Stroke Cerebrovasc
Dis 2003;12:119-26.
4. Fisher M. Characterizing the target of
acute stroke therapy. Stroke 1997;28:866-
72.
5. Lo EH, Dalkara T, Moskowitz MA.
Mechanisms, challenges and opportuni-
ties in stroke. Nat Rev Neurosci 2003;4:
399-415.
6. Asahi M, Wang X, Mori T, et al. Ef-
fects of matrix metalloproteinase-9 gene
knock-out on the proteolysis of blood-
brain barrier and white matter compo-
nents after cerebral ischemia. J Neurosci
2001;21:7724-32.
7. Jones TH, Morawetz RB, Crowell RM,
et al. Thresholds of focal cerebral ische­
mia in awake monkeys. J Neurosurg 1981;
54:773-82.
8. Darby DG, Barber PA, Gerraty RP, et
al. Pathophysiological topography of
acute ischemia by combined diffusion-
weighted and perfusion MRI. Stroke 1999;
30:2043-52.
9. Hoylaerts M, Rijken DC, Lijnen HR,
Collen D. Kinetics of the activation of
plasminogen by human tissue plasmino-
gen activator: role of fibrin. J Biol Chem
1982;257:2912-9.
10. Marder VJ, Novokhatny V. Direct fibri-
nolytic agents: biochemical attributes,
preclinical foundation and clinical poten-
tial. J Thromb Haemost 2010;8:433-44.
11. The National Institute of Neurologi-
cal Disorders and Stroke rt-PA Stroke
Study Group. Tissue plasminogen activa-
tor for acute ischemic stroke. N Engl J
Med 1995;333:1581-8.
12. Kwiatkowski TG, Libman RB, Frankel
M, et al. Effects of tissue plasminogen ac-
tivator for acute ischemic stroke at one
year. N Engl J Med 1999;340:1781-7.
13. Hacke W, Kaste M, Fieschi C, et al.
Intravenous thrombolysis with recombi-
nant tissue plasminogen activator for
acute hemispheric stroke: the European
Cooperative Acute Stroke Study (ECASS).
JAMA 1995;274:1017-25.
14. Hacke W, Kaste M, Fieschi C, et al.
Randomised double-blind placebo-con-
trolled trial of thrombolytic therapy with
intravenous alteplase in acute ischaemic
stroke (ECASS II). Lancet 1998;352:1245-
51.
15. Clark WM, Wissman S, Albers GW,
Jhamandas JH, Madden KP, Hamilton S.
Recombinant tissue-type plasminogen
activator (alteplase) for ischemic stroke
3 to 5 hours after symptom onset: the
­ATLANTIS study: a randomized con-
trolled trial. JAMA 1999;282:2019-26.
16. Brott T, Bogousslavsky J. Treatment of
acute ischemic stroke. N Engl J Med 2000;
343:710-22.
17. Hacke W, Kaste M, Bluhmki E, et al.
Thrombolysis with alteplase 3 to 4.5 hours
after acute ischemic stroke. N Engl J Med
2008;359:1317-29.
18. Jauch EC, Cucchiara B, Adeoye O, et
al. Part 11: adult stroke: 2010 American
Heart Association guidelines for cardio-
pulmonary resuscitation and emergency
cardiovascular care. Circulation 2010;122:
Suppl 3:S818-S828.
19. Adams HP Jr, Davis PH, Leira EC, et
al. Baseline NIH Stroke Scale score
strongly predicts outcome after stroke: a
report of the Trial of Org 10172 in Acute
Stroke Treatment (TOAST). Neurology
1999;53:126-31.
20. Adams HP Jr, Lyden P. Assessment of
a patient with stroke: neurological exami-
nation and clinical rating scales. In: Fish-
er M. Stroke part III: investigation and
management. Vol. 94 of Handbook of
clinical neurology. 3rd series. New York:
Elsevier, 2008:971-1009.
21. Johnston SC, Easton JD. Are patients
with acutely recovered cerebral ischemia
more unstable? Stroke 2003;34:2446-50.
22. Johnston SC, Leira EC, Hansen MD,
Adams HP Jr. Early recovery after cerebral
ischemia risk of subsequent neurological
deterioration. Ann Neurol 2003;54:439-44.
23. The NINDS t-PA Stroke Study Group.
Intracerebral hemorrhage after intra­venous
t-PA therapy for ischemic stroke. Stroke
1997;28:2109-18.
