New Guidelines on tPA in
Stroke: Putting Out Fires
With Gasoline?
by WILLIAM B. MILLARD, PhD
Special Contributor to
Annals News & Perspective
W
hen a joint panel representing
the American College of Emergency Physicians (ACEP) and
the American Academy of Neurology
(AAN) issued guidelines1 on the use of
recombinant tissue-type plasminogen activator (rt-PA, alteplase, or tPA) in patients receiving a diagnosis of ischemic
stroke, proponents of this treatment may
have heaved a sigh of relief.
Nearly 2 decades after tPA received
Food and Drug Administration (FDA)
approval for this indication, the muchdebated National Institute of Neurological Disorders and Stroke trials2 appeared
vindicated, with these influential organizations elevating intravenous tPA treatment within 3 hours of symptom onset to
a level A recommendation. The actual
wording specifies that “IV tPA should be
offered,” not that it must always be
given, “to acute ischemic stroke patients
who meet National Institute of Neurological Disorders and Stroke (NINDS)
inclusion/exclusion criteria.” Thrombolysis proponents might infer that entrenched resistance, particularly among
emergency physicians,3 is likely to dwindle. The only known acute treatment for
stroke can reach more patients and benefit most of them.
Not so fast, say some observers of the
controversy. Many things about tPA are
Volume , .  : July 
uncertain; its association with more intracranial hemorrhages is not one of
them. Whether the clot-busting treatment correlates with improved outcomes clearly enough to outweigh that
risk, particularly when the urgent time
factor (only treatment within the
3-hour window receives the ACEP/
AAN level A recommendation, whereas
treatment within 4.5 hours gets a level
B) adds pressure to the uncertainties
inherent in a diagnosis of exclusion, is a
settled question to some and an open
question to others. At least 1 prominent skeptic toward tPA views the
available evidence as not only inconclusive at best but also perhaps inconsistent with the proposed mechanism of
action altogether.
With widespread reluctance to use
tPA acknowledged by both proponents
and skeptics, and with shifting incentives affecting therapeutic policies, the
new guidelines may foster as much
confusion and polarization as they resolve. Experience with tPA can fit into
either a narrative of progress and
obstructionism or one of earnest (albeit
profit-enhanced) wishful thinking. The
physician seeking a definitive answer
may be in the position of solitude and
inescapable responsibility that JeanPaul Sartre described in a 1946 lecture:
“[I]f you seek counsel . . . at bottom
you already knew, more or less, what [a
given counselor] would advise. In other
words, to choose an adviser is nevertheless to commit oneself by that choice.”4
RESPONSIBLE AND
IRRESPONSIBLE
CRITIQUES
T
hrombolytics for stroke arouse strong
opinions. Without naming names,
and for the most part without invoking ad hominem arguments, commentators on both the pro and con sides of this
debate choose their words carefully but
rarely mince them.
“I think skeptics and critics fall into
basically 2 camps,” said Patrick D.
Lyden, MD, FAAN, chairman of the department of neurology and director of the
stroke program at Cedars-Sinai Medical
Center in Los Angeles and a major participant in the original NINDS studies.
“One camp includes very well-intentioned clinician-scientists who appropriately challenge the data. They felt maybe
the results were too good to be true,
wanted to see replication, and sort of
dragged the field down a little bit for a
few years until more data came in. The
second group includes, unfortunately,
self-appointed professional critics who
had some form of undisclosed conflict of
interest, and unfortunately the latter
camp was disproportionately influential.”
(The latter, he added, have shown a tendency to plagiarize ideas from the former.)
NINDS, Dr. Lyden contends, has
withstood extensive analysis and received
support from subsequent studies (particularly the third European Cooperative
Acute Stroke Study,5 the Third International Stroke Trial,6 and the Japan Alteplase Clinical Trial,7 which used lower
tPA doses). NINDS was an actual trial,
not an artificial academic exercise: most
subjects were enrolled at community hospitals in San Diego, Cincinnati, Houston,
New York, and elsewhere. The NINDS
findings, he says, are at least as substantially beneficial and methodologically robust as those supporting many other established treatments.
