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MR CLEAN

A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke

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Year of Publication: 2015

Authors: Olvert A. Berkhemer, Puck S. S. Fransen, Debbie Beumer, ..., for the MR CLEAN Investigators

Journal: New England Journal of Medicine

Citation: Berkhemer OA, Fransen PSS, Beumer D, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med. 2015;372(1):11–20.

Link: https://doi.org/10.1056/NEJMoa1411587

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true

Clinical Question

Does intraarterial treatment (intraarterial thrombolysis, mechanical treatment, or both) improve outcomes in patients with acute ischemic stroke caused by proximal intracranial occlusion in the anterior circulation?

Bottom Line

Intraarterial treatment (intraarterial thrombolysis, mechanical treatment, or both) with modern devices significantly improved functional outcomes in patients with anterior circulation proximal intracranial occlusion compared to usual care alone.

Major Points

  • First positive RCT demonstrating benefit of intraarterial treatment (predominantly retrievable-stent thrombectomy) for acute ischemic stroke due to proximal anterior circulation occlusion — published December 2014, catalyzed 4 subsequent positive trials (ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT).
  • Eligible vessels: proximal anterior circulation occlusion — distal intracranial ICA, MCA M1 or M2 segment, or ACA A1 or A2 segment — confirmed on CTA, MRA, or DSA.
  • 502 patients underwent randomization at 16 Dutch centers; 500 included in the intention-to-treat analysis (233 intervention, 267 control) after 2 control-group representatives withdrew consent. IV alteplase was given to 87.1% (203/233) of the intervention group and 90.6% (242/267) of the control group (89.0% overall) — one of the highest co-treatment rates in thrombectomy trials.
  • Median time from stroke onset to groin puncture: 260 minutes (IQR 210–313). Median onset to randomization: 204 minutes (intervention) / 196 minutes (control).
  • Primary outcome (ordinal mRS shift at 90 days): adjusted common OR 1.67 (95% CI 1.21–2.30). Functional independence (mRS 0–2): 32.6% vs 19.1% (absolute difference 13.5 percentage points, 95% CI 5.9–21.2; adjusted OR 2.16, 95% CI 1.39–3.38; NNT ≈ 7.4).
  • Absence of residual intracranial occlusion on CTA at 24 hours: 75.4% (141/187) intervention vs 32.9% (68/207) control, adjusted OR 6.88 (95% CI 4.34–10.94). Intra-procedural good reperfusion (mTICI 2b–3): 58.7% (115/196) of treated patients.
  • No significant increase in symptomatic ICH (7.7% vs 6.4%) or in mortality at 7, 30 (18.9% vs 18.4%), or 90 days. However, new ischemic stroke in a different vascular territory was more common with intervention (5.6% vs 0.4%, P<0.001).
  • Devices used: retrievable stents in 190/233 (81.5%) of the intervention group, other mechanical devices in 5/233 (2.1%); additional intra-arterial thrombolytic agents in 24/233 (10.3%); IA thrombolytic monotherapy in 1/233 (0.4%).
  • Pragmatic design — no advanced imaging selection (CTP or MRI perfusion) required, no ASPECTS cutoff mandated, M2 occlusions included.

Design

Study Type: Multicenter, pragmatic phase 3, randomized, open-label, blinded endpoint (PROBE) trial

Randomization: 1

Blinding: Blinded endpoint assessment (Web-based randomization; permuted blocks stratified by center, IV alteplase use, planned treatment method, and NIHSS severity ≤14 vs >14)

Enrollment Period: December 2010 – March 2014

Follow-up Duration: 90 days

Centers: 16

Countries: Netherlands

Sample Size: 500

Analysis: Intention-to-treat (500 of 502 randomized; 2 control-group representatives withdrew consent). Primary analysis: multivariable ordinal logistic regression (shift analysis) of mRS at 90 days, adjusted for age, baseline NIHSS, time from stroke onset to randomization, prior stroke, atrial fibrillation, diabetes mellitus, and occlusion of the internal-carotid-artery terminus.