24. Larrue V, von Kummer RR, Müller A,
Bluhmki E. Risk factors for severe hemor-
rhagic transformation in ischemic stroke
patients treated with recombinant tissue
plasminogen activator: a secondary analy-
sis of the European-Australasian Acute
Stroke Study (ECASS II). Stroke 2001;32:
438-41.
25. Levy DE, Brott TG, Haley EC Jr, et al.

2144 n engl j med 364;22  nejm.org  june 2, 2011

The New England Journal of Medicine

Downloaded from nejm.org at UNIVERSITE DE GENEVE on June 2, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Factors related to intracranial hematoma
formation in patients receiving tissue-
type plasminogen activator for acute is­
chemic stroke. Stroke 1994;25:291-7.
26. Selim M, Fink JN, Kumar S, et al. Pre-
dictors of hemorrhagic transformation
after intravenous recombinant tissue plas-
minogen activator: prognostic value of the
initial apparent diffusion coefficient and
diffusion-weighted lesion volume. Stroke
2002;33:2047-52.
27. Tanne D, Kasner SE, Demchuk AM, et
al. Markers of increased risk of intracere-
bral hemorrhage after intravenous recom-
binant tissue plasminogen activator ther-
apy for acute ischemic stroke in clinical
practice: the Multicenter rt-PA Stroke Sur-
vey. Circulation 2002;105:1679-85.
28. Adams HP Jr, del Zoppo G, Alberts
MJ, et al. Guidelines for the early manage-
ment of adults with ischemic stroke: a
guideline from the American Heart Asso-
ciation/American Stroke Association Stroke
Council, Clinical Cardiology Council, Car-
diovascular Radiology and Intervention
Council, and the Atherosclerotic Periph-
eral Vascular Disease and Quality of Care
Outcomes in Research Interdisciplinary
Working Groups: the American Academy
of Neurology affirms the value of this
guideline as an educational tool for neu-
rologists. Stroke 2007;38:1655-711. [Errata,
Stroke 2007;38(6):e38, 38(9):e96.]
29. Larrue V, von Kummer R, del Zoppo
G, Bluhmki E. Hemorrhagic transforma-
tion in acute ischemic stroke: potential
contributing factors in the European Co-
operative Acute Stroke Study. Stroke 1997;
28:957-60.
30. Nakagawara J, Minematsu K, Okada
Y, et al. Thrombolysis with 0.6 mg/kg in-
travenous alteplase for acute ischemic
stroke in routine clinical practice: the Ja-
pan post-Marketing Alteplase Registration
Study (J-MARS). Stroke 2010;41:1984-9.
31. Yamaguchi T, Mori E, Minematsu K,
et al. Alteplase at 0.6 mg/kg for acute
ischemic stroke within 3 hours of onset:
Japan Alteplase Clinical Trial (J-ACT).
Stroke 2006;37:1810-5.
32. Tanswell P, Modi N, Combs D, Danays
T. Pharmacokinetics and pharmacody-
namics of tenecteplase in fibrinolytic
therapy of acute myocardial infarction.
Clin Pharmacokinet 2002;41:1229-45.
33. Haley EC Jr, Lyden PD, Johnston KC,
Hemmen TM. A pilot dose-escalation
safety study of tenecteplase in acute is­
chemic stroke. Stroke 2005;36:607-12.
34. Haley EC Jr, Thompson JL, Grotta JC,
et al. Phase IIB/III trial of tenecteplase in
acute ischemic stroke: results of a prema-
turely terminated randomized clinical
trial. Stroke 2010;41:707-11.
35. Furlan AJ, Eyding D, Albers GW, et al.
Dose Escalation of Desmoteplase for
Acute Ischemic Stroke (DEDAS): evidence
n engl j med 364;22  nejm.org  june 2, 2011
The New England Journal of Medicine
Downloaded from nejm.org at UNIVERSITE DE GENEVE on June 2, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
clinical Ther apeutics
of safety and efficacy 3 to 9 hours after
stroke onset. Stroke 2006;37:1227-31.
36. Hacke W, Albers G, Al-Rawi Y, et al.
The Desmoteplase in Acute Ischemic
Stroke Trial (DIAS): a phase II MRI-based
9-hour window acute stroke thrombolysis
trial with intravenous desmoteplase. Stroke
2005;36:66-73.
37. Hacke W, Furlan AJ, Al-Rawi Y, et al.
Intravenous desmoteplase in patients with
acute ischaemic stroke selected by MRI
perfusion-diffusion weighted imaging or
perfusion CT (DIAS-2): a prospective, ran-
domised, double-blind, placebo-controlled
study. Lancet Neurol 2009;8:141-50.
