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. 2026 Jul 31;19:17562864261473898. doi: 10.1177/17562864261473898

Sex-specific effects of methylprednisolone on outcomes after endovascular treatment for acute ischemic stroke due to large vessel occlusion: A secondary analysis of the MARVEL trial

Lijiao Zhang 1,*, Jie Pan 2,*, Lilan Wang 3,*, Chunye Chen 3,*, Mingrui Zhou 4, Sheng Zhou 5, Haoxuan Zhu 2,3, Xiaolei Shi 3, Shihai Yang 3, Mingyang Chen 3, Yihui Yang 3, Yuhan Fan 3, Binghan Wang 3, Guojian Liu 3, Linyu Li 3,6, Chawen Ding 6, Jiaxing Song 6, Lingyu Zhang 7,✉, Gaoming Li 3,✉
PMCID: PMC13428103  PMID: 42542723

Abstract

Background

Sex-based differences in treatment response to neuroprotective strategies during endovascular treatment (EVT) for acute ischemic stroke remain poorly understood.

Objectives

This study aimed to evaluate sex-specific effects of methylprednisolone on outcomes after EVT for acute ischemic stroke due to large vessel occlusion.

Design

Secondary analysis of the MARVEL (Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke) randomized controlled trial.

Methods

We compared outcomes following methylprednisolone versus placebo, stratified by sex. We also compared outcomes between women and men receiving methylprednisolone. The primary outcome was defined as the 90-day modified Rankin Scale score (mRS) ordinal shift. Secondary outcomes included mRS score of 0-4, 0-3, 0-2, 0-1 at 90 days. Safety outcomes included mortality within 90 days and symptomatic intracranial hemorrhage (sICH) within 48 hours.

Results

This study included 1680 patients (49.9% methylprednisolone, 56.7% men). Stratified by sex, among men, the methylprednisolone group was more likely to have a primary outcome compared with placebo [adjusted OR (aOR) 1.26 (1.00-1.59), P = 0.047] and reduce mortality (P < 0.01) and sICH (P = 0.031); among women, the primary outcome was similar between two treatment arms (P = 0.66), with similar findings for the safety outcomes. Additionally, stratified by different treatment arms, no significant difference was found in the primary outcome between men and women treated with methylprednisolone (P = 0.31) and placebo (P = 0.68).

Conclusions

In this exploratory analysis, methylprednisolone appeared to be associated with better clinical outcomes in men compared with placebo. Nevertheless, the interaction between treatment and sex was not statistically significant. Furthermore, among patients receiving methylprednisolone, clinical outcomes did not differ significantly between men and women.

Registration

ChiCTR.org.cn Identifier: ChiCTR2100051729.

Keywords: acute ischemic stroke, large vessel occlusion, endovascular treatment, methylprednisolone, sex, outcomes

Plain language summary

This study looked at whether an anti-inflammatory drug called methylprednisolone has different effects in men and women who had a severe stroke caused by a large blood clot in a brain artery and underwent a procedure called endovascular treatment to remove the clot. The research was based on data from a large clinical trial that included 1,680 patients. About half received methylprednisolone and the other half received a placebo. The researchers compared outcomes between men and women who received the drug versus placebo, and also directly compared men and women who received the drug. The results showed that among men, those who received methylprednisolone had better recovery of daily functions 90 days after the stroke compared to men who received placebo. They also had lower rates of death and symptomatic bleeding in the brain. Among women, however, there was no significant difference in recovery between those who received methylprednisolone and those who received placebo. When researchers directly compared men and women who both received methylprednisolone, their recovery outcomes were not significantly different. In summary, this study suggests that methylprednisolone may be more helpful for recovery in men with this type of stroke, while the benefit in women was less clear. These findings indicate that sex may be an important factor to consider when using this medication in future stroke treatment.

Introduction

The management of acute ischemic stroke (AIS) due to large vessel occlusion (LVO) has been revolutionized by endovascular treatment (EVT). 1 Technical maturation has increased recanalization rates for acute intracranial LVO to 80-90%. 2 However, among these successfully recanalized patients, fewer than 50% subsequently attain a favorable clinical outcome.3,4 This unresolved clinical need has prompted the investigation of adjunctive neuroprotective strategies aimed at improving long-term recovery.5,6

Corticosteroids have been investigated as potential neuroprotective agents, largely because of their ability to regulate inflammation, reduce pro-inflammatory cytokine levels, alleviate the inflammatory response, and decrease apoptosis of neuronal cells in central nervous system injury. 7 The recent MARVEL (Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke) trial sought to address this gap by evaluating the efficacy and safety of adjunctive methylprednisolone in patients with LVO undergoing EVT. 8 Although the MARVEL trial did not demonstrate the superiority of methylprednisolone over placebo in the overall population of patients with LVO, the possibility remains that its pharmacokinetic profile and anti-inflammatory potency, as a synthetic glucocorticoid, may differ between sexes due to established sex differences in steroid metabolism and inflammatory pathophysiology. 9 Moreover, prior research has demonstrated that glucocorticoids and sex hormones exhibit interrelated actions and may exert reciprocal influences on each other. 10 Therefore, it is critically important to investigate the effects of glucocorticoids on endovascular therapy across different sexes.

In this context, using the data from the MARVEL trial, 8 our study aimed to evaluate sex-specific effects of methylprednisolone on outcomes after EVT for acute ischemic stroke due to large vessel occlusion.

Methods

Study design and patient selection

Data are from the MARVEL trial, an investigator-initiated, randomized, double-blind, placebo-controlled clinical trial that tested the superiority of intravenous methylprednisolone, 2mg/kg/d (maximum dose, 160mg) for 3 days plus EVT versus placebo plus EVT in patients with LVO stroke. It was conducted at 82 stroke centers across China from February 9, 2022, to June 30, 2023, with follow-up for 3 months.

