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Clinical Review Extracts from “Clinical Evidence”

Acute ischaemic stroke

BMJ 2000; 320 doi: (Published 11 March 2000) Cite this as: BMJ 2000;320:692

Rapid Response:

Thrombolysis for acute ischemic stroke works

disagree with the thrust of Gubitz' and Sandercock's interpretation of the
evidence. The quoted meta-analysis includes three different thrombolytic
agents, different time windows, and different doses(1). While there may
be no statistical evidence of heterogeneity of treatment effect, there are
clinical grounds to believe that these factors make for critically
important differences. In the same meta-analysis, the more homogeneous
data drawn from the three trials which treated with intravenous tissue
plasminogen activator (alteplase) within 3 hours of onset is also
reported. A major treatment effect is observed with an OR of 0.55 (95%CI
0.42 to 0.72) in favour of treatment. These numbers include those who
suffered early intracerebral haemorrhage. In this 0-3h group, there is no
increased mortality. The same 0-3h analysis for the streptokinase trials
shows no benefit, but is impaired by the very small numbers of patients
treated within 3h of symptom onset. A similar style 3-6h analysis for
alteplase treated patients is not available but the pooled streptokinase
and alteplase 3-6h results show no benefit with an OR of 0.93 (95%CI 0.78
to 1.10) in favour of treatment. This result is in keeping with that seen
in the recently reported ATLANTIS trial Part B(2). Ultimately, it seems
likely that the treatment effect in the 3-6h time window with alteplase is
of lesser magnitude than that seen under 3h.

Post-marketing experience in North America and Germany, largely from
centres that developed experience with acute ischemic stroke thrombolysis
during clinical trials, has been remarkably positive. Symptomatic
hemorrhage rates and 90d outcomes have been exactly in line with the
published data from the NINDS trial(3,4,5,6,7). These results add
tremendous weight to the argument that the meta-analysis is biased because
of the heterogeneity of included trials. While we agree that the
treatment needs refining, there is no doubt that intravenous alteplase is
an efficacious treatment when administered within 3 hours of stroke onset
using the NINDS criteria.

Stating, "…we found little evidence on balance between benefits and
harms from thombolysis in acute ischemic stroke…", does little to further
the development of acute stroke therapy and may stifle emerging enthusiasm
for stroke thrombolysis in the 0-3h window in Britain. Further trials to
define the benefit or harm of thrombolysis after 3h will be welcome.

Michael D. Hill

Philip A. Barber

Andrew M. Demchuk

Alastair M.

Department of Clinical Neurosciences,
University of Calgary,
Calgary, AB

Drs. Hill, Demchuk and Buchan have received speaker fees from Hoffman
-La Roche Canada Ltd. Dr. Barber has received travel assistance from
Knoll Pharma Co.

1. Wardlaw JM, del Zoppo G, Yamaguchi T. Thrombolysis for acute
ischaemic stroke. The Cochrane Library 1999 Issue 4: 1-25

2. Clark WM, Wissman S, Albers GW, Jharmandas JH, Madden KP, Hamilton S
for the ATLANTIS Study Investigators. Recombinant tissue-type plasminogen
activator (alteplase) for ischemic stroke 3 to 5 hours after symptom
onset. The ATLANTIS Study: a randomised controlled trial. JAMA 1999;
282: 2019-2026

3. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA.
Intravenous tissue-type plasminogen activator for treatment of acute
stroke: The standard treatment with alteplase to reverse stroke (STARS)
study. JAMA 2000; 283: 1145-1150

4. Grond M, Stenzel C, Schmulling S, Rudolf J, Neveling M, Lechleuthner A,
Schneweis S, Heiss WD. Early intravenous thrombolysis for acute ischemic
stroke in a community-based approach. Stroke 1998 Aug;29(8):1544-9

5. Buchan AM, Barber PA, Newcommon NJ, Karbalai HG, Demchuk AM, Hoyte KM,
Klein GM, Feasby TE. Effectiveness of t-PA in acute ischemic stroke:
outcome relates to appropriateness. Neurology 1999; 54: 679-684

6. Tanne D, Bates VE, Verro P, Kasner SE, Binder JR, Patel SC, Mansbach
HH, Daley S,Schultz LR, Karanjia PN, Scott P, Dayno JM, Vereczkey-Porter
K, Benesch C, Book D,Coplin WM, Dulli D, Levine SR, and the t-PA Stroke
Survey Group. Initial clinical experience with IV tissue plasminogen
activator for acute ischemic stroke: A multicenter survey. Neurology

7. Hill MD, Buchan AM for the CASES Investigators. The Canadian Activase
for Stroke Effectiveness Study (CASES). Abstract. Stroke 2000; 31: 315

Competing interests: No competing interests

09 May 2000
Michael D Hill
clinical stroke fellow
foothills hospital