IV Thrombolysis 3-4.5 Hours after Stroke: Time for a Change?

Abstract & Commentary

By Alan Z. Segal, MD, Associate Professor of Clinical Neurology, Weill-Cornell Medical College. Dr. Segal reports no financial relationships relevant to this field of study. This article originally appeared in the November 2008 Neurology Alert. It was edited by Matthew Fink, MD, and peer reviewed by M. Flint Beal, MD. Dr. Fink is Vice Chairman, Professor of Neurology, Weill Cornell Medical College; Chief of Division of Stroke and Critical Care Neurology, NewYork-Presbyterian Hospital, and Dr. Beal is Professor and Chairman, Department of Neurology, Cornell University Medical College. Drs. Fink and Beal report no financial relationships relevant to this field of study.

Synopsis: Intravenous thrombolysis is safe and effective for the treatment of ischemic stroke in the time window of 3-4.5 hours after the onset of symptoms.

Sources: Hacke W, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329; Wahlgren N, et al. Thrombolysis with alteplase 3-4.5 h after acute ischemic stroke (SITS-ISTR): an observational study. Lancet. 2008 Sept 12 [E pub ahead of print]

Intravenous recombinant tissue plasminogen activator (tPA) for acute ischemic stroke benefits a tiny minority of patients due to its strict limitation to a three-hour period following symptom onset. Until now, attempts to extend this narrow time window have failed. Clinical trials enrolling patients between 3-6 hours have produced negative results, and protocol violations (notably, "late" treatment) contribute to increases in hemorrhagic complications. Even under three hours, there is more benefit (nearly double) for tPA in the 0-90 minute than in the 90-180 minute time interval. As each moment elapses following stroke, our ability to help patients diminishes.

Despite these data, there has been a growing body of evidence that three hours may not be as strict a line in the sand as previously thought. In pooled analysis of the NIH tPA trial, the European ECASS trials, and two ATLANTIS trials, Hacke et al1 showed that the odds ratio for benefit from tPA was 1.4 in the 180-270 minute time period. Although this was not as profound as for 0-90 minutes (OR 2.8) or for 90-180 minutes (OR 1.6), it was superior to the group treated between 270 and 360 minutes. Patients treated beyond 4.5 hours showed no benefit, but had increased hemorrhage and mortality rates.

Wahlgren et al reported findings from the SITS-ISTR registry that examined 664 patients in the 3-4.5 hour range, and showed that these patients were equivalent to 0-3 hour patients, spanning multiple endpoints, including clinical outcome, mortality, and hemorrhage rates. Of note, the patients treated in the SITS-ISTR "late" group were three years younger and had milder strokes (1 point lower on NIH-SS) than those treated early. Also, half of the patients treated late were actually treated only 15 minutes after the three-hour window. Even more striking was that the 3-3.5 hour time window comprised 72% of SITS-ISTR patients, compared with 20% in the 3.5-4 hour period and only 8% in the final 30 minutes (4-4.5 hours).

Now, Hacke et al, reporting for the ECASS III trial, provide randomized data to support the use of tPA in the 3-4.5 hour time period. ECASS included 821 patients assigned to tPA compared to placebo. A favorable outcome (defined as a score of 0-1 on the Rankin scale) was found in 52% of tPA-treated patients compared with 45% for placebo, for a statistically significant odds ratio of 1.34 (CI 1.02 to 1.76). Interestingly, this odds ratio nearly exactly matches that found in the previous pooled analysis for patients in this time period — a modest, but nevertheless meaningful difference. The incidence of total hemorrhages in the tPA arm was 27%, compared with 17.6% for placebo; however, importantly, symptomatic hemorrhage rates in tPA-treated patients were only 2.4%. Although this was 10-fold higher than symptomatic hemorrhages in placebo-treated patients (0.2%), it was lower than the 6% symptomatic hemorrhage rate found in the NINDS study. Mortality did not significantly differ between tPA and placebo patients.

Patients with severe stroke (NIH Stroke Scale > 25) were excluded from this study, differentiating this study from the NINDS cohort and producing an overall milder stroke population. Mean NIH Stroke Scale in ECASS III was approximately 11, compared with 14 in NINDS. Overall rates of favorable outcomes were more than 10% higher in ECASS III tPA patients compared with NINDS, and this difference was nearly 20% in the placebo group.


As both the ECASS III study and its accompanying editorial emphasize,2 these data are not an invitation to relax our efforts to trim door-to-needle times to the shortest possible time frame, or to forget that "time is brain" and every minute counts. To paraphrase Hacke et al and the great Yogi Berra, "having more time does not mean we have more time." The true excitement of ECASS III is that we can hopefully extend the benefit of IV tPA for acute ischemic stroke to a larger cohort of patients.

It is likely that not every patient in the 3-4.5 hour time window will be an ideal candidate for IV tPA. Patient age will be a factor. Although IV tPA has been deemed safe for patients who are 80+ in observational studies, ECASS III did not include patients older than age 80; the oldest patient enrolled in SITS-ISTR was 73. Stroke severity also will be important. Milder strokes might not justify the risk, while large strokes (such as complete middle cerebral artery syndromes), which were excluded from ECASS III, will still most optimally be treated with endovascular therapies such as mechanical clot extraction. Advanced imaging with MRI diffusion-perfusion or CT perfusion also might be helpful in defining patients who have an ischemic penumbra. Diabetes may be an additional limitation. Hyperglycemia has been shown to cause more complications among patients treated with tPA. ECASS III excluded patients with a prior history of diabetes and stroke, and thus had a lower incidence of diabetes than did NINDS.

It can be expected that the American Stroke Association and other governing bodies (such as the FDA) will modify recommendations for the treatment of stroke based on these data and that the labeling for IV tPA will change in the coming months. It is not completely clear at this time what exact conclusions will be drawn. In the interim, it is quite certain that the three-hour time window should no longer be an inviolable rule. Should Cinderella have a stroke at 9 p.m., the stagecoach should not be expected to turn into a pumpkin at 12:01 a.m.


1. Hacke W, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774.

2. Lyden P. Thrombolytic therapy for acute stroke — not a moment to lose. N Engl J Med 2008;359:1393-1395.