Endovascular treatment of acute ischaemic stroke after 6 h of symptom onset: safe but is it efficacious?

Approximately 20% of patients with acute ischaemic stroke present to the hospital between 6 and 24 h after symptom onset [1]. Due to the availability of new thrombectomy devices and advanced neuroimaging techniques, thrombolysis after the first 6 h of symptom onset (thrombolysis for delayed arrival) is being evaluated for such patients with ischaemic stroke [2]. In this issue, Jung et al. [3] report a comparison between 654 acute ischaemic stroke patients who were treated before 6 h and 205 patients treated after 6 h or an unknown time interval from symptom onset. Endovascular treatment was performed in all patients using a combination of pharmacological thrombolytics and mechanical thrombectomy. There was no significant difference in the rate of intracranial hemorrhage (ICH) or favorable clinical outcome [by modified Rankin scale (mRS) at 3 months] between the two groups after adjusting for potential confounders. Two previous studies also demonstrated that endovascular treatment was associated with acceptable rates of ICH ( 9%) in patients treated after 6 h of symptom onset and underwent advanced neuroimaging [4,5]. Jung et al. [3] observed a symptomatic ICH rate of 4% among those treated after 6 h of symptom onset. The authors conclude that selected ischaemic stroke patients who wake up with a stroke or who have symptoms for more than 6 h or for an unknown time can be treated safely with endovascular treatment. Despite encouraging results demonstrating safety, concerns remain regarding efficacy, and have been highlighted by the results of Desmoteplase in Acute Ischemic Stroke Trial (DIAS)-2 study. The study did not observe any clinical benefit with i.v. desmoteplase (compared with placebo) administered within 3–9 h after the onset of ischaemic stroke [6]. A total of 117 (63%) of the 186 patients had received i.v. desmoteplase after 6 h of symptom onset. A case–control study compared 52 patients who underwent endovascular treatment after 6 h of symptom onset with placebotreated patients matched by baseline National Institutes of Health Stroke Scale (NIHSS) score and non-lacunar anterior circulation location from the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) [7]. After adjustment for gender, time interval between symptom onset to treatment, hypertension, hyperlipidemia and history of cigarette smoking, the rate of neurological improvement at 24 h and favorable outcome at 7 days or discharge were similar between patients undergoing endovascular treatment and control patients. The low rate of symptomatic ICH (6%) again confirmed the safety of the endovascular treatment in these patients. In the study by Jung et al. [3], the rate of favorable outcome (mRS 0–2) was significantly higher among patients treated within 6 h compared with those treated after 6 h (46% vs. 35%, P = 0.04) in unadjusted analysis. Therefore, the current evidence remains inconclusive regarding efficacy of thrombolysis for delayed arrival. The lack of effectiveness needs to be considered based on the exponential loss of clinical benefit of i.v. thrombolysis within a short time interval between symptom onset and treatment [8]. In a pooled analysis of 2775 patients randomly allocated to i.v. thrombolysis or placebo within 360 min of symptom onset, the odds of a favorable 3-month outcome with i.v. thrombolysis were not different compared with placebo after 271 min [9]. Such concerns are further highlighted due to occurrence of futile recanalization following endovascular treatment [10]. In one study, 49% of the patients treated with endovascular treatment have unfavorable outcome (mRS 3) at 1 month despite complete angiographic recanalization. There has been a sixfold increase in patients who underwent endovascular treatment for acute ischaemic stroke in USA [11]; however, the rates of disability continue to be high following endovascular treatment mandating evidence-based application of these procedures. The recent studies including that by Jung et al. [3] support instituting large multicenter prospective registries to develop and validate criteria for patient selection and interpretation of advanced neuroimaging tests, and provide estimates of the rate of favorable outcomes at 3–6 months in patients treated after 6 h of symptom onset. The definitive answer will require a randomized trial that is poised to provide the answer regarding the efficacy of endovascular treatment in patients treated after 6 h of symptom onset after necessary pilot data have been acquired for appropriate trial design.