April 11, 2018

EJRC Article Review

EJRC Article Review

In the last 3 years, a number of randomised controlled trials[1-6] (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, DEFUSE 3 and EXTEND IA) and two meta-analyses[7,8] have explored the effect of mechanical, endovascular interventions versus or added to standard treatment. These recent trials focused on larger vessels pathologies, patients with less extensive brain tissue damage, simultaneous endovascular reperfusion techniques (rt-PA and thrombectomy) and next generation devices, within 12 hours of symptom onset. Results confirmed that patients undergoing adjunctive intra-arterial mechanical thrombectomy are twice as likely to be without disability and 1.5 times as likely to be functionally independent 90 days after an ischaemic stroke caused by occlusion of anterior large vessels, without increased mortality or symptomatic intracerebral haemorrhage.[8]

The DAWN trial (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo)[9] compared the effect of endovascular thrombectomy that is performed 6 to 24 hours after the onset of ischaemic stroke to standard treatment, in patients with a clinical deficit that is disproportionately severe relative to the infarct volume. As co-primary endpoints, the mean score for disability on the utility-weighted modified Rankin scale at 90 days and the rate of functional independence (defined as a score of 0, 1, or 2 on the modified Rankin scale) at 90 days were used. Pre-specified secondary end points were an early therapeutic response, death from any cause at 90 days, centrally adjudicated infarct volume and change from baseline in the infarct volume at 24 hours and evidence of recanalisation of the occluded vessel on CT angiography or magnetic resonance angiography at 24 hours, whereas the main safety end point was stroke-related death at 90 days.

The trial was stopped early, as the predictive probability of superiority of thrombectomy for the first primary end point (95%) was exceeded, with 107 patients assigned to the intervention and 99 to the control group. The mean score for disability on the utility-weighted modified Rankin scale at 90 days was 5.5 in the former group as compared with 3.4 in the later (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999). The second primary end point of the rate of functional independence at 90 days was 49% in the thrombectomy group compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 21 to 44; posterior probability of superiority, >0.999). The rates of safety end points and serious adverse did not differ significantly between the two treatment groups.

Strengths and Limitations
The DAWN trial addresses the very pertinent issue of late patient presentation with large cerebral vessel occlusion. It is a prospective, multi-centred, multi-national trial with clearly defined inclusion and exclusion criteria, and pre-specified, early interim analyses. The authors chose an adaptive design, which offers efficient patient enrolment, as it allows for refinement of the target population and increased sample size in the groups that demonstrate treatment benefit. Depending on the results of the interim analyses, unnecessary randomisation is avoided by modifying enrolment as the study progresses. Unfortunately, the statistics involved in a Bayesian adaptive trial design are not familiar to the wider readers’ group, resulting in potentially variable understanding of the methodology and difficulty in accepting the results. Equally unfamiliar and potentially confusing is the use of the weighted modified Rankin Score (mRS) as the primary outcome. As the authors explain in the supplement, use of a utility-weighted mRS ‘permits a trial to capture all the effects a treatment can have on a subject to the degree each is important to the subject and society’. Despite the advantage of using an outcome that directly reflects patient and society valuation of outcome, its benefit is likely limited by its ‘exotic’ nature; a fact counterbalanced by the use of the more commonly used mRS for the co-primary endpoint (rate of functional independence).

The trial reports a rate of functional independence at 90 days (mRS 0-2) of 49% in the intervention group vs. 13% in the standard group; a result which is strikingly similar to the one reported in the DEFUSE 3 trial, a RCT reported in the February issue of the New England Journal of Medicine (45% vs. 17%)[5]. This fact further strengthens the evidence supporting the use of mechanical thrombectomy for late presentation strokes. The use of intravenous alteplase (5% vs.10%), the imaging modalities used to estimate the volume of the ischaemic core and penumbral regions (diffusion-weighted magnetic resonance imaging/ perfusion CT, use of automated software [RAPID, ischaemaView]) and the infarct volumes (7.6% vs. 9.4%) were also comparable between the interventions arms of the two trials, as were 90-day mortality (19% vs. 19%) and incidence of intracranial haemorrhage (6% vs. 7%). Of note, the 13% rate of functional independence in the control group in the DAWN trial was lower than the 26% rate in the respective one in a recent meta-analysis[2], probably reflecting the worse outcomes linked with absence of recanalisation by 24 hours.

In conclusion, for patients with stroke due to occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, outcomes for disability and functional independence at 90 days were better with thrombectomy plus standard medical care than with standard medical care alone. Whether these results will be replicated by the trials still waiting to report their results (WAKE-UP, ClinicalTrials.gov number, NCT01525290; ECASS-4 EXTEND, EudraCT number, 2012-003609-80); EXTEND, EudraCT number, 2014-002864-33), thus changing the way the ischaemic tissue is measured and treated[10], remains to be seen. Furthermore, the unavoidable shift for a number of patients from a mRS of 6 (death) to 5 (severe disability) and the socio-economic impact that may have warrants more research and planning.

Article review was submitted by EJRC member Victoria Metaxa.


1. Berkhemer OA, Fransen PS, Beumer D, et al. A randomised trial of intraarterial treatment for acute ischaemic stroke. N Engl J Med 2015; 372: 11–20.
2. Goyal M, Demchuk AM, Menon BK, et al. Randomised assessment of rapid endovascular treatment of ischaemic stroke. N Engl J Med 2015; 372: 1019–30.
3. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; 372: 2285–95.
4. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischaemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372: 1009–18.
5. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med 2018; 378:708-18.
6. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischaemic stroke. N Engl J Med 2015; 372: 2296–306.
7. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387: 1723–31.
8. Rodrigues FB, Neves JB, Caldeira D, et al. Endovascular treatment versus medical care alone for ischaemic stroke: systematic review and meta-analysis. BMJ 2016; 353:i1754.
9. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018; 378:11-21.
10. Powers WJ, Derdeyn CP, Biller J, et al. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 guidelines for the early management of patients with acute ischaemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2015; 46: 3020–35.

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