Phase-3
clinical trial results demonstrate first effective treatment for severe type of
bleeding stroke
Newswise, February 19,
2016 — The use of clot-busting drugs to clear blood from the brain’s ventricles
may be the first effective strategy to decrease mortality for a type of
catastrophic bleeding stroke, according to phase-3 clinical trial results
announced Thursday at the International Stroke Conference in Los Angeles.
The treatment also
significantly reduced post-stroke disability in a subset of patients, according
to data presented by trial leaders from Johns Hopkins University and the
University of Chicago.
“Hemorrhage in the brain
used to be an essentially untreatable condition, but we now have hope with a
therapy that may be effective at saving lives,” said Issam
Awad, MD, John Harper Seeley Professor of Surgery at the University of
Chicago Medicine, who was co-chair and surgical director for the CLEAR III
clinical trial.
CLEAR III tested the
benefits of the clot-busting drug alteplase, also known as tPA, in improving
outcomes for intraventricular hemorrhage. In this particularly severe form of
stroke, blood pools and clots in the brain’s ventricles—cavities that normally
hold cerebrospinal fluid.
The randomized,
double-blinded and controlled trial enrolled 500 patients from 73 clinical
sites around the world. Every patient received either tPA or saline through a
brain catheter, and were otherwise treated by current standards of critical
care.
Researchers found that
swift application of tPA directly into the ventricle, combined with a drainage
catheter, reduced overall death rates by 10 percent, or about a third relative
to death rates in the saline group.
Treatment with tPA
almost doubled the likelihood of good functional recovery in patients with high
volume bleeds who had most of the blood removed. Patients with smaller clots
did not benefit, but no adverse side effects were observed when compared to the
control group.
“For many patients, this
approach can significantly reduce disability after a stroke, and can be the
difference between going home instead of going to a nursing home,” Awad said.
Hemorrhagic strokes are
triggered by ruptured blood vessels that leak blood into the brain, increasing
intracranial pressure and causing severe damage to brain tissues.
Accumulated blood
quickly clots and is difficult to remove even by open brain surgery. Around 15
percent of strokes are hemorrhagic, but they account for roughly 40 percent of
all stroke deaths.
Nearly half of these
bleeding strokes involve some degree of intraventricular hemorrhage (IVH), a
complication where blood pools in the ventricles. IVH can be particularly
catastrophic, with an estimated mortality rate between 60 and 80 percent. Among
those who survive, as many as 90 percent become severely disabled.
An
international effort
Early studies suggested
tPA, an FDA-approved clot buster for conditions such as heart attacks and
non-bleeding strokes, might be effective in removing accumulated blood and
alleviating its damaging effects after a hemorrhagic stroke. To study the
feasibility of this approach, a phase-2 clinical trial (CLEAR-IVH), initially
tested tPA in a small group of IVH patients.
After patients were
stabilized, tPA was administered directly into the ventricle through an
external, surgically placed catheter. The patients received the tPA for three
days and a catheter continually drained blood until the ventricle cleared.
The study confirmed the
safety and efficacy of the procedure, and supported the need for a large-scale
phase-3 trial.
CLEAR III, which was
overseen by Awad and Daniel Hanley Jr., MD, the Harriett Legum Professor of
Acute Care Neurology at Johns Hopkins Medicine, began in 2009 and was completed
in 2015. Roughly half of the 500 enrolled patients received tPA and the other half
received saline.
Both groups had
extraventricular drains and were treated by the current best standards for
critical care. All patients were monitored remotely to maintain consistent
treatment across centers, which could vary greatly in facilities, staff and
languages. Data analysis and overall trial oversight was provided by the Johns
Hopkins team.
To ensure safety and
accurate catheter placement, surgical oversight was provided by Awad and his
staff at the University of Chicago Medicine, which served as the surgical
center for the trial. Before tPA could be given, images of catheter placement
for every patient had to be sent to and analyzed by the UChicago team, who were
on call 24/7 throughout the five-year trial.
“We had to verify that
all the criteria were met in order to deploy that treatment safely,” Awad said.
“Every single patient was monitored in real time, often over an iPad or iPhone,
to make sure the drug reached the right part of the brain.”
Immediate
impact
The results of CLEAR III
show tPA treatment significantly decreases mortality in one of the worst forms
of hemorrhagic stroke. Analyses led by Awad and his team revealed the most
important factor in improving functional recovery was the volume of blood
removed.
The likelihood of a good
outcome in patients with larger clots, defined as greater than 20 mL of pooled
blood, improved by nearly 20 percent. The more blood that was cleared, the
greater the odds were of reduced disability—rising to nearly double in patients
who had 90 percent of their clots removed.
Patients who received
additional doses of tPA and had multiple drainage catheters inserted had higher
clot removal. In patients who started with less than 20 mL of blood in the
ventricles, no benefits were observed.
“Outside our study this
drainage was only used in 8 percent of hemorrhagic stroke cases, and we showed
this technique can really make a difference,” Hanley said. “Our results suggest
that physicians should begin to think about routinely using it for stable
hemorrhagic stroke patients.”
CLEAR III data now
support the use of tPA and a ventricular drain as the most effective treatment
for patients with high volume IVH strokes.
Awad notes that, if
possible, these patients should be treated at comprehensive stroke centers,
which have access to neurosurgeons, neurocritical care specialists and other
resources for severe strokes. The CLEAR III team is now implementing an
educational strategy on how to manage IVH with tPA at comprehensive stroke
centers around the U.S.
“When we entered into
the trial, we knew very little about how this therapy ought to be used, in whom
it should be used, and whether it was safe,” Awad said.
“We now have clear data
on how best to implement the procedure, and for at least a group of patients,
we know it can nearly double the likelihood of a favorable outcome.”
A sister clinical trial,
MISTIE, co-led by Awad and Hanley, is currently underway to test the safety and
efficacy of tPA as a treatment for patients with hemorrhagic strokes in which
bleeding occurs in brain tissue but does not leak into the ventricles. Patients
for that study are currently being enrolled.
CLEAR III was supported
by the National Institute of Neurological Disorders and Stroke (5U01 NS062851)
and Genentech.
For more information,
visit www.braininjuryoutcomes.com/clear-about and www.uchospitals.edu/specialties/neurosciences/stroke-neurovascular/stroke.html
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