May 09, 2014

NICE, France — Giving simvastatin in the first few days after subarachnoid hemorrhage (SAH) had no effect on functional outcome at 6 months in the most definitive study to look at statins in this indication.

Presenting the results of the Simvastatin in Aneurysmal Subarachnoid Hemorrhage (STASH) trial at the XXIII European Stroke Conference (ESC) here, Peter Kirkpatrick, MBChB, consultant neurosurgeon at Addenbrooke's Hospital, Cambridge, United Kingdom, concluded: "There is no place for the generalized treatment of subarachnoid hemorrhage patients with simvastatin during the acute stages."

He explained that following an SAH, bleeding on the surface of the brain causes the blood vessels to go into spasm, which can trigger a further ischemic stroke.

"A whole host of therapies have been tested in an attempt to prevent this vasospasm, but all have failed except nimodipine, which showed a reduction of about 30% in strokes from this process in a small study in the 1980s. Nimodipine is now universally used even though there is some doubt about the validity of the study."

Dr. Kirkpatrick noted that statins have a multitude of potential beneficial effects that could stop vessels going into spasm, and animal models and phase 2 studies have suggested a benefit.

"The STASH study is the biggest and purest trial to be done in this area. It was very thorough. Of the 800 patients included, only 6 were angiogram negative (ie, the aneurysm could not be found on the angiogram). The results are clearly disappointing given the positive findings in phase 2, but they are unequivocal," he commented to Medscape Medical News.

The STASH hypothesis was that simvastatin, 40 mg, given within 96 hours of ictus over 3 weeks may reduce the incidence and duration of delayed ischemic deficits, leading to improvements in the short- and long-term clinical outcome.

But shift in modified Rankin scale (mRS) score at 6 months showed no effect between the simvastatin group and the placebo group, with an odds ratio of 0.97 (95% confidence interval [CI], 0.75 - 1.25).

"You can't get much more neutral than that," Dr. Kirkpatrick said.

All secondary outcomes — including time in intensive care, sepsis, rescue therapy, and discharge time and destination — were also neutral. "Some of the literature suggests statins reduce sepsis, but we couldn't identify that in this study," he commented.

"Even when we discount noncompliant patients, and focus only on those who took all their medication, there was still no difference. We also titrated LDL [low-density lipoprotein] measures. As expected, simvastatin reduced LDL cholesterol, but there was no relationship between this and outcomes."

Chinese Dose-Response Study

A smaller study of simvastatin in patients with SAH, also presented at ESC, found no difference in outcome between 2 different doses of simvastatin: 40 mg and 80 mg.

Presenting the data from the High Dose Simvastatin in Subarachnoid Hemorrhage (HDS-SAH) study, G Wong, MD, Chinese University of Hong Kong, said the investigators designed the study as a supplement to the STASH trial to look at whether there may be a dose effect. But they found no difference between the 2 doses.

Table 1. HDS-SAH Study Results

Endpoint Simvastatin, 40 mg (n = 124) (%) Simvastatin, 80 mg (n = 131) (%) Odds Ratio (95% CI)
Delayed ischemic deficit 24 27 1.2 (0.7 - 2.0)
Clinical vasospasm 12 15 1.2 (0.6 - 2.5)
Delayed cerebral infarction 17 16 1.0 (0.5 - 1.8)
Favorable mRS score (0 - 2) 72 73 1.1 (0.6 - 1.9)


What Now?

Dr. Kirkpatrick told Medscape Medical News that because the acute treatment of SAH has improved in recent years, there is less need for approaches to prevent vasospasm.

"We have made big gains in treating subarachnoid hemorrhage, with better surgical techniques for repairing the aneurysm and improved intensive care management," he said. "Vasospasm-related deficits are less frequent than they used to be — around 15% compared with 40% a few years ago — so to show a benefit would take a mega-trial."

He added, "I think the pharmaceutical approach to subarachnoid hemorrhage may be going to stop. If we get the basics right, the vast majority of patients do well. Getting over the initial storm is key, and that is all down to surgery and intensive care. The problem of vasospasm has become a small player now in the disability of this condition."

Mortality Falling: New Danish Data

The suggestion that treatment of SAH is improving was reinforced by new population data from Denmark. The study showed that although the incidence rate appears to have increased from 12 per 100,000 to 15 per 100,000 during the past 30 years, mortality rates have decreased substantially.

Table 2. Mortality After SAH

Endpoint 1983 - 1987 2008 - 2012
30-day mortality (%) 38 25
1-year mortality (%) 43 31
5-year mortality (%) 51 37


In addition, the mean age at which SAH occurs has increased by a decade: from 54 to 64 years in women and from 53 to 62 years in men.

XXIII European Stroke Conference (ESC). Presented May 7 and 8, 2014.


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