Alteplase A Review of Its Use in the Management of Acute Ischaemic Stroke

Alteplase (Actilyse (R), Activase (R)) is a recombinant tissue-type plasminogen activator that activates plasminogen directly to plasmin. It is the only pharmacological treatment currently approved for patients with acute ischaemic stroke. This article reviews the efficacy and tolerability of alteplase, focusing on data relevant to treatment between 0 and 4.5 hours after onset of stroke, and summarizes its pharmacological properties. Well designed clinical trials showed that alteplase administered within 3 hours (in the NINDS trial) and between 3 and 4.5 hours (in the ECASS III trial) after stroke onset significantly improved clinical outcomes at 90 days relative to placebo. Alteplase was generally well tolerated in these trials, with no significant difference observed between alteplase and placebo recipients in the 90-day mortality rates, despite significantly higher incidences of any and symptomatic intracranial haemorrhages in alteplase recipients. These results were generally supported by those of the SITS-MOST and SITS-ISTR observational studies, which showed that alteplase was effective and generally well tolerated when administered within 4.5 hours of stroke onset in routine clinical practice. However, results from SITS-ISTR indicated that the safety and functional outcomes were generally less favourable when alteplase was administered 3-4.5 hours after stroke onset than within 3 hours of stroke onset. Additionally, results from pooled analyses of randomized clinical trials indicated that the benefit of alteplase therapy over placebo decreased as the time between stroke onset and treatment initiation increased, with no significant benefit observed when treatment was initiated >4.5 hours after stroke onset. Moreover, the odds of mortality increased as the time between stroke onset and treatment initiation increased. Thus, the greatest benefit of alteplase therapy is gained with early treatment. Based on these results, current EU labelling and treatment guidelines recommend that alteplase should be administered as early as possible within 4.5 hours of symptom onset in patients with acute ischaemic stroke. However, recent results from a meta-analysis and IST-3 suggest that some patients may benefit from treatment up to 6 hours after stroke onset. Patients for whom alteplase therapy is contraindicated as per current EU licensing criteria, such as those aged >80 years, may also benefit from therapy. Further randomized trials of alteplase administered >4.5 hours after stroke in selected patients are required to confirm these findings.