Clazosentan reduces “second stroke” after aneurysm rupture


An experimental drug, clazosentan, reduced the risk of blood vessel spasm in patients with a brain aneurysm, according to research presented at the American Stroke Association’s International Stroke Conference 2012.

In patients with a subarachnoid haemorrhage, even after the burst weak spot in the vessel is closed, irritation from the initial bleeding can cause angiographic vasospasm, cutting off normal blood supply and resulting in even more brain damage. This is often called a “second stroke.” This vessel constriction can occur about three to 14 days after aneurysm rupture.


“We do not have very effective treatments for this complication,” said R Loch Macdonald, study lead author and head of neurosurgery, St Michael’s Hospital, University of Toronto, Ontario, Canada. “The treatment in use now is very expensive and risky and does not work very well, and about half of the patients suffer permanent problems from it.”


The CONSCIOUS-3 (Effect of clazosentan on clinical outcome after aneurysmal subarachnoid hemorrhage and endovascular coiling) study included 571 patients with a ruptured aneurysm treated with an endovascular coil.


Researchers divided patients into three groups, each given a placebo, 5 mg clazosentan or 15 mg clazosentan. They halted CONSCIOUS-3 prematurely after patients in CONSCIOUS-2 (a trial of patients whose ruptured aneurysm was secured by coiling), which ran simultaneously, showed no benefit from the drug.


In CONSCIOUS-3, 27% of patients on placebo died, had vasospasm-related blood clots or neurological problems, or had rescue therapy to treat vasospasm, compared with 24% in the 5 mg/h and 15% in the 15 mg/h clazosentan groups. The odds of this combined endpoint were 53% lower at the higher clazosentan dose than with a placebo.


“Despite having less than half of the intended patients in the study, we were encouraged to see that at a high dose there was a significant reduction in vasospasm in patients initially treated with endovascular coiling,” Macdonald said.


In other findings:

  • Neurological deficits decreased with increasing clazosentan dose.
  • Rescue therapy was three times less in patients with 15 mg/h clazosentan (7%) compared to those receiving placebo (21%).
  • The occurrence of poor functional outcome or deaths within 12 weeks was not significantly different between placebo and medication groups.
  • Patients receiving clazosentan had more lung complications, anaemia and low blood pressure than those on placebo.

“The data suggests that the drug is effective at reducing delayed cerebral ischaemia, its side effect profile is acceptable, and further studies with different doses, administration regimens, and the avoidance of other vasodilators may allow an improvement in outcome to be demonstrated,” Macdonald said.


Co-authors are: Randall Higashida, Emanuela Keller, Stephan A Mayer, Andrew J Molyneux, Andreas Raabe, Peter Vajkoczy, Isabel Wanke, Doris Bach, Aline Frey, Pegah Nowbakht, Sébastien Roux, and Neal F Kassell.


Actelion Pharmaceuticals funded the study.