Edaravone dexborneol for the treatment of acute ischemic stroke: A systematic review and meta-analysis

Abstract

Background

Edaravone dexborneol has been developed as a novel neuroprotective agent and showed a promising result in treatment of stroke. The current meta-analysis aimed to assess the feasibility and efficacy of the edaravone dexborneol in the treatment of stroke.

Method

We performed a systematic review and meta-analysis of literature in four electronic databases. Binary outcomes were analyzed through the risks ratio (RR) and 95% confidence interval (CI), while the continuous outcomes were analyzed through the standardized mean difference (SMD) and 95% CI. Also, we did a subgroup analysis to show more feasibility and safety dimensions.

Results

Five studies with a total of 2415 patients were included. There were 1119 patients in edaravone dexborneol group and 1216 patients in control group. The 90-mRS 0–1 (RR 1.17 [95% CI 1.09–1.25]; p < 0.0001) and 90-day mRS 0–2 (RR 1.12 [95% CI 1.07–1.18]; p < 0.0001) were statistically significant higher in intervention group compared with control group. There was no significant difference between intervention group and control group concerning 90-day mRS 0–3 (RR 1.03 [95% CI 0.99–1.06]; p = 0.07), 90-day mortality rate (RR 0.71 [95% CI 0.45–1.11]; p = 0.13), serious adverse events (RR 0.91 [95% CI 0.72–1.16]; p = 0.45), and NIHSS score ≤1 at days 14 (RR 0.96; p = 0.69), 30 (RR 1.08; p = 0.18), and 90 (RR 1.06; p = 0.15). No heterogeneity in treatment effect was seen in the analysis, and any potential discrepancies were addressed by sensitivity analysis.

Conclusion

Edaravone dexborneol can be a favorable treatment option for patients with stroke. However, more randomized controlled trials are required to confirm our findings.

Introduction

Stroke is the second leading cause of death worldwide and is associated with health and socioeconomic burdens. ¹ Epidemiological studies have revealed that the prevalence of stroke has increased during the last decades. ¹ Up to now, medical and interventional approaches have been established for the treatment of acute ischemic stroke (AIS), mainly to preserve the penumbra. ² Although thrombolysis and endovascular thrombectomy are the optimal treatment approaches for patients with large vessel occlusion (LVO),^2–4 incomplete reperfusion rate is high for patients with AIS due to LVO and this is associated with high mortality, disability, and recurrence rates.^4,5

Neuroprotective agents are associated with decreasing ischemic injury through different targets than the ischemic process.^6,7 Findings revealed that neuroprotective agents in stroke might be a promising treatment approach and combining with reperfusion therapies are recommended in patients with AIS. ⁶ Edaravone is an anti-oxidant agent that received first approval for patients with AIS in Japan in 2001. The clinical utility of edaravone has grown and is currently used for other neurologic pathologies such as amyotrophic lateral sclerosis (ALS).^8–10 Chinese and Japanese guidelines recommend edaravone for patients with AIS.^9,10 Oxidative damage and inflammation pose significant challenges to ischemic tissue of patients with AIS. A multitarget strategy with antioxidant and anti-inflammatory effects is urgently needed to improve clinical stroke management. A new neuroprotective agent called edaravone dexborneol has been developed, and comprises of two active ingredients, edaravone and (+)borneol. Studies in animal models have shown that it has synergistic antioxidant and anti-inflammatory effects. Therefore, we performed a systematic review and meta-analysis to assess the effectiveness of edaravone dexborneol in neurological outcomes for patients with AIS.

Methods

Methodology and criteria

We performed a PRISMA guided literature search up to August 21, 2024. A comprehensive search of all studies was conducted using PubMed/Medline, Google Scholar, Web of Science, and Scopus for studies comparing edaravone dexborneol and control in patients with AIS. The MeSH phrases “Edaravone Dexborneol,” “Acute Ischemic Stroke,” “Cerebrovascular Accident,” and “Placebo” were used in conjunction. In addition, we searched all relevant cited references of the included studies to find studies which were not indexed by the mentioned databases. We included double-arm studies published in a scientific journal which evaluated edaravone dexborneol in AIS and excluded case reports, editorials, conference abstracts, studies with less than 40 patients in each arm to enhance the analysis, animal studies, and studies included pediatric population (Supplemental Material).

