Therapeutics
Alteplase given 3 to 4.5 hours after stroke
reduced disability and improved global
outcome
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.
Clinical impact ratings: F ★★★★★★✩ E ★★★★★★✩ h ★★★★★★✩ H ★★★★★★✩ N ★★★★★★★
Question
Patient follow-up: 89% (intention-to-treat analysis).
What is the efficacy and safety of alteplase given 3 to 4.5 hours
after onset of acute ischemic stroke?
Main results
Methods
Design: Randomized placebo-controlled trial (European
Cooperative Acute Stroke Study [ECASS] III).
ClinicalTrials.gov NCT00153036.
Allocation: Concealed.*
Conclusion
Blinding: Blinded (patients and clinicians).*
Alteplase given 3 to 4.5 hours after acute ischemic stroke reduced
disability and improved global outcome.
Follow-up period: 90 days.
Setting: 130 sites in 19 countries in Europe.
Patients: 821 patients (mean age 65 y, 60% men) who had acute
ischemic stroke with symptoms lasting ≥ 30 minutes without
improvement before treatment and were able to receive the study
drug within 3 to 4.5 hours after onset. Exclusion criteria included
intracranial hemorrhage (ICH); severe stroke; seizure at stroke
onset; major surgery, stroke, or trauma in the past 3 months; previous stroke and diabetes mellitus; heparin within 48 hours before
stroke; platelet count < 100 000/mm3; blood pressure > 185/110
mm Hg; and blood glucose level < 50 mg/dL (2.8 mmol/L) or
> 400 mg/dL (22.2 mmol/L).
Intervention: Alteplase, 0.9 mg/kg, 10% bolus, followed by
continuous intravenous (IV) infusion over 60 minutes (n = 418)
or matching placebo (n = 403).
Outcomes: Favorable outcome for disability (modified Rankin
Scale [mRS] score 0 to 1) and global outcome (based on mRS,
Barthel Index, National Institutes of Health Stroke Scale
[NIHSS], and Glasgow Outcome Scale). Safety outcomes
included any ICH, symptomatic ICH (increase in NIHSS score
≥ 4 points from baseline or leading to death), and death.
Alteplase vs placebo given 3 to 4.5 hours after acute ischemic
stroke†
Outcomes at 90 d
Alteplase Placebo
RBI (95% CI)
NNT (CI)
52%
45%
19% (1 to 37)
12 (6 to 204)
63%
50%
51%
59%
43%
45%
8.4% (−3 to 19) Not significant
16% (0.6 to 32)
15 (8 to 410)
12% (−3 to 27) Not significant
RRI (CI)
NNH (CI)
Any intracranial hemorrhage 27%
18%
53% (19 to 94)
11 (7 to 30)
Modified Rankin Scale
score 0 to 1‡
Barthel Index score ≥ 95§
NIHSS score 0 to 1||
Glasgow Outcome Scale
score 1¶
Any symptomatic
intracranial hemorrhage**
2.4%
0.2%
864% (26 to 6401)
47 (7 to 1555)
†NIHSS = National Institutes of Health Stroke Scale; other abbreviations defined in
Glossary. RBI, RRI, NNT, NNH, and CI calculated from data in article based on the
intention-to-treat population.
‡Score range 0 (no symptoms) to 6 (death). Analysis adjusted for baseline NIHSS score and
time to start of treatment.
§Score range 0 (complete dependence) to 100 (independence).
||Score range 0 to 42, higher values = more severe neurologic impairment.
¶Score range 1 (independence) to 5 (death).
**NIHSS score ≥ 4 points from baseline or leading to death.
20 January 2009 | ACP Journal Club | Volume 150 • Number 1
More patients in the alteplase group than in the placebo group
had favorable outcome for disability (Table) and global outcome
(odds ratio 1.3, 95% CI 1.0 to 1.6; individual components in
Table). The alteplase group had a higher incidence of ICH
(Table), but groups did not differ for death.
*See Glossary.
Source of funding: Boehringer Ingelheim.
For correspondence: Dr. W. Hacke, University of Heidelberg, Heidelberg,
Germany. E-mail [email protected]. ■
Commentary
In a < 3-hour time window, IV tissue plasminogen activators provide a large effect size in preventing death or disability (number
needed to treat [NNT] 8), yet remain controversial. The ECASS
III trial by Hacke and colleagues should cement the evidence.
Thrombolysis for stroke unequivocally works.
In the trial, the effect size in a 3- to 4.5-hour time window was 7%
(NNT 14). As time elapses, benefit erodes sharply (1). Although a
longer time window is still of some benefit to patients, stroke teams
must strive for a target door-to-needle time of < 60 minutes.
The ECASS III trial differed from previous trials by excluding
severe strokes, defined as an NIHSS score > 25 and/or evidence
of severe ischemic change on computed tomography (CT) scan
(2). Caution is warranted in treating patients with unfavorable
CT scans regardless of time window. Patients with high NIHSS
scores but favorable CT scans should be considered for treatment.
ICH varied from 1.9% to 7.9% depending on the definition,
emphasizing the importance of ongoing discussion on the definition of symptomatic ICH. The rates are concordant with previous
studies, similar to the < 3-hour time window, and were included
in the overall primary outcome.
Most strokes are mild, and therefore the benchmark for thrombolysis rates could ideally never be > 25% of all ischemic strokes.
Currently, too few patients arrive in time, too few systems are
organized to provide stroke thrombolysis, and too little expertise
exists to judge when thrombolysis is appropriate. The largest
gains will be made by closing the evidence-to-practice gap.
Michael D. Hill, MD, MSc, FRCPC
Hotchkiss Brain Institute, University of Calgary
Calgary, Alberta, Canada
References
1. Hacke W, Donnan G, Fieschi C, et al. Lancet. 2004;363:768-74.
2. Dzialowski I, Hill MD, Coutts SB, et al. Stroke. 2006;37:973-8.
© 2009 American College of Physicians
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