Moreover, considering the long-range
benefit/risk advantage that tPA confers,
in Dr. Lyden’s analysis, delays in its acAnnals of Emergency Medicine 13A
ceptance constitute a large-scale disservice to patients. “If you calculate the
absolute numbers of patients [who] could
benefit, had they been treated,” he suggested, “go back to 1996, which is actually the first year of approval, and carry it
forward, let’s say, to 2006, so just do 10
years . . . let’s say in 2006, the tide began
to turn and [emergency] physicians wised
up to some of this crap that was being
thrown around. So for 10 years, there was
a break on treatment, a damper on treatment. You can do some estimates: you
can say, ’Well, what if twice as many
people had been treated? What if 3 times
as many people had been treated?’ You
can begin to estimate the number of lives
that were damaged as a result of people
believing this junk that was written
about us.”
THE GIFTS THAT KEPT
ON GIVING
“
I
’d like to address 3 points that were
said that are totally false, that led
[emergency] physicians down the
wrong path,” Dr. Lyden continued. “The
first one,” he said, involves suspected conflict of interest; some of Genentech’s past
conduct, indeed, made it plausible. “It
was alleged by some of these self-appointed critics that somehow Genentech
influenced the results of the study. And
this was an easy low blow to get away
with, because 10 years prior to the stroke
study, there was a heart attack study
where in fact there were issues. Genentech did have inappropriate influence
over the drafting of the manuscript. So it
was very easy to hit us below the belt,
because there was a precedent.” Dr.
Lyden referred here to the Thrombolysis
in Myocardial Infarction (TIMI) trial,8
some of whose authors had accepted benefits from Genentech.9
The company’s conduct and statements relevant to previous heart studies
comparing tPA and streptokinase—including the damning and recurrently
cited quote by Genentech senior vice
president Elliott Grossbard, MD, that a
repeated study “may be a good thing for
America, but it wasn’t going to be a good
thing for us”10,11—set the stage for renewed skepticism toward NINDS. Yet
precisely because of experiences like
TIMI, Dr. Lyden reports, the NINDS
14A Annals of Emergency Medicine
investigators set up careful firewalls
against company contact with the drafting of the protocol, the data, and the
writing of the article. At one point, Dr.
Lyden and colleagues even rejected a Genentech representative’s offer of a cup of
coffee.
Allegations of bias continue to shadow
NINDS; Dr. Lyden quoted an attending
physician in his own hospital recently,
asking, “Oh, yeah, that tPA study: that
was the one [in which] Genentech
bought the results, right?” He laughed
but dismissed conspiratorialism: “What
every [emergency] physician needs to
know is that we were holier than Caesar’s
wife, for obvious reasons.” Edward C.
Jauch, MD, MS, director of the division of
emergency medicine at the Medical University of South Carolina, chair of the
Stroke Council of the American Heart Association/American Stroke Association, and
a member of the International Liaison
Committee on Resuscitation, concurred
that “the pendulum has swung . . . to the
side of caution” on conflict of interest. “If
you look at recent NIH-funded trials,
where the drug [or] device is provided in
kind from the companies, the companies
have no access to the data, no access to the
analysis of the data, no access to the trial
design, even though it would be in their
best interest so they could get FDA approval . . . . I can tell you personally,
being on the executive committee of several of these trials, they have no access to
what we do.”
CRUNCHING THE
NUMBERS
T
he second myth Dr. Lyden wants to
dispel is “that the results were not
very significant: that, ‘well, maybe it
worked, but it doesn’t mean that much;
you only have 11% benefit.’ And this one
is really, really devious.” In contrast to
mortality-rate differences of a few percentage points in some fields such as cardiac tPA treatment or some cancer treatments, he said, “when it came to the
stroke study, we increased the good outcome rate 30% to 41%. So that’s 11%
absolute increase,” not relative risk, and
the relative-risk enhancement is “11 over
30 . . . basically one third . . . . This is
huge in medicine. It’s one of the most
powerful things that’s ever been done,
besides maybe penicillin for pneumonia.”
“The third point is that it’s dangerous,” Dr. Lyden said; he readily acknowledged that the drug induces hemorrhages. “Stroke patients have a severe
illness, and some patients die from their
stroke. But nobody dies because they get
tPA. Nobody. What happens is a small
number of the patients who have a massive stroke convert from an ischemic to a
hemorrhagic stroke. And those people
die. But it’s the people who were going to
die anyway.” Bleeding rates, he noted,
went from 1% to 6% in the tPA-treated
group in NINDS (with rates closer to 3%
in more recent studies), “but if you look
at the overall mortality statistics for tPAtreated patients, it’s actually lower than
natural history. And the mortality rate
had never been statistically significant
until people [conducted] meta-analysis.