Patients were eligible if they met the following criteria: age ≥18 years, baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 6, pre-stroke modified Rankin Scale (mRS) score < 2, baseline Alberta Stroke Program Early CT Score (ASPECTS) 3-10, and presentation within 24 hours of last known well. Occlusion of the intracranial internal carotid artery or the M1/M2 segment of the middle cerebral artery was confirmed by computed tomographic angiography, magnetic resonance angiography, or digital subtraction angiography. Comprehensive details regarding the patient selection criteria, trial protocol, and end point adjudication have been published previously. 8 The study report followed the guidelines from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.

Data collection

Demographic information, risk factors for stroke, laboratory findings, stroke severity (based on NIHSS score), collateral status (based on the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral grading system [ASITN/SIR]), baseline core infarct (based on the ASPECTS), stroke etiology (based on the Trial of ORG10172 in Acute Stroke Treatment [TOAST] classification), occlusion site, time from symptom onset or last known well to puncture, time from symptom onset or last known well to randomization, time from symptom onset or last known well to recanalization and time from randomization to initial treatment were recorded.

Outcome measures

The primary outcome was the distribution of modified Rankin Scale (mRS) score at 90 days. The secondary outcomes included the following prespecified dichotomizations of the mRS score at 90 days: 0-4, 0- 3, 0-2, and 0-1, the NIHSS score at 5 to 7 days or at early discharge. The safety outcomes were mortality within 90 days and symptomatic intracranial hemorrhage (sICH), as assessed according to the modified Heidelberg bleeding classification 11 and any intracranial hemorrhage within 48 hours after EVT.

Statistical analysis

Two parallel analyses assessed sex differences in outcomes: one evaluated sex as an effect modifier for the efficacy and safety of methylprednisolone versus placebo, and the other compared outcomes between women and men specifically within the methylprednisolone-treated and placebo group.

Descriptive statistics for continuous and categorical variables were presented as median with interquartile range and number with percentage, respectively. Comparisons were performed using the Mann-Whitney U test for continuous variables and the Pearson χ2 or Fisher’s exact test for categorical variables, as appropriate. Binary logistic regression was used to analyze dichotomous outcomes, including mRS scores 0-4, 0-3, 0-2, 0-1, mortality at 90 days, sICH and any intracranial hemorrhage. Ordinal logistic regression was applied to analyze shifts across the entire range of the mRS score. A linear regression model was used to assess the NIHSS scores at 5-7 days or early discharge. The results from these logistic regression analyses were presented as odds ratios (OR) and beta coefficients with 95% confidence intervals (CIs). The primary analyses for all outcomes were adjusted for the following seven prespecified covariates: age, baseline NIHSS score, pre-stroke mRS score, baseline ASPECTS, use of intravenous thrombolysis, time from onset to randomization, and occlusion location. Testing for modification of the treatment effect on the primary efficacy outcome was conducted in 9 subgroups: age, sex, NIHSS score, ASPECTS, intravenous thrombolysis, time to randomization, occlusion location and stroke etiology. To formally evaluate whether the effect of methylprednisolone on outcomes differed by sex, we included a treatment and sex interaction term in the multivariable ordinal logistic regression model for the primary outcome, and in the logistic regression models for all secondary and safety outcomes. The P-value for interaction was reported for each outcome.

For statistical assessment, IBM SPSS Statistics 26 (SPSS Inc.) and R version 4.4.2 (R Foundation for Statistical Computing, Vienna, Austria) were employed. All tests were two-sided and considered statistically significant at a P value < 0.05.

Results

Methylprednisolone versus placebo, stratified by sex

Baseline characteristics were balanced between treatment groups within each sex. Among the 727 women (49.4% methylprednisolone, 50.6% placebo), all characteristics were comparable except for age, which was lower in the methylprednisolone group (71 [64-77] vs. 74 [67-79], P = 0.005). In contrast, among the 953 men (50.4% methylprednisolone, 49.6% placebo), all characteristics, including age, were well-matched (Table 1).

Table 1.

Baseline characteristics by treatment arm, stratified by sex.