Two investigators separately evaluated the title and abstracts of articles and one investigator assessed the full-text of articles that were considered to be eligible. One investigator performed manual collection of the required data. The extraction of variables was focused on presenting symptoms and patient characteristics (age, gender proportion, and past medical history), and outcomes (90-day Mortality, Functional Outcome, National Institutes of Health Stroke Scale (NIHSS) score, and Adverse Event). Furthermore, the current meta-analysis not registered in any databases.

Risk of bias assessment

We used Cochrane a revised tool for assessing the risk of bias in randomized trials (RoB2) for randomized clinical trials (RCTs) and Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I) for observational studies.

Statistical analysis

The analysis was conducted using R Software and meta package. Binary outcomes were analyzed and reported through the risk ratio (RR) and 95% confidence interval (CI). The continuous outcomes were analyzed using standardized mean differences (SMD). The heterogeneity of results among the included studies was examined using Cochrane’s Q-test and the I² statistic. The common-effects (fixed-effect) model was used for outcomes without significant heterogeneity, while the random-effects model was used for outcomes with significant heterogeneity. Heterogeneity was assessed through visual inspection of the forest plots and measured using the I² and chi-square (χ2) tests. The χ2 test was employed to determine the presence of significant heterogeneity, while the I² test was utilized to quantify the magnitude of heterogeneity, if present. The interpretation of the I² test followed the recommendations provided by the Cochrane Handbook. ¹¹ For testing statistical heterogeneity, a significance level (α) below 0.1 was considered indicative of significant heterogeneity, as recommended by the Cochrane Handbook. ¹¹ Publication bias was visually assessed with a funnel plot and confirmed by Egger’s test if possible. All p-values were two-sided, and a p-value < 0.05 was considered statistically significant. Also, statistical significance was assessed in alliance with confidence interval range.

Results

Study selection and evaluation

The initial database search yielded a total of 192 records. After conducting a thorough screening of titles and abstracts and the removal of duplicate entries, we refined the list to encompass 12 studies. During a full-text article assessment seven articles failed to meet the inclusion criteria, and five studies included in our quantitative synthesis.^12–16 A comprehensive depiction of the selection process can be found in Figure 1. A total of 2415 patients initially enrolled patients were included in this analysis.

Figure 1.

PRISMA study selection flow chart.

Study characteristics

The fundamental attributes of the included studies are comprehensively outlined in Table 1. In addition, pooled baseline characteristics of included patients are shown in Table 2. Hypertension was the most common medical history (76.7% vs 73.8%), and almost one out of four patients (27.1%) had a history of prior stroke among the two groups. Among TOAST subtypes, large-artery atherosclerosis was the most prevalent while lowest percentage belonged to cardioembolism in the intervention group Table 2.

Table 1.

Characteristics of included studies.

Study	Design	Groups	Treatment	Sample size	Males	Age		Heart disease	Dyslipidemia	Diabetes	Hypertension	Alcohol (prior and current)	Smoking (current and former)	Prior stroke	mRS score 0–1 before onset	Baseline NIHSS
						Mean	SD									Mean	SD
TASTE	RCT	Intervention	Edaravone, 30 mg; (+)-Dexborneol, 7.5 mg	599	404	62.4	10.09	75	44	151	390	66	233	174	599	6.6	2.9
TASTE	RCT	Control	Edaravone, 30 mg	595	407	62.9	10.7	96	41	148	377	57	214	150	595	6.3	2.2
TASTE-SL	RCT	Intervention	Ddaravone, 30 mg; dexborneol, 6 mg	450	309	63.3	10.26	132	217	184	367	N/A	N/A	124	450	7.33	0.7436
TASTE-SL	RCT	Control	Dexborneol, 60 μg (placebo dose for taste)	464	299	64.36	10.63	136	221	187	366	N/A	N/A	143	464	7.33	0.7437
Hu et al., 2023	Retrospective study with randomization	Intervention	Edaravone 10 mg; dexborneol 2.5 mg	69	45	65.8	11	28	N/A	19	53	14	22	11	N/A	10	6.1
Hu et al., 2023	Retrospective study with randomization	Control	Placebo	73	44	66.6	12.7	34	N/A	19	44	15	25	21	N/A	10.6	6.4
Chen et al., 2024	Retrospective	Intervention	Edaravone dexborneol (37.5 mg/12 hours, IV)+antiplatelet or anticoagulation, statin, and control of risk factors	41	26	65.15	10.82	14	N/A	9	27	N/A	N/A	6	N/A	6	3.84
Chen et al., 2024	Retrospective	Control	Antiplatelet or anticoagulation, statin, and control of risk factors	44	30	68.06	11.55	18	N/A	9	30	N/A	N/A	7	N/A	6.3	4.59
Mi et al., 2024	Retrospective study with randomization	Intervention	Edaravone dexborneol combined with tirofiban	40	25	61.9	8.9	N/A	N/A	17	21	N/A	N/A	N/A	N/A	28.1	5.1
Mi et al., 2024	Retrospective study with randomization	Control	Routine treatment combined with tirofiban	40	23	62.5	8.7	N/A	N/A	15	19	N/A	N/A	N/A	N/A	28.3	5.6