Inclusion Criteria

  • Age ≥18 years (no upper age limit)
  • Acute ischemic stroke with proximal intracranial arterial occlusion in the anterior circulation (distal intracranial carotid artery, M1 or M2 MCA, or A1 or A2 ACA)
  • Occlusion confirmed on CTA, MRA, or DSA
  • Initiation of intraarterial treatment possible within 6 hours of symptom onset
  • NIHSS score ≥2

Exclusion Criteria

  • No intracranial arterial occlusion on CTA, MRA, or DSA.
  • Posterior circulation occlusion only (vertebral, basilar, PCA).
  • Symptom onset >6 hours before planned treatment.
  • NIHSS score <2.
  • Contraindications to iodine contrast or endovascular procedure.
  • Detailed criteria per study protocol (patients with prestroke mRS >2 were not strictly excluded — 4.3% of intervention and 4.1% of control patients had prestroke mRS >2).

Baseline Characteristics

CharacteristicControlActive
N267233
Age (median)65.765.8
Male (%)58.8%57.9%
NIHSS (median)1817
ASPECTS (median)99
Prior Stroke (%)9.4%12.4%
Atrial Fibrillation (%)25.8%28.3%
Diabetes (%)12.7%14.6%
IV alteplase use (%)90.6%87.1%
Occlusion Site - Intracranial ICA (%)1.1%0.4%
Occlusion Site - ICA with M1 involvement (%)28.2%25.3%
Occlusion Site - M1 MCA (%)62.0%66.1%
Occlusion Site - M2 MCA (%)7.9%7.7%
Occlusion Site - A1/A2 ACA (%)0.8%0.4%
Extracranial ICA occlusion (%)26.3%32.2%
Onset to randomization (median, min)196204
Onset to IV alteplase start (median, min)8785
Prestroke mRS >2 (%)4.1%4.3%
Onset to groin puncture (median, min)260

Arms

FieldIntraarterial Treatment + Usual CareControl
InterventionUsual care (including IV alteplase if eligible per guidelines) plus intraarterial treatment: arterial catheterization with microcatheter to the level of occlusion, followed by intra-arterial thrombolytic (alteplase up to 90 mg or urokinase up to 1,200,000 IU; reduced to 30 mg alteplase or 400,000 IU urokinase if IV alteplase given), mechanical thrombectomy, or both. Retrievable stents were used in 190/233 (81.5%); other mechanical devices in 5 (2.1%); additional IA thrombolytics in 24 (10.3%); IA thrombolytic monotherapy in 1 (0.4%). Device/technique choice at operator discretion. General anesthesia in 37.8%. Simultaneous acute cervical carotid stenting in 12.9%.Usual care per Dutch national stroke guidelines, including IV alteplase if eligible (within 4.5 hours, meeting standard criteria). No endovascular treatment permitted (one patient crossed over to intraarterial treatment). Included BP management, antiplatelet/anticoagulation per guidelines, and stroke unit care.
DurationSingle procedure initiated within 6 hours of onset, 90-day follow-up90-day follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Distribution of scores on the modified Rankin Scale (mRS) at 90 days (ordinal shift analysis)PrimarymRS 0–2 in 19.1%; median mRS 4 (IQR 3–5)mRS 0–2 in 32.6%; median mRS 3 (IQR 2–5)7.4
mRS 0 or 1 at 90 daysSecondary6.0% (16/267)11.6% (27/233)Adjusted OR 2.07 (95% CI 1.07–4.02)
Functional independence (mRS 0–2) at 90 daysSecondary19.1% (51/267)32.6% (76/233)Adjusted OR 2.16 (95% CI 1.39–3.38)
mRS 0–3 at 90 daysSecondary35.6% (95/267)51.1% (119/233)Adjusted OR 2.03 (95% CI 1.36–3.03)
NIHSS at 24 hours (median, IQR)Secondary16 (12–21)13 (6–20)Adjusted beta 2.3 (95% CI 1.0–3.5) points lower with intervention
NIHSS at 5–7 days or discharge (median, IQR)Secondary14 (7–18)8 (2–17)Adjusted beta 2.9 (95% CI 1.5–4.3) points lower with intervention
Barthel index 19–20 at 90 daysSecondary29.8% (73/245)46.0% (99/215)Adjusted OR 2.1 (95% CI 1.4–3.2)
EQ-5D score at 90 days (median, IQR)Secondary0.66 (0.30–0.81)0.69 (0.33–0.85)Adjusted beta 0.06 (95% CI −0.01–0.13)
Absence of intracranial occlusion on CTA at 24 hoursSecondary32.9% (68/207)75.4% (141/187)Adjusted OR 6.88 (95% CI 4.34–10.94)
Final infarct volume on CT at 5–7 days (median, IQR, mL)Secondary79 (34–125)49 (22–96)Adjusted beta 19 mL (95% CI 3–34) lower with intervention
Death at 7 daysAdverse12.4% (33/267)11.6% (27/233)
Death at 30 daysAdverse18.4% (49/267)18.9% (44/233)
HemicraniectomyAdverse4.9% (13/267)6.0% (14/233)
Any serious adverse eventAdverse42.3% (113/267)47.2% (110/233)0.31
Symptomatic intracerebral hemorrhage (any type)Adverse6.4% (17/267)7.7% (18/233)
New ischemic stroke in different vascular territory (within 90 days)Adverse0.4% (1/267)5.6% (13/233)<0.001
Progressive ischemic strokeAdverse17.6% (47/267)19.7% (46/233)
PneumoniaAdverse15.4% (41/267)10.7% (25/233)
Other infectionAdverse3.4% (9/267)6.9% (16/233)
Cardiac ischemiaAdverse1.5% (4/267)0.4% (1/233)
Extracranial hemorrhageAdverse0.7% (2/267)0

