MR CLEAN

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Berkhemer OA, et al. "A randomized trial of intraarterial treatment for acute ischemic stroke". The New England Journal of Medicine. 2015. 372(1):11-20.
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Clinical Question

In patients with large proximal anterior circulation strokes, does intra-arterial (IA) intervention in addition to usual care offer improved neurological outcomes?

Bottom Line

In patients with large proximal anterior circulation strokes, intra-arterial therapy within 6 hours of symptom onset improved functional independence at 90 days without increasing ICH or mortality.

Major Points

Large artery occlusions of the proximal anterior circulation (involving the ICA, M1, M2, A1, A2) accounts for about one-third of anterior ischemic strokes.[1] However, conventional IV tissue plasminogen activator (tPA) therapy is able to achieve recanalization in perhaps only a fifth of patients with proximal arterial occlusions and perhaps only in under 5% of patients with ICA occlusions.[2] Unfortunately, the remainder of these patients typically go on to have poor functional prognoses.

Intra-arterial (IA) interventions in acute stroke have been performed ever since 1999 when PROACT II[3] demonstrated that for MCA occlusions <6 hours in duration, IA recombinant pro-urokinase (r-pro-UK) in addition to IV heparin was superior to IV heparin alone for vessel recanalization and improved functional outcomes at 3 months. Despite significant anecdotal evidence from neuro-interventionalists, RCTs prior to MR CLEAN using IA interventions alone or in combination with IV tPA compared to IV tPA in acute ischemic stroke had all been negative (i.e. IMS III[4], SYNTHESIS Expansion[5] and MR RESCUE[6]).The authors of MR CLEAN suggested that the failure of previous trials were due to lack of consistent neuro-imaging documentation of proximal vessel occlusion and use of older devices such as the MERCI device compared to newer stent-retrievers.

MR CLEAN randomized 500 patients with a radiographically confirmed proximal arterial occlusion in the anterior circulation to treatment with IA intervention within 6 hours of symptom onset versus usual care. Prior to randomization, about 90% of patients in both arms received IV tPA. After randomization, about 82% of the IA intervention arm received mechanical thrombectomy with retrievable stents. MR CLEAN demonstrated that the IA intervention arm had significantly improved 90-day outcomes (with lower modified Rankin scale scores) compared with the usual care arm (adjusted OR 1.67, 95% CI 1.21-2.30). There was no significant difference in the rates of symptomatic ICH or mortality between the two arms, but the IA intervention arm had a higher rate of ischemic strokes in another territory compared to usual care (5.6 vs. 0.4%).

MR CLEAN was the first and largest of five multicenter, open-label RCTs (MR CLEAN, Canadian ESCAPE,[7] Australian EXTEND-IA ,[8] Spanish REVASCAT,[9] and SWIFT PRIME[10]) which demonstrated that early IA interventions with second-generation mechanical thrombectomy devices dramatically improved neurological outcome after ischemic stroke involving a documented large artery occlusion in the proximal anterior circulation compared to standard IV tPA alone without a significant increase in rates of symptomatic ICH or 90-day mortality. The announcement of the preliminary results from the MR CLEAN trial at the 9th World Stroke Conference in October 2014 led to the early termination of the other trials. Unlike the other trials, there was no specific Alberta Stroke Program Early CT score (ASPECTS) criterion for eligibility in the MR CLEAN trial and it was the only positive trial that permitted enrollment of patients with ASPECTS <6.

MR CLEAN is the first trial since ECASS III to dramatically alter the management of acute ischemic stroke. It is felt that approximately 10% of all stroke patients will now be candidates for acute endovascular interventions as it is currently studied only in patients with hyper-acute strokes due to occlusion of a proximal cerebral vessel.[11]

Guidelines

2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment:[12]

