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Geoffrey A. Donnan, MD; Stephen M. Davis, MD; Brian R. Chambers, MD; Peter C. Gates, MBBS; Graeme J. Hankey, MD; John J. McNeil, PhD; David Rosen, PhD; Edward G. Stewart-Wynne, MBBS; Roger R. Tuck, PhD

JAMA. 1996;276(12):961-966.

Abstract
Objectives.
—To determine whether the administration of 1.5 million units of streptokinase intravenously within 4 hours of the onset of acute ischemic stroke would reduce morbidity and mortality at 3 months and whether outcomes may be better for those receiving therapy within 3 hours of stroke onset compared with those receiving it after 3 hours.

Design.
—Randomized, double-blind, placebo-controlled trial with 3-month follow-up.

Participants.
—A total of 340 patients, aged 18 to 85 years, with moderate to severe strokes were randomized from 40 centers throughout Australia from June 1992 to November 1994.

Intervention.
—Administration of 1.5 million units of streptokinase or placebo intravenously in 100 mL of normal saline over 1 hour.

Main Outcome Measure.
—Combined death and disability score (Barthel index <60) 3 months after the stroke.

Results.
—Using an intention-to-treat analysis with a combined death and disability score at 3 months after stroke as the primary end point, we found a nonsignificant overall trend toward unfavorable outcomes for streptokinase vs placebo (relative risk [RR] of unfavorable outcome, 1.08; 95% confidence interval [CI], 0.74-1.58) and an excess of hematomas (13.2% [12.6% symptomatic] in the treated group, 3% [2.4% symptomatic] for placebo [P<.01] ). However, poor outcomes were confined to patients receiving therapy more than 3 hours after stroke onset (RR of unfavorable outcome, 1.22; 95% CI, 0.80-1.86). In contrast, among the 70 patients who were entered into the trial within 3 hours of stroke onset, there was a trend toward improved outcomes for those who received streptokinase (RR of unfavorable outcome, 0.66; 95% CI, 0.28-1.58), and this outcome pattern was significantly better than for those receiving therapy after 3 hours (P=.04). Streptokinase administration resulted in excess deaths in the group treated after 3 hours (RR, 1.98; 95% CI, 1.18-3.35), but not among those treated within 3 hours (RR, 1.11; 95% CI, 0.38-3.21).

Conclusion.
—The administration of streptokinase within 4 hours of acute ischemic stroke increased morbidity and mortality at 3 months. While treatment within 3 hours of stroke was safer and associated with significantly better outcomes than later treatment, it showed no significant benefit over placebo. The timing of thrombolytic therapy for acute stroke is critical.

Author Affiliations
for the Australian Streptokinase (ASK) Trial Study Group

From the Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia (Drs Donnan and Chambers); Royal Melbourne Hospital, Melbourne, Victoria, Australia (Dr Davis); Geelong Hospital, Geelong, Victoria, Australia (Dr Gates); Royal Perth Hospital, Perth, Western Australia (Drs Hankey and Stewart-Wynne); Alfred Hospital, Melbourne, Victoria, Australia (Dr McNeil); Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (Dr Rosen); and Woden Valley Hospital, Canberra, Australian Capital Territory (Dr Tuck).

Footnotes
A complete list of the Australian Streptokinase Trial Study Group appears at the end of this article.

Reprints: Geoffrey A. Donnan, MD, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia.

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