News from the International Stroke Conference: Clazosentan Prevents Secondary Vasospasm but Fails to Reduce Stroke Mortality
NEW ORLEANS—The investigative endothelin receptor inhibitor clazosentan managed to meet its trial endpoint in a truncated phase 3 trial — the reduction of vasospasm-related complications following subarachnoid aneurysm rupture, researchers said here at the American Stroke Association's International Stroke Conference.
But use of clazosentan did not reduce mortality in these stroke patients, nor did it improve functional outcomes, reported R. Loch Macdonald, MD, head of neurosurgery at St. Michael's Hospital at the University of Toronto. The use of the drug in the patients also appeared to increase adverse events, he noted.
Researchers suggested that clazosentan as an endothelin inhibitor would lessen vasospasm caused by endothelin, a potent vasoconstrictor. Dr. Macdonald explained that clazosentan was designed to help patients who survived the initial rupture to avoid a second stroke caused by vasospasm, which can be triggered by leaking blood that irritates blood vessels.
The future of the drug was in doubt, because a parallel randomized, double-blind, placebo-controlled trial — Clazosentan to Overcome Neurological Ischemia and Infarct Occurring after Subarachnoid Hemorrhage (CONSCIOUS-2) — was prematurely halted by Actelion, the sponsor of the trial, after results showed that the drug at a 5 mg dose had no impact on outcomes among patients whose aneurysm rupture was treated with a clip.
In CONSCIOUS-3, investigators reported here that they randomized 571 patients with subarachnoid hemorrhage aneurysm caused by a ruptured saccular aneurysm to two doses of intravenous clazosentan — at 5 mg and 15 mg — as well as placebo: 194 were given 5 mg/hour clazosentan; 188 patients receive 15 mg/hour clazosentan, and 189 patients who were given placebo. In all the cases, their aneurysms were closed with a coil. Patients received the drug from day nine to day 14 following coiling.
The low-dose clazosentan showed no benefit, but the higher dose significantly reduced the risk of angiographic confirmed vasospasm. Compared with placebo, the use of clazosentan was associated with a 53 percent reduction in the “second stroke” within three to 14 days later due to irritation from the initial bleeding. About 27 percent of patients taking the placebo experienced a second stroke compared with 24 percent of patients taking the 5 mg dose of clazosentan (p=0.340) and 15 percent of those receiving the high dose 15 mg of the drug (p=0.007). In addition, Dr. Macdonald noted there was a three-fold greater use of rescue therapy — additional therapies in attempts to alleviate vasospasm — among the placebo group than those treated with 15 mg/hour clazosentan — about 21 percent of placebo patients required rescue therapy compared with 7 percent of those on the high-dose clazosentan.
But while the drug may have prevented the second stroke, there was no statistical difference between clazosentan and placebo in the more important outcomes of ability to function and overall survival. “The low dose (5 mg/hour) didn't work in either the CONSCIOUS-2 or CONSCIOUS-3 trial, but the 15 mg/hour dose, which wasn't tested in CONSCIOUS-2, worked in CONSCIOUS-3,” said Dr. Macdonald, a neurosurgeon.
In terms of adverse events, clazosentan was associated with an increase in lung complications, anemia, and hypotension.
Dr. Macdonald indicated he is optimistic about the 15 mg/hour dose. “That dose probably does work. If we randomize patients with that dose and avoid nimodipine, it will reduce the side effects of clazosentan, and we should see an improvement in outcomes.” He suggested that performing another study with the high dose of clazosentan, with both the clipped and coiled aneurysm closure method might yield better findings. He also suggested that use of the Glasgow Outcome Scale Extended at 90 days — a measure accepted by the Food and Drug Administration as an outcome — might not be sensitive to patient suffering from aneurysmal subarachnoid hemorrhages.
“We think a better outcome measure might allow us to demonstrate a clinical benefit with a smaller number of patients,” Dr. Macdonald said. “We also think that, based on some preliminary analyses in these studies, patients who get clazosentan and nimodipine may have a higher risk of side effects. If we can reduce those adverse side effects, the chances of a good outcome increase.”
“The company is discussing whether the data we have is enough for some type of Food and Drug Administration approval,” Dr. Macdonald said in a news briefing. “I would do another study with the 15 mg/hour dose to show benefit on clinical outcomes at one or three months.”
Dr. Macdonald noted that another trial with clazosentan is ongoing in Japan and that also may shed light on the usefulness of clazosentan in this patient population.
Claudette Brooks, MD, assistant professor of neurology at West Virginia University, Morgantown, who was not involved with the study, said: “For this drug to move forward, I think we are going to have to see improvement in survival — as well as improvement in function among patients receiving clazosentan. The whole reason for trying to prevent vasospasm is to try and give these patients some ability to function after surviving these strokes. The mortality in subarachnoid hemorrhage is about 30 percent after 30 days. When these subarachnoid hemorrhages occur they are often described as ‘the worst headache of my life.’;”
Dr. Brooks said that treatment by clipping the aneurysm may be associated with larger aneurysms while coils may be reserved for smaller bleeds.
Added Steven M. Greenberg, MD, PhD, director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital, who also was not involved with the study: “It would be great to see another trial. I hope this drug doesn't die on the vine. My feeling is the regulatory agencies won't approve clazosentan based on these data.”
DATA ON CLAZOSENTAN
- The primary endpoint of vasospasm-related mortality or all-cause mortality within six weeks was experienced by 27 percent of the patients assigned to placebo.
- Twenty-four percent of the patients in the low-dose clazosentan group (p=.340) achieved the endpoint as did 15 percent of the high-dose clazosentan patients (p=.007).
- The prevention of vasospasm-related events, however, failed to translate into good outcomes as defined by the Glasgow Outcome Scale Extended. Poor functional outcome was observed in 24 percent of the placebo patients; 25 percent of the low-dose clazosentan patients (p=.748) and in 28 percent of the high-dose clazosentan patients (p=.266).
- At week 12, mortality rates were 6 percent among placebo patients; 6 percent among the high-dose clazosentan patients and 4 percent with low-dose clazosentan.