Table 2.

Pooled baseline characteristics of included patients.

Characteristics	Edaravone dexborneol group (n = 1199)	Control group (n = 1216)
Patient age, mean (SD), y	63 (23)	59.3 (24.5)
Males, n/N (%)	319/716 (44.5%)	319/743 (42.3%)
Past medical history, n/N (%)
Heart disease	249/1159 (21.5%)	284/1176 (24.1%)
Dyslipidemia	261/1049 (24.9%)	262/1059 (24.7%)
Diabetes	380/1199 (31.7%)	378/1216 (31%)
Hypertension	858/1118 (76.7%)	836/1132 (73.8%)
Alcohol (current and former)	80/668 (12%)	72/668 (10.7%)
Smoking (current and former)	255/668 (38%)	239/668 (35.8%)
Prior stroke	315/1159 (27.1%)	321/1176 (27.3%)
mRS score at admission, mean (SD)	3.9 (1.3)	3.8 (1.2)
NIHSS at admission, mean (SD)	7.8 (6.8)	6.7 (6.8)
TOAST subtype, n/N (%)
Large-artery atherosclerosis	608/1090 (55.8%)	613/1103 (55.6%)
Cardioembolism	44/1090 (4%)	211/1103 (19.1%)
Small-vessel occlusion	376/1090 (34.5%)	220/1103 (20%)
Other	52/1090 (4.7%)	50/1103 (4.5%)
Time from onset to treatment, n/N (%)
≤24 h	574/1049 (54.7%)	579/1059 (54.7%)
>24 h	475/1049 (45.3%)	480/1059 (45.3%)

NIHSS: National Institutes of Health Stroke Scale; TOAST: Trial of Org 10172 in Acute Stroke Treatment.

Functional outcomes

Rates of functional excellence (modified ranking score [mRS] scores 0–1) between intervention group and control group among 2332 patients were compared across four studies.^12–15 The rate of mRS 0–1 at day 90 in edaravone dexborneol group (768 [66.2%] of 1159 vs 660 [56.3%] of 1173, RR 1.17 [95% CI 1.09–1.25]; p < 0.0001) was observed to be statistically significantly higher than the control group Table 3 and Figure 2(A). Notably, there was no heterogeneity among the studies included, with I² = 0.0% and p-value = 0.63.

Table 3.

Efficacy and safety outcomes.

