Intravenous drug did not significantly reduce stroke deaths, complications

Intravenous drug did not significantly reduce stroke deaths, complications
American Stroke Association Meeting Report: Abstract LB 9


This abstract will be presented in a news conference.
Video interview clips available at embargo at ISC 2011 Multimedia: AHA/ASA Multimedia Resources Library.

Study Highlight:

•Despite earlier positive results, compared with placebo, the drug clazosentan did not significantly reduce the incidence of death and severe complications related to uncontrolled blood vessel contractions after a subarachnoid hemorrhage.


LOS ANGELES, Feb. 11, 2010 — A previously promising drug only modestly reduced death and serious complications after a subarachnoid hemorrhage – a type of bleeding stroke – according to late-breaking science presented at the American Stroke Association’s International Stroke Conference 2011.

Compared with those receiving placebo, patients receiving the intravenous drug clazosentan were 17 percent less likely to reach a composite endpoint including stroke, neurological problems, and the necessity for rescue treatment related to uncontrolled blood vessel contractions, as well as death from any cause. However, that was not significantly different from placebo, and could have been due to chance, researchers said.

“The composite primary outcome showed a trend in the right direction, but was not statistically significant,” said Robert Loch Macdonald, M.D., Ph.D., lead author and head of the Division of Neurosurgery at St. Michael’s Hospital, University of Toronto. “We need to do more analysis to explore why there was not a significant effect on the primary outcome.”

Clazosentan is in a class of drugs called endothelin receptor antagonists — a group of drugs that decrease cellular calcium, which in high levels can cause excessive muscular contractions. When these uncontrolled contractions occur in blood vessels, blood and oxygen flow may be temporarily blocked, causing tissue death, neurological impairment and even death.

Researchers also noted that pulmonary complications, anemia and hypotension were more common in clazosentan-treated patients – but it was not analyzed for statistical significance.

Sudden blood vessel constriction in the brain — cerebral vasospasm — is a dangerous complication of subarachnoid hemorrhage (bleeding between the brain and the tissue that covers it).

In the clinical study CONSCIOUS-2 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid haemorrhage), researchers examined aneurysmal subarachnoid hemorrhage, which occurs when a brain aneurysm bursts and blood spills into the subarachnoid space. The death rate is about 45 percent and long-term, serious disability is prevalent among survivors.

A total of 764 aSAH patients received clazosentan and 383 received a placebo for up to two weeks. All had undergone surgery to clip the aneurysm to prevent further bleeding. They were 68 percent female, and their average age was 52 years. Nearly three-fourths (71 percent) were Caucasian and 25 percent were Asian. The international study ran from December 2007 to July 2010 at 102 sites in 27 countries.

Six weeks post-aSAH, investigators assessed the incidence of serious complications related to blood vessel spasms, which they confirmed with special imaging techniques.

These serious complications related to spasms occurred in 21 percent of patients on clazosentan, compared to 25 percent of those on placebo. Follow-up continued for 12 weeks, when researchers also assessed overall functional outcome, which did not appear to be any better in the clazosentan-treated patients. On a standard test of functioning ability known as the Glasgow Outcome Scale, 29 percent of patients who received the study drug performed poorly, compared to 25 percent on placebo.

Among adverse events: lung complications occurred in 34 percent of clazosentan vs. 18 percent of placebo patients; anemia in 22 percent of treated patients vs. 15 percent of placebo patients; and abnormally low blood pressure in 12 percent of treated patients vs. 4 percent of placebo patients.

The trial’s findings are surprising because they don’t support those of a 2008 study (CONSCIOUS-1) that found that clazosentan significantly reduced the incidence of blood vessel spasms after stroke, said Macdonald, who was also first author of the initial study. It’s unclear why the latest study didn’t find a similar benefit on the complications related to spasms.

“We don’t think it’s due to sample size,” Macdonald said. “There’s a fundamental problem with either the drug, its side effects, or the effect of the drug not translating into improving those parts of the outcome measured, even though the primary endpoint was selected to specifically respond to the known action of the drug.”

Aneurysmal subarachnoid hemorrhage affects about 30,000 Americans annually and comprises about 5 percent of all strokes, according to the American Stroke Association.

Co-authors are Randall Higashida, M.D.; Emanuela Keller, M.D.; Stephan A. Mayer, M.D.; Andrew J. Molyneux, F.R.C.P.; Andreas Raabe, M.D.; Peter Vajkoczy, M.D.; Isabel Wanke, M.D.; Doris Bach, Ph.D.; Aline Frey, Pharm.D.; Angelina Marr, BSc.; Sébastien Roux, M.D.; and Neal F. Kassell, M.D. Author disclosures are on the abstract.

Actelion Pharmaceuticals Ltd. funded the research.

Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position. The association makes no representation or warranty as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing science content. Revenues from pharmaceutical and device corporations are available at www.heart.org/corporatefunding.

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NR11-1021 (ISC 2011/Macdonald)


(Note: Actual presentation time is 11:42 a.m. PT., Friday, Feb. 11, 2011)


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•What You Should Know About Cerebral Aneurysms


Intravenous drug did not significantly reduce stroke deaths, complications