麻豆传媒

PHOENIX -- A short course of low-dose methylprednisolone added to endovascular thrombectomy after acute ischemic stroke did not improve outcomes overall, though there was a lower rate of mortality, the randomized MARVEL trial from China showed.

Both patients who received 3 days of IV methylprednisolone at 2 mg/kg per day and those who received placebo had median 90-day modified Rankin Scale scores of 3, reported Raul Nogueira, MD, of the University of Pittsburgh, at the American Stroke Association's International Stroke Conference. The findings were also published in .

However, the adjusted generalized odds ratio favored a trend for a lower level of disability with the corticosteroid (1.10, 95% CI 0.96-1.25), which was driven by a significantly lower mortality rate (23.2% vs 28.5%, adjusted risk ratio [aRR] 0.84, 95% CI 0.71-0.98).

Symptomatic intracranial hemorrhage was also significantly less common in the corticosteroid group than with placebo (8.6% vs 11.7%, aRR 0.74, 95% CI 0.55-0.99).

The overall lack of benefit was not surprising and corroborates findings from the 1980s and '90s, argued Jose Biller, MD, chair of the neurology department at Loyola Medicine in Chicago, who was not involved in the MARVEL trial.

Those prior trials failed to show benefit of adjunctive corticosteroids in acute ischemic stroke, leading to guideline recommendations against use of conventional or large doses of methylprednisolone. But, those trials used longer courses that might have increased complications and were largely conducted in the pre-thrombectomy era, the researchers noted, and thus "under the more challenging conditions of permanent, as opposed to transient, brain ischemia."

Whereas Biller urged caution about the secondary findings, a survival impact is biologically plausible, noted an by James E. Siegler, MD, and Shyam Prabhakaran, MD, MS, both of the University of Chicago.

The anti-inflammatory corticosteroid could tackle the "robust activation of peripherally circulating and central immune cells that contribute to cytotoxic and vasogenic edema, leading to progressive tissue injury, hemorrhagic transformation, and ultimately poorer clinical outcomes" in acute ischemic stroke, they wrote. Such a possibility warrants further validation, "using volumetric analyses of infarct size and/or surrogate measures of malignant edema (e.g., decompressive craniectomy rates or length of intensive care unit stay)," they suggested.

The researchers also pointed to reduced symptomatic intracranial hemorrhage as evidence in support of "stabilization of the blood-brain barrier as a potential beneficial effect of methylprednisolone."

A potential survival advantage could also relate to a lower risk of pneumonia with steroid use (46.5% vs 55.4% with placebo) – a trend also seen in the of hydrocortisone/fludrocortisone in severe traumatic brain injury – or to the "potential benefit of corticosteroids for circulatory support even without overt septic shock, which is supported by a prior of randomized clinical trials," Siegler and Prabhakaran wrote.

However, they cautioned "any potential benefit of adjunctive corticosteroid use in these patients ought to be carefully weighed against the risks of hyperglycemia and diabetes."

The trial showed a higher proportion of patients requiring insulin treatment during their admission (19.7% vs 13.1% with placebo) and more new-onset diabetes (4.8% vs 2.9%, respectively).

Nogueira and team included 1,680 patients treated at 82 hospitals in China with stroke and proximal intracranial large vessel occlusion presenting within 24 hours of time last known to be well and treated with endovascular thrombectomy. Median age was 69 years, and 43.3% were women.

While one of the largest endovascular therapy trials ever done, the sample size still couldn't capture the kind of 1.1% to 1.5% gain in proportion of patients with a modified Rankin Scale score in the 0 to 2 range that experts suggest would be expected as the minimal clinically important impact, the researchers noted.

Other limitations included the inclusion of a broad range of patients with small to moderate ischemic cores, potentially including those with "minimal blood-brain barrier disruption who potentially do not respond to corticosteroid treatment" and a slightly higher IV thrombolysis rate in the placebo group.

Biller suggested that the results should be generalizable outside of China and praised the trial's robust, double-blind design.

If methylprednisolone were to have an impact on cerebral edema, it would be in the first few days after stroke onset when it peaks, he noted, so the trial targeted the right time period.

Adjuvant therapy "is the logical next step" and needs to be tested in the current era of thrombolysis plus endovascular recanalization, Biller told 麻豆传媒. "Whether this was the best pharmacological agent to choose is a different story."

He argued that it's time to look elsewhere.

"The story of neuroprotection in stroke is a story of many studies that turn out to be negative," he said, "probably [due to] questions of design, among other issues. But I think that now that we are able to reopen occluded blood vessels, it is critical that we work on adjuvant therapies."