Thrombolysis in the 3- to 4.5-Hour Window
What Do ECASSkeptics Want?
Magdy H. Selim, MD, PhD; Carlos A. Molina, MD, PhD
O
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and 183 (instead of 182) in the placebo group achieved modified Rankin Scale score ≤1! In addition, the benefit of rtPA
was less robust when the global test statistic based on modified Rankin Scale, National Institutes of Health Stroke Scale,
Barthel Index, and Glasgow Outcome Score was used as the
outcome measure (odds ratio, 1.28; 95% confidence interval,
1.00–1.45; P=0.05).
ECASS-III followers cite results from observational studies, such as the Safe Implementation of Treatment in Stroke
International Stroke Thrombolysis Register (SITS-ISTR), and
national registries, such as the Canadian Alteplase for Stroke
Effectiveness Study (CASES), showing similar outcomes in
patients treated within 3 to 4.5 hours after stroke when compared with those treated within 3 hours1,2 and pooled analyses
of data from previous thrombolysis trials supporting the benefit of intravenous rtPA ≤4.5 hours.3,4 However, SITS-ISTR
patients treated in the 3- to 4.5-hour window had significantly
lower stroke severity, were younger, and more likely to have
small vessel disease. After adjusting for baseline imbalances,
outcomes were slightly better in the 0 to 3-hour group. An
updated analysis of the 3- to 4.5-hour cohort of SITS-ISTR
patients treated in compliance with the European Union
approval criteria showed that the 3-month outcomes were
favorable for patients treated within 3 to 4.5-hours when compared with patients treated within 3 hours in the unadjusted
analysis but less favorable in the adjusted analysis.5 In CASES,
the rates of symptomatic intracranial hemorrhage and deaths
were higher in the 3 to 4.5-hour group and seemed to rise significantly in later time windows, leading the investigators to
caution that although patients can be successfully treated with
intravenous rtPA in the 3- to 4.5-hour window, later time window treatment may result in greater adverse events.
ECASS-III skeptics state that no other randomized controlled trial has supported the 3- to 4.5-hour window and cite
data from the Third International Stroke trial (IST-3), which
did not support the benefit of intravenous rtPA between 3
and 4.5 hours, despite randomizing 1177 patients in this time
ur patient has no contraindications for intravenous
thrombolysis and meets the eligibility criteria specified
in European Cooperative Acute Stroke Study (ECASS) III.
Therefore, at first glance it seems that there is no basis for
disagreement or controversy. He should be treated immediately with intravenous recombinant tissue-type plasminogen activator (rtPA) in line with the results of ECASS-III,
a blinded, randomized, placebo-controlled trial, and professional guidelines including the American Heart Association/
American Stroke Association (class I; Level of Evidence B
recommendation). This position is strongly articulated by Drs
Schellinger and Köhrmann.
Is it really true that the 4.5-hour window for intravenous
rtPA is so firmly established? Dr Wechsler expresses some
doubts, and he is not alone. The United States Food and Drug
Administration, the largest agency regulating medical products on planet earth, denied an application to extend the time
window for intravenous rtPA treatment to 4.5 hours. The
details of the application and the reasons behind the Food
and Drug Administration’s denial have not been released to
the scientific community, leading to speculations that the evidence from ECASS-III and supporting data were not sufficient in the Food and Drug Administration’s opinion.
ECASS-III is a landmark study in the history of stroke
therapy. It demonstrated a marginally significant statistical
increase in the likelihood of having normal or near-normal
recovery (modified Rankin Scale, ≤1) after rtPA treatment;
219/418 (52.4%) patients in the rtPA group had a score ≤1
at day 90 when compared with 182/403 (45.2%) patients in
the placebo group (unadjusted odds ratio, 1.34; 95% confidence interval, 1.02–1.76; P=0.04). Although the incidence
of intracranial hemorrhage was higher with rtPA, mortality did not differ significantly between the groups, leading
many to conclude that the risk of symptomatic intracranial
hemorrhage is modest and acceptable relative to the benefit.
Interestingly, this marginal benefit from rtPA could have been
negated if only 218 (instead of 219) patients in the rtPA group
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 3 of a 3-part article.
Parts 1 and 2 appear on pages 912 and 914, respectively.
Received December 24 2013; final revision received December 24, 2013; accepted December 27, 2013.
From the Stroke Division, Beth Israel Deaconess Medical Center, Boston, MA (M.H.S.); and Stroke Unit, Department of Neurology, Hospital Vall
d’Hebron-Barcelona, Barcelona, Spain (C.A.M.).
Presented in part at the International Stroke Conference of the American Heart Association, San Diego, CA, February 12-14, 2014.
Correspondence to Magdy H. Selim, MD, PhD, Stroke Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Palmer 127, Boston, MA
02215. E-mail [email protected]; or Carlos A. Molina, MD, PhD, Stroke Unit, Department of Neurology, Hospital Vall d'Hebron-Barcelona,
Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain. E-mail [email protected]
(Stroke. 2014;45:916-917.)
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.004265
916
Selim and Molina tPA in the 3- to 4.5-Hours Window 917
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window.6 ECASS-III had weaknesses as Dr Wechsler points
out. Patients with severe strokes were excluded; the placebo
group had higher rates of prior stroke, which may have resulted
in worsened outcomes; and baseline imbalances in stroke
severity favored the rtPA group. Like most other thrombolysis
trials, the vast majority of patients had a plain head computed
tomographic scan and lacked vascular imaging data, precluding accurate assessment of stroke subtype, or the presence of
arterial occlusion. Would a lacunar versus nonlacunar infarct
influence the decision making? Most likely, not. However,
knowing the distribution of stroke subtypes in ECASS-III and
their response to rtPA would be helpful especially for those
who argue that lacunar infarcts caused by lipohyalinosis and
occlusion of small penetrating arteries do not benefit from
thrombolysis. The same applies to the value of vascular imaging. What about penumbral imaging? It is intuitive to think
that penumbral imaging would be helpful during this late time
window because the salvageable tissue decreases over time.
However, Dr Wechsler raises an important practical point, the
time it takes to perform advanced imaging during the narrow
3 to 4.5-hour window. Furthermore, the clinical usefulness of
penumbral imaging still requires more examination. Analysis
of the patients treated within the 3 to 4.5 hours in the ongoing
EXTEND trial could provide helpful clues.
Further studies of thrombolysis in the 3- to 4.5-hour window are needed, but will they occur. The stroke community
has been longing for ways to extend the narrow 3-hour window for rtPA; ECASS-III delivered what we wished for. The
stroke community also deserves to know the details behind
the Food and Drug Administration’s refusal to extend the use
of intravenous rtPA to 4.5 hours. So, how should we treat our
patient? In Spain and most other countries, we would treat
him with intravenous rtPA without any delays. In Boston and
planet USA, we would thoroughly discuss the risks versus
benefit with the patient or his family to make an informed
decision, albeit time-consuming, and treat with rtPA if they
agree. However, the big question remains as to whether the
benefit is firmly established.
Disclosures
None.
References
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2.Shobha N, Buchan AM, Hill MD; Canadian Alteplase for Stroke
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ischemic stroke onset–evidence from the Canadian Alteplase for Stroke
Effectiveness Study (CASES) registry. Cerebrovasc Dis. 2011;31:223–228.
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Key Words: stroke ◼ tissue plasminogen activator
Thrombolysis in the 3- to 4.5-Hour Window: What Do ECASSkeptics Want?
Magdy H. Selim and Carlos A. Molina
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Stroke. 2014;45:916-917; originally published online February 13, 2014;
doi: 10.1161/STROKEAHA.113.004265
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