Controversies in Stroke
Section Editors: Carlos A. Molina, MD, PhD, and Magdy H. Selim, MD, PhD
The Case:
A healthy 60-year-old man presents with acute left-sided weakness 4 hours after symptom onset. National Institutes of
Health Stroke Scale score is 8. Head computed tomography shows no hemorrhage or early signs of ischemia. Routine laboratory tests are within normal.
The Questions:
1.Should he be treated with intravenous thrombolysis?
2.Are other tests needed before initiation of treatment?
The Controversy:
Is the 4.5-hour time window for intravenous thrombolysis with recombinant tissue-type plasminogen activator (rtPa) firmly established?
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4.5-Hour Time Window for Intravenous Thrombolysis
With Recombinant Tissue-Type Plasminogen Activator Is
Established Firmly
Peter D. Schellinger, MD, PhD, FESO, FAHA; Martin Köhrmann, MD, PhD
his is a clear case. Yes! The patient should immediately be treated with the standard dose of rt-PA as per
approval in Europe and many other countries on this planet.
After the results of all pooled analyses (National Institute
of Neurological Disorders and Stroke [NINDS], European
Cooperative Acute Stroke Study 1–2 [ECASS 1–2], Alteplase
Thrombolysis for Acute Noninterventional Therapy in
Ischemic Stroke [ATLANTIS]), Cochrane Analyses, Safe
Implementation of Treatment in Stroke International Stroke
Thrombolysis Register (SITS-ISTR), and others,1 the effect
size with an odds ratio for a favorable (modified Rankin Scale,
0–1) versus unfavorable outcome was established at ≈1.4 from
3 to 4.5 hours. Safety in terms of bleedings did not differ from
what was seen within the first 3 hours and neither did mortality.
Then came ECASS 3, positive for the primary end point.2 The
European conditional approval was changed to a full approval
in 2010 by the European Medicines Agency (EMA) taking
the congruent results of the pooled analyses, meta-analyses,
SITS-ISTR, and ECASS 3 into account. According to label
and guidelines, this patient fulfills all criteria for treatment
also in a legal obligatory sense in the country of these authors.
Apart from that, in many countries, withholding a treatment
that is off label but where there is firm scientific evidence that
it causes benefit and no harm can be judged and accounted for
as malpractice by court with all due consequences.
Is advanced imaging necessary to make this decision? Why,
No?! Would a lacunar versus nonlacunar syndrome make a
difference here? No!! It would not make a difference within
3 hours, would it? And what about an MRI without perfusion
imaging/diffusion weighted imaging mismatch or with proof
of a lacunar stroke, would this make a difference? Hell, no!!!
There is no evidence at all for this conclusion. And is there any
reason to believe that rt-PA does not work in the 3- to 4.5-hour
time window or that it does work only in “a carefully selected
set of patients”?1 What the h…, No, No No!!!!
It is a widely held misbelief that ECASS 3 looked at carefully selected patients only. In fact, ECASS 3 inclusion criteria followed exactly the stricter label of rt-PA as it was
given by the EMEA in 2002 and extended in 2004, with 1
exception, the 3- to 4.5-hour time window. By label, Europe
and many other countries exclude patients >80, National
Institutes of Health Stroke Scale >25, diabetes mellitus and
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 1 of a 3-part article.
Parts 2 and 3 appear on pages 914 and 916, respectively.
Received October 29, 2013; accepted December 24, 2013.
From the Departments of Neurology and Neurogeriatry, Johannes Wesling Clinic Minden, Minden, Germany (P.D.S.); and Department of Neurology,
University Clinic at Erlangen, Germany (M.K.).
Presented in part at the International Stroke Conference of the American Heart Association, San Diego, CA, February 12-14, 2014.
Correspondence to Peter D. Schellinger, MD, PhD, Departments of Neurology and Neurogeriatry, Johannes Wesling Klinikum Minden, Hans-Nolte-Str
1, D-32429 Minden, Germany. E-mail [email protected]
(Stroke. 2014;45:912-913.)