Characteristic Women (N=727) Men (N=953)
Methylprednisolone (N=359) Placebo (N=368) P value Methylprednisolone (N=480) Placebo (N=473) P value
Age, median (IQR), y 71 (64-77) 74 (67-79) 0.005 66 (57-74) 66 (57-74) 0.597
Medical history
 Hypertension 210 (58.5) 237 (64.4) 0.102 294 (61.3) 286 (60.5) 0.804
 Atrial fibrillation 191 (53.2) 202 (54.9) 0.648 157 (32.7) 151 (31.9) 0.796
 Hyperlipidemia 114 (31.8) 97 (26.4) 0.109 153 (31.9) 148 (31.3) 0.846
 Diabetes 82 (22.8) 68 (18.5) 0.146 88 (18.3) 84 (17.8) 0.818
 Coronary heart disease 88 (24.5) 100 (27.2) 0.413 59 (12.3) 69 (14.6) 0.299
 Cerebral ischemia 62 (17.3) 56 (15.2) 0.453 74 (15.4) 61 (12.9) 0.265
 Valvular heart disease 80 (22.3) 72 (19.6) 0.367 34 (7.1) 43 (9.1) 0.256
 Intracranial hemorrhage 6 (1.7) 2 (0.5) 0.145 6 (1.2) 8 (1.7) 0.571
 Transient ischemic attack 2 (0.6) 2 (0.5) 0.980 4 (0.8) 2 (0.4) 0.423
 Smoking (current) 6 (1.7) 5 (1.4) 0.730 230 (47.9) 236 (49.9) 0.541
Prestroke modified Rankin Scale score 1-4 16 (4.5) 10 (2.7) 0.207 20 (4.2) 14 (3.0) 0.315
Glucose level at hospital arrival * , median (IQR), mmol/L 7.6 (6.4-9.3) 7.4 (6.3-9.1) 0.163 7.0 (6.0-8.5) 6.8 (5.8-8.2) 0.169
Baseline NIHSS score, median (IQR) 19 (17-22) 19 (17-21) 0.957 18 (16-21) 19 (16-21) 0.956
Baseline ASPECTS † , median (IQR) 6 (4-7) 5 (4-7) 0.666 5 (4-7) 6 (4-7) 0.400
Stroke etiology ‡ ​ ​ 0.786 ​ ​ 0.235
 Large artery atherosclerosis 85 (23.7) 99 (26.9) ​ 217 (45.2) 235 (49.7) ​
 Cardioembolic 230 (64.2) 227 (61.7) ​ 192 (40.0) 166 (35.1) ​
 Others 8 (2.2) 9 (2.4) ​ 24 (5.0) 32 (6.8) ​
 Unknown 35 (9.8) 33 (9.0) ​ 47 (9.8) 40 (8.5) ​
Occlusion site § ​ ​ 0.051 ​ ​ 0.241
 ICA 128 (35.8) 113 (30.7) ​ 158 (33.0) 180 (38.1) ​
 M1 186 (52.0) 187 (50.8) ​ 266 (55.) 239 (50.5) ​
 M2 44 (12.3) 68 (18.5) ​ 55 (11.5) 54 (11.4) ​
 Other 1 (0.3) 0 (0.0) ​ 1 (0.3) 0 (0.0) ​
IVT 133 (37.0) 143 (38.9) 0.615 162 (33.8) 190 (40.2) 0.040
Time from last known well, median (IQR), h
 To puncture 340 (230-570) 330 (214-556) 0.231 360 (234-624) 390 (250-625) 0.223
 To randomization 351 (235-579) 339 (220-571) 0.206 357 (241-641) 387 (261-629) 0.313
 To recanalization 413 (305-650) 411 (295-636) 0.270 444 (320-725) 474 (333-729) 0.248
Time from randomization to initial treatment , median (IQR), min 8 (6-14) 8 (6-14) 0.956 8 (6-14) 8 (6-13) 0.482
Blood pressure at hospital arrival, median (IQR), mm Hg
 Systolic 140 (125-159) 146 (130-162) 0.046 144 (128-160) 143 (126-160) 0.642
 Diastolic 80 (73-90) 83 (75-92) 0.046 85 (75-94) 85 (74-95) 0.995
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Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; ICA, Intracranial internal carotid artery; IQR, Interquartile Range; IVT, Intravenous thrombolysis; M1, M1 middle cerebral artery segment; M2, M2 middle cerebral artery segment; NIHSS, National Institutes of Health Stroke Scale.

*Data on glucose level at hospital arrival were missing for 92 patients in the women group and 116 patients in the men group.

†Data on baseline ASPECTS were missing for 3 patients in the women group and 3 patients in the men group.

‡Data on stroke etiology were missing for 1 patient in the women group.

§Data on occlusion site were missing for 1 patient in the women group and 1 patient in the men group.

Data on time from randomization to initial treatment were missing for 1 patient in the women group and 1 patient in the men group.

Among women, there was no significant difference in the distribution of 90-day mRS between the methylprednisolone and placebo group [3 (2-6 vs 3 (2-6); common Odds Ratio (cOR), 1.06 (95% CI, 0.81-1.39), P = 0.66]. Regarding secondary outcomes, no significant differences were observed for mRS 0-4 [OR, 1.18 (95% CI 0.84-1.65); P = 0.35], mRS 0-3 [OR, 1.14 (95% CI 0.82-1.58); P = 0.43], mRS 0-2 [OR, 0.96 (95% CI 0.69-1.33); P = 0.80], mRS 0-1 [OR, 0.99 (95% CI 0.68-1.44); P = 0.96], or NIHSS score at 5-7 days [β, -0.48 (95% CI -2.37-1.41); P = 0.62]. With respect to safety outcomes, mortality [OR, 0.85 (95% CI 0.60-1.21); P = 0.37], sICH [OR, 0.83 (95% CI 0.49-1.39); P = 0.47], and any ICH [OR, 1.00 (95% CI 0.73-1.37); P = 0.99] were comparable between treatment groups (Table 2).

Table 2.

Clinical outcomes by treatment arm, stratified by sex.

Outcomes Women (N=727) Men (N= 953) P for interaction
Methylpre-dnisolone (N=359) Placebo (N=368) Adjusted OR P value Methylpre-dnisolone (N=480) Placebo (N=473) Adjusted OR P value
Primary outcome
 mRS score at 90 days # 3 (2-6) 3 (2-6) 1.06 (0.81-1.39) 0.659 3 (1-5) 3 (1-6) 1.26 (1.00-1.59) 0.047 0.362
Secondary outcomes
 mRS 0 to 4 at 90 days * 238 (67.4) 234 (63.9) 1.18 (0.84-1.65) 0.347 356 (74.6) 320 (68.2) 1.43 (1.04-1.96) 0.027 0.416
 mRS 0 to 3 at 90 days * 191 (54.1) 185 (50.5) 1.14 (0.82-1.58) 0.430 302 (63.3) 273 (58.2) 1.30 (0.97-1.74) 0.082 0.651
 mRS 0 to 2 at 90 days * 134 (38.0) 143 (39.1) 0.96 (0.69-1.33) 0.798 232 (48.6) 199 (42.4) 1.34 (1.01-1.78) 0.041 0.133
 mRS 0 to 1 at 90 days * 82 (23.2) 84 (23.0) 0.99 (0.68-1.44) 0.960 136 (28.5) 135 (28.8) 0.99 (0.73-1.34) 0.94 0.867
 NIHSS score at 5-7 days & 11 (4-27) 12 (4-31) -0.48 (-2.37-1.41) 0.617 10 (4-20) 12 (3-23) -1.57 (-3.13--0.01) 0.047 0.407
Safety outcomes
 Mortality within 90 days * 96 (27.2) 110 (30.1) 0.85 (0.60-1.21) 0.370 96 (20.1) 127 (27.1) 0.64 (0.46-0.89) <0.01 0.229
 sICH within 48 hours * 31 (8.9) 38 (10.5) 0.83 (0.49-1.39) 0.473 39 (8.3) 58 (12.5) 0.62 (0.40-0.96) 0.031 0.382
 Any ICH within 48 hours * 129 (37.0) 132 (36.4) 1.00 (0.73-1.37) 0.987 182 (38.8) 175 (37.6) 1.05 (0.80-1.38) 0.70 0.854
 Pneumonia * 155 (43.5) 197 (53.7) 0.67 (0.50-0.91) 0.011 234 (49.0) 267 (56.7) 0.73 (0.56-0.95) 0.019 0.716
 Gastrointestinal bleeding within 7 days after EVT * 15 (4.2) 13 (3.5) 1.20 (0.55-2.61) 0.648 18 (3.8) 36 (7.6) 0.46 (0.25-0.82) 0.009 0.066
 New diabetes * 19 (5.3) 12 (3.3) 1.65 (0.77-3.51) 0.196 21 (4.4) 12 (2.5) 1.69 (0.81-3.51) 0.160 0.949
 New hyperglycemia * 151 (42.4) 118 (32.2) 1.60 (1.17-2.18) 0.003 166 (34.7) 170 (36.1) 0.95 (0.73-1.25) 0.730 0.009
 Insulin use in hospital stay * 77 (21.6) 48 (13.1) 1.85 (1.24-2.76) 0.003 86 (18.0) 62 (13.2) 1.43 (1.00-2.05) 0.049 0.367
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Abbreviations: Any ICH, any intracranial hemorrhage; mRS, Modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OR, Odds Ratio; sICH, Symptomatic intracranial hemorrhage.