But when you do meta-analysis and you
lump all the studies into one, you find the
statistically significant lowering of mortality when you give tPA. So the idea that
it’s a dangerous treatment is just dead
wrong.”
Though the original NINDS data set
was not made publicly available until
2003,12 the findings have undergone repeated scrutiny. To address methodologic
questions, including allegations that subgroup mismatches in stroke severity accounted for the results, NINDS investigators performed post hoc subgroup
analyses that supported the initial claims
of statistical and clinical benefits.13 The
National Institutes of Health (NIH) also
engaged Mayo Clinic biostatistical consultant W. Michael O’Fallon to assemble
an independent committee to review the
data14; O’Fallon’s group, Dr. Lyden said,
“basically confirmed” the analysis. “If you
don’t believe O’Fallon because the NIH
paid O’Fallon, and you have this bizarre
conspiracy-theory mentality, the FDA
hired a third agnostic statistician, and in
the FDA analysis of the data, which allowed for licensure, they confirmed that
the drug was powerful and effective.”
WHO DO YOU BELIEVE: P
VALUES OR YOUR OWN
EYES?
“
B
ut even if you don’t trust us, and
you don’t trust O’Fallon, and you
don’t trust the FDA, all 3 of
which are not connected and totally inVolume , .  : July 
dependent of each other,” Dr. Lyden continued, “look at history”: subsequent
studies such as the third European Cooperative Acute Stroke Study, Third International Stroke Trial, and Japan Alteplase
Clinical Trial. It is in this broader history
that complications arise. The ACEP/
AAN clinical guidelines cite the third
European Cooperative Acute Stroke
Study as an additional source of support
for the treatment, though not as dramatic
as the NINDS findings and not decisively
favoring extending the time window to
4.5 hours; the guideline panel found that
the Third International Stroke Trial,
which studied a 6-hour period and a different cohort of patients, did not affect
the recommendations and did not consider the Japan Alteplase Clinical Trial.
Yet these and other reports, which found
no benefit from thrombolytics and were
stopped in some cases because of excessive
mortality (eg, Alteplase Thrombolysis for
Acute Noninterventional Therapy in
Ischemic Stroke15), complicate the picture. NINDS, opponents contend, has to
be viewed within a context suggesting it
may be an anomaly, and it has not been
subjected to the test of replication.
Jerome R. Hoffman, MD, MA professor of emergency medicine at Los Angeles
County USC School of Medicine and professor emeritus at University of California, Los Angeles, is one of the most
prominent dissidents on tPA. He is inclined to trust rank-and-file physicians’
views over those of the guideline development panel. “Recent polls where emergency physicians have been asked their
opinion—nonrepresentative polls, to be
fair, but with results concordant with
everything that’s ever been asked before—suggest that at least a majority of
emergency physicians feel at least that
this is an unproven and potentially very
dangerous therapy,” he commented.
“Given that, it seems sort of striking that
ACEP would come out with a policy at
odds with that. Now, it would be understandable if that policy were based in
science . . . [but] it’s certainly not based
on any new evidence that is favorable.”
Dr. Hoffman objects to the new
guidelines on 2 general grounds, raising
questions about process and questions
about scientific content. The processbased qualms involve panel selection, inVolume , .  : July 
cluding both commercial conflicts (cited
in the official disclosures) and the range
of scientific opinion represented. “I’m
pretty sure,” he said, “from having talked
to many of the people who are leading
skeptics about this, and from looking at
the people who participated in the guideline writing, that not only were there no
skeptics on the guideline writing panel,
but . . . as far as I can tell, none were asked
to be on the panel, and none actually even
got to comment about this . . . . In a specialty where there is huge divergence of
beliefs, the panel ended up entirely,
100%, composed of people with one belief. And zero input from very prominent,
very well-known, very academic physicians who believe the opposite.”
QUESTIONING THE BASE
AND THE BIAS
D
r. Hoffman preferred to focus on the
scientific evidence while noting the
scale of promotional expense in some
segments of the opposing camp and commenting that “for any serious person to
believe that the problem of bias and selfpromotion and conflict is more on the side
of those who are skeptical than on the
side of those who are pushing this: that’s
an amazing, stunning assertion.” Years of
examining the range of tPA studies, he
said, have led him from caution to firmer
opposition.