Outcomes	Edaravone dexborneol group	Control group	Effect size (95% CI)	p value
Primary Outcome
mRS score ≤1 on day 90, n/N. (%)	768/1159 (66.2%)	660/1173 (56.3%)	RR 1.18 (1.1–1.26)	< 0.0001
Secondary outcomes
mRS score ≤2 on day 90, n/N. (%)	909/1159 (78.4%)	821/1173 (70%)	RR 1.12 (1.07–1.17)	< 0.0001
mRS score ≤3 on day 90, n/N. (%)	1016/1159 (87.7%)	1000/1173 (85.3%)	RR 1.03 (0.99–1.06)	0.07
Mortality rate on day 90, n/N. (%)	31/1118 (2.8%)	45/1132 (3.97%)	RR 0.71 (0.45 – 1.11)	0.13
NIHSS score ≤1 on day 14, n/N. (%)	187/1035 (18.1%)	195/1044 (18.7%)	RR 0.96 (0.80–1.15)	0.69
NIHSS score ≤1 on day 30, n/N. (%)	382/1035 (36.9%)	355/1044 (34%)	RR 1.08 (0.97 – 1.22)	0.18
NIHSS score ≤1 on day 90, n/N. (%)	553/1035 (53.4%)	524/1044 (50%)	RR 1.06 (0.98–1.15)	0.15
Safety outcomes
Overall adverse events, n/N. (%)	969/1089 (89%)	982/1099 (89.3%)	RR 0.99 (0.97–1.02)	0.75
Serious adverse events, n/N. (%)	110/1118 (9.8%)	123/1132 (10.9%)	RR 0.91 (0.72–1.16)	0.45

Figure 2.

Meta-analysis forest plots for 90-day mRS 0–1 (A), 90-day mRS 0–2 (B), and 90-day mRS 0–3 (C).

The rate of functional independence (mRS scores 0–2) was provided by four studies^12–15 for 2332 patients. The proportion of patients with functional independence at three months was significantly higher in the intervention group (909 [78.4%] of 1159 vs 821 [70%] of 1173, RR 1.12 [95% CI 1.07–1.18]; p < 0.0001) compared with the control group Table 3 and Figure 2(B). There was no significant heterogeneity among studies, with I² = 24% and p-value = 0.27. However, the subgroup analysis for comparison of RCTs^12,13 versus observational studies^14,15 showed no significant difference in functional independence (RR 1.127 vs 1.09 [95% CI 1.07–1.2 vs 0.9–1.3]; p = 0.7).

The proportion of patients achieved functional ambulatory (mRS scores 0–3) was reported by four studies^12–15 included for 2332 patients. The 90-day functional ambulatory rate was insignificantly higher in the intervention group (1016 [87.7%] of 1159 vs 1000 [85.3%] of 1173, RR 1.03 [95% CI 0.99–1.06]; p = 0.07) than in the control groups (Table 3 and Figure 2(C)). There was no observed heterogeneity among the studies, with I² = 0.0% and p-value = 0.59.

Mortality rate at three months

The analysis included 2250 patients from three studies^12,13,15 and compared the 90-day mortality rate of patients who received edaravone dexborneol and placebo. The mortality rates at day 90 were insignificantly higher in patients who received the placebo (31 [2.8%] of 1118 vs 45 [3.97%] of 1132, RR 0.71 [95% CI 0.45–1.11]; p = 0.13) compared with the intervention group (Table 3 and Figure 3(A)). There was no significant heterogeneity among studies, with I² = 8.7% and p-value = 0.33.

Figure 3.

Meta-analysis forest plots for 90-day mortality rate (A), overall adverse events (B), and adverse events (C).

National institutes of health stroke scale (NIHSS)

Data on NIHSS score ≤1 at days 14, 30, and 90 post-randomization were available for 2079 patients across two trials.^12,13 The rates of NIHSS score ≤1 on day 30 (382 [36.9%] of 1035 vs 355 [34%] of 1044, RR 1.08 [95% CI 0.97–1.22]; p = 0.18) and 90 (553 [53.4%] of 1035 vs 524 [50%] of 1044, RR 1.06 [ 95% CI 0.98–1.15]; p = 0.15) were non statistically significantly higher, while NIHSS score ≤1 on days 14 (187 [18.1%] of 1035 vs 195 [18.7%] of 1044, RR 0.96 [95% CI 0.80–1.15]; p = 0.69) was insignificantly lower in the edaravone dexborneol group than in the placebo group (Table 3). There was no significant heterogeneity among all analyses for NIHSS in two trials with I² = 0% and p-value = 0.68.

Adverse events

Results from three studies^12,13,16 involving 2188 patients indicated that intervention group (969 of [89%] 1089 vs 982 [89.3%] of 1099, RR 0.99 [95% CI 0.97–1.02]; p = 0.68) had an insignificant higher rate of overall adverse events than control group with an acceptable heterogeneity with I² = 0% and p-value = 0.9, (Table 3 and Figure 3(B)). On the other hand, data on 2250 patients from three studies^12,13,15 showed that the rates of serious adverse events were insignificantly lower in the intervention group (110 [9.8%] of 1118 vs 123 [10.9%] of 1132, RR 0.91 [95% CI 0.72–1.16]; p = 0.45) compared with the control group with no remarkable heterogeneity with I² = 64.9% and p-value = 0.06, (Table 3 and Figure 3(C)).