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.002700
Schellinger and Köhrmann tPA in the 3- to 4.5-Hours Window 913
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prior stroke, among other criteria, from intravenous thrombolysis. It is daily practice, however, that these criteria are
not followed to the letter, especially after several analyses
from the Virtual International Stroke Trials Archive (VISTA)
group and thrombolysis trialists (references 15–18, 20–21,
and 28, summarily discussed in Frank et al3), as well as IST3.4 In fact, even IST-3, a randomized off-label thrombolysis trial, was nearly positive for the primary end point and
positive for a change across the whole range of the Oxford
Handicap Scale (which in practical terms is nearly identical
to the modified Rankin Scale). Furthermore, most countries
on this planet have a label similar or equal to the European
label including the whole of Europe, Australasia, Russia,
some countries in Africa and South America. In fact, the US
label is the exception to the rule, not vice versa. As a consequence, in countries such as Germany, currently 10% of all
patients with ischemic stroke receive thrombolytic therapy,
with much lower door-to-needle times than recently reported
in a Get With the Guidelines study, where only 18% of the
golden hour patients received rt-PA within 60 minutes from
door to needle.5
Final Comments
1.These authors understand the difficulty of adapting a
label change in the United States and Canada, necessitating 2 different labels for the 2 time windows as opposed
to Europe, where just the time window was extended.
2.These authors cannot follow the actual class I level
B rating of thrombolysis within 3 to 4.5 hours1 when
compared with the same rating given for, for example,
decompressive surgery in space occupying cerebellar
infarction or thrombectomy. Strikingly, there seemed to
be little hesitation to treat many patients with thrombectomy during the past few years with no evidencebased proof of efficacy over standard intravenous
3.For us, as stroke physicians in a country were the described
patient falls into the label of rt-PA, which is based on
clear evidence from many analyses and more importantly
a positive randomized controlled large clinical trial, there
is only 1 rational conclusion to the question: the patient
must be treated, quod erat demonstrandum.
Drs Schellinger and Köhrmann received honoraria, travel grants,
and consulting fees from Boehringer Ingelheim and Cerevast, and
both are members of the steering committee for ECASS 4 EXTEND
(Extending the Time for Thrombolysis in Emergency Neurological
Deficits) and CLOTBUST-ER (Combined Lysis of Thrombus With
Ultrasound and Systemic Tissue Plasminogen Activator [tPA] for
Emergent Revascularization in Acute Ischemic Stroke).
1. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk
BM, et al; American Heart Association Stroke Council; Council on
Cardiovascular Nursing; Council on Peripheral Vascular Disease;
Council on Clinical Cardiology. Guidelines for the early management
of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2013;44:870–947.
2. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D,
et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours
after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329.
3. Frank B, Grotta JC, Alexandrov AV, Bluhmki E, Lyden P, Meretoja A,
et al; VISTA Collaborators. Thrombolysis in stroke despite contraindications or warnings? Stroke. 2013;44:727–733.
4. Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G
et al. 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.
5. Saver JL, Smith EE, Fonarow GC, Reeves MJ, Zhao X, Olson DM,
et al; GWTG-Stroke Steering Committee and Investigators. The “golden
hour” and acute brain ischemia: presenting features and lytic therapy
in >30,000 patients arriving within 60 minutes of stroke onset. Stroke.
Key Words: controlled clinical trials, randomized ◼ stroke ◼ thrombolytic
4.5-Hour Time Window for Intravenous Thrombolysis With Recombinant Tissue-Type
Plasminogen Activator Is Established Firmly
Peter D. Schellinger and Martin Köhrmann
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Stroke. 2014;45:912-913; originally published online February 13, 2014;
doi: 10.1161/STROKEAHA.113.002700
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Copyright © 2014 American Heart Association, Inc. All rights reserved.
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