For the first time, the Multicentre randomised clinical trial of endovascular treatment for acute ischaemic stroke in the Netherlands (MR CLEAN) has shown better outcomes in favour of intervention in patients with acute ischaemic stroke.
The long-awaited study was released online by the New England Journal of Medicine (NEJM) yesterday. MR CLEAN, a pragmatic, phase 3 clinical trial, compared intra-arterial treatment (intra-arterial thrombolysis, mechanical treatment, or both) plus usual care (which could include intravenous administration of alteplase) with usual care alone (control group) in patients with acute ischaemic stroke and a proximal intracranial arterial occlusion of the anterior circulation that was confirmed on vessel imaging.
Study authors, Diederik Dippel et al, report that between December 2010 and March 2014, 500 patients with acute ischaemic stroke caused by an intracranial occlusion in the anterior circulation artery were randomised in 16 Dutch centres. Initiation of intra-arterial treatment had to be possible within six hours after stroke onset. Eligible patients had an occlusion of the distal intracranial carotid artery (M1 or M2), or anterior cerebral artery (A1 0r A2), established with computed tomography angiography (CTA), magnetic resonance angiography (MRA), or digital-subtraction angiography (DSA), and a score of 2 or higher on the National Institutes of Health Stroke Scale (NIHSS). All patients underwent clinical assessment at baseline, after 24 hours, and at five to seven days or at discharge if earlier.
According to the study, 233 patients (46.6%) were assigned to the intervention group and 267 patients (53.4%) were assigned to the control group. Actual intra-arterial therapy (with or without mechanical thrombectomy) was performed in 196 of the 233 patients in the intervention group. Mechanical treatment was performed in 195 of the 233 patients. Retrievable stents were used in 190 patients (81.5%), and other devices were used in five patients. Additional intra-arterial thrombolytic agents were given to 24 patients. Intra-arterial thrombolytic agents were used as monotherapy in one of the 233 patients. No intervention was given in 37 patients.
The authors report that the results show a shift in the distribution of the primary-outcome scores in favour of the intervention. “The shift toward better outcomes in favour of the intervention was consistent for all categories of the modified Rankin scale, except death. The absolute between-group difference in the proportion of patients who were functionally independent (modified Rankin score, 0 to 2) was 13.5 percentage points (95% CI, 5.9 to 21.2) in favour of the intervention (32.6% vs. 19.1%), with an adjusted odds ratio of 2.16 (95% CI, 1.39 to 3.38).”
In terms of secondary outcomes, the results show that intervention was also more favourable: “The NIHSS score after five to seven days was, on average, 2.9 points lower in the intervention group than the control group.” Additionally, an absence of residual occlusion at the target site was more common in the intervention group than in the control group.”
Dippel et al conclude, “Our results show that patients with acute ischaemic stroke caused by a proximal intracranial arterial occlusion of the anterior circulation have a benefit with respect to functional recovery when intra-arterial treatment is administered within six hours after stroke onset. This treatment leads to a clinically significant increase in functional independence in daily life by three months, without an increase in mortality. Our findings stand in clear distinction to those of recent randomised, controlled trials that failed to show a benefit of intra-arterial treatment.”
Comparing this study to the Interventional management of stroke III trial (IMS III), the authors say that the cohort is similar to IMS III, in which intravenous alteplase alone was compared with intravenous altepase plus intra-arterial treatment. They say, “Approximately 90% of patients in each treatment group of MR CLEAN received intravenous alteplase; however, in the IMS III trial, patients had to be enrolled and undergo randomisation within 40 minutes after the start of intravenous alteplase. This requirement may have led to the inclusion of more patients who had a favourable response to intravenous alteplase than in MR CLEAN, which had a median time from the start of intravenous alteplase to randomisation that was considerably longer than the maximum time in the IMS III trial. It is likely that intra-arterial treatment will not alter the natural history of acute ischaemic stroke in the absence of a proximal arterial occlusion…. Our study benefited from the widespread availability of retrievable stents, which were used in 82% of the patients in the intervention group. These devices were recently shown to be superior to the first-generation Merci device for both revascularisation and clinical outcomes.”
Commenting on the results, Dippel told NeuroNews that going forward, “the challenge for the future will be to identify all patients who are eligible for this treatment: those with an occlusion who can be treated within six hours, and transfer them quickly to an intervention centre.”