MR RESCUE

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Kidwell CS, et al. "A trial of imaging selection and endovascular treatment for ischemic stroke". The New England Journal of Medicine. 2013. 368(10):914-923.
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Clinical Question

In patients with acute ischemic stroke, does the presence of viable ischemic brain tissue on neuroimaging identify those most likely to benefit from endovascular thrombectomy?

Bottom Line

In patients with acute ischemic stroke within 8 hours after symptom onset, a favorable ischemic penumbral pattern on neuroimaging did not identify those who benefited from endovascular thrombectomy compared to standard of care, nor was embolectomy superior to standard care.

Major Points

Few studies have provided support for penumbral-imaging selection for the treatment of acute ischemic stroke (including DEFUSE[1], DEFUSE2[2], and EPITHET[3]). However, there was no RCT showing that patients selected for revascularization on the basis of penumbral-imaging pattern had better clinical outcomes than patients treated medically or those with unfavorable penumbral imaging pattern.

MR RESCUE randomly assigned 118 patients with ischemic stroke involving the the large vessels of the anterior circulation to endovascular thrombectomy or standard care within 8 hours of stroke onset. Of note, even those patients who received intravenous tPA were eligible as long as the target vessel had a persistent occlusion. Patients were stratified by neuroimaging to a favorable prenumbral pattern defined by a small infarct core and substantial salvageable tissue, or an unfavorable prenumbral pattern defined by a large infarct core or minimal salvageable tissue. The primary outcome was functional outcome at 90 days assessed by modified Rankin score. At 90 days, embolectomy was not superior to standard care for patients in either a favorable or unfavorable penumbral pattern. Thus, in this study, pretreatment neuroimaging did not identify patients who would benefit from endovascular thrombectomy for acute ischemic stroke. A major criticism of this study is its use of older first generation devices which were associated with lower recanalization rates.

This was one of three trials published in 2013 that heightened the controversy over the role of endovascular therapy in acute ischemic stroke (see also IMS III and SYNTHESIS Expansion[4]). In 2015, the results of five randomized clinical trials (MR CLEAN[5], EXTEND-IA[6], ESCAPE[7], SWIFT-PRIME[8], and REVASCAT[9]) showed in resounding fashion that endovascular therapy is highly beneficial compared to IV tPA alone. A meta-analysis of 5 studies, including MR CLEAN, published in February 2015 concluded that endovascular therapy was associated with superior outcomes in acute stroke compared to conventional therapy alone.[10]

Guidelines

American Heart Association/American Stroke Association [11]

  • Use of stent retrievers is indicated in preference to the MERCI device. (Class I; Level of Evidence A). The use of mechanical thrombectomy devices other than stent retrievers maybe reasonable in some circumstances. (Class IIb, Level B-NR)
  • Emergency imaging of the brain is recommended before initiating any specific treatment for acute stroke (Class I; LOE A). In most instances, non-enhanced CT will provide the necessary information to make decisions about emergency management.
  • Further RCTs may be helpful to determine whether advanced imaging paradigms employing CT perfusion, CTA, and MRI perfussion and diffusion imaging, including measures of infarct core, collateral flow status, and penumbra, are beneficial for selecting patients for acute reperfusion therapy who are within 6 hours of symptom onset and have an ASPECTS <6.

Design

  • Multicenter, open-label, assessor-blinded, phase 2b, randomized, controlled trial
  • N=118 patients with acute anterior circulation large-vessel ischemic stroke within 8 hours of symptom onset
    • Embolectomy (n=64)
    • Standard care (n=54)
  • Setting: 22 centers in North America
  • Enrollment: 2004-2011
  • Analysis: nonparametric two-way analysis of variance using permutational methods
  • Primary outcome: 90-day modified Rankin score

Population

Inclusion Criteria

  • Ages 18-85
  • NIHSS scores 6-29 
  • Large vessel, anterior-circulation ischemic stroke within 8 hours after symptom onset 
  • Premorbid modified Rankin score 0-2 
  • Treatment with IV tPA without successful recanalization were eligible if MRA or CTA after treatment showed persistent target occlusion 

Exclusion Criteria

  • NIHSS ≥30 
  • Acute intracranial hemorrhage 
  • Coma 
  • Rapidly improving signs 
  • Pre-existing neurological, psychiatric, or medical disease that would confound the neurological, functional, or imaging evaluations 
  • Pregnancy 
  • Known allergy to iodine previously refractory to pretreatment medications 
  • MRA Neck w/ contrast or CTA suggests proximal ICA occlusion, proximal carotid stenosis > 67% or dissection 
  • PTT > 3x normal; INR > 3.0; Cr > 2.0 or GFR < 30 
  • Contraindication to MRI or iodinated contrast 

Baseline Characteristics

  • Age: 65.5 years 
  • Male sex: 57% 
  • Time to enrollment: 5.5 hours 
  • Median NIHSS: 17
    • Embolectomy group (penumbral vs. non-penumbral): 16 vs. 19 (P=0.004) 
    • Standard care group (penumbral vs. non-penumbral): 16 vs. 20.5 (P=0.005) 
  • Administration of IV tPA: 44% 
  • Pairwise differences noted in CHF and ETOH use. 
  • Median at-risk volume: 177.6 ml
    • Penumbral vs. nonpenumbral: 131.4 vs. 228.4 ml (P<0.001) 
  • Median predicted core volume: 60.2 ml
    • Penumbral vs. nonpenumbral: 36.7 vs. 116.7 ml (P<0.001) 

