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Adding low-dose methylprednisolone therapy to endovascular treatment for acute ischemic stroke did not significantly improve the degree of overall disability in a new randomized trial. However, there were some other potentially beneficial effects that could warrant further investigation.

The MARVEL study was presented at the International Stroke Conference 2024 being held this week in Phoenix, Arizona. They were also published online in JAMA on February 8.

The authors, led by Wenjie Zi, MD, and Fengli Li, MD, Neurology, Army Medical University, Chongqing, China, noted that preclinical models have suggested potential benefits of corticosteroids in stroke treatment, including the reduction of infarct area, regulation of cerebral blood flow, stabilization of the blood-brain barrier, prevention of angiogenic edema, inhibition of oxygen-free radical-induced lipid peroxidation, and modulation of the immune response. Yet none of these potential effects have been validated in clinical trials.

Prior trials investigating corticosteroids in stroke were mostly conducted before the advent of thrombectomy as a viable treatment option and in the more challenging conditions of permanent, as opposed to transient, brain ischemia. The presence or lack of reperfusion has also been identified as a critical determinant of corticosteroid effectiveness in animal models, they said.

The current study sought to determine the effects of intravenous low-dose methylprednisolone in patients with acute ischemic stroke due to large vessel occlusion in the setting of rapid cerebral reperfusion now attainable by endovascular treatment.

The MARVEL trial, conducted at 82 hospitals in China, enrolled 1680 patients with stroke and proximal intracranial large vessel occlusion presenting within 24 hours of time last known to be well. They were randomly assigned to intravenous methylprednisolone (2 mg/kg/d) or placebo for 3 days adjunctive to endovascular thrombectomy.

The primary endpoint, disability level at 90 days as measured by the overall distribution of the modified Rankin Scale (mRS) scores, was not significantly different between the two groups. The median 90-day mRS score was 3 in both groups, and the adjusted generalized odds ratio for a lower level of disability in the methylprednisolone group was 1.10 (95% CI, 0.96-1.25; P = .17).

The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours.

There was a lower mortality rate in the methylprednisolone group (23.2% vs 28.5%; adjusted risk ratio, 0.84; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74; P = .04) than in the placebo group.

In addition, the secondary outcome of mRS score of 0-4 at 90 days occurred in 71.5% in the methylprednisolone group and 66.2% in the placebo group, giving an adjusted relative risk of 1.07 (95% CI, 1.00-1.14; P = .04).

The authors said the trial "provides new insights on the effects of corticosteroids in stroke therapy when used as an adjunct to endovascular therapy."

They noted that current American Heart Association/American Stroke Association guidelines recommend avoiding the use of conventional or large doses of methylprednisolone because of a lack of efficacy and the potential to increase the risk for infectious complications.

But in this study, low-dose methylprednisolone was associated with lower mortality, a lower rate of symptomatic intracranial hemorrhage, and less pneumonia. A similar effect of low-dose corticosteroids has been observed in the prevention of hospital-acquired pneumonia in patients with traumatic brain injury and patients with severe community-acquired pneumonia, they reported.

"This study is therefore one of the first, to our knowledge, to provide evidence regarding the potential role of corticosteroid therapy in the setting of endovascular stroke reperfusion," they commented.

The researchers suggested that although the primary outcome was neutral, the secondary outcome finding that a higher proportion of patients in the methylprednisolone group were alive and not bedridden (mRS score, 0-4) at 90 days suggests that corticosteroid therapy has the potential effect of increasing the proportion of patients with an outcome of not requiring constant nursing care.

They said that the finding of reduced symptomatic intracranial hemorrhage supports stabilization of the blood-brain barrier as a potential beneficial effect of methylprednisolone.

Favorable Shift

In an accompanying editorial, James E. Siegler, MD, and Shyam Prabhakaran, MD, University of Chicago, Chicago, Illinois, acknowledged the survival benefit with a shift toward moderate disability in the steroid group, but said it is unclear why there was not a favorable shift in the overall distribution of the 90-day mRS scores.

"Perhaps the lower mortality without significant improvement in rate of functional independence may have been mediated by the lower risk of pneumonia with steroid use," they surmised.

The editorialists add that there is also the potential benefit of corticosteroids for circulatory support and in reducing cytotoxic or vasogenic cerebral edema following a large cerebral infarction.

"Overall, the findings from the MARVEL randomized clinical trial add to a literature indicating a lack of efficacy of adjunctive corticosteroids in acute ischemic stroke. That said, the secondary analyses from this trial suggest a potential survival advantage, which might be mediated by a reduction in cytotoxic or vasogenic edema following malignant infarction," the editorialist concluded, adding that these findings warrant further investigation.

But they also point out that there was a twofold higher risk for new diabetes (4.8% vs 2.9%) in the steroid group in this study, which they said is a concern for concern, and may mitigate or counter any neuroprotective effects.

This study was supported by the National Natural Science Foundation of China, the Chongqing Science and Health Joint Project, and the National Natural Science Foundation of China Major Program. Zi and Li reported no relevant disclosures; disclosures for coauthors appeared in the paper. Prabhakaran reported receiving grants from the National Institutes of Health and the Agency for Healthcare Research and Quality and personal fees from UpToDate. Siegler reported no disclosures.