Subgroup analysis for the primary outcome

Analyzing the subgroup data shows the benefits of edaravone dexborneol over placebo for treating AIS (Figure 4). No evidence of heterogeneity of treatment effect across the prespecified subgroups was noted with respect to any included variable. The dichotomous variables examined encompassed sex (male and female), age (≥65 and <65), past medical history (hypertension, diabetes, hyperlipidemia, and heart disease), TOAST subtypes (large-artery atherosclerosis, cardioembolism, small-vessel occlusion, and other), and time of randomization (≥24 and <24 h). A further subgroup analysis on comparing RCTs versus observational studies showed no significant difference (p-value = 0.7) and confirmed the previous findings. Additionally, the findings showed that studies used only intravenous edaravone dexborneol demonstrated the better 3-months functional outcomes (RR 1.15 [95% CI 1.1–1.23]; p-value <0.0001) than control group and confirmed the prior our results.

Figure 4.

Forest plot showing treatment effect (RR) for the primary outcome in prespecified subgroups.

Risk of bias

The quality assessment showed a low and moderate risk of bias in three^12–14 and two studies,^15,16 respectively.

Discussion

This systematic review and meta-analysis study on five studies investigated the feasibility and safety of edaravone dexborneol compared to placebo in patients with AIS. Our findings revealed the superiority of edaravone dexborneol compared to placebo in functional outcomes, with no significant difference in mortality rate, adverse events, or serious adverse events. Our findings showed that the use of edaravone dexborneol was associated with significantly higher functional excellence (mRS 0–1), functional independence (mRS 0–2), and functional ambulatory (mRS 0–3) at day 90 than in control. However, current study demonstrated no significant difference between the two groups in the NIHSS ≤1 at days 14, 30, and 90. Edaravone dexborneol demonstrated a safety profile similar to that of the control group. There were no significant differences in adverse events, serious adverse events, and 90-day mortality rates.

Clinical trials on neuroprotection in stroke patients have not been successful in the past decade. Single-pathway strategies did not yield benefits, as multiple pathways of damage in the ischemic cascade progress simultaneously. Combination treatments targeting multiple pathways may offer more advantages.

In a recent preclinical investigation, (+)-borneol, a naturally occurring terpene and bicyclic organic compound, has been found to inhibit the production of inflammatory factors and preserve brain function. This promising discovery has led to the development of edaravone dexborneol, a novel neuroprotective agent that could potentially advance stroke treatment. ¹⁷ (+)-Bornel has been tested in preclinical models and found to have powerful neuroprotective effects in ischemia/reperfusion injury. These effects are achieved through various molecular pathways, including reducing reactive oxygen species generation, inhibiting NO and NO synthase (iNOS [inducible NO synthase]/ NO) pathways, and inhibiting caspase-related apoptosis and inflammatory processes. ¹⁸ Moreover, (+)-Bornel’s high permeability can aid in increasing the permeability of other agents through the blood–brain barrier, which helps them function more effectively. ¹⁹ Pharmacological research has provided conclusive evidence that the combined use of edaravone and dexborneol exhibits a synergistic effect markedly superior to the effects achieved with edaravone alone in safeguarding the brain against ischemic injury. ¹⁷ This robust evidence should instill confidence in the potential of this novel treatment.

The TASTE trial ¹² evaluated 585 patients treated with intravenous infusion of edaravone dexborneol within 48 h after AIS onset, and 580 patients received edaravone. This study remarked that patients in the edaravone dexborneol group showed significantly better 90-day functional outcomes. Hu et al. ¹⁵ studied 142 patients with AIS with LVO randomly allocated to the study group, intravenous infusion of edaravone dexborneol twice a day for 10–14 days, as well as alteplase, and the control group received alteplase only. This study revealed that patients who received edaravone dexborneol had a higher rate of NIHSS≤5 at day 90 than the control group. Also, the mRS score ≤1 at day 90 was significantly higher in the edaravone dexborneol group compared with the control. However, our study did not find a significant difference in NIHSS≤1 between the edaravone dexborneol and control groups.