“Many of us who were skeptical about
this way back when,” he said, “expressed
the belief not that this doesn’t work, but
that it’s unproven to work: that it requires far more evidence before we should
believe that it works . . . . Second, I have
always said, long before I ever did my
own reanalysis of NINDS, that even if
NINDS were 100% correct and there
were no problems with it . . . the notion
that NINDS stands alone and is adequate
evidence on its own, I think, is contrary
to everything I learned about science.”
“Any time a relatively small study
finds a relatively small effect,” Dr. Hoffman said, “a single study should be
viewed with enormous skepticism.” Research history is full of large effects in an
initial study contradicted by more definitive studies; he cited a trial of snake
venom for acute ischemic stroke as a salient case.16,17
Because other studies failed to find the
same effect NINDS did—“none as large,
almost none positive at all by any interpretation, but multiple of them negative,” he said—the post hoc confirmations NINDS has received, although
useful, are not decisive. In addition, he
contended, “the statistical review of
NINDS merely said that it is impossible
to prove that baseline biases, baseline differences, were responsible for the differences found in outcome. There’s an enormous difference between saying ’We
can’t prove that they were responsible’
and saying ’We know they weren’t responsible.’”
Greater statistical power, he believed,
would have allowed stronger conclusions.
When Dr. Hoffman and colleague David
L. Schriger, MD, MPH, performed a detailed graphic reanalysis of the original
NINDS data,18 they found only a small
effect on NIH Stroke Scale scores when
90-day changes in that variable were considered. “If you actually look at the different subgroups,” he said, “they didn’t
look the same. To the naked eye, they
look quite different. But statistically they
look the same, of course, because there is
no power to find that they were different.” Dr. Lyden, among others,19 found
Dr. Hoffman and Schriger’s unorthodox
graphic analysis “bizarre [and] idiosyncratic,” observing that they are admittedly not statisticians; the ACEP/AAN
guidelines noted that their observations
did not dispute the statistical significance
of the NINDS conclusions.
Dr. Hoffman distinguished 2 key
terms applied to treatments: efficacy in the
statistical sense, an artificial mathematical
construct, versus effectiveness in realistic clinical settings. “I think what most people
would acknowledge for virtually any intervention in medicine is that efficacy is likely
to produce results that are better than realworld effectiveness. That’s almost a universal principle. When something is done under ideal circumstances in a trial, where
you have exclusions of patients who are
least likely to benefit, and you carefully
pick the patients, and you have a neuroradiologist and a neuro-ICU, you’ve got a
big team and everything’s going ideally,
it is almost certain that the results in that
circumstance will be better than the results in other circumstances.”
Annals of Emergency Medicine 15A
This principle applies in particular to
the setting of suspected stroke, where
“there’s enormous pressure to do things
in a huge hurry. Time is brain; you’ve got
to do it right now; most of the patients,
at best, [are] very close to whatever cutoff
you’re going to use; so you’d better do it
before you really think too hard, before
you say ’Is this really a stroke mimic, and
I can hurt and I can’t help?’” It is not so
much a choice between aggressive interventionism and the precautionary principle, he summarized, as an application of
evidence to temper one’s best intentions:
“The more harm you can do to real human beings, the more you should suppress your personal urge to be a hero, if
what you do might not be beneficial.”
CHERRY PICKING, KOL
MINING, OR REPLICATION
D
r. Hoffman also objected to selectivity
in literature reviews. “NINDS has
never been replicated, so we really
don’t know whether the difference in outcome reflects simply chance alone or
whether it reflects some real difference
between NINDS and the others. But we
do have a lot of other studies, and I
believe that any fair, unbiased scientist
would tell you that when you have multiple studies that differ from each other in
marginal ways, they all provide evidence,
and that it is completely inappropriate to
throw out all the studies that have results
you don’t like and say ’They don’t count
because they’re different.’” To dismiss
negative findings from meta-analyses, he
charged, and “then, remarkably, do a
meta-analysis which says the results are
positive, that’s inevitable: it’s a self-fulfilling prophecy, and it has nothing to do
with science.” Noting that tPA/streptokinase comparisons and other negative
findings “are presumed not to count . . .
because they got the ‘wrong’ results,” he
likened this approach to shooting an arrow into a wall and then drawing a bull’seye around it.
