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23-05-2012 | Vascular medicine | Article

IST-3 stroke reveals thrombolysis benefits in ‘off-label’ patients

Abstract

Journal

MedWire News: Recombinant tissue plasminogen activator (rtPA) treatment benefits stroke patients not eligible to receive the treatment under current European Union licensing restrictions, show the results of the third international stroke trial (IST-3).

Patients now known to benefit from treatment include those older than 80 years (53% of the IST-3 cohort), who comprise about a third of stroke patients in Western European countries.

IST-3 researcher Richard Lindley (University of Sydney, Australia) told reporters at the European Stroke Conference in Lisbon, Portugal: "What's really amazing in the data is that the benefit for the over 80s was just as good as in the under 80s. And that really was against our expectation… we were expecting the benefit to be less in the older age group."

The trial, presented by Peter Sandercock (University of Edinburgh, UK), included 3035 patients who were "promising" candidates for rtPA, but for whom the benefits were unproven. They were randomly assigned to receive rtPA or usual treatment without rtPA (controls). Patients with clear, proven indications or contraindications for rtPA were not enrolled in the trial.

The primary trial outcome was actually neutral: rtPA treatment did not significantly increase the proportion of patients achieving a 6-month Oxford Handicap Score (OHS) of 0‑2. In all, 37% of treated versus 35% of control patients met this outcome, which was a nonsignificant increase of 14 per 1000 patients.

However, ordinal analysis ‑ assessing the shift across the entire range of OHS outcomes ‑ showed that patients given rtPA had a 27% increase in the odds of surviving with less disability. IST-3 was designed more than 10 years ago, before ordinal analysis became a widely accepted method in clinical trials.

Also, in prespecified subgroup analyses, the primary outcome was significant for patients treated within 3 hours of onset, with 30.6% of treated versus 22.7% of control patients achieving an OHS of 0‑2.

The overall neutral primary outcome appeared to be caused by the much smaller benefits of treatment among patients treated more than 3 hours after onset.

The importance of time to treatment is also apparent in an updated Cochrane analysis, presented by Joanna Wardlaw (University of Edinburgh, UK). It included 7012 patients from 12 trials (including IST-3), and shows an overall benefit within 6 hours, with 46.3% of patients given rtPA versus 42.1% of those given control treatment being alive and independent at follow up. This equated to an absolute increase of 42 per 1000 people treated.

The effect was largest in patients treated within 3 hours of onset, at an absolute increase of 90 per 1000 people treated, compared with a nonsignificant increase of 18 per 1000 people treated later after onset.

Wardlaw noted that, during the first 7 days after treatment, there was an excess of deaths among patients given rtPA versus control treatment (8.9 vs 6.4%), most of which was caused by symptomatic intracranial hemorrhage (7.7 vs 1.8%). But this was balanced by better long-term survival among patients given rtPA, so that mortality rates were similar by the end of follow up (19.1 vs 18.5%).

The IST-3 results and the Cochrane analysis are available (open access, requires registration) on The Lancet website.

By Eleanor McDermid

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