Interventions

  • All patients underwent pretreatment multimodal CT or MRI of the brain, which permitted stratification according to presence of a favorable penumbral pattern versus a non-penumbral pattern.  
  • Favorable penumbral pattern defined small infarct core (≤90 mL) and substantial salvageable tissue (proportion of predicted infarcted tissue within the at-risk region of ≤70%). Non-penumbral pattern defined as large infarct core or small or absent penumbra.  
  • Using the biased coin technique, patients were randomized within 8 hours after onset of symptoms to either
    • Mechanical embolectomy (Merci Retriever or Penumbra System) or 
    • Standard medical care 
  • Functional outcome assessed with modified Rankin scale (0 to 6, with higher scores indicating greater disability) 
  • Successful revascularization assessed with use of Thrombolysis in Cerebral Infraction (TICI) scale (0 no perfusion to 3 full perfusion) 

Outcomes

All outcomes listed in order of embolectomy, penumbral vs. Standard care, penumbral vs. Embolectomy, nonpenumbral vs. Standard care, nonpenumbral.

Primary Outcome

Mean 90-day modified Rankin Score

3.9 vs. 3.4 vs. 4.0 vs. 4.4 (unadjusted; P=0.23)

3.8 vs. 3.4 vs. 4.3 vs. 4.2 (adjusted for age; P=0.30)

  • Embolectomy was not superior to standard care (3.9 vs. 3.9; P=0.99) in patients with either a favorable penumbral pattern (3.9 vs. 3.4; P=0.23; adjusted P=0.43) or a nonpenumbral pattern (4.0 vs. 4.4; P=0.32; adjusted P=0.36) 
  • Primary analysis of 90-day modified Rankin scale, no interaction between pretreatment imaging pattern and treatment assignment (P=0.14) 

Secondary Outcomes

Median final infarct volume (mL)
58.1 vs. 37.3 vs. 172.6 vs. 217.1 (P<0.001)
Median absolute infarct growth for reperfusion (mL)
27.1 vs. 6.7 vs. 55.1 vs. 83.8 (P=0.009)
Reperfusion (%)
57 vs. 52 vs. 37 vs. 50 (P=0.59)
Partial or complete revascularization (%)
67 vs. 93 vs. 77 vs. 78 (P=0.13)

Adverse Events

  • Rates of 90-day mortality 21% (P=0.75) and symptomatic hemorrhage 4% (P=0.24) did not differ significantly across groups. 

Criticisms

  • This study used older devices (Merci Retriver and Penumbra System) that have been associated with lower recanalization rates and higher complication rates than newer stent-treiver devices.[12][13]
  • Potential factors contributing to neutral results include: extended time from imaging to embolectomy, use of intravenous tPA in some patients in standard care, and the heterogeneity of imaging approaches (both MRI and CT). Patients evaluated with CT tended to have larger predicted infarct core volumes than those evaluated with MRI.
  • The on-site imaging software successfully processed only 58% of real-time images, while the core laboratory's tally of automatically processed images was 98%. Additionally, core laboratory review changed the penumbral pattern in 8% of real-time processed images.

Funding

  • Supported by the NINDS.
  • Concentric Medical provided study catheters and devices from beginning of study until August 2007; thereafter, costs for all study catheters and devices were covered by study funds or third-party payers.

Further Reading

  1. Albers GW, et al. "Magnetic resonance imaging profiles predict clinical response to early reperfusion: the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study". Ann Neurol 2006;60:508-517
  2. Lansberg MG, et al. "Results of DEFUSE 2: clinical endpoints". Stroke 2012;43:A73-A73.
  3. Davis SM, et al. "Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial." Lancet Neurol 2008;7:299-309.
  4. Ciccone A, et al. "Endovascular treatment for acute ischemic stroke". N Engl J Med 2013;368:904-913
  5. Berkhemer OA, et al. "Endovascular treatment for acute ischemic stroke." N Engl J Med 2013;368:904-913
  6. Campbell BC, et al. "Endovascular therapy for ischemic stroke with perfusion-imaging selection." N Engl J Med2015;372:1009-1018.
  7. Goyal M, et al. "Randomized assessment of rapid endovascular treatment of ischemic stroke." N Engl J Med 2015;372:1019-1030.
  8. Saver JL, et al. "Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke." N Engl J Med. DOI: 10.1056/NEJMoa1415061.
  9. Jovin TG, et al. "Thrombectomy within 8 hours after symptom onset in ischemic stroke." N Engl J Med. DOI: 10.1056/NEJMoa1503780.
  10. Fargen KM, et al. "A meta-analysis of prospective randomized controlled trials evaluating endovascular therapies for acute ischemic stroke." J Neurointerv Surg. 2015 Feb;7(2):84-9.
  11. Powers, WJ et al. "2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment" Stroke. 2015;46:000-000.
  12. Nogueira RG, et al. "Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial." Lancet 2012;380:1231-1240
  13. Saver JL, et al. "Solitaire flow restoration device versus the Merci retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial." Lancet 2012;380:1241-1249