Some studies alleged to add support
for tPA, Dr. Hoffman charged, do nothing of the kind when viewed neutrally.
He is particularly critical of reports on
the Third International Stroke Trial (converted in midstream from a double-blind
design to an unblinded one), in which
16A Annals of Emergency Medicine
“despite cherry-picked patients and despite enormous bias—not little bias,
enormous bias in favor of the treatment
group—it was resoundingly negative.
[According to] its own authors, its primary outcome was resoundingly negative, and despite that, remarkably, they
concluded it’s great . . .. What’s really
wonderful is that many advocates of this
take a study, a very flawed, biased study
that nevertheless was negative, and somehow say it was positive. That’s stunning.”
The Third International Stroke Trial authors, he said, publicly dismissed certain
secondary outcomes as unreliable20 and
then reversed course and based their
claim of benefit on them when primary
outcomes (death or dependence at 6
months) showed no benefit.21
Having published comments around
the time of NINDS and other studies
that were discordant with it, advocating a
repeated study to seek definitive evidence
whether tPA really was a useful therapy,
Dr. Hoffman now leans toward the view
that it is “not really unproven; it is almost certainly not valuable.” Three recent studies of endovascular approaches
reported in the March 7, 2013, New England Journal of Medicine,22-24 he said, “all
suggested that making the clot go away
isn’t what did it . . . . Patients who have
a clot that goes away when you go and
pull it out with one of these devices, they
do better than patients where the clot
doesn’t get removed. But, that happens
just as much when you give them placebo
as when you use the device. In fact, the
single best group in the largest study . . .
was the patients who have everything
perfect on MRI: a small infarct, lots of
perfusion defects, a big clot. The single
best group [was] those patients who have
the favorable circumstances and get no
treatment, suggesting that the favorable
circumstances are what [make] a good
outcome, not the intervention.”
These reports, one of which (Kidwell
et al24) included a no-intervention group
that fared as well as the group receiving
embolectomy, alongside other reports of
patients receiving thrombolysis who were
found on imaging to have stroke mimics25 and other nonthrombotic conditions, strike Dr. Hoffman as calling the
entire physiologic basis for tPA’s claimed
benefits into question. In cases in which
imaging found no acute clots, “they come
up with all sorts of reasons why it still
was a stroke, and we gave them tPA, and
they did just as well as [patients in]
NINDS. And they somehow remarkably
interpret that to mean that it’s magic: it
works even when it’s not doing the job
it’s supposed to be doing. I think a more
reasonable interpretation is, if it works
just as well when it can’t be doing anything, because its mechanism of action is
it gets rid of a clot and there’s no clot to
get rid of, that suggests it isn’t doing
anything.”
Replicating the one recognized positive-result study, Dr. Hoffman contended, would be a more scientifically
responsible investment than various
forms of marketing, and one that would
express confidence in tPA.
“If I were an executive of the drug
company that makes this, and I really
wanted doctors to use it, and I believed
that this is really important . . . and I also
believed, as has been stated many times
in public, that those darn emergency
physicians who are skeptical are preventing its use from lots and lots of patients
who would benefit, and I really wanted to
fix that, there are a couple of ways I could
do that. One way would be to try to
spend a lot of money on key opinion
leaders . . . and there are many things I
could do. But if I really wanted to fix it,
the easiest and simplest and quickest way
to get rid of that resistance would be to
repeat NINDS . . . . If I really believed
[skepticism were] preventing thousands
of patients from getting the wonderful
drug, I’d say; ‘Let’s do it. Let’s get this
cleared up once and for all.’”
STROKE UNITS: THE
CENTER CAN HOLD
O
bserving that less dramatic measures, from aspirin to good basic
nursing care delivered in modern
stroke units, also contribute to better
outcomes, Dr. Hoffman saluted the hospitals that are prepared for cases of stroke,
with or without onsite stroke neurologists or tPA. In this, he and Dr. Lyden are
in agreement. Not every institution will
be able and willing to manage the logistics of stroke care so that patients are
eligible for consideration of tPA within
Volume , .  : July 
the window, and coordination with emergency medical services (EMS) so that patients reach the appropriate facility is essential. Remote imaging (teleradiology
or “telestroke”) brings the necessary diagnostic expertise within reach of even
remote rural hospitals that would previously have required a neurologist willing
to wake up in the middle of the night and
travel. “Telestroke is now,” Dr. Lyden
said; “it’s not in the future.”
