More Time to Act, No Time to Waste

This American Heart Association/American Stroke Association (AHA/ASA) scientific advisory addresses the issue of expansion of the time window for the use of intravenous recombinant tissue plasminogen activator [rt-PA (alteplase)] for the treatment of acute ischemic stroke to 4.5 hours, based on the recent publication of the ECASS-III study results.[1] The authors have outlined the history behind the design of this trial. Its rationale was supported by a meta-analysis [2] of rt-PA clinical trials that included time windows beyond the 3 hours used in the pivotal NINDS rt-PA study [3], as well as by the European Union's observational registry data included in the SITS-MOST [4] and SITS-ISTR [5] studies. These European registry data included the experience with the use of intravenous rt-PA within the currently approved 3-hour window [4], as well as at various times beyond 3 hours [5], as part of the collective, multinational experience in Europe with the use of this agent in clinical practice, outside the context of randomized clinical trials. The SITS-ISTR experience with use of rt-PA from 3 to 4.5 hours from stroke onset showed similar benefit and no significant increase in the rate of symptomatic intracerebral hemorrhage (SICH) or mortality in comparison with the results of treatment within 3 hours from stroke onset in the same registry.[5] Although some concern was expressed because the majority of patients were treated shortly after the 3-hour period (close to 60% of patients treated within 20 minutes from the end of the 3-hour window), the more even distribution of subjects across the 3 to 4.5 hour window in ECASS-III (about 10% treated between 3 and 3.5 hours, 45% between 3.5 and 4.0 hours, and 40% between 4.0 and 4.5 hours) provides assurances that the conclusions about efficacy and safety in ECASS-III apply to the full 3 to 4.5 hour window.

The ECASS-III results showed a significantly higher proportion of patients with a favorable outcome at 3 months in the rt-PA group, with significantly higher rates of SICH, but without differences in mortality. These results were achieved in a study group that had inclusion and exclusion criteria slightly different from those currently applied for the Food and Drug Administration-approved use of rt-PA within 3 hours from stroke onset. The differing criteria applied in ECASS-III where exclusion of patients older than 80 years, those with a severe stroke with National Institutes of Health Stroke Scale (NIHSS) greater than 25, patients with prior stroke and history of diabetes, and patients receiving oral anticoagulants [irrespective of international normalized ratio (INR) levels].

How do these different inclusion/exclusion criteria for ECASS-III impact the applicability of its results to clinical practice? Based on these data, it would be appropriate for practitioners to use intravenous rt-PA in patients who can be treated within the extended time window of 4.5 hours, applying the same inclusion/exclusion criteria used in ECASS-III, because there is no evidence that benefit can be accrued for patients who were not tested in the trial by virtue of having the above exclusion criteria. For those ineligible patients, it is reasonable to consider them for other forms of revascularization procedures, either intra-arterial rt-PA or device-based thrombus removal procedures.

The results of ECASS-III are encouraging in that an extension of the window should allow increasing numbers of patients to benefit from the use of intravenous rt-PA, beyond the disappointingly low 4% for the 3-hour window.[6] However, these results should not be interpreted as meaning that "there is plenty of time" to prepare for the use of rt-PA in a patient who arrives in the hospital within 3 hours from stroke onset. It has been clearly established that the benefits of intravenous rt-PA in acute ischemic stroke are strongly time dependent, with early treatment yielding the largest benefit: the magnitude of the benefit declines progressively from the first 90 minutes to the 90 minutes to 3 hour period to the 3 to 4.5 hour time period.[2]

Treatment in the latter window should be administered to the patients who arrive in the hospital after 3, 3.5, or 4 hours after stroke onset, not to the one that arrives after 1 to 2.5 hours after stroke onset. The greatest disservice we could do to our patients would be to relax the sense of urgency upon arrival to the hospital with an acute ischemic stroke within 1 to 2 hours from onset, and subject them to this highly efficacious agent at a later time, when the golden opportunity for early intervention was partially lost.