  • Patients eligible for IV r-tPA should receive IV r-tPA even if endovascular treatments are being considered (Class I; Level of Evidence A). (Unchanged from the 2013 guideline)
  • Patients should receive endovascular therapy with a stent retriever if they meet all the following criteria (Class I; Level of Evidence A). (New recommendation):
    • prestroke mRS score 0 to 1,
    • acute ischemic stroke receiving IV r-tPA within 4.5 hours of onset,
    • causative occlusion of ICA or proximal MCA (M1),
    • age ≥18 years,
    • NIHSS score of ≥6 and ASPECTS ≥6, and
    • treatment can be initiated (groin puncture) within 6 hours of symptom onset
  • As with IV r-tPA, reduced time from symptom onset to reperfusion with endovascular therapies is highly associated with better clinical outcomes. To ensure benefit, reperfusion to TICI grade 2b/3 should be achieved as early as possible and within 6 hours of stroke onset (Class I; Level of Evidence B-R). (Revised from the 2013 guideline)
  • When treatment is initiated beyond 6 hours from symptom onset, the effectiveness of endovascular therapy is uncertain for patients with acute ischemic stroke who have causative occlusion of the internal carotid artery or proximal MCA (M1) (Class IIb; Level of Evidence C). Additional randomized trial data are needed. (New recommendation)

Design

  • Multi-center, open label, randomized controlled trial
  • N=500
    • Intra-arterial therapy in addition to usual care (n=233)
    • Usual Care (n=267)
  • Setting: 16 centers in Netherlands
  • Enrollment: 2010-2014
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: Modified Rankin Score at 90 days for functional independence (7 point scale, 0 is no symptoms and 6 is death, scores <2 suggests good independence)

Population

Inclusion Criteria

  • Age >18
  • Acute ischemic stroke due to occlusion of the distal intracranial carotid artery, MCA at M1/M2, or ACA at A1/A2; as seen on CTA, MRA, digital subtraction angiography (DSA), or trans-cranial doppler (TCD)
  • NIH Stroke Scale ≥2 (out of 42, higher is more severe neurological deficits)
  • Possibility of treatment within 6 hours of symptom onset

Exclusion Criteria

  • History of ICH, or ICH seen on CT or MRI
  • History of severe head injury or contusion in previous 4 weeks
  • BP >185/110 mmHg
  • Blood glucose <2.7 or >22.2 mmol/L
  • Platelets <90, APTT>50 sec, or INR>1.7
  • IV Alteplase dose exceeding 0.9 mg/kg or 90 mg max.
  • IV Alteplase given despite contraindication for thrombolytics (i.e. major surgery, GI/GU bleeding within previous 2 weeks, arterial puncture on a non-compressible site within previous7 days, etc.)
  • Infarction within distribution of the relevant occluded artery in previous 6 weeks

Baseline Characteristics

  • Median age: 65
  • Gender: 58.4% male
  • SBP: 145 mmHg
  • Risk factors: History of stroke (10.8%); AF (27%); Diabetes (13.6%)
  • Median NIHSS score: 18
  • Median ASPECTS: 9
  • Pre-stroke mRs score: 0 (80.8%); 1 (10%); 2(5.0%); >3 (4.2%)
  • Stroke located in left hemisphere: 53.6%
  • Intracranial arterial occlusion:
    • M1 of MCA: 64%
    • ICA involvement of M1 of MCA: 26.8%
    • M2 of MCA: 7.8%
  • Extracranial ICA disease: 29.2%
  • Treatment with IV alteplase: 88.9%
  • Median time from stroke onset to start of IV alteplase: 86 mins
  • Median time from stroke onset to randomization: 200 min
  • Median time from stroke onset to groin puncture for IA therapy: 260 min

Interventions

  • Randomization to Intra-arterial therapy plus usual care (46.6%) vs. usual care alone (53.4%).
  • Patients randomized to IA intervention arm, received one of the following:
    • (1) Intra-arterial tPA (0.4%)
      • Maximum dose of 90 mg of alteplase, or 1,200,000 IU of urokinase (if no IV TPA given), OR
      • Maximum dose of 30 mg of alteplase, or 400,000 IU of urokinase (if IV TPA given)
    • (2) Mechanical thrombectomy (83.7% ), including thrombus retraction, aspiration, wire disruption or use of a stent retriever
      • Retrievable stents (81.5%); other devices in (2.1%); additional intra-arterial thrombolytics in (10.3%)
    • (3) No intervention (15.9%)

Outcomes

Comparisons are Intra-arterial therapy + usual care vs. usual care.