Dr. Lyden advocates a can-do resolve
while acknowledging that such resolve
will inevitably vary among institutions.
“In my opinion, there’s no hospital in
America that owns a CAT scanner that
can’t give tPA within 1 hour of patient
arrival. No place, if they’re willing to do
it. If you’re not willing, you should not
be open for emergency ambulances to
come to your hospital. If you don’t want
to do it, which is perfectly fine, if a
hospital makes the decision ‘we don’t
want to do it,’ notify the EMS: you’re not
ready for stroke patients.”
Dr. Jauch, noting that stroke has
dropped from the third to the fourth
leading cause of mortality nationwide,
pointed to the broader evolution of stroke
care during the past 2 decades. Prevention, he conjectured, means “patients
probably are having smaller strokes,
[which] are probably more amenable to
tPA.” A meta-analysis of drug safety
data,26 he commented, supports the idea
that well-organized systems of care, following treatment guidelines, can improve on the 6% hemorrhage rate in
NINDS. Still, because most patients do
not meet criteria for tPA treatment,
“what really makes a difference is putting
these systems of care in place where everybody gets the best patient care for that
specific patient, some of which benefit
from getting tPA, some of which benefit
from going to the cath lab. Many
shouldn’t get either of those . . . but still
need good stroke care.”
“I obviously believe that tPA, when
given appropriately, is very beneficial to
the patient,” Dr. Jauch said, “but I don’t
want it done in the absence of a total
system that evaluates and manages the
patient. So I can understand why an average practicing physician in a small hospital which has no neurology backup
would feel uncomfortable making a unilateral decision to treat with tPA.”
Volume , .  : July 
Policies suited to local conditions and
capabilities, Dr. Jauch said, are preferable
to “a unilateral, singular mandate . . .
that puts all the burden on the [emergency] physician.” A plan in place before
acute stroke cases arrive is essential; coordinated regional planning involving
hospitalists, neurologists, executives,
nurse managers, and EMS should determine protocols, including bypassing facilities without stroke units in favor of
dedicated centers (“Our VA hospital
doesn’t have a [computed tomography]
scanner after 5 [PM],” he noted; “Why
would you ever take a stroke patient
there?”) and knowing the point at which
a case exceeds local capacity and requires
a transfer. From the legal perspective, he
added, patients and families want to
know that every therapeutic option is at
least considered, whether or not it is applied in a given case; physicians deviating
from a hospital’s written standard of care
risk liability. “First and foremost, if a
policy exists, know it, and if it doesn’t
make sense, fix it.”
THE HELSINKI MODEL
“
W
hen you look at systems of care
that really work,” Dr. Jauch
continued, “you have to go outside the United States, unfortunately.”
The world’s best integrated stroke-care
system, he believes, is in Helsinki, where
“stroke champion zealot” Markku Kaste,
MD, PhD, and colleagues decided that one
fully resourced, well-organized, patient-oriented stroke center with a neurologist stationed in the emergency department (ED)
continuously was preferable to delivering
care through 20 different EDs.
“The patient can’t choose where they
go in Helsinki; if you’re having a stroke,
and they think you’re having a stroke,
you go to this one hospital . . . . Their
outcomes are fantastic; their bleeding
rates are great because they have an entire
system.” In the United States, he said,
Washington University’s system of comanagement by emergency physicians
and neurologists, applying the Toyota
lean-management principles to evaluation and treatment procedures from EMS
to the floor, has also brought impressive
results. “If you’re not in a hospital that’s
committed to doing that,” Dr. Jauch
said, “I would argue you should never get
a stroke patient. And I would champion
the idea that EMS bypasses hospitals that
don’t do that, just like we do for [STsegment elevation myocardial infarctions].”
The addition of tPA to emergency
care has undoubtedly been disruptive.
The challenge is to make this a constructive disruption, spurring systematic rethinking and upgrades. “It was not introduced into the medical community in a
very good way back in the 1990s,” Dr.
Jauch recalled. “It was just kind of thrown
out there, saying ‘Here you go, we’ve got
this great new drug; give it to everybody.’”
Whether its benefits will emerge more
clearly from further application and study,
a drug with such narrow applicability in
both time and patient characteristics requires systems conducive to disciplined decisions; these will benefit everyone.
