Futile reperfusion (poor functional status despite successful reperfusion) was observed in up to 67% of patients enrolled in recent endovascular treatment (EVT) clinical trials. We investigated the impact of baseline stroke severity on both futile reperfusion and therapeutic benefit of successful EVT. Using a prospective multicenter stroke registry, we identified consecutive ischemic stroke patients with anterior circulation large artery occlusion, who were reperfused successfully by EVT (Thrombolysis in Cerebral Infarction grade 2b–3). The rate of futile reperfusion was assessed across the initial National Institutes of Health Stroke Scale (NIHSS) scores. The frequency of poor outcomes (modified Rankin scale [mRS] 3–6) according to NIHSS scores was compared between patients revascularized successfully by EVT and those who did not receive EVT, after standardizing for age. Among 21,591 patients with ischemic stroke, 972 (4.5%) received EVT within 12 h of onset, including 440 who met study eligibility criteria. Futile reperfusion was observed in 226 of the 440 study-eligible patients (51.4%) and was associated with stroke severity: 20.9% in NIHSS scores ≤5, 34.6% in 6–10, 58.9% in 11–20, and 63.8% in > 20 (p < 0.001). Nonetheless, the therapeutic benefit of EVT also increased with increasing stroke severity (p for interaction < 0.001): 0.1% in NIHSS ≤5, 18.6% in 6–10, 28.7% in 11–20, and 34.3% in > 20. EVT is more beneficial with increasing stroke severity, although futile reperfusion also increases with higher stroke severity.

Background: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy. Methods: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received—placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0–2 at 12 weeks. Results: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P =0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92–2.60) between the placebo and low-dose groups and 1.61 (0.94–2.76) between the placebo and high-dose groups. No serious adverse events were reported. Conclusions: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0–2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT02831088.

Background: The beneficial effects of endovascular therapy (EVT) in acute ischemic stroke have been demonstrated in recent clinical trials using new-generation thrombectomy devices. However, the comparative effectiveness and safety of preceding intravenous thrombolysis (IVT) in this population has rarely been evaluated. Methods: From a prospective multicenter stroke registry database in Korea, we identified patients with acute ischemic stroke who were treated with EVT within 8 h of onset and admitted to 14 participating centers during 2008-2013. The primary outcome was a modified Rankin Scale (mRS) score at 3 months. Major secondary outcomes were successful recanalization defined as a modified Treatment in Cerebral Ischemia score of 2b-3, functional independence (mRS score 0-2), mortality at 3 months, and symptomatic hemorrhagic transformation (SHT) during hospitalization. Multivariable logistic regression analyses using generalized linear mixed models were performed to estimate the adjusted odds ratios (ORs) of preceding IVT. Results: Of the 639 patients (male, 61%; age 69 ± 12; National Institutes of Health Stroke Scale score of 15 [11-19]) who met the eligibility criteria, 458 received preceding IVT. These patients showed lower mRS scores (adjusted common OR, 1.38 [95% CI 0.98-1.96]). Preceding IVT was associated with successful recanalization (1.96 [1.23-3.11]) and reduced 3-month mortality (0.58 [0.35-0.97]) but not with SHT (0.96 [0.48-1.93]). Conclusion: In patients treated with EVT within 8 of acute ischemic stroke onset, preceding IVT may enhance survival and successful recanalization without additional risk of SHT, and mitigate disability at 3 months.

The potential of neuroprotective agents should be revisited in the era of endovascular thrombectomy (EVT) for acute large-artery occlusion because their preclinical effects have been optimized for ischemia and reperfusion injury. Neu2000, a derivative of sulfasalazine, is a multi-target neuroprotectant. It selectively blocks N-methyl-D-aspartate receptors and scavenges for free radicals. This trial aimed to determine whether neuroprotectant administration before EVT is safe and leads to a more favorable outcome. This trial is a phase-II, multicenter, three-arm, randomized, double-blinded, placebo-controlled, blinded-endpoint drug trial that enrolled participants aged ≥ 19 years undergoing an EVT attempt less than 8 h from symptom onset, with baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 8, Alberta Stroke Program Early CT score ≥ 6, evidence of large-artery occlusion, and at least moderate collaterals on computed tomography angiography. EVT-attempted patients are randomized into control, low-dose (2.75 g), and high-dose (5.25 g) Neu2000KWL over 5 days. Seventy participants per group are enrolled for 90% power, assuming that the treatment group has a 28.4% higher proportion of participants with functional independence than the placebo group. The primary outcome, based on intention-to-treat criteria is the improvement of modified Rankin Scale (mRS) scores at 3 months using a dichotomized model. Safety outcomes include symptomatic intracranial hemorrhage within 5 days. Secondary outcomes are distributional change of mRS, mean differences in NIHSS score, proportion of NIHSS score 0–2, and Barthel Index > 90 at 1 and 4 weeks, and 3 months. The trial results may provide information on new therapeutic options as multi-target neuroprotection might mitigate reperfusion injury in patients with acute ischemic stroke before EVT. ClinicalTrials.gov, ID: NCT02831088 . Registered on 13 July 2016.

BACKGROUND: Early neurological deterioration (END) is a frequent complication of acute ischemic stroke. Although END worsens clinical outcomes, standardized treatment strategies remain undefined, resulting in variability in clinical practice. This study examines real-world treatment patterns for END and compares the effects of different strategies on neurological and functional outcomes. METHODS: This study analyzed data from a nationwide, prospective, multicenter stroke registry in South Korea, including patients with noncardioembolic stroke who developed END due to stroke progression between January 2019 and August 2024. END was defined as new or worsening neurological symptoms meeting National Institutes of Health Stroke Scale criteria (≥2-point total or ≥1 point in consciousness or motor subscores) with radiological confirmation. Patients were classified into conservative management, antithrombotics change, and induced hypertension (iHTN). The primary outcomes were neurological improvement, defined as a ≥2-point reduction in the National Institutes of Health Stroke Scale score, and 3-month functional outcome measured by modified Rankin Scale ordinal shift. Secondary outcomes included good functional recovery (modified Rankin Scale score, 0–2) and composite vascular events (death, stroke, and myocardial infarction). Multivariable analyses adjusted for age, sex, prestroke modified Rankin Scale, initial National Institutes of Health Stroke Scale score, vascular risk factors, the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification, acute thrombolysis, and laboratory covariates. RESULTS: Among 3067 patients with END due to stroke progression, 1840 (60.0%) received conservative management, 747 (24.4%) underwent antithrombotic changes, and 480 (15.7%) were treated with iHTN. Neurological improvement occurred in 34.2% of patients, with the highest in the iHTN group (41.5%) compared with the conservative (32.2%) and antithrombotics change groups (34.4%; P <0.001). In adjusted analyses, iHTN increased the odds of neurological improvement (adjusted odds ratio, 1.55 [95% CI, 1.25–1.92]) and a favorable 3-month modified Rankin Scale shift (adjusted odds ratio, 1.24 95% CI, 1.03–1.48]) compared with conservative management, particularly in patients with large artery atherosclerosis. Antithrombotics change showed no significant association with neurological or functional recovery. CONCLUSIONS: In patients with noncardioembolic ischemic stroke who developed END due to stroke progression, iHTN was associated with favorable clinical outcomes.

Kim DY, et al. J Korean Med Sci. 2024 Aug;39(34):e278. https://doi.org/10.3346/jkms.2024.39.e278