Missing data: 27 patients had missing sICH and Any ICH, 7 patients had missing mRS, 3 patients had missing NIHSS score at 5-7 d or discharge.

*The odds ratios were estimated from a binary logistic regression model.

#The odds ratios were estimated from an ordinal regression model.

&The β values were estimated from a multivariable linear regression model.

Among men, methylprednisolone was associated with a higher odds of better outcome [aOR, 1.26 (95% CI 1.00-1.59, P = 0.047)]. For secondary outcomes, a higher proportion of men in the methylprednisolone group achieved an mRS of 0-4 [aOR, 1.43 (95% CI 1.04-1.96), P = 0.027] and mRS 0-2 [aOR, 1.34 (95% CI 1.01-1.78), P = 0.041]. Additionally, methylprednisolone group was associated with lower NIHSS scores at 5-7 days [aβ -1.57, (95% CI -3.13 to -0.01), P = 0.047]. Regarding safety outcomes, men receiving methylprednisolone had significantly lower mortality [aOR, 0.64 (95% CI 0.46-0.89), P < 0.01] and lower incidence of sICH [aOR 0.62, (95% CI 0.40-0.96), P = 0.031] (Table 2). The findings were consistent across different effect measures (Supplement Table 3). The interaction between treatment and sex was not statistically significant for the primary outcome (P for interaction = 0.362). The distribution of the 90-day mRS stratified by sex is shown in Figure 1.

Figure 1.

Figure 1.

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Horizontal stacked bar graphs of Modified Rankin Scale score at 90 days.

(a) Horizontal stacked bar graphs of Modified Rankin Scale score at 90 days stratified by treatment arm in women. (b) Horizontal stacked bar graphs of Modified Rankin Scale score at 90 days stratified by treatment arm in men. (c) Horizontal stacked bar graphs of Modified Rankin Scale score at 90 days stratified by sex in methylprednisolone group. (d) Horizontal stacked bar graphs of Modified Rankin Scale score at 90 days stratified by sex in placebo group. Abbreviations: mRS, modified Rankin Scale.

Women versus men, stratified by treatment arm

There were 839 participants assigned to methylprednisolone (42.8% women, 57.2% men) and we observed several differences in baseline characteristics. Compared with men, women were older [71 (64-77) vs 66 (57-74), P < 0.001], more likely to have atrial fibrillation (53.2% vs 61.3%, P < 0.001), coronary heart disease (24.5% vs 12.3%, P < 0.001), valvular heart disease (22.3% vs 7.1%, P < 0.001), higher baseline glucose [7.6 (6.4-9.3) vs 7.0 (6.0-8.5), P < 0.001], higher baseline NIHSS score [19 (17-22) vs 18 (16-21)] and less likely to have smoking history (1.7% vs 47.9%, P < 0.001) and lower diastolic blood pressure [80 (73-90) vs 85 (75-94), P = 0.001]. The prevalence of stroke etiology according to TOAST criteria was significantly different between groups (P<0.001). LAA was higher in men, while cardioembolism was higher in women. Among the 841 participants assigned to placebo treatment (43.8% women, 56.2% men), the pattern of sex differences in baseline characteristics was generally consistent with that observed in the methylprednisolone group. However, a distinct sex disparity emerged in the placebo group regarding the time from last known well to puncture (P < 0.001), randomization (P < 0.001), and recanalization (P < 0.001), where men required longer time intervals than women. In addition, significant sex-based differences were observed in occlusion site, with a higher proportion of internal carotid artery occlusions among men (P = 0.006). (Table 3).

Table 3.

Baseline characteristics by sex, stratified by treatment arm.