Primary Outcomes

Median Modified Rankin Score at 90 days
3 vs. 4 (Adjusted OR: 1.67; 95% CI 1.21-2.30)

Secondary Outcomes

NIHSS at 24 hours
13 vs. 16 (Adjusted Beta 2.3, 95% CI 1.0-3.5)
NIHSS at 5-7 days or discharge (if earlier than 5-7 days)
8 vs. 14 (Adjusted Beta 2.9, 95% CI 1.5-4.3)
ADL using Barthel Index of 19 or 20 at 90 days
46.0% vs. 29.8% (Adjusted OR 2.1; 95% CI 1.4-3.2)
Median EuroQoL Group 5-dimension Self Reported Questionnaire at 90 days
0.69 vs. 0.66 (Adjusted Beta 0.06, 95% CI -0.01-0.13)
Arterial re-canalization as assessed on CTA/MRA at 24 hours (using modified arterial occlusion lesion score)
75.4% vs. 32.9% (Adjusted OR 6.88, 95% CI 4.34-10.94)
Median final infarct volume on non-contrast CT at 5-7 days post stroke (Patients evaluated 59.2% vs. 59.9%)
49 ml vs. 79 ml (Adjusted Beta 19, 95% CI 3 to 34)

Subgroup Analysis

No significant interactions between subgroups and treatment effect when subgroup analysis for age, NIHSS, and ASPECTS was completed.

Adverse Events

No significant difference in death or symptomatic ICH between both arms, but IA treatment arm had higher rates of new ischemic stroke in a different vascular territory within 90 day followup compared with usual care arm (5.6% vs. 0.4%; P<0.001)

Criticisms

  • Randomization was slightly unbalanced (more people in the control group) due to stratification in randomization process
  • Recanalization rate in MR CLEAN (TICI score of 2b/3= 58.7%) is lower than seen in other case series using the Solitaire Stent (TICI score of 2b/3 >80%)[13] [14] and in the SWIFT PRIME trial (TICI score of 2b/3= 88%) [15]
  • Unclear if higher rate of ischemic stroke in 90 day follow up for treatment group was affected by concurrent cervical carotid stenting done in 30 patients of the IA intervention group. In contrast, stenting of underlying carotid stenosis or occlusion was discouraged in the ESCAPE study protocol.

Funding

  • Dutch Heart Foundation
  • Private, unrestricted grants (AngioCare Covidien/ev3, Medac/Lamepro, Penumbra)
  • Authors with conflicts of interest

Further Reading

  1. Heldner MR et al. National Institutes of Health stroke scale score and vessel occlusion in 2152 patients with acute ischemic stroke. Stroke 2013. 44:1153-7.
  2. Bhatia R et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke 2010. 41:2254-8.
  3. Furlan A et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999. 282:2003-11.
  4. Broderick JP et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N. Engl. J. Med. 2013. 368:893-903.
  5. Ciccone A et al. Endovascular treatment for acute ischemic stroke. N. Engl. J. Med. 2013. 368:904-13.
  6. Kidwell CS et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N. Engl. J. Med. 2013. 368:914-23.
  7. Goyal M et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N. Engl. J. Med. 2015. 372:1019-30.
  8. Campbell BC et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N. Engl. J. Med. 2015. 372:1009-18.
  9. Jovin TG et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N. Engl. J. Med. 2015. 372:2296-306.
  10. Saver JL et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N. Engl. J. Med. 2015. 372:2285-95.
  11. Furlan AJ & Endovascular therapy for stroke--it's about time. N. Engl. J. Med. 2015. 372:2347-9.
  12. Powers WJ et al. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015. 46:3020-35.
  13. Dorn F et al. Endovascular treatment of acute intracerebral artery occlusions with the solitaire stent: single-centre experience with 108 recanalization procedures. Cerebrovasc. Dis. 2012. 34:70-7.
  14. Pereira VM et al. Prospective, multicenter, single-arm study of mechanical thrombectomy using Solitaire Flow Restoration in acute ischemic stroke. Stroke 2013. 44:2802-7.
  15. Saver JL et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N. Engl. J. Med. 2015. 372:2285-95.