Opinion
EDITORIAL
Adjunctive Steroids as Stroke Reperfusion Strategy
James E. Siegler, MD; Shyam Prabhakaran, MD, MS
With recent advances in endovascular devices and tech-
niques for the treatment of large-vessel occlusion (LVO) stroke,
rates of successful recanalization are as high as 90%.1 While
technologies may continue to improve, it would be unreason-
able to anticipate significant
gains in this measure of mac-
Related article
roperfusion. Instead, efforts
are increasingly turned toward neuroprotection and augment-
ing the microcirculation to promote tissue viability during acute
cerebral ischemia. Adjunctive intra-arterial thrombolysis2
and the recombinant variant of human activated protein C
(3K3A-APC)3 have shown promising preliminary results, but
warrant additional validation. Inflammatory mechanisms fol-
lowing acute cerebral infarction are also the subject of much
clinical research. Following acute ischemic stroke, there is ro-
bust activation of peripherally circulating and central im-
mune cells that contribute to cytotoxic and vasogenic edema,
leading to progressive tissue injury, hemorrhagic transforma-
tion, and ultimately poorer clinical outcomes.4 The evidence
that heightened acute inflammation mediates poor out-
comes following infarction is also supported by evidence sug-
gesting potential benefit of anti-inflammatory treatments in-
cluding the toll-like receptor 4 antagonist ApTOLL,5 and the
combination antioxidant/anti-inflammatory compound edara-
vone dexborneol6 in acute cerebral infarction; however, more
research is needed.
In this issue of JAMA, the MARVEL Investigators explore
the potential benefits of acute anti-inflammatory treatment in
patients with acute stroke treated with endovascular throm-
bectomy by randomizing patients with acute LVO of the inter-
nal carotid or proximal middle cerebral artery to intravenous
methylprednisolone or placebo.7 Patients were eligible for in-
clusion if they had severe stroke-related deficits as defined by
a National Institutes of Health Stroke Scale (NIHSS) score of 6
or greater and early evidence of ischemic injury on the base-
line computed tomography (CT) scan, as measured by the
Alberta Stroke Program Early CT Score (ASPECTS) of 3 or greater
(where 3 indicates as much as 70% of the middle cerebral ar-
tery territory showing ischemic changes). The primary effi-
cacy outcome was the distribution in functional disability at
90 days using the modified Rankin Scale (mRS), with scores
ranging from 0 to 6, where 0 represents no symptoms, 2 rep-
resents the inability to carry out all activities of daily living but
remaining independent, and 6 indicates death.
Among the 1687 included patients treated across the 82
sites in China, the stroke severity according to the NIHSS score
was expectedly high (median, 19 [IQR, 16-21]), with a median
ASPECTS of 6 (IQR, 4-7). Regarding the primary outcome of a
shift in the distribution of the mRS score 90 days after stroke,
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there was no significant improvement with intervention, al-
though the effect estimate favored the corticosteroid group
(adjusted generalized odds ratio, 1.10 [95% CI, 0.96-1.25]). From
the analysis of the prespecified secondary efficacy and safety
outcomes, it is apparent that any potential benefit from cor-
ticosteroids was driven by the lower mortality rate (23.2% vs
28.5%, respectively; adjusted risk ratio [aRR], 0.84 [95% CI,
0.71-0.98]) and concomitantly higher proportion of patients
who survived with moderate disability according to the mRS
at 3 months (aRR, 1.07 [95% CI, 1.00-1.14]). There was also a
3% absolute risk reduction of symptomatic intracerebral hem-
orrhage in the corticosteroid group (aRR, 0.74 [95% CI, 0.55-
0.99]), although there was no significant difference in the rate
of any intracerebral hemorrhage (38.2% in the steroid group
vs 37.1% in the control group; aRR, 1.03 [95% CI, 0.91-1.16]).
There was no significant difference in the proportion of pa-
tients achieving functional independence (mRS, 0-2) at 3
months, which is one of the most common measures of effi-
cacy for endovascular thrombectomy in stroke trials (aRR, 1.07
[95% CI, 0.95-1.19]).
