The Reperfusion Paradox and the Need for Multi-Target Cytoprotection
Acute ischaemic stroke (AIS) remains a leading cause of disability and mortality worldwide. While endovascular thrombectomy (EVT) has revolutionized the management of large vessel occlusion (LVO) by achieving high rates of recanalization, a significant proportion of patients fail to achieve functional independence despite successful technical procedures. This phenomenon, often termed futile recanalization, is partly attributed to ischemia-reperfusion injury (IRI). During reperfusion, the sudden influx of oxygenated blood triggers a cascade of oxidative stress, neuroinflammation, and calcium overload, leading to further neuronal death.
Traditional neuroprotective agents focusing on single pathways have largely failed in clinical trials. However, edaravone dexborneol represents a novel approach by combining a free-radical scavenger (edaravone) with an anti-inflammatory agent ((+)-dexborneol). This multi-target mechanism aims to mitigate the multifaceted pathways of IRI. The TASTE-2 trial was designed to evaluate whether this cytoprotectant could enhance the benefits of EVT in a real-world clinical setting.
Study Design and Methodology
TASTE-2 was a multicentre, double-blind, randomised, placebo-controlled trial conducted across 106 hospitals in China. The study enrolled 1362 patients between March 2022 and May 2023. Eligible participants were adults (18-80 years) diagnosed with AIS within 24 hours of symptom onset. Specifically, patients required a National Institutes of Health Stroke Scale (NIHSS) score between 6 and 25, an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 6-10, and confirmed LVO in the anterior circulation with a planned EVT.
Intervention Protocols
Participants were randomized in a 1:1 ratio to receive either edaravone dexborneol (37.5 mg; comprising 30 mg edaravone and 7.5 mg dexborneol) or a matching placebo. The initial dose was administered intravenously before the start of the EVT procedure. Following the initial dose, the regimen was continued twice daily for a period of 10 to 14 days. The primary efficacy endpoint was functional independence at 90 days, defined as a modified Rankin Scale (mRS) score of 0-2.
Key Findings: Efficacy and Functional Outcomes
In the intention-to-treat analysis involving 1360 patients, the edaravone dexborneol group demonstrated a superior rate of functional independence compared to the placebo group. At the 90-day follow-up, 55.0% (379/689) of patients in the intervention group achieved an mRS score of 0-2, compared to 49.6% (333/671) in the placebo group.
This represented a risk ratio (RR) of 1.11 (95% confidence interval [CI] 1.00 to 1.23; P=0.05) and a risk difference of 5.4% (95% CI 0.1% to 10.7%). While the P-value sits exactly at the traditional threshold for statistical significance, the clinical implication of a 5.4% absolute increase in functional independence is substantial in the context of acute stroke care.
The Critical Role of Clinical-Radiological Mismatch
One of the most compelling findings of TASTE-2 emerged from the pre-specified subgroup analysis. Patients presenting with a clinical-radiological mismatch at admission—defined as high clinical severity (NIHSS ≥10) despite relatively preserved imaging (ASPECTS ≥9), or NIHSS ≥20 with ASPECTS ≥7—showed a much more pronounced response to the therapy.
In this subgroup, 55.5% of patients treated with edaravone dexborneol achieved functional independence, compared to only 42.9% in the placebo group. This resulted in a risk ratio of 1.29 (95% CI 1.10 to 1.52) and a risk difference of 13.0% (95% CI 5.6% to 20.3%). The P for interaction was 0.003, suggesting that the presence of salvageable brain tissue, indicated by mismatch, may be a primary driver of the drug’s efficacy.
Safety Profile and Serious Adverse Events
Safety is a paramount concern when introducing adjunctive therapies in acute stroke. TASTE-2 reported no significant increase in serious adverse events (SAEs) with edaravone dexborneol. The rate of SAEs was 27.2% in the intervention group and 25.7% in the placebo group (RR 1.06, 95% CI 0.89 to 1.26; P=0.53). These events typically included post-stroke complications such as pneumonia, recurrent stroke, or symptomatic intracranial hemorrhage, which were balanced between the two arms. This data supports the tolerability of the drug when administered alongside the intense physiological stress of mechanical thrombectomy.
Expert Commentary and Clinical Implications
Biological Plausibility and Mechanism
The success of edaravone dexborneol in TASTE-2, following the positive results of the earlier TASTE trial (which focused on AIS patients receiving only medical management), reinforces the importance of multi-target neuroprotection. Edaravone acts as a potent scavenger of hydroxyl radicals and inhibits lipid peroxidation, thereby protecting cell membranes from oxidative damage. Dexborneol complements this by inhibiting the expression of pro-inflammatory cytokines such as TNF-α and IL-1β, and modulating the NF-κB signaling pathway. Together, they address the dual threats of oxidative stress and inflammation that characterize the reperfusion phase.
Interpreting the Mismatch Data
The pronounced benefit in the mismatch group suggests that edaravone dexborneol is most effective when there is a significant volume of ‘penumbra’ or tissue at risk. In patients where the clinical deficit far outweighs the established infarct size on imaging, cytoprotectants may provide the necessary window of stability to allow the brain to recover after the vessel is reopened. This aligns with modern precision medicine trends in stroke, where imaging markers guide therapeutic intensity.
Study Limitations
While the results are promising, several limitations must be considered. First, the study was conducted entirely within the Chinese healthcare system, which may limit generalizability to other populations with different genetic backgrounds or stroke etiologies. Second, the primary endpoint reached statistical significance with a P-value of 0.05, which some may interpret as borderline. However, the consistency of the secondary analyses and the strength of the subgroup findings provide robust support for the overall conclusion.
Conclusion
The TASTE-2 trial provides high-quality evidence that edaravone dexborneol is a safe and effective adjunctive therapy for AIS patients undergoing endovascular thrombectomy. By improving the rates of functional independence at 90 days, particularly in those with clinical-radiological mismatch, this multi-target cytoprotectant addresses a critical unmet need in stroke reperfusion therapy. These findings suggest that edaravone dexborneol should be considered as part of the pharmacological armamentarium for anterior circulation LVO stroke patients receiving EVT.
Funding and Registration
This trial was supported by grants from the National Key R&D Program of China and the Beijing Municipal Science & Technology Commission. The trial is registered at ClinicalTrials.gov (NCT05249920).
References
1. Wang C, Gu H, Huo X, et al. Edaravone dexborneol versus placebo on functional outcomes in patients with acute ischaemic stroke undergoing endovascular thrombectomy (TASTE-2): randomised controlled trial. BMJ. 2026;392:e086850.
2. Xu J, Wang A, Meng X, et al. Edaravone dexborneol versus edaravone alone for the treatment of acute ischemic stroke (TASTE): a randomized, double-blind, comparative phase III clinical trial. Stroke. 2021;52(3):772-780.
3. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731.