Characteristic Methylprednisolone (N=839) Placebo (N=841)
Women (N=359) Men (N=480) P value Women (N=368) Men (N=473) P value
Age, median (IQR), y 71 (64-77) 66 (57-74) < 0.001 74 (67-79) 66 (57- 74) <0.001
Medical history
 Hypertension 210 (58.5) 294 (61.3) 0.420 237 (64.4) 286 (60.5) 0.243
 Atrial fibrillation 191 (53.2) 157 (32.7) < 0.001 202 (54.9) 151 (31.9) <0.001
 Hyperlipidemia 114 (31.8) 153 (31.9) 0.971 97 (26.4) 148 (31.3) 0.118
 Diabetes 82 (22.8) 88 (18.3) 0.108 68 (18.5) 84 (17.8) 0.788
 Coronary heart disease 88 (24.5) 59 (12.3) <0.001 100 (27.2) 69 (14.6) <0.001
 Cerebral ischemia 62 (17.3) 74 (15.4) 0.471 56 (15.2) 61 (12.9) 0.335
 Valvular heart disease 80 (22.3) 34 (7.1) < 0.001 72 (19.6) 43 (9.1) <0.001
 Intracranial hemorrhage 6 (1.7) 6 (1.2) 0.611 2 (0.5) 8 (1.7) 0.128
 Transient ischemic attack 2 (0.6) 4 (0.8) 0.638 2 (0.5) 2 (0.4) 0.801
 Smoking (current) 6 (1.7) 230 (47.9) <0.001 5 (1.4) 236 (49.9) <0.001
Prestroke modified Rankin Scale score 1-4 16 (4.5) 20 (4.2) 0.837 10 (2.7) 14 (3.0) 0.834
Prestroke modified Rankin Scale score ​ ​ 0.652 ​ ​ 0.547
 0 343 (95.5) 460 (95.8) ​ 358 (97.3) 459 (97.0) ​
 1 13 (3.6) 15 (3.1) ​ 5 (1.4) 9 (1.9) ​
 2 2 (0.6) 4 (0.8) ​ 5 (1.4) 3 (0.6) ​
 3 1 (0.3) 0 (0.0) ​ 0 (0.0) 1 (0.2) ​
 4 0 (0.0) 1 (0.2) ​ 0 (0.0) 1 (0.2) ​
Glucose level at hospital arrival * , median (IQR), mmol/L 7.6 (6.4-9.3) 7.0 (6.0-8.5) < 0.001 7.4 (6.3-9.1) 6.8 (5.8-8.2) <0.001
Baseline NIHSS score, median (IQR) 19 (17-22) 18 (16-21) 0.043 19.0 (17.0- 21.0) 19.0 (16.0-21.0) 0.043
Baseline ASPECTS † , median (IQR) 6 (4-7) 5 (4-7) 0.680 5.0 (4.0-7.0) 6.0 (4.0-7.0) 0.477
Stroke etiology ‡ ​ ​ < 0.001 ​ ​ <0.001
 Large artery atherosclerosis 85 (23.7) 217 (45.2) ​ 99 (26.9) 235 (49.7) ​
 Cardioembolic 230 (64.2) 192 (40.0) ​ 227 (61.7) 166 (35.1) ​
 Others 8 (2.2) 24 (5.0) ​ 9 (2.4) 32 (6.8) ​
 Unknown 35 (9.8) 47 (9.8) ​ 33 (9.0) 40 (8.5) ​
Occlusion site § ​ ​ 0.589 ​ ​ 0.006
 ICA 128 (35.8) 158 (33.0) ​ 113 (30.7) 180 (38.1) ​
 M1 186 (52.0) 266 (55.5) ​ 187 (50.8) 239 (50.5) ​
 M2 44 (12.3) 55 (11.5) ​ 68 (18.5) 54 (11.4) ​
 Other 1 (0.3) 0 (0.0) ​ 0 (0.0) 0 (0.0) ​
 IVT 133 (37.0) 162 (33.8) 0.322 143 (38.9) 190 (40.2) 0.700
Time from last known well, median (IQR), h
 To puncture 340 (230-570) 360 (234-624) 0.311 330 (214- 556) 390 (250- 625) <0.001
 To randomization 351 (235-579) 357 (241-641) 0.288 339 (220- 571) 387 (261- 629) <0.001
 To recanalization 413 (305-650) 444 (320-725) 0.111 411 (295- 636) 474 (333- 729) <0.001
 Time from randomization to initial treatment , median (IQR), min 8 (6-14) 8 (6-14) 0.987 8 (6-14) 8 (6- 13) 0.447
Blood pressure at hospital arrival, median (IQR), mm Hg
 Systolic 140 (125-159) 144 (128-160) 0.175 146 (130-162) 143 (126-160) 0.193
 Diastolic 80 (73-90) 85 (75-94) 0.001 83 (75- 92) 85 (74-95) 0.241
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Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; ICA, Intracranial internal carotid artery; IQR, Interquartile Range; IVT, Intravenous thrombolysis; M1, M1 middle cerebral artery segment; M2, M2 middle cerebral artery segment; NIHSS, National Institutes of Health Stroke Scale.

*Data on glucose level at hospital arrival were missing for 103 patients in the methylprednisolone group and 105 patients in the placebo group.

†Data on baseline ASPECTS were missing for 3 patients in the methylprednisolone group and 3 patients in the placebo group.

‡Data on stroke etiology were missing for 1 patient in the placebo group.

§Data on occlusion site were missing for 2 patients in the methylprednisolone group.

Data on time from randomization to initial treatment were missing for 2 patients in the placebo group.

In the methylprednisolone group, after adjustment for confounding factors, there was no significant difference in primary outcome between men and women [aOR 1.14, (95% CI 0.88-1.47), P = 0.31]. Similarly, no significant sex differences were observed mRS 0-4 [OR 1.11 (95% CI 0.79 -1.56), P = 0.54], mRS 0-3 [OR 1.15 (95% CI 0.84-1.58), P = 0.37], and mRS 0-2 [OR 1.28 (95% CI 0.94-1.75), P = 0.12], mRS 0-1 [OR 1.07 (95% CI 0.76-1.52), P = 0.69], lower NIHSS scores at 5-7 days [β -1.23 (95% CI -2.95 to 0.48), P = 0.16]. As for safety outcomes, there were no significant differences in the risk of mortality [OR 0.86 (95% CI 0.60-1.23), P = 0.42], sICH [OR 0.98 (0.58-1.64), P = 0.93] and any ICH [OR 1.11 (0.82-1.50), P = 0.49].

In the placebo group, there was no significant difference in primary outcome between men and women after adjustment [aOR 1.02, (95% CI 0.74-1.41), P = 0.91]. For all secondary and safety outcomes, no significant sex differences were observed (Table 4). The findings were consistent across different effect measures (Supplement Table 4). The interaction between treatment and sex was not statistically significant for the primary outcome (P for interaction = 0.362). The distribution of the 90-day mRS stratified by treatment arm is shown in Figure 1.

