MR CLEAN-LATE results presented at the World Stroke Congress 2022
The MR CLEAN-LATE prospective, randomized study of over 500 patients with acute ischemic stroke showed that endovascular thrombectomy (EVT) provides a significant benefit on functional outcomes after 90 days, compared to no EVT in the 6–24-hour time window. Trial inclusion was based on the presence of collaterals and thus, has demonstrated that collateral flow on CT angiography is an adequate criterion for patient selection in the late time window.
Research elucidates that acute ischemic stroke (AIS) is a major cause of mortality and lasting disability globally, with large vessel occlusions (LVOs) being responsible for an estimated 24% to 46% of all AIS cases.1 Endovascular thrombectomy (EVT) has been proven as a highly effective treatment for LVO patients and has quickly become the standard of care. However, guidelines from the European Stroke Organization (ESO) and the American Heart Association/American Stroke Association (AHA/ASA) advise that EVT should be utilized within 6 hours of symptom onset.2,3 In contrast, recent randomized controlled trials (RCT) suggest that EVT could be beneficial to LVO patients between 6-24 hours after symptom onset, although the inclusion criteria for patients were highly specific and required advanced imaging, limiting widespread implementation. Considering this, the MR CLEAN-LATE trial uses wide inclusion criteria to investigate the safety and efficacy of using EVT to treat the “late” AIS patient group, with specific focus on the presence of collaterals on CT angiography (CTA) as a more pragmatic imaging criterion.4
EVT is a long-standing treatment option for LVO AIS patients. The first break through trial showing positive results of mechanical thrombectomy (MT) was the MR CLEAN trial in 2015, which found that AIS patients demonstrated better functional recovery when MT plus usual care was administered within 6 hours after stroke onset, compared to usual care alone.5 Furthermore, collateral status on CTA showed an interaction with treatment effect while ASPECTS score did not, with patients with higher collateral grades showing larger treatment effects. Launched in 2021, the MR CLEAN-LATE trial was established to build on the results of the MR CLEAN study by investigating whether the presence of collaterals could be a pragmatic alternative for selecting patients with a potential treatment benefit beyond the 6-hour time window.4
MR CLEAN-LATE was a multicenter, randomized, open-label trial with blinded endpoint evaluation (PROBE design). In total, 535 patients were randomized into either the treatment group, where they received EVT and best medical treatment, or the control group, where patients received best medical treatment only. Inclusion criteria for patients required the presence of any collateral flow on CTA (poor, moderate, or good), with a restriction of 100 patients included with poor collateral flow.4 Based on the success of the earlier DAWN and DEFUSE 3 trials, patients were excluded from MR CLEAN-LATE if they presented with a small infarct core (< 25ml) on baseline imaging and had moderate to severe neurological deficit at presentation, as the treatment benefit of EVT beyond 6 hours has already been demonstrated.6,7 The primary endpoint of the trial was functional outcome at 90 days, evaluated by the modified Rankin Scale (mRS). Furthermore, secondary endpoints included clinical stroke severity at 24 hours and 5–7 days assessed by the National Institutes of Health Stroke Scale (NIHSS), symptomatic intracranial hemorrhage occurrence, recanalization at 24 hours, follow-up infarct size, and mortality at 90 days.4
Results from the MR CLEAN-LATE trial demonstrate that patients in the intervention group were approximately 1.7 times more likely to achieve a better functional outcome after 90 days than the control group (adjusted common odd ratio 1.68; 95% CI 1.21-2.33).8 Higher mortality was observed in the control group, although this was not significant. There was a significant increase in symptomatic intracranial hemorrhage rate in the intervention group (6.7% vs. 1.6% in the control arm), which is similar to the results of the DAWN trial (6%) and the DEFUSE 3 trial (7%).
Regarding secondary outcomes, the NIHSS was 17% better after 24 hours and 27% better at 5-7 days, in the intervention group.8 The infarct size at follow-up was 32% smaller in the intervention group than the control group, and the intervention group showed 29% higher recanalization at 24h. The researchers observed that patients with tandem occlusion had a higher effect estimate than those who did not (p > 0.01). Furthermore, there was a treatment interaction with occlusion location, showing that the more distal M2 and M3 occlusions had lower treatment benefit compared to the other occlusion sites. There was no significant statistical interaction with collateral grades (p=0.10).8
Principal investigator, Wim H. van Zwam, MD, Maastricht University Medical Center, Maastricht, The Netherlands, spoke with VJNeurology about the findings of MR CLEAN-LATE, as presented at the World Stroke Congress 2022.
“The easiest way to select patients for treatment in the late window for EVT is by looking at their collaterals because we know these patients will benefit.”
In conclusion, the MR CLEAN-LATE trial evidenced that EVT for AIS in the anterior circulation 6-24 hours after symptom onset or last seen well is safe and effective after selection based on the presence of collateral flow on CTA. The implications of these findings are important since selection based on collateral flow has identified an additional group of patients eligible for late-window EVT, in addition to patients eligible based on the DAWN/DEFUSE 3 perfusion and clinical criteria. The researchers recommend implementation of collateral selection in routine clinical practice because it is time-efficient and a low complexity assessment. In case of absent collaterals, or doubt, CT perfusion can be utilized.
Written by Annabel Tordoff
- Rennert RC, Wali AR, Steinberg JA, et al. Epidemiology, Natural History, and Clinical Presentation of Large Vessel Ischemic Stroke. Neurosurgery. Jul 2019; 85(Suppl 1): S4–S8.
- Turc G, Bhogal P, Fischer U, et al. European Stroke Organisation (ESO) – European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischemic Stroke. J Neurointerv Surg. Feb 2019;neurintsurg-2018-014569.
- Powers WJ, Rabinstein AA, Ackerson T, et al. American Heart Association Stroke Council. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. Mar 2018; 49(3):e46-e110.
- Pirson FAVA, Hinsenveld WH, Goldhoorn RB, et al. MR CLEAN-LATE, a multicenter randomized clinical trial of endovascular treatment of acute ischemic stroke in The Netherlands for late arrivals: study protocol for a randomized controlled trial. Trials. Feb 2021; 22(1):160.
- Berkhemer O, Beumer F, van den Berg L, et al. A randomized trial of intraarterial treatment for acute ischemic stroke (MR CLEAN). NEJM. Jan 2015; 372(1):11-20.
- Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. NEJM. Jan 2018; 378(1):11-21.
- Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. NEJM. Feb 2018; 378(8):708-718.
- Olthuis SGH. MR CLEAN-LATE: A Randomized Trial of Endovascular Treatment of Ischemic Stroke for Late Arrivals. [Conference Presentation]. World Stroke Congress 2022, 26-29 Oct 2022.