Portland, Ore.

OHSU participates in trial of clazosentan, which prevents brain blood vessel spasms

Louisa Miller of Eugene knows the brain hemorrhage she had in August 2005 could have been much worse.

Miller, 30, had a good chance of suffering a severe, potentially deadly stroke as a result of the subarachnoid hemorrhage, when a burst aneurysm bleeds into the subarachnoid space between the brain and one of its protective membranes. In fact, 27 percent of people who've experienced such a hemorrhage, despite doctors' ability to stop the bleeding, die within a week.

But a clinical trial Miller participated in through the Oregon Stroke Center at Oregon Health & Science University soon after being treated for the hemorrhage may have prevented a stroke.

Miller was a volunteer in CONSCIOUS-1, a study testing dosage and overall potential of the drug clazosentan in preventing cerebral vasospasm. This uncontrollable contraction or tightening of brain blood vessels occurs when blood leaking into subarachnoid space of the brain breaks down, causing blood byproducts to attach to a receptor called endothelin A on the blood vessel, triggering vasospasm. The resulting reduction of blood flow prevents the delivery of oxygen to cells, leading to stroke.

"It's a devastating problem," said Wayne Clark, M.D., professor of neurology in the OHSU School of Medicine, director of the Oregon Stroke Center and a co-investigator in the study. "Patients who have had their aneurysms successfully treated suddenly, a week later, suffer a major stroke."

The study, presented last month at the Congress of Neurological Surgeons in Chicago, showed that the rate of cerebral vasospasm among subarachnoid hemorrhage research subjects given the highest of three intravenous doses of clazosentan - 15 milligrams per hour - was 20 percent, compared with 70 percent among a standard therapy group. Clazosentan is believed to block the attachment of blood byproducts to the endothelin A receptor.

"It's really, really impressive," study co-investigator Johnny Delashaw, M.D., professor of neurological surgery, and otolaryngology/head and neck surgery, OHSU School of Medicine, said of the drug's effects. "This may result in our saving more lives."

The standard therapy for treating subarachnoid hemorrhage has been fluids and nimodipine, a calcium blocker intended to prevent vasospasm by increasing blood flow to injured brain tissue, and fluids. "Unfortunately, vasospasm still occurs in up to 70 percent of cases," Clark said. But clazosentan "seems much more effective."

OHSU was the second-largest recruiter of subjects among 52 sites in 11 countries taking part in CONSCIOUS-1, or "Clazosentan to Overcome Neurological Ischemia and Infarct Occurring after Subarachnoid Hemorrhage." OHSU treated 17 of the study's 413 volunteers.

While vasospasm incidence dropped significantly, Delashaw said the study's results were more "radiologically" than clinically significant, meaning the differences between subjects receiving clazosentan and nimodipine were more obvious to doctors viewing angiographic images during administration of the drugs.

"The angiograms were so different," he recalled. "It was pretty obvious because some of the patients didn't have a lot of spasms."

While it's not known whether Miller received clazosentan since the study was blinded, Miller said, "I sort of assumed that maybe I did." Otherwise, she doesn't believe she'd be around to talk about it.

"I just am very, very thankful I'm even here to have this conversation," said Miller, a bookkeeper for small manufacturing firm in west Eugene and mother of a 3-year-old girl. "Yes, it was months before I was back at work full time, but I feel like it could have been worse. More than anything, I want to make sure I'm around for my daughter."

While these early results are encouraging to doctors, research on clazosentan continues. OHSU will be the only Northwest hospital involved in a large, confirmatory, phase III trial of the drug starting in January.

"Hopefully, someday, we'll be able to keep everybody alive that makes it to the hospital after a hemorrhage," Delashaw said.