Table 4.

Clinical outcomes by sex, stratified by treatment arm.

Outcomes Methylprednisolone (N=839) Placebo (N=841) P for interaction
Women (N=359) Men (N=480) Adjusted OR P value Women (N=368) Men (N=473) Adjusted OR P value
Primary outcome
 mRS score at 90 days # 3 (2-6) 3 (1-5) 1.14 (0.88-1.47) 0.309 3 (2-6) 3 (1-6) 0.95 (0.73-1.23) 0.679 0.362
Secondary outcomes
 mRS 0 to 4 at 90 days * 238 (67.4) 356 (74.6) 1.11 (0.79-1.56) 0.541 234 (63.9) 320 (68.2) 0.87 (0.62-1.21) 0.403 0.416
 mRS 0 to 3 at 90 days * 191 (54.1) 302 (63.3) 1.15 (0.84-1.58) 0.368 185 (50.5) 273 (58.2) 1.02 (0.74-1.41) 0.906 0.651
 mRS 0 to 2 at 90 days * 134 (38.0) 232 (48.6) 1.28 (0.94-1.75) 0.115 143 (39.1) 199 (42.4) 0.97 (0.71-1.33) 0.858 0.133
 mRS 0 to 1 at 90 days * 82 (23.2) 136 (28.5) 1.07 (0.76-1.52) 0.693 84 (23.0) 135 (28.8) 1.15 (0.81-1.63) 0.449 0.867
 NIHSS score at 5-7 days & 11 (4-27) 10 (4-20) -1.23 (-2.95-0.48) 0.159 12 (4-31) 12 (3-23) <0.01 (-1.83-1.83) 0.998 0.407
Safety outcomes
 Mortality within 90 days * 96 (27.2) 96 (20.1) 0.86 (0.60-1.23) 0.418 110 (30.1) 127 (27.1) 1.24 (0.88-1.76) 0.226 0.229
 sICH within 48 hours * 31 (8.9) 39 (8.3) 0.98 (0.58-1.64) 0.927 38 (10.5) 58 (12.5) 1.31 (0.82-2.10) 0.254 0.382
 Any ICH within 48 hours * 129 (37.0) 182 (38.8) 1.11 (0.82-1.50) 0.492 132 (36.4) 175 (37.6) 1.01 (0.75-1.37) 0.924 0.854
 Pneumonia * 155 (43.5) 234 (49.0) 1.47 (1.10-1.98) 0.010 197 (53.7) 267 (56.7) 1.36 (1.01-1.84) 0.043 0.716
 Gastrointestinal bleeding within 7 days after EVT * 15 (4.2) 18 (3.8) 1.00 (0.49-2.07) 0.991 13 (3.5) 36 (7.6) 2.22 (1.11-4.42) 0.024 0.066
 New diabetes * 19 (5.3) 21 (4.4) 0.91 (0.47-1.75) 0.781 12 (3.3) 12 (2.5) 0.85 (0.35-2.04) 0.713 0.949
 New hyperglycemia * 151 (42.4) 166 (34.7) 0.74 (0.55-0.99) 0.044 118 (32.2) 170 (36.1) 1.39 (1.02-1.89) 0.038 0.009
 Insulin use in hospital stay * 77 (21.6) 86 (18.0) 0.82 (0.58-1.17) 0.285 48 (13.1) 62 (13.2) 1.03 (0.67-1.58) 0.899 0.367
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Abbreviations: Any ICH, any intracranial hemorrhage; mRS, Modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OR, Odds Ratio; sICH, Symptomatic intracranial hemorrhage.

Missing data: 27 patients had missing sICH and Any ICH, 7 patients had missing mRS, 3 patients had missing NIHSS score at 5-7 d or discharge.

*The odds ratios were estimated from a binary logistic regression model.

#The odds ratios were estimated from an ordinal regression model.

&The β values were estimated from a multivariable linear regression model.

Women versus men in all patients

Among the 1,680 participants enrolled in the study who underwent EVT (43.3% women, 56.7% men), we observed several sex differences in baseline characteristics. Detailed information is provided in Supplementary Table 1.

After adjustment for confounding factors, no significant statistical differences were observed between men and women in primary outcome [aOR 1.04 (0.87-1.25), P = 0.67]. Similarly, no significant sex differences were observed in secondary outcomes. Regarding safety outcomes, there were no significant differences between sexes in 90-day mortality [1.03 (0.81-1.32), P = 0.81], sICH [1.19 (0.85-1.68), P = 0.31] and any ICH [1.09 (0.88-1.35), P = 0.43] (Supplement Table 2). The findings were consistent across different effect measures (Supplement Table 5). The distribution of the 90-day mRS stratified by sex is shown in Supplement Figure 2.

Sensitivity analyses

Results for prespecified subgroup analyses are displayed in Figure 2. The distribution shift of mRS at 90 days remained consistent across the pre-defined subgroups except for occlusion location of ICA. There was no interaction between sex and pre-defined subgroups in terms of the treatment effect modification in EVT outcomes.

Figure 2.

Figure 2.

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Heterogeneity of Sex Effect for Primary Outcome Among Prespecified Subgroups.

Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; ICA, Intracranial internal carotid artery; M1, M1 middle cerebral artery segment; M2, M2 middle cerebral artery segment; NIHSS, National Institutes of Health Stroke Scale; Missing data: 7 patients had missing Modified Rankin Scale score, 7 patients had missing baseline ASPECTS, 1 patient had missing stroke etiology.

The predicted probabilities of favorable outcome (mRS 0-2) and mortality were significantly influenced by baseline stroke severity, age and baseline ASPECTS, but showed no significant sex-based differences across all three prognostic factors (Supplement Figures 3–5).

Discussion

In this exploratory analysis, we found that methylprednisolone appeared to be associated with better clinical outcomes in men compared with placebo. Nevertheless, the interaction between treatment and sex was not statistically significant. Furthermore, among patients receiving methylprednisolone, clinical outcomes did not differ significantly between men and women.