Subgroup Analysis

No significant interactions between prespecified subgroups and treatment effect. Prespecified subgroups: NIHSS score (2–15, 16–19, ≥20), age (<80 vs ≥80), occlusion of the internal-carotid-artery terminus (yes vs no), additional extracranial ICA occlusion (yes vs no), time from stroke onset to randomization (≤120 vs >120 min), and ASPECTS (0–4, 5–7, 8–10). Treatment effect was consistent across subgroups. The ASPECTS 0–4 subgroup point estimate was close to unity with a very wide confidence interval (adjusted common OR 1.09; 95% CI 0.14–8.46), reflecting the small number of patients in that stratum.

Criticisms

  • Open-label (PROBE) design introduces potential bias despite blinded outcome assessment.
  • Relatively long onset-to-groin puncture (260 min median) compared to later trials (ESCAPE ≈185 min, SWIFT PRIME ≈224 min) — reflects real-world Netherlands workflow in 2010–2014.
  • Pragmatic design with no ASPECTS cutoff — included patients with large cores who may not benefit, potentially diluting treatment effect.
  • Multiple device types and techniques used (stent retrievers, aspiration, IA lytics) — cannot isolate which technique was most effective.
  • Only Netherlands sites enrolled — may not generalize to other healthcare systems.
  • Modest absolute benefit (13.5 percentage points) compared with some later trials with stricter imaging selection.
  • Only ~8% M2 occlusions — too few for meaningful subgroup analysis.
  • Reperfusion rate (mTICI 2b–3 in 58.7%) lower than in contemporary case series (≥80%).
  • Nearly 9% of intervention patients had embolization to a new vascular territory, and 13% underwent simultaneous acute cervical carotid stenting — added procedural complexity that complicates interpretation.

Funding

Dutch Heart Foundation, with unrestricted grants from AngioCare Covidien/ev3, Medac/Lamepro, and Penumbra.

Based on: MR CLEAN (New England Journal of Medicine, 2015)

Authors: Olvert A. Berkhemer, Puck S. S. Fransen, Debbie Beumer, ..., for the MR CLEAN Investigators

Citation: Berkhemer OA, Fransen PSS, Beumer D, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med. 2015;372(1):11–20.

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