38. Furlan A, Higashida R, Wechsler L, et
al. Intra-arterial prourokinase for acute
ischemic stroke: the PROACT II study: a
randomized controlled trial. JAMA 1999;
282:2003-11.
39. Stahl JE, Furie KL, Gleason S, Gazelle
GS. Stroke: effect of implementing an
evaluation and treatment protocol com-
pliant with NINDS recommendations.
Radiology 2003;228:659-68.
40. Sandercock P, Berge E, Dennis M, et
al. Cost-effectiveness of thrombolysis
with recombinant tissue plasminogen ac-
tivator for acute ischemic stroke assessed
by a model based on UK NHS costs.
Stroke 2004;35:1490-7.
41. Moodie ML, Carter R, Mihalopoulos
C, et al. Trial application of a Model of
Resource Utilization, Costs, and Out-
comes for Stroke (MORUCOS) to assist
priority setting in stroke. Stroke 2004;
35:1041-6.
42. Albers GW, Bates VE, Clark WM, Bell
R, Verro P, Hamilton SA. Intravenous tis-
sue-type plasminogen activator for treat-
ment of acute stroke: the Standard Treat-
ment with Alteplase to Reverse Stroke
(STARS) study. JAMA 2000;283:1145-50.
43. Hill MD, Buchan AM. Thrombolysis
for acute ischemic stroke: results of the
Canadian Alteplase for Stroke Effective-
ness Study. CMAJ 2005;172:1307-12.
44. Wahlgren N, Ahmed N, Dávalos A, et
al. Thrombolysis with alteplase for acute
ischaemic stroke in the Safe Implementa-
tion of Thrombolysis in Stroke-Monitor-
ing Study (SITS-MOST): an observational
study. Lancet 2007;369:275-82. [Erratum,
Lancet 2007;369:826.]
45. The NINDs t-PA Stroke Study Group.
Generalized efficacy of t-PA for acute
stroke: subgroup analysis of the NINDS
t-PA Stroke Trial. Stroke 1997;28:2119-25.
46. Chen CI, Iguchi Y, Grotta JC, et al. In-
travenous TPA for very old stroke patients.
Eur Neurol 2005;54:140-4.
47. Sylaja PN, Cote R, Buchan AM, Hill
MD. Thrombolysis in patients older than
80 years with acute ischaemic stroke: Ca-
nadian Alteplase for Stroke Effectiveness
Study. J Neurol Neurosurg Psychiatry
2006;77:826-9.
48. Demchuk AM, Morgenstern LB,
Krieger DW, et al. Serum glucose level
and diabetes predict tissue plasminogen
activator-related intracerebral hemorrhage
in acute ischemic stroke. Stroke 1999;30:
34-9.
49. Saqqur M, Tsivgoulis G, Molina CA,
et al. Symptomatic intracerebral hemor-
rhage and recanalization after IV rt-PA:
a multicenter study. Neurology 2008;71:
1304-12.
50. Molina CA, Alvarez-Sabín J, Montaner
J, et al. Thrombolysis-related hemorrhag-
ic infarction: a marker of early reperfu-
sion, reduced infarct size, and improved
outcome in patients with proximal mid-
dle cerebral artery occlusion. Stroke 2002;
33:1551-6.
51. Broderick J, Connolly S, Feldmann E,
et al. Guidelines for the management of
spontaneous intracerebral hemorrhage in
adults: 2007 update: a guideline from the
American Heart Association/American
Stroke Association Stroke Council, High
Blood Pressure Research Council, and the
Quality of Care and Outcomes in Re-
search Interdisciplinary Working Group.
Stroke 2007;38:2001-23.
52. Rasler F. Emergency treatment of
hemorrhagic complications of thrombol-
ysis. Ann Emerg Med 2007;50:485.
53. Goldstein JN, Marrero M, Masrur S, et
al. Management of thrombolysis-associ-
ated symptomatic intracerebral hemor-
rhage. Arch Neurol 2010;67:965-9.
54. Engelter ST, Fluri F, Buitrago-Téllez C,
et al. Life-threatening orolingual angio-
edema during thrombolysis in acute is­
chemic stroke. J Neurol 2005;252:1167-70.
55. Hill MD, Lye T, Moss H, et al. Hemi-
orolingual angioedema and ACE inhibi-
tion after alteplase treatment of stroke.
Neurology 2003;60:1525-7.