Current evidence regarding sex-based differences in the efficacy and outcomes of EVT remains inconsistent.12–14 While some retrospective studies and post-hoc analyses of large clinical trials have reported no significant sex differences in EVT results or treatment effects,15,16 other investigations have found that women exhibit a higher degree of disability at 90-day follow-up.17,18 In light of these inconsistent findings, this study introduces a novel perspective by investigating the modifying effect of neuroprotective strategies in the reperfusion era on sex-based differences.

Compared with the existing literature, this study offers new insights into neuroprotective strategies in the reperfusion era. Historically, glucocorticoids have not shown consistent benefit in the overall population with acute ischemic stroke and have even raised safety concerns such as hyperglycemia and infection.19,20 However, in the context of widespread use of mechanical thrombectomy and intravenous thrombolysis, the peri-reperfusion immune-inflammatory response, blood-brain barrier disruption, and reperfusion injury have become key determinants of outcomes and hemorrhagic transformation.21,22 Animal experiments and small clinical studies suggest that glucocorticoids may attenuate cerebral edema and hemorrhagic transformation by inhibiting proinflammatory signaling pathways and stabilizing the endothelium and the blood-brain barrier.20,23 The observed reduction in sICH among men in this study is biologically plausible in light of these mechanisms. Our results provide new data on whether sex modifies the treatment effect of methylprednisolone.

We note that one finding in our results warrants further clarification. On one hand, among men, methylprednisolone was associated with a borderline significant improvement in the primary outcome compared with placebo (aOR 1.26, 95% CI: 1.00–1.59, P = 0.047). On the other hand, when directly comparing men and women within the methylprednisolone arm, no significant difference was observed (P = 0.31). At first glance, these two findings may seem inconsistent; however, they can be reconciled through several statistical considerations. First, the formal test of the treatment-sex interaction showed no statistically significant difference (interaction P = 0.362), indicating that the current data do not provide sufficient evidence to conclude that the treatment effect of methylprednisolone truly differs between sexes. Second, while the sex-stratified analyses yielded nominally different results, these should be regarded as hypothesis-generating findings rather than definitive evidence of a sex-specific treatment effect, which suggests that the above findings should be interpreted with caution.

Several key baseline disparities between male and female participants should be noted when interpreting sex-stratified treatment effects of methylprednisolone. First, women in our analysis were significantly older than men (P<0.001). Advanced age is independently associated with poorer stroke outcomes and may be accompanied by altered immune function and attenuated inflammatory responses to corticosteroid therapy.24,25 It is therefore plausible that the older age profile of women partially accounts for the absence of a detectable treatment benefit in this subgroup, independent of any true sex-specific biological effect. Second, stroke etiology differed markedly between sexes, with cardioembolic stroke being more prevalent in women and large artery atherosclerosis more common in men. These etiological differences are clinically relevant because the neuroinflammatory cascades activated following cardioembolic versus atherosclerotic stroke may differ substantially. 26 Specifically, the reperfusion injury-associated neuroinflammation that is particularly prominent in atherosclerotic large vessel occlusion may be more amenable to corticosteroid suppression, potentially explaining the more pronounced benefit observed in men. 27 Third, comorbidity profiles differed between sexes, with women exhibiting higher rates of atrial fibrillation (54.1% vs 32.3%, P <0.001) and men demonstrating higher rates of smoking (1.5% vs 48.9%, P <0.001). These differences may reflect distinct pathophysiological contexts that independently influence inflammatory responses, corticosteroid metabolism, and ultimately, treatment outcomes. 28 Fourth, differences in baseline stroke severity between men and women may independently influence functional recovery trajectories. Similar to previous studies, our research found that women presented with more severe neurological deficits, which may partially affect the therapeutic efficacy of methylprednisolone. 29

We observed a beneficial effect of methylprednisolone on clinical outcomes specifically in men, which may be explained by a multilayered set of mechanisms. First, sex-related differences in immunophenotype may influence both the magnitude and temporal window of the inflammatory response: estrogens and progesterone generally confer neurovascular protection and may partially substitute for or mask the effects of exogenous glucocorticoids 30 ; meanwhile, sex differences in androgens, hypothalamic-pituitary-adrenal (HPA) axis responses, peripheral neutrophil mobilization, and microglial activation may render men more likely to benefit from potent anti-inflammatory therapy in the acute phase. Second, basic research evidence indicates sex differences in glucocorticoid receptor expression, sensitivity, and downstream transcriptional responses, suggesting that the same drug dose may produce different pharmacodynamic effects across sexes. 31 Third, sex differences in pharmacokinetics and drug distribution-such as corticosteroid-binding globulin levels, CYP3A metabolic activity, and body fat proportion and distribution-may lead to differing effective exposure, thereby influencing clinical endpoints. 9 These hypotheses are biologically plausible but require dedicated clinical and translational studies for validation.

In the second comparison, clinical outcomes did not differ significantly between women and men in either the methylprednisolone or the placebo group. This finding is consistent with the interpretation that the treatment effect was not significantly modified by sex,16,32 and also suggests that in modern, standardized LVO reperfusion care systems, sex may no longer be a major driver of prognosis. 15 In clinical practice, the decision to use methylprednisolone should not be based solely on sex, but rather on individualized risk-benefit assessment (considering factors such as inflammatory markers, high-risk features for hemorrhage, metabolic status, and susceptibility to infection).33,34 It is also essential to ensure equally stringent safety monitoring for both sexes regarding blood glucose, infections, delirium, and other relevant parameters.

