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Meta-analysis: Thrombolytic therapy increases the risk for early death and intracranial hemorrhage after acute ischemic stroke, but by the end of follow-up the combined end point of death or dependency decreases

ACP J Club. 1997 Mar-Apr;126:35. doi:10.7326/ACPJC-1997-126-2-035

Source Citation

Wardlaw JM, Yamaguchi T, del Zoppo G, Hacke W. The efficacy and safety of thrombolytic therapy in acute ischaemic stroke: a systematic review of the randomised trials comparing thrombolysis with control. In: Warlow C, Van Gijn J, Sandercock P, eds. The Cochrane Database of Systematic Reviews [updated 06 September 1996]. In The Cochrane Library [database on disk and CD-ROM]; Issue 3. BMJ Publishing Group, London; 1996.



To determine whether thrombolytic therapy is safe and effective for acute ischemic stroke.

Data sources

MEDLINE and EMBASE were searched using the Cochrane Stroke Review Group search strategy. Bibliographies were scanned and investigators were contacted.

Study selection

Randomized controlled trials that compared thrombolytic therapy with control medication that was started within 14 days of definite or probable acute ischemic stroke were included. Studies were excluded if the groups received another form of active therapy or if computed tomography was not done before randomization.

Data extraction

Data were extracted on patient numbers and characteristics, early death during the first 2 weeks after stroke, intracranial hemorrhage (IH), fatal IH, and death or dependency at the end of follow-up.

Main results

12 trials involving 3286 patients met the selection criteria. Data pooled from 4 trials showed that early mortality was increased in patients who received thrombolytic therapy compared with patients who received control medication {P = 0.036}*. {The absolute risk increase of 9% means that 1 additional death occurred for every 12 patients who received thrombolytic therapy rather than control medication, 95% CI 6 to 166; the relative risk (RR) increase was 74%, CI 26% to 140%.}* By the end of follow-up (3 or 6 mo), however, differences in mortality between the groups had narrowed. More patients who received thrombolytic therapy compared with patients who received control medication had a symptomatic IH {absolute risk increase 2%, P < 0.001}* or fatal IH {absolute risk increase 3%, P < 0.001}*. Pooled data from 7 trials showed that, at the end of follow-up, fewer patients who received thrombolytic therapy had died or had become dependent than patients in the control group {absolute risk reduction (ARR) 7%, P = 0.016}*. {This ARR of 7% means that 16 patients would need to receive thrombolytic therapy (rather than control medication) to prevent 1 additional death or dependency at the end of follow-up, CI 9 to 82; the RR reduction was 10%, CI 2% to 17%.}* Heterogeneity was seen in all trials except those that assessed IH.


Thrombolytic therapy after acute ischemic stroke increases the risk for early death and intracranial hemorrhage but decreases a combined end point of death or dependency at the end of follow-up.

Sources of funding: University of Edinburgh; Medical Research Council (UK); Stroke Association (UK).

For article reprint: Dr. J. Wardlaw, Department of Clinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK.

*Numbers calculated from data in article.


Thrombolysis is a promising therapy for acute ischemic stroke, but more evidence is needed about the benefits, risks, and costs of this potentially lethal treatment.

Wardlaw and colleagues found that for every 100 patients treated with thrombolysis, 9 additional deaths occurred within the first 2 weeks. However, by 3 to 6 months, 7 fewer patients had died or become dependent (16 if patients were treated within 3 h of onset).

Alteplase, a tissue plasminogen activator (t-PA), has been recently approved in the United States for treating stroke, provided that it is given within 3 hours of onset of symptoms and IH has been ruled out (1). However, this recommendation is based on only 1 of the 12 trials in this overview (2).

Many questions need to be answered before these recommendations are implemented outside research settings. Are the results of these carefully done trials robust and generalizable? If so, which patients with stroke who present within a few hours of onset will benefit from thrombolysis in the long term? Which patients will have a symptomatic IH if given thrombolysis (3)? Is t-PA safer and more effective than streptokinase or urokinase? This overview found no differences in mortality among the thrombolytic agents; randomized trials are required to determine which drug has the least toxicity and the most benefit. What is the optimum dose? How long after the onset of stroke is the administration of thrombolysis still beneficial? The overview suggests that the time window may extend beyond 3 to 6 hours. What is the optimum administration route: intravenous or intra-arterial? Is concurrent early use of aspirin or heparin associated with an increased rate of IH and poor outcome? If so, when can they be safely commenced? Also, is thrombolysis safe for patients who have been taking aspirin? Results of nonrandomized comparisons suggest that an adverse interaction exists between thrombolysis and antithrombotic drugs. How should hypertension be managed during thrombolytic therapy?

Graeme J. Hankey, MBBS, MD
Royal Perth HospitalPerth, Western Australia, Australia

Graeme J. Hankey, MBBS, MD
Royal Perth Hospital
Perth, Western Australia, Australia


1. Lancet. 1996;347:1822.

2. N Engl J Med. 1995;333:1581-7.

3. The NIH t-PA Stroke Study Investigators. Cerebrovascular Diseases. 1996; 6(Suppl 2):26.