Treatment with tPA may bear out Dr.
Lyden’s enthusiastic prediction of both
clinical benefit to patients and long-term
systemwide cost savings; because sparing
some patients costly inpatient care or
long-term nursing-home care outweighs
the high direct cost of the drug, he ranks
tPA alongside childhood immunizations
and prenatal care among “things where
you spend some money and not only do
you save lives [but also] you save money.”
However, Dr. Jauch cautioned, “there’s
another myth out there: that stroke
makes money”: its treatment, in his experience, tends to be budget-neutral and
is by no means a profit center comparable
to angioplasty, endoscopy, and other procedures. Preferable measures, he believes,
are the quality of life benefits from individual and societal standpoints. The
benefits in NINDS held up during at
least a year in one report.27 Whatever
else they accomplish, the guidelines
may now expand the chances to put
that single study’s implications to a far
broader test.
Section editor: Truman J. Milling, Jr, MD
Funding and support: By Annals policy, all
authors are required to disclose any and all
commercial, financial, and other relationships in any way related to the subject of
this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The
author has stated that no such relationships exist.
Annals of Emergency Medicine 17A
The views expressed in News and Perspective are those of the authors, and do
not reflect the views and opinions of the
American College of Emergency Physicians or the editorial board of Annals of
Emergency Medicine.
http://dx.doi.org/10.1016/j.annemergmed.
2013.05.010
REFERENCES
1. American College of Emergency
Physicians and American Academy of
Neurology. Clinical policy: use of
intravenous tPA for the management of
acute ischemic stroke in the emergency
department. Ann Emerg Med. 2013;
61:225-243. http://dx.doi.org/
10.1016/j.annemergmed.2012.11.005.
2. National Institute of Neurological
Disorders and Stroke rt-PA Stroke Study
Group. Tissue plasminogen activator for
acute ischemic stroke. N Engl J Med.
1995;333:1581-1588. doi:10.1056/
NEJM199512143332401.
3. Brown DL, Barsan WG, Lisabeth LD, et
al. Survey of emergency physicians
about recombinant tissue plasminogen
activator for acute ischemic stroke. Ann
Emerg Med. 2005;46:56-60. http://
dx.doi.org/10.1016/j.annemergmed.
2004.12.025.
4. Sartre JP. Existentialism is a humanism.
In: Kaufman W, ed. Existentialism From
Dostoevsky to Sartre. New York, NY:
Meridian; 1989. Trans. Philip Mairet.
Original pub.: Cleveland, OH: World
Publishing Co; 1956. Reprinted at:
http://www.marxists.org/reference/
archive/sartre/works/exist/
sartre.htm. Accessed April 30, 2013.
5. 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;359:1317-1329.
doi:10.1056/NEJMoa0804656.
6. IST-3 Collaborative Group. The benefits
and harms of intravenous thrombolysis
with recombinant tissue plasminogen
activator within 6 h of acute ischaemic
stroke (the third International Stroke
Trial [IST-3]): a randomised controlled
trial. Lancet. 2012;379:2352-2363. doi:
10.1016/S0140-6736(12)60768-5.
7. 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;37:1810-1815. http://dx.doi.
org/10.1161/01.STR.0000227191.
01792.e3.
18A Annals of Emergency Medicine
8. Chesebro JH, Knatterud G, Roberts R, et
al. Thrombolysis in Myocardial Infarction
(TIMI) Trial, phase I: a comparison
between intravenous tissue
plasminogen activator and intravenous
streptokinase. Clinical findings through
hospital discharge. Circulation. 1987;
76:142-154.
9. Maatz CT. University physician-researcher
conflicts of interest: the inadequacy of
current controls and proposed reform.
Berkeley Technol Law J. 7:1(Spring 1992).
Available at: http://www.law.berkeley.
edu/journals/btlj/articles/vol7/Maatz.
pdf. Accessed April 30, 2013.
10. Marsa L. Prescription for Profits: How
the Pharmaceutical Industry Bankrolled
the Unholy Alliance Between Science
and Business. New York, NY: Scribner;
1997:160.
11. Lenzer J. Alteplase for stroke: money
and optimistic claims buttress the
“brain attack” campaign. BMJ. 2002;
324723-729. Available at: http://
www.ncbi.nlm.nih.gov/pmc/articles/
PMC1122648. Accessed April 30,
2013.