In our subgroup analysis, we observed that men with internal carotid artery occlusion had better outcomes, which may be associated with the following reasons. First, there are significant vascular anatomical differences between men and women, with men exhibiting larger internal carotid artery diameters and lower vessel tortuosity, which provides more favorable conditions for endovascular device navigation and manipulation, contributing to shorter recanalization times and reduced risk of procedure-related complications. 35 Second, women experience stroke at older ages with a greater comorbidity burden, and may present with higher baseline stroke severity and a greater proportion of cardioembolic etiology. 36 Third, the loss of estrogen-mediated protection after menopause leads to impaired vascular endothelial function in women, whereas men are not subject to this effect, thereby demonstrating a relative advantage in endovascular treatment outcomes. 37

Our findings suggest that methylprednisolone, administered during the peri-reperfusion phase as an immunomodulatory strategy, may confer potential benefits in reducing symptomatic intracranial hemorrhage (sICH) and mortality. A consistent signal was observed particularly in the man population with LVO. However, the current evidence remains insufficient to recommend sex-specific treatment selection. In clinical practice, the known risks of corticosteroids, including hyperglycemia, infection, gastrointestinal bleeding, myopathy, and delirium must be carefully weighed. Enhanced monitoring of blood glucose and vigilance for infections are warranted, especially in patients with diabetes, immunocompromised status, or advanced age. The observed reduction in sICH is clinically meaningful. If replicated in larger, rigorously designed studies, these results could pave a new avenue for preventing reperfusion-related hemorrhagic complications.

Limitations

Our study has several limitations. First, as a secondary analysis of a randomized controlled trial, it lacks the statistical power to fully detect sex-based differences and may have limited generalizability to real-world practice. Second, substantial baseline differences existed between men and women in our cohort, including age, stroke etiology, comorbidities, and stroke severity. Although multivariable adjustment was performed, residual confounding cannot be entirely excluded. Additionally, the lack of systematic data on menopausal status, sex hormone levels, and receptor expression limits deeper interpretation of sex-related biological mechanisms. Third, the absence of robust systematic monitoring for glucocorticoid-related adverse events, including infection, hyperglycemia, and delirium, may undermine risk quantification and distort the estimated net clinical benefit. Fourth, although we observed a nominally significant treatment effect in men but not in women, the formal interaction test between treatment and sex did not reach statistical significance (P for interaction = 0.362). Therefore, our findings should be regarded as hypothesis-generating and exploratory rather than as definitive evidence of sex-specific treatment effects. Caution should be exercised in clinical interpretation.

Conclusion

In this exploratory analysis, methylprednisolone appeared to be associated with better clinical outcomes in men compared with placebo. Nevertheless, the interaction between treatment and sex was not statistically significant. Furthermore, among patients receiving methylprednisolone, clinical outcomes did not differ significantly between men and women. The above findings should be interpreted with caution and future studies are warranted to fully elucidate the sex-specific effects of methylprednisolone on outcomes after EVT for AIS due to LVO.

Supplemental material

Supplemental material - Sex-specific effects of methylprednisolone on outcomes after endovascular treatment for acute ischemic stroke due to large vessel occlusion: A secondary analysis of the MARVEL trial
sj-pdf-1-tan-10.1177_17562864261473898.pdf (805.4KB, pdf)

Supplemental material for Sex-specific effects of methylprednisolone on outcomes after endovascular treatment for acute ischemic stroke due to large vessel occlusion: A secondary analysis of the MARVEL trial by Lijiao Zhang, Jie Pan, MD, Lilan Wang, MD, Chunye Chen, MD, Mingrui Zhou, MD, Sheng Zhou, MD, Haoxuan Zhu, MD, Xiaolei Shi, MD, Shihai Yang, MD, Mingyang Chen, MD, Yihui Yang, MD, Yuhan Fan, MD, Binghan Wang, MD, Guojian Liu, MD, Linyu Li, MD, Chawen Ding, MD, Jiaxing Song, MD, Lingyu Zhang, MD, Gaoming Li, MD in Therapeutic Advances in Neurological Disorders

Acknowledgements

We are deeply grateful to all the clinicians and research coordinators at the participating centers for their invaluable contributions to patient recruitment, clinical care, and meticulous data collection throughout this study.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China Young Scientists Fund Project (Category C) (No. 82501597)

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental material: Supplemental material for this article is available online.

ORCID iDs

Mingrui Zhou https://orcid.org/0009-0009-3281-749X

Shihai Yang https://orcid.org/0009-0001-9628-4938

Jiaxing Song https://orcid.org/0000-0002-1945-2360

Gaoming Li https://orcid.org/0000-0002-4068-3139

Ethical considerations

This study was approved by the Ethics Committee of Xinqiao Hospital Ethics Committee (Ethics ID: 2021-131-01). This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Consent to participate

All participants provided written informed consent prior to enrolment in the study.

Data Availability Statement

The datasets generated during and/or analyzed during the current study are not publicly available due to the protection of patient privacy, but are available from the corresponding author on reasonable request.*

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental material - Sex-specific effects of methylprednisolone on outcomes after endovascular treatment for acute ischemic stroke due to large vessel occlusion: A secondary analysis of the MARVEL trial
sj-pdf-1-tan-10.1177_17562864261473898.pdf (805.4KB, pdf)

Supplemental material for Sex-specific effects of methylprednisolone on outcomes after endovascular treatment for acute ischemic stroke due to large vessel occlusion: A secondary analysis of the MARVEL trial by Lijiao Zhang, Jie Pan, MD, Lilan Wang, MD, Chunye Chen, MD, Mingrui Zhou, MD, Sheng Zhou, MD, Haoxuan Zhu, MD, Xiaolei Shi, MD, Shihai Yang, MD, Mingyang Chen, MD, Yihui Yang, MD, Yuhan Fan, MD, Binghan Wang, MD, Guojian Liu, MD, Linyu Li, MD, Chawen Ding, MD, Jiaxing Song, MD, Lingyu Zhang, MD, Gaoming Li, MD in Therapeutic Advances in Neurological Disorders

Data Availability Statement

The datasets generated during and/or analyzed during the current study are not publicly available due to the protection of patient privacy, but are available from the corresponding author on reasonable request.*

Articles from Therapeutic Advances in Neurological Disorders are provided here courtesy of SAGE Publications

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