Alongside the neurological outcomes, Hu et al. ¹⁵ investigated the level of inflammatory cytokines and showed that patients who received edaravone dexborneol had a significantly lower interleukin 6 (IL-6) and C-reactive protein (CRP) than the control group. Moreover, imaging outcomes documented that intracranial hemorrhage was significantly lower in the edaravone dexborneol group than in control.

TASTE-SL trial ¹³ investigated the clinical outcomes of 450 patients treated with sublingual edaravone dexborneol group compared to 464 patients given dexborneol as a placebo. Similarly, after randomization, 90-day good functional outcome was significantly higher in patients of the edaravone dexborneol group than in the placebo group besides the similar safety profile. Furthermore, they ¹³ showed that patients in the intervention group started receiving sublingual edaravone dexborneol within 48 h after the onset of AIS. Moreover, two other studies^12,15 investigated the intravenous administration of edaravone dexborneol, while the other one used a sublingual form. Sublingual agents disintegrate quickly in saliva, leading to faster absorption through the sublingual mucosa. Sublingual edaravone dexborneol has several clinical advantages, such as faster onset of action, lower dose requirement, improved patient compliance, and increased bioavailability, making it a promising treatment option for patients with AIS. Its rapid action and patient-friendly administration method may allow for earlier treatment of patients with AIS in various clinical settings.^9,10,20

All the studies included patients with moderate severity on NIHSS classification, resulting in non-significant secondary outcomes. Subgroup analysis revealed the remarkable role of sex difference on the outcome of good functional outcomes, whereas Xu et al. ¹² showed that females had a greater benefit than males. However, our study showed no significant difference between males and females was evident in subgroup analysis for primary outcomes.

Strengths and limitations

This is the first systematic review and meta-analysis study that investigated the clinical profile of edaravone dexborneol. Four of the studies included in the current review utilized randomization, encompassing two randomized trials and two observational studies with randomization, which increases the robustness of outcomes and decreases the heterogeneity of outcomes. Additionally, the number of patients investigated in the present meta-analysis was relatively high and not significant heterogeneity, increasing the strength of outcome interpretation. However, the number of included studies is low. However, the edaravone dexborneol is still investigational, but our study is a significant step forward and also highlights the need for further research. The number of included studies is low, and all were conducted in China, suggesting the potential influence of genetic differences and limiting the generalizability of our findings. The route of edaravone dexborneol administration was different, whereas four studies^12,14–16 used intravenous edaravone dexborneol, while Fu et al. ¹³ used sublingual form. However, subgroup analysis showed no significant difference and confirmed the previous findings, the different routes of edaravone dexborneol administration also warrant further investigation. Hu et al. ¹⁵ study used intravenous alteplase as baseline treatment for the control and study group and Mi et al. ¹⁶ combined edaravone dexborneol with tirofiban for the intervention group, while Fu et al. ¹³ and Xu et al. ¹² excluded patients who received intravenous or intra-arterial thrombolysis. Therefore, we encourage our future studies to include different routes of administration. Moreover, due to the rapid development of endovascular techniques in patients with AIS, further studies should investigate the effect of edaravone dexborneol adjunct to endovascular therapies. Also, studies can consider patients with higher NIHSS scores to signal the outcomes of the edaravone dexborneol and control groups.

Conclusion

The present systematic review and meta-analysis study not only demonstrated the brain cytoprotective effect of edaravone dexborneol but also revealed significant finding-patients treated with edaravone dexborneol within 48 hours after the onset of AIS had improved functional outcomes, regardless of the route of administration. This finding, irrespective of the type of administration, is a crucial advancement in our understanding of the clinical profile of edaravone dexborneol.

ORCID iDs

Ali Mortezaei https://orcid.org/0000-0002-7217-3264

Mohamed Emara https://orcid.org/0000-0003-1331-6365

Mohammad Amin Habibi https://orcid.org/0000-0001-7600-6925

Adam A Dmytriw https://orcid.org/0000-0003-0131-5699