56. von Kummer R. After European Co-
operative Acute Stroke Study 3: mission
accomplished? Stroke 2009;40:2268-70.
57. Albers GW, Thijs VN, Wechsler L, et
al. Magnetic resonance imaging profiles
predict clinical response to early reperfu-
sion: the Diffusion and perfusion imag-
ing Evaluation for Understanding Stroke
Evolution (DEFUSE) study. Ann Neurol
2006;60:508-17.
58. Kidwell CS, Wintermark M. The role
of CT and MRI in the emergency evalua-
tion of persons with suspected stroke.
Curr Neurol Neurosci Rep 2010;10:21-8.
59. Lev MH, Segal AZ, Farkas J, et al. Util-
ity of perfusion-weighted CT imaging in
acute middle cerebral artery stroke treat-
ed with intra-arterial thrombolysis: pre-
diction of final infarct volume and clini-
cal outcome. Stroke 2001;32:2021-8.
60. Mishra NK, Albers GW, Davis SM, et
al. Mismatch-based delayed thrombolysis:
a meta-analysis. Stroke 2010;41(1):e25-
e33. [Erratum, Stroke 2010;41(4):e399.]
2145
 clinical Ther apeutics

61. Alexandrov AV, Demchuk AM, Burgin
WS, Robinson DJ, Grotta JC. Ultrasound-
enhanced thrombolysis for acute ische­
mic stroke: phase I. Findings of the
CLOTBUST trial. J Neuroimaging 2004;
14:113-7.
62. Alexandrov AV, Demchuk AM, Felberg
RA, et al. High rate of complete recanali-
zation and dramatic clinical recovery dur-
ing tPA infusion when continuously mon-
itored with 2-MHz transcranial Doppler
monitoring. Stroke 2000;31:610-4.
63. Alexandrov AV, Molina CA, Grotta JC,
et al. Ultrasound-enhanced systemic throm-
bolysis for acute ischemic stroke. N Engl J
Med 2004;351:2170-8.
64. Eggers J, König IR, Koch B, Händler
G, Seidel G. Sonothrombolysis with tran-
scranial color-coded sonography and re-
combinant tissue-type plasminogen acti-
vator in acute middle cerebral artery main
stem occlusion: results from a random-
ized study. Stroke 2008;39:1470-5.
65. Tsivgoulis G, Eggers J, Ribo M, et al.
Safety and efficacy of ultrasound-enhanced
thrombolysis: a comprehensive review and
meta-analysis of randomized and non­
randomized studies. Stroke 2010;41:280-7.
66. Daffertshofer M, Gass A, Ringleb P, et
al. Transcranial low-frequency ultrasound-
mediated thrombolysis in brain ischemia:
increased risk of hemorrhage with com-
bined ultrasound and tissue plasminogen
activator: results of a phase II clinical tri-
al. Stroke 2005;36:1441-6.
67. The European Stroke Organisation
(ESO) Executive Committee and The ESO
Writing Committee. Guidelines for man-
agement of ischaemic stroke and transient
ischaemic attack. (http://www.eso-stroke
.org/pdf/ESO08_Guidelines_Original_
english.pdf.)
68. Del Zoppo GJ, Saver JL, Jauch EC,
Adams HP Jr. Expansion of the time win-
dow for treatment of acute ischemic
stroke with intravenous tissue plasmino-
gen activator: a science advisory from the
American Heart Association/American
Stroke Association. Stroke 2009;40:2945-
8. [Erratum, Stroke 2010;4(9):e562.]
69. The European Stroke Organisation
(ESO) Executive Committee and The
ESO Writing Committee. Guidelines for
management of ischaemic stroke and
transient ischaemic attack. (http://www
.eso-stroke.org/pdf/ESO%20Guidelines_
update_Jan_2009.pdf.)
70. Work Group on Thrombolytic Therapy
in Stroke. Position statement of the Amer-
ican Academy of Emergency Medicine on
the use of intravenous thrombolytic ther-
apy in the treatment of stroke. (http://
www.aaem.org/positionstatements/
thrombolytictherapy.php.)
71. Clinical practice statement: tissue plas-
minogen activator (tPA) and stroke: a clini-
cal practice advisory (4/12/10). (http://www
.aaem.org/emtopics/tissue_plasminogen
_activator_references.pdf.)
72. American College of Emergency Phy-
sicians. Use of intravenous tPA for the
management of acute stroke in the emer-
gency department. (http://www.acep.org/
practres.aspx?id=29834.)
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