NICE, FRANCE—Treatment with low-dose recombinant t-PA decreases the rate of death and disability in patients with intracerebral hemorrhage, according to a study presented at the 17th European Stroke Conference. Until recently, said Daniel Hanley, MD, no treatment had existed for this subset of stroke.
“We’ve gone from what’s usually an 80% death rate in patients with this condition to an 80% survival rate,” said Dr. Hanley, Jeffrey and Harriet Legum Professor and Director of the Brain Injury Outcomes Division, Department of Neurology, Johns Hopkins University, Baltimore.
Typically, t-PA is contraindicated in patients with intracerebral hemorrhage, because it can further increase the risk of bleeding. However, since high-dose t-PA (80 to 100 mg) is effective at breaking up clots in patients who have had a heart attack and some types of ischemic stroke, and because previous studies reported that t-PA instilled directly in the cerebral ventricles did not significantly increase bleeding or death in patients with intracerebral hemorrhage, Dr. Hanley and colleagues attempted to determine if a lower dose of intraventricular t-PA might be safe and effective in individuals with this condition.
In the phase II Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) study, 52 patients recently diagnosed with intracerebral hemorrhage received usual treatment for the condition: placement of a catheter in the brain to release trapped blood. Each patient was assigned to one of three t-PA regimens: 0.3 mg every 12 hours, 1 mg every 12 hours, or 1 mg every eight hours. The first dose was given anywhere from 12 to approximately 60 hours (median, 42 hours) posthemorrhage.
The main inclusion criterion was occlusion of the third and/or fourth ventricle. According to Dr. Hanley, the bleeds occurred in the caudate thalamus, putamen, globus palidus, and in some cases, white matter. A major exclusion criterion was supratentorial intracerebral hemorrhage of more than 30 cc.
The patients’ progress was monitored daily with use of CT scans. Patients receiving t-PA showed rapid decline of clot volume within three to four days—almost a 70% decline. Dr. Hanley reported that third and fourth ventricle clots dissolved approximately one day faster in patients who received 1 mg of t-PA every eight hours, compared with those who received the other treatment regimens.
“t-PA appears to be safe,” said Dr. Hanley. Additional bleeding was minimal; symptomatic bleeding occurred at a rate of 6%, which was comparable to the rate observed among patients who received placebo in an earlier safety trial. Patients treated with t-PA were not more likely to have further hemorrhaging, compared with patients who received placebo in a previous safety trial. The researchers also reported that one month after treatment, more than 80% of patients were alive. Of these, 10% were completely normal and had been able to return to their jobs.
Dr. Hanley emphasized that CLEAR-IVH follow-up is ongoing, with the last outcome visit scheduled for August 2008.
Plans for a phase III study are now under review with the NIH. “We’ve met all the Good Clinical Practice criteria for a phase III trial, and the estimated treatment effect is significant,” he noted. Approximately 500 patients from 50 sites will be enrolled. Inclusion and exclusion criteria will be similar to those of the phase II study, and the treatment benefit assumption will be a 15% shift in the number of subjects with a Modified Rankin Scale score of 0 to 3. “We hope to start the trial in late 2008 or early 2009,” said Dr. Hanley.
—Karen L. Spittler