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The Benefits and Harms of Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator Within 6 H of Acute Ischaemic Stroke (The Third International Stroke Trial [IST-3]): A Randomised Controlled Trial
Study Questions:
What are the benefits and harms of thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) in patients who do not exactly meet the license criteria for its use (especially elderly patients), and would a wider range of patients benefit from this treatment?
Methods:
In this international, multicenter, randomized, open-treatment trial, patients were allocated to 0.9 mg/kg intravenous rt-PA or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0–2 at 6 months. The primary analysis of the effect of treatment on the primary outcome was adjusted by logistic regression analysis.
Results:
A total of 3,035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1,515 in the rt-PA group vs. 1,520 in the control group), of whom 1,617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0–2; adjusted odds ratio [OR], 1.13; 95% confidence interval [CI], 0.95–1.35; p = 0.181; a nonsignificant absolute increase of 14/1,000, 95% CI, –20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR, 1.27 (95% CI, 1.10–1.47; p = 0.001). Fatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR, 6.94; 95% CI, 4.07–11.8; absolute excess 58/1,000, 95% CI, 44–72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR, 1.60; 95% CI, 1.22–2.08; p = 0.001; absolute increase 37/1,000, 95% CI, 17–57), but between 7 days and 6 months, there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs. 407 [27%] in the control group).
Conclusions:
The authors concluded that despite the early hazards, thrombolysis within 6 hours improved functional outcome.
Perspective:
The study suggests that on average, patients treated with intravenous thrombolysis up to 6 hours after stroke survived with less disability. Overall, the data support the policy of treating patients as soon as possible, and also justify extending treatment to patients older than 80 years of age. Furthermore, the present analysis does not support any restriction of treatment on the basis of stroke severity or the presence of early ischemic change on the baseline brain scan. Additional randomized trials of thrombolysis in selected patients more than 4.5 hours after stroke are indicated to identify an optimal window for treatment.
Keywords: Odds Ratio, Thrombolytic Therapy, Stroke, Intracranial Hemorrhages, Patient Selection, Coronary Angiography, Confidence Intervals, Tissue Plasminogen Activator, Angioplasty, Balloon, Coronary, Logistic Models, Brain
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