Clot lysis treatment

A clot lytic treatment strategy with low-dose recombinant tissue-type plasminogen activator (rtPA) speeds clot removal in patients with intracerebral hemorrhage (ICH) that is complicated by intraventricular hemorrhage (IVH), results of a phase 2 trial confirm. Moreover, it does so with an "acceptable safety profile compared to placebo and historical controls," the authors, led by Neal Naff, MD, from Johns Hopkins University, Baltimore, Maryland, write. One caveat with the novel treatment, however, is that it appears to be associated with more bleeding,said senior author Daniel F. Hanley, MD, also from Johns Hopkins. Still, the aim in treating this condition, which can be almost 100% fatal, is to reduce the patient's exposure to blood, thereby reducing injury to the brain. "This drug has to be used carefully because of the increased risk of bleeding, but it will dissolve the blood clot that has formed in the intraventricular space," Dr. Hanley said. "Most of the blood clot is like an iceberg that sits under the water, doing nothing. Getting that blood clot out eliminates one big part of that iceberg that can damage the brain." Results of this phase 2 trial were published in the November issue of Stroke. The current study was done to assess the safety of low-dose rtPA administered via extraventricular drainage catheter for the treatment of ICH with massive IVH with regard to mortality, ventricular infection, and bleeding events. The study also tested whether administration of 3 mg of rtPA via external ventricular device (EVD) every 12 hours increased the rate of intraventricular clot lysis compared with placebo (normal saline)-irrigated catheters. The study included 48 patients aged between 18 and 75 years with a small supratentorial ICH of 30 mL or less and massive IVH. All had an EVD already placed for the treatment of obstructive hydrocephalus. A computed tomography scan was done to ensure that the EVD had been properly placed and that the clot was stable. The patients were then randomly assigned to receive either 3 mg/3 mL of rtPA (n = 26 patients) or 3 mL of normal saline (n = 22 patients) injected into the ventricular spaces via the EVD. This continued every 12 hours until computed tomography showed that clot resolution was sufficient for safe removal of the catheter or until the occurrence of symptomatic bleeding, infection, or death. The median duration of dosing was 7.5 days for rtPA and 12 days for placebo. The researchers report that the frequency of death and ventriculitis was substantially lower than expected. The predicted 30-day mortality was 75% for both treatment groups. The actual mortality was 19% in the rtPA-treated group and 23% in the placebo group. Ventriculitis occurred in 8% of the rtPA-treated group and 9% of the placebo group. Symptomatic bleeding was higher with rtPA, affecting 23% of patients compared with 5% of patients receiving placebo (P = .1). The study showed that the greatest amount of lysing activity in patients receiving rtPA occurred during the first 3 days. There was a significant beneficial effect of rtPA on the rate of clot resolution. The authors report that the estimated resolution for rtPA-treated patients during the first 3 days was 22.3% per day (95% confidence interval, 16.7% - 28.0%), and for patients receiving placebo, it was 9.9% per day (95% confidence interval, 3.5% - 16.2%). As a result of these findings, the researchers concluded that low-dose rtPA for the treatment of ICH with IVH has an acceptable safety profile and call for more data from a "well-designed phase 3 clinical trial, such as [Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR)] III," to fully evaluate the treatment. "We concluded that because there was no difference in infection, no difference in death rate, and the difference in bleeding rate was not statistically significant," Dr. Hanley explained. He added that the dose of rtPA should probably be lower, "or at least lower doses should be tested," because of the increased bleeding that was seen in this study. This treatment strategy for ICH with IVH has been explored in other studies by the same group. In 2008, at the 17th European Stroke Conference, Dr. Hanley presented results of the CLEAR-IVH trial, which showed that administration of 1 mg of tissue plasminogen activator every 8 hours for up to 4 days reduced expected mortality by 70% and also resulted in a dramatic improvement in functional outcomes in patients with IVH. The next year, at the American Stroke Association International Stroke Conference 2009, Dr. Hanley announced that the National Institutes of Health was set to fund a multicentre, 500-patient study to expand on the findings of the CLEAR-IVH trial. Finally, in July 2010, the American Heart Association/American Stroke Association released a new guideline on the management of spontaneous ICH, emphasizing that ICH is a very treatable disorder. The new guideline makes mention of the CLEAR-IVH trial, noting that the efficacy and safety of intraventricular rtPA in IVH are still "uncertain and considered investigational." In an accompanying editorial, Heinrich P. Mattle, MD, and Andreas Raabe, MD, from the University of Bern in Switzerland, point out that the results raise the issue of whether rtPA is the best thrombolytic for this application. Most of the animal and early patient work with this approach was done with urokinase, and there is some evidence to suggest rtPA may be toxic or enhance formation of edema, they write. In fact, they note, "the principal investigators of this trial were forced to terminate an earlier study because commercial withdrawal of urokinase in the United States precluded additional enrollment of patients. Was the choice of rtPA in this study a regulatory issue, or is there a good scientific reason for the selection of rtPA?" Nevertheless, they conclude that Dr. Naff, Dr. Hanley, and their team "have made a great achievement and they have to be congratulated for this successful phase II trial." The editorialists concur with the researchers that the treatment must be studied in further phase 3 trials and point out that CLEAR III is already underway, as is the Dutch Intraventricular Thrombolysis after Cerebral Hemorrhage study (DITCH), a smaller trial being conducted in the Netherlands. They also voice concern about the bleeding that was seen in the rtPA-treated patients. The current study "shows the slippery slope of using thrombolytics in cerebral hemorrhage," they note. "It is nothing else but logical to accelerate clot removal with rtPA," but the trend toward more bleeding "could be a signal that the expected benefit of rtPA might easily turn into harm.