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Abciximab Shows No Benefits in Emergency Stroke Treatment Trial: Presented at ESC
Abciximab shows no efficacy in the treatment of patients with acute ischaemic stroke, while it does promote significant increases in fatal or symptomatic intracerebral haemorrhage (ICH) in specific patient subpopulations.
The results of this randomized, double-blind, placebo-controlled, phase 3 trial were presented here on May 19th at the 15th European Stroke Conference (ESC).
"This medication has been shown to be effective in treatment of patients with acute coronary artery conditions, and has also been demonstrated to improve microcirculatory blood flow in the brain in animal models," said the study's coprincipal investigator, Harold Adams, MD, professor of neurology, University of Iowa, Iowa City, Iowa, United States, speaking on behalf of the Abciximab in Emergent Stroke Treatment Trial - II (AbESTT-II) investigators.
In their own phase 1, dose-escalation study, the AbESTT-II researchers previously found that abciximab was safe. And in their phase 2 trial of 400 patients with acute ischaemic stroke, 0.25 mg/kg and 12-hour infusion of 0.125 mcg/kg/minute showed reasonable safety and a trend towards improved outcomes within 6 hours of stroke onset.
Their phase 3 trial was designed to investigate the benefits of abciximab in patients with acute ischaemic stroke across 112 centers. The goal was to enrol 1,800 patients. Three study populations were defined -- those who were enrolled within 4.5 hours of stroke (primary); those enrolled between 4.5 and 5.5 hours of stroke (companion); those enrolled within 2.5 hours of waking up (wake up).
When safety concerns arose for patients in the wake-up cohort, this part of the study was stopped in May 2005. In September 2005, the Safety Committee suspended patient enrolment for a full safety analysis, and the trial was stopped in October 2005.
The primary endpoints included efficacy (expressed as the proportion of modified Rankin Scale [mRS] responders at 90 days in the primary population), and safety (expressed as fatal ICH), nonfatal symptomatic parenchymal haemorrhage, or other symptomatic ICH to discharge/day 5 in the primary population.
Response was defined as follows:
• Baseline National Institute of Health Stroke Scale (NIHSS) score of 4-7, mRS 0;
• Baseline NIHSS score of 8-14, mRS 0-1;
• Baseline NIHSS score of 15-22, mRS 0-2.
After screening 8,207 patients, 221 patients were randomised to abciximab and 218 to placebo. The most common exclusions included: minor stroke with NIHSS score < 4 (35%); treatment with thrombolytics (13%); evidence of ICH by computer tomography (9%); other serious illness (7%); prestroke disability (6%); and baseline NIHSS score > 22 (5%).
After randomisation, baseline characteristics of the primary population for placebo and abciximab were well matched for randomisation timing:
• 3 to 4.5 hours, 77.1% versus 78.3%;
• > 4.5 hours, 0.5% versus 1.4%
The 2 groups were also well matched for mean NIHSS scores (9.6 vs 9.9) and grouped NIHSS scores (4-7, 46.3% vs 46.2%; 8-14, 33.9% vs 31.7%; 15-22, 19.7% vs 22.2%).
Mean age of the 2 groups were 70.2 and 68 years, respectively, and male ratios were 55.5% and 53.4%, respectively.
For the primary endpoint, no significant differences were seen between placebo and abciximab for efficacy at 90 days for overall mRS response in the primary (33.0% vs 32.1%), companion (23.3% vs 25.6%), and wake-up (14.3% vs 4.5%) populations, as for when the primary population was subdivided according to baseline NIHSS scores (4-7, 34.7% vs 33.3%; 8-14, 44.5% vs 37.1%; 15-22, 9.3% vs 22.4%).
Dr. Adams noted the surprising trend for a positive effect of abciximab treatment among the more seriously ill patients.
For the mRS distributions at 90 days in the primary population, there was an increase in mortality over placebo (11.5%) for abciximab (15.8%). This was not seen in the companion population, while it was more pronounced in the wake-up population (14.3% vs 27.3%).
For the secondary efficacy measures at 90 days, there were again no significant treatment differences in the overall mRS responders for neuro-recovery (42.2% vs 43.4%), mRS 0-1 (44.5% vs 42.5%), stroke recurrence (1.4% vs 3.2%), and Barthel Index 95-100 (56.9% vs 57.0%).
As a follow-up on increased mortality, the symptomatic or fatal ICH showed a significant increase for the abciximab group at both discharge/day 5 (placebo, 0.5%; abciximab, 5.5%; P =.002) and 90 days (0.5% vs 6.5%; P <.001), although only in the primary population.
For other bleeding conditions, as well as negative trends for abciximab, with thrombocytopenia to discharge/day 5, this reached significance (placebo, 0.0%; abciximab, 2.8%; P =.014).
Thus, Dr. Adams said, "In conclusion, this trial demonstrates a lack of efficacy of abciximab in the treatment of patients with acute ischaemic stroke, and we could not find a single population or subgroup that seemed to benefit from this treatment."
In addition, abciximab promoted an increase in fatal or symptomatic ICH in the primary and wake-up populations, he added.
Therefore, this study did not confirm the previous findings that early administration of abciximab would be effective and be accompanied by an acceptable safety profile in the treatment of patients with acute ischaemic stroke.