While the primary efficacy end point of the MARVEL trial
was not significantly different for the corticosteroid vs con-
trol groups, there is biologic plausibility to support the ben-
efit of anti-inflammatory treatment in acute cerebral infarc-
tion based on animal studies.8 Unfortunately, the preclinical
evidence supporting steroid use is unsubstantiated by hu-
man trials.9 This may be related to the fact that prior to highly
effective endovascular thrombectomy, where recanalization
rates are close to 90%, we have been unable to replicate in
human studies the animal model of transient proximal intra-
cranial arterial occlusion in which adjunctive and neuropro-
tective therapies have proven beneficial. The MARVEL
Investigators also note that prior human studies included
patients with stroke as well as suspected stroke, and treated
patients with longer courses of corticosteroids likely leading
to the poorer outcomes in the intervention group. By con-
trast, the MARVEL Investigators used a low dose of intrave-
nous methylprednisolone (2 mg/kg/d) over 3 days to reduce
the risk of toxic adverse effects, which may be particularly
deleterious in the acute setting of cerebral infarction. Even
so, the investigators reported a higher use of insulin in the
steroid group (19.7% vs 13.1%, P < .01) and a 2-fold higher risk
of new diabetes (4.8% vs 2.9%, P = .04), but no significant
increase in the rate of new hyperglycemia (38.1% vs 34.2%,
P = .10). The physiologic “stress” response (manifesting with
acute hyperglycemia) in the setting of acute cerebral infarc-
tion, coupled with the high incidence of diabetes in these
patients, are cause for concern and may mitigate or counter
any neuroprotective effects.
(Reprinted) JAMA Published online February 8, 2024 E1
 Opinion Editorial

Although the MARVEL trial did not demonstrate a ben-
efit of steroids with respect to its primary end point, when vi-
sualizing the distribution of the mRS scores at 90 days, there
appears to be a benefit in survival with a shift toward moder-
ate disability. Assuming this finding were to be validated ex-
ternally, 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 (46.5% vs 55.4%, respec-
tively). A similar, albeit nonsignificant, reduction in the risk
of pneumonia has been previously reported by the Corti-TC
investigators from a phase 3 placebo-controlled randomized
clinical trial of hydrocortisone/fludrocortisone in severe trau-
matic brain injury (28-day rate of pneumonia, 45% vs 53% in
the control group).10 There is also the potential benefit of cor-
ticosteroids for circulatory support even without overt septic
shock, which is supported by a prior meta-analysis of random-
ized clinical trials.9 It is also possible that the survival advan-
tage could have been due to a reduction in cytotoxic or vaso-
genic cerebral edema with adjunctive methylprednisolone
following large cerebral infarction. Because most patients with
malignant hemispheric edema following LVO stroke are un-
likely to achieve functional independence, it is more plau-
sible that any treatment-related benefit would reduce mortal-
ity and subsequently increase the chances of survival with
moderate disability. Without additional imaging analyses, it
is not possible to know whether the lower mortality rate with
steroid use was mediated by a reduction in infarct volume or
edema formation vs other general medical benefits of acute
corticosteroid therapy.
Overall, the findings from the MARVEL randomized clini-
cal trial add to a literature indicating a lack of efficacy of ad-
junctive corticosteroids in acute ischemic stroke. That said, the
secondary analyses from this trial suggest a potential sur-
vival advantage, which might be mediated by a reduction in
cytotoxic or vasogenic edema following malignant infarc-
tion. These findings could be explored using volumetric analy-
ses of infarct size and/or surrogate measures of malignant
edema (eg, decompressive craniectomy rates or length of in-
tensive care unit stay) and warrant further validation. Finally,
any potential benefit of adjunctive corticosteroid use in these
patients ought to be carefully weighed against the risks of
hyperglycemia and diabetes.

ARTICLE INFORMATION
Author Affiliations: Department of Neurology,
University of Chicago, Chicago, Illinois.
Corresponding Author: Shyam Prabhakaran, MD,
MS, Division of the Biological Sciences, University of
Chicago, 5841 S Maryland Ave, MC 2030, A-223,
Chicago, IL 60637 (shyam1@bsd.uchicago.edu).
Published Online: February 8, 2024.
doi:10.1001/jama.2024.0526
Conflict of Interest Disclosures: Dr Prabhakaran
reported receiving grants from the National
Institutes of Health and the Agency for Healthcare
Research and Quality, and personal fees from
UpToDate. No other disclosures were reported.
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