12. Dachs RJ, Burton JH, Joslin J. A user’s
guide to the NINDS rt-PA stroke trial
database. PLoS Med. 5:e113. http://
dx.doi.org/10.1371/journal.pmed.
0050113.
13. Kwiatkowski T, Libman R, Tilley BC, et
al. The impact of imbalances in
baseline stroke severity on outcome in
the National Institute of Neurological
Disorders and Stroke Recombinant
Tissue Plasminogen Activator Stroke
Study. Ann Emerg Med. 2005;45:377384. http://dx.doi.org/10.1016/
j.annemergmed.2004.06.021.
14. Ingall TJ, O’Fallon WM, Asplund K, et al.
Findings from the reanalysis of the
NINDS Tissue Plasminogen Activator for
Acute Ischemic Stroke Treatment Trial.
Stroke. 2004;35:2418-2424. http://
dx.doi.org/10.1161/01.STR.0000140891.
70547.56.
15. Clark WM, Wissman S, Albers GW, et al.
Recombinant tissue-type plasminogen
activator (alteplase) for ischemic stroke
3 to 5 hours after symptom onset (the
ATLANTIS Study: a randomized
controlled trial). JAMA. 1999;282:20192026. http://dx.doi.org/10.1001/
jama.282.21.2019.
16. Sherman DG, Atkinson RP, Chippendale
T, et al. Intravenous ancrod for
treatment of acute ischemic stroke: the
STAT study: a randomized controlled
trial. JAMA. 2000;283:2395-2403.
17. Hennerici M, Kay R, Bogousslavsky J, et
al. Intravenous ancrod for acute
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
ischaemic stroke in the European
Stroke Treatment with Ancrod Trial: a
randomised controlled trial. Lancet.
2006;368:1871-1878.
Hoffman JR, Schriger DL. A graphic
reanalysis of the NINDS Trial. Ann
Emerg Med. 2009;54:329-336. http://
dx.doi.org/10.1016/j.annemergmed.
2009.03.019.
Saver JL, Gornbein J, Starkman S.
Graphic reanalysis of the two NINDS-TPA
trials confirms substantial treatment
benefit. Stroke. 2010;41:2381-2390.
doi:10.1161/STROKEAHA.110.583807.
Sandercock P, Lindley R, Wardlaw J, et
al. Update on the Third International
Stroke Trial (IST-3) of thrombolysis for
acute ischaemic stroke and baseline
features of the 3035 patients recruited.
Trials. 2011;12:252. doi:10.1186/
1745-6215-12-252.
Hoffman JR, Cooper RJ. How is more
negative evidence being used to support
claims of benefit? the curious case of
the Third International Stroke Trial (IST3). Emerg Med Australas. 2012;24:473476. http://dx.doi.org/10.1111/
j.1742-6723.2012.01604.x.
Broderick JP, Palesch YY, Demchuk AM,
et al. Endovascular therapy after
intravenous t-PA versus t-PA alone for
stroke. N Engl J Med. 2013;368:893903. http://dx.doi.org/10.1056/
NEJMoa1214300.
Ciccone A, Valvassori L, Nichelatti M, et
al. Endovascular treatment for acute
ischemic stroke. N Engl J Med. 2013;
368:904-913. http://dx.doi.org/
10.1056/NEJMoa1213701.
Kidwell CS, Jahan R, Gornbein J, et al. A
trial of imaging selection and
endovascular treatment for ischemic
stroke. N Engl J Med. 2013;368:914923. http://dx.doi.org/10.1056/
NEJMoa1212793.
Artto V, Putaala J, Strbian D, et al.
Stroke mimics and intravenous
thrombolysis. Ann Emerg Med. 2012;
59:27-32. http://dx.doi.org/10.1016/
j.annemergmed.2011.09.011.
Graham GD. Tissue plasminogen
activator for acute ischemic stroke in
clinical practice: a meta-analysis of
safety data. Stroke. 2003;34:28472850. http://dx.doi.org/10.1161/
01.STR.0000101752.23813.C3.
Kwiatkowski TG, Libman RB, Frankel M,
et al. Effects of tissue plasminogen
activator for acute ischemic stroke at
one year. N Engl J Med. 1999;340:
1781-1787. http://dx.doi.org/10.
1056/NEJM199906103402302.
Volume , .  : July 