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infarction, and reactions such as anaphylaxis or angioedema, although these events are rare.298 Debate about time of initiation of rtPA treatment merits attention. The NINDS investigators reported a time-to-treatment interaction in a subgroup analysis of the NINDS rtPA Trial.60 Treatment with rtPA initiated within 90 minutes of symptom onset was associated with an odds ratio of 2.11 (95% confidence interval, 1.33 to 3.55) for favorable outcome at 3 months as compared with placebo. In comparison, the odds ratio for good outcome at 3 months for treatment with rtPA initiated within 90 to 180 minutes was 1.69 (95% confidence interval, 1.09 to 2.62). The investigators concluded that the earlier that treatment is initiated, the better the result. A subsequent pooled analysis of all large, multicenter, placebo-controlled trials of rtPA for acute stroke confirmed a time effect, but the upper limit of the treatment window may be as late as 5 to 6 hours.316 Investigation of the early time epoch in the NINDS trial revealed a potential confounder in the original data: 19% of the patients treated with rtPA between 91 and 180 minutes after stroke onset had an NIHSS score of ≤5 compared with 4% of the placebo patients. On the basis of this observation, it has been suggested that the relative preponderance of mild strokes with a likely good outcome in the rtPA treatment group may explain the entire benefit reported for patients treated between 91 and 180 minutes. Subsequent reanalysis showed that the imbalance in patients with minor stroke did not explain the difference between treatment and placebo.317 The adjusted odds ratio for 3-month favorable outcome (odds ratios for treatment compared with placebo) for the subgroup of patients from the NINDS rtPA Stroke Trial with NIHSS score of ≥5 at baseline and time from stroke onset to treatment of 91 to 180 minutes was statistically significant in favor of treatment. Indeed, when all possible subgroups were examined separately, no effect of the severity imbalance could be shown to influence the overall result that rtPA therapy positively influenced outcome. In a separate analysis by an independent group, an identical finding was reached: Baseline imbalances in the numbers of patients with mild stroke do not explain the overall study result.318 B. Other Thrombolytic Agents Clinical trials of streptokinase were halted prematurely because of unacceptably high rates of hemorrhage, and this agent should not be used.319–322 Other intravenously administered thrombolytic agents, including reteplase, urokinase, anistreplase, and staphylokinase, might have been considered for treatment of patients with acute ischemic stroke. None of these agents has been tested extensively. Tenecteplase appears promising as an effective thrombolytic with fewer bleeding complications than wild-type rtPA, but pivotal studies are under way.323 Desmoteplase has been tested in a pilot study; results appear promising.189,324 C. Defibrogenating EnzymesAncrod, an enzyme derived from snake venom that degrades fibrinogen, was tested in a series of clinical studies. A preliminary trial found that ancrod treatment improved outcomes after stroke, with patients with blood fibrinogen levels <100 mg/dL having the best responses.325,326 A subsequent study found a favorable benefit–risk profile for patients. Further studies of ancrod continue, given the potentially favorable combination of antithrombotic activity and mild thrombolytic effect.327,328 D. Conclusions and Recommendations Intravenous administration of rtPA is the only FDA-approved medical therapy for treatment of patients with acute ischemic stroke.3 Its use is associated with improved outcomes for a broad spectrum of patients who can be treated within 3 hours of stroke onset. Earlier treatment (ie, within 90 minutes)
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