Endovascular treatment (EVT) alone for acute ischemic stroke was neither superior nor noninferior to treatment with intravenous alteplase before EVT in terms of 90-day disability outcome, the randomized MR CLEAN-NO IV trial found.
For the primary outcome of modified Rankin scale scores 90 days after stroke, median scores for EVT alone or EVT with alteplase were 3 and 2, respectively, with an adjusted common odds ratio of 0.84 (95% CI 0.62-1.15, P=0.28), reported Yvo Roos, PhD, of Amsterdam UMC in the Netherlands, and co-authors in The New England Journal of Medicine.
The researchers specified a margin of 0.8 for the lower boundary of the 95% confidence interval for the common odds ratio to assess the superiority of EVT alone over alteplase with EVT, as well as noninferiority.
“In this European trial of anterior-circulation stroke, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with respect to functional outcomes at 90 days in patients presenting directly to centers capable of providing both treatments,” Roos and colleagues wrote.
The group randomized 539 patients to receive EVT alone (n=273) or EVT preceded by alteplase (n=266; standard of care) between January 2018 and October 2020. “We allowed for rescue intravenous alteplase in the EVT-alone group if reperfusion did not occur; this was administered to 19 patients in our trial,” the authors noted.
All participants had large vessel occlusion acute ischemic stroke and were eligible for EVT and alteplase within 4.5 hours of symptom onset.
The median age of the cohort was 71 (72 in the EVT alone group and 69 in the combined therapy group) and 56.6% were men (59% in the EVT alone group and 54.1% in the combined therapy group). Atrial fibrillation was present in 31.5% of the EVT alone group and 23.7% of the combined therapy group. Median NIHSS score was 16 for both groups.
Location of the obstruction for EVT alone versus combined therapy, respectively, was intracranial internal carotid artery (ICA) in 1.5% versus 0%; terminal ICA in 23.5% versus 18.8%; M1 ICA segment in 57.4% versus 65.4%; and proximal M2 ICA segment in 16.5% versus 15.0%.
Successful recanalization after 24 hours was seen in 78.2% of the EVT-only group and 84.7% of the combined treatment group (OR 0.82, 95% CI 0.52-1.28).
Death within 90 days for the EVT-only group was 20.5% compared to 15.8% for the EVT-alteplase group (adjusted OR 1.39, 95% CI 0.84-2.30). Symptomatic intracerebral hemorrhage was seen in 5.9% for EVT alone and 5.3% when preceded by alteplase (adjusted OR 1.30, 95% CI 0.60-2.81).
“The mortality was slightly higher in the EVT-alone group but did not differ substantially between the two groups, and the incidence of symptomatic intracerebral hemorrhage was similar in the two groups,” Roos and colleagues wrote. “The incidence of any intracranial bleeding was approximately 35% in both groups.”
In an accompanying editorial, Alfonso Ciccone, MD, of the Azienda Socio Sanitaria Territoriale di Mantova in Italy, pointed to mixed evidence regarding EVT alone or combined with alteplase.
MR CLEAN-NO IV is the fourth trial to test whether thrombolysis can be omitted before thrombectomy for stroke, Ciccone noted. A 2020 randomized controlled trial (DIRECT-MT) in China reported EVT alone was noninferior compared with EVT preceded by alteplase on a 90-day modified Rankin scale outcome. A 2021 trial (DEVT) in China also reported noninferiority, but a 2021 trial in Japan (SKIP) failed to demonstrate noninferiority.
“The fundamental question is whether the finding of noninferiority of thrombectomy alone in some trials but not in others is enough to omit intravenous thrombolysis before thrombectomy,” Ciccone wrote.
“To decide on a noninferiority margin for thrombectomy alone, investigators in MR CLEAN–NO IV had to estimate a priori the worst acceptable outcome with thrombectomy alone as compared with the expected outcome of combined treatment,” he added. “This margin should have incorporated advantages of thrombectomy alone in terms of more rapid treatment, greater safety, easier administration, and lower cost.”
“Yet alteplase before thrombectomy has not increased mortality or symptomatic intracranial hemorrhage, it is easy to administer, and its costs are negligible, especially as compared with those of thrombectomy,” Ciccone continued. “Therefore, the absence of a finding of superiority of thrombectomy alone in MR CLEAN–NO IV (superiority was not tested in the other trials) supports not prematurely abandoning thrombolysis before thrombectomy for stroke.”
“The incidence of functional independence and endovascular reperfusion grades in both groups in our trial were similar to those in the DIRECT-MT, DEVT, and SKIP trials,” Roos and co-authors noted.
Limitations of MR CLEAN-NO IV include a cohort consisting only of patients presenting directly to an EVT-capable center. In addition, treatment groups differed with respect to atrial fibrillation, age, and occlusion location, with more a unfavorable distribution in the EVT alone group, the researchers acknowledged.
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Endovascular treatment (EVT) alone for acute ischemic stroke was neither superior nor noninferior to treatment with intravenous alteplase before EVT in terms of 90-day disability, the randomized MR CLEAN-NO IV trial found.
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MR CLEAN-NO IV is the fourth trial to test whether thrombolysis can be omitted before thrombectomy for stroke.
Paul Smyth, MD, Contributing Writer, BreakingMED™
This research was supported by the Collaboration for New Treatments of Acute Stroke (CONTRAST) consortium which is supported by the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation; the Brain Foundation Netherlands; the Ministry of Economic Affairs by means of the PPP Allowance made available by Top Sector Life Sciences and Health to stimulate public–private partnerships; and unrestricted funding by Stryker, Medtronic, and Cerenovus.
Roos reports owning stock in Nico-Lab.
Ciccone reports personal fees from Alexion Pharma Italy.
Cat ID: 306
Topic ID: 74,306,730,306,308,745,8,914,130,38,748,192,925
