SAN DIEGO—A counterintuitive idea about a form of intracerebral hemorrhage now classified as an “orphan” disease may lead to an expanded use of thrombolysis in the treatment of acute stroke. The results of the Intraventricular Thrombolysis trial offer considerable hope that a minimally invasive technique for removing intraventricular clots is feasible—and the prospects come from a rather surprising therapeutic source. Patients receiving standard treatment plus ultra-low-dose recombinant tissue plasminogen activator (t-PA) demonstrated a higher rate of clot reduction per day—in some cases improving reduction by as much as 80%—than patients receiving standard treatment plus placebo.

CONTRA CONTRAINDICATION?

Clinically, t-PA—the first agent approved by the FDA for the treatment of acute ischemic stroke—is contraindicated in patients with hemorrhage. In this study, according to the investigators, participants treated with t-PA had fewer adverse events, ventilation complications, and instances of prolonged or multiple catheter use. Symptomatic bleeding was greater in the t-PA arm, and a follow-up, phase II trial, CLEAR IVH (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage), is already under way to assess, in part, whether the dose can be optimized to minimize bleeding, the investigators reported at the American Stroke Association’s 29th International Stroke Conference.

The CLEAR IVH trial was a multicenter clinical safety study led by researchers at the Johns Hopkins Medical Institutions, that had, as a secondary end point, a surrogate variable for efficacy. It investigated both the counterintuitive idea that t-PA may be useful in brain hemorrhage when used in extremely low doses and the intuitive idea that measuring and removing the clot might be beneficial to patients, said Daniel F. Hanley, MD.

For ischemic stroke, “the main contraindication for use of t-PA in [acute] stroke is brain hemorrhage,” he said. “For intraventricular hemorrhage, the critical, time- sensitive diagnostic maneuver is early CT in order to demonstrate that bleeding has ceased and the patient is now stable and a candidate for clot removal. This is critical because the size of the clot is directly related to the likelihood of dying.”

The results of the study are consistent with this idea that removing the clot is beneficial to the patient, observed Dr. Hanley, who directed the study along with his colleague at Johns Hopkins, Neal Naff, MD. “These data are [also] consistent with the idea that relatively risky invasive procedures such as surgery or surgery plus low-dose thrombolytic irrigation can be safely accomplished.”

ACCELERATING BLOOD CLOT REMOVAL

In designing the CLEAR IVH trial, the investigators posited two hypotheses. First and foremost, they believed—despite the counterintuitive underpinning—that t-PA used in ultra-low doses for intraventricular hemorrhage would be safe compared to placebo. Secondarily, they examined the surrogate end point of whether t-PA, when used with the standard of care of external ventricular drainage, actually increased clot lysis compared to placebo plus standard of care. Patients in the trial were among the sickest group of intracerebral hemorrhage patients ever reported on, Dr. Hanley noted, with severe hypertension, low presenting median Glasgow Coma Scale scores (7 to 8), and high presenting median National Institutes of Health Stroke Scale (NIHSS) scores (25).

In terms of efficacy, the study was powered to test only for daily clot size difference. Clot reduction was 18% per day in the group of patients receiving t-PA versus 10% per day in those receiving placebo. Some t-PA patients achieved as high as a 50% reduction per day, and reduction in the t-PA arm overall correlated to normalization on the Glasgow Coma Scale. Catheter management appeared to be improved in the t-PA patients, and the median number of treatment days was also decreased among this group. A nonsignificant trend toward improved 30-day outcome (as measured on the Barthel, Glasgow Coma, NIHSS, and Rankin scales) was seen in the t-PA arm, Dr. Hanley reported.

In tracking the daily clot volumes over time, the investigators sometimes found the differences between patients in the two groups to be remarkable, Dr. Hanley observed. “It appears that we were accelerating—and this was a very robust statistical finding—blood clot removal,” he said.

With respect to safety outcomes, t-PA was shown to be safe overall when compared to placebo and especially to predicted severity from natural history studies. There were more adverse events in the placebo arm, a trend that approached statistical significance. Mortality was slightly lower in the treatment arm and, in fact, was substantially lower overall than severity-adjusted predicted mortality—a surprising result given the fact that Dr. Hanley and his colleagues had established a safety threshold of 75% for mortality based on natural history.

“In point of fact, more than 75% survived, which we believe is quite remarkable,” he said, comparing the results to those of two previous prospective series that demonstrated a high likelihood of mortality. “With aggressive attempts to empty the ventricular system and standardize intensive care unit [ICU] support, a very low mortality is seen.”

As for the increased rate of symptomatic bleeding in the t-PA arm, it serves as a signal to clinicians to exercise caution, however expected it may have been to the trial’s investigators. “The statement I want to make [here] is that this treatment is not free of complications,” Dr. Hanley emphasized. “The expected complications more likely than not are there, although they don’t reach statistical significance in this group of patients at this time.”

A LIFE-SPARING SQUIRT

From an overall clinical perspective, however, Dr. Hanley sees the results as offering hope for a disease that leads to death in more than half of the new cases occurring in the United States every year, a disproportionate number of which affect African-Americans and other racial/ ethnic minorities.

The impetus for the study came as much from anecdotal evidence involving t-PA use as from more definitive experimental data. Part of the problem with current standard treatment is that catheters remove the blood slowly and can become blocked or have a lot of clots in them, Dr. Hanley explained. “You can break up those clots by squirting in a little bit of low-dose t-PA,” he said. “In the ICU and operating rooms people do that all the time.”

The practice has been employed at Johns Hopkins, for example, in a few instances when clinicians thought the t-PA could keep the catheter open, break up the clot in the ventricle more quickly, and ultimately spare the life of patients whose intraventricular hemorrhage was massive. With somewhere between 50 and 100 published cases documenting the benefit of low-dose t-PA or urokinase in such subtypes, the use is increasing.

“We did the ethical thing,” Dr. Hanley declared, describing how he and his colleagues took their counterintuitive study concept to such entities as the Ethics Committee at Johns Hopkins. “We proclaimed it as experimental.”

NR

—Fred Balzac

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