B. C. V. Campbell, P. J. Mitchell, T. J. Kleinig, H. M. Dewey, L. Churilov, N. Yassi,
et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. The EXTEND-IA
Investigators. N Engl J Med. 2015 Feb 11. [Epub ahead of print]
The result of the Multicenter Randomized Clinical Trial of Endovascular Treatment
for Acute Ischemic Stroke (MR CLEAN) trial,[1] which showed reduced disability among patients with ischaemic stroke who were treated
with endovascular thrombectomy, represent an advance in stroke care. Several trials
later had neutral findings with respect to the use of endovascular thrombectomy.[2]
[3] However none of the previous studies raised any safety concerns, with rates of symptomatic
haemorrhage of approximately 6% in both the alteplase group and the endovascular-therapy
group. More recent advances in device technology have significantly improved the speed
and efficacy of recanalisation.[4]
[5] The computed tomographic (CT) perfusion imaging can indicate the extent of irreversibly
injured brain in the ischaemic core and potentially salvageable but hypo-perfused
ischemic penumbra.[6]
[7]
[8] In Extending the Time for Thrombolysis in Emergency Neurological Deficits—Intra-Arterial
(EXTEND-IA) trial, it was hypothesised that the patients with anterior circulation
ischemic stroke who are selected with a dual target of vessel occlusion and evidence
of salvageable tissue on perfusion imaging within 4.5 hours after the onset of stroke
will have improved reperfusion and early neurologic improvement when treated with
early endovascular thrombectomy after intravenous administration of alteplase as compared
with alteplase alone.
The present trial was an investigator-initiated, multicenter, prospective, randomised,
open label, blinded-end-point study involving 100 patients at 14 centres in Australia
and New Zealand. They randomly assigned patients with ischemic stroke who were receiving
0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset
of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire
FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All
the patients had occlusion of the internal carotid or middle cerebral artery and evidence
of salvageable brain tissue and ischaemic core of less than 70 ml on CT perfusion
imaging. The primary outcomes were reperfusion at 24 hours and early neurologic improvement
(≥ 8-point reduction on the National Institutes of Health Stroke Scale, [ranges from
0 (normal) to 42 (death)] or a score of 0 or 1 at day 3). Secondary outcomes were
the score on the modified Rankin scale at 90 days [which ranges from 0 (normal) to
6 (death)], death due to any cause, symptomatic intra-cranial haemorrhage and subarachnoid
haemorrhage associated with clinical symptoms.
The trial was stopped early because of efficacy after 70 patients had undergone randomization
(35 patients in each group). From August 2012 through October 2014, a total of 70
patients underwent randomization (35 to the endovascular-therapy group and 35 to the
alteplase-only group) at 10 study centres (9 in Australia and 1 in New Zealand). Around
25% of clinically eligible patients with vessel occlusion were excluded on the basis
of perfusion-imaging criteria The percentage of ischemic territory that had undergone
reperfusion at 24 hours was greater in the endovascular-therapy group than in the
alteplase only group (median, 100% vs. 37%; P < 0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset
of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P = 0.002) and improved the functional outcome at 90 days, with more patients achieving
functional independence (score of 0–2 on the modified Rankin scale, 71% vs. 40%; P = 0.01). There were no significant differences in rates of death or symptomatic intracerebral
haemorrhage.
In patients with acute ischemic stroke with major vessel occlusion and salvageable
tissue on CT perfusion imaging, early mechanical thrombectomy with the Solitaire FR
stent retriever after the intravenous administration of alteplase was associated with
faster and more complete reperfusion than the use of alteplase alone. The increase
in reperfusion led to a reduction in infarct growth and substantial clinical benefit
in early neurologic recovery and functional outcome at 3 months. This reduction in
infarct growth is consistent with salvage of ischemic penumbra as the mechanism of
underlying clinical benefit.[9]
The magnitude of the clinical benefit of endovascular thrombectomy was larger in this
study than that in previous trials. The main differences between this study and the
previous trials was inclusion of CT perfusion imaging to select patients with the
greatest potential to benefit from endovascular therapy, shorter time to the onset
of treatment, and improved rates of angiographic revascularization. However CT perfusion
imaging was also performed in about 65% of patients in the MR CLEAN trial. Such imaging
was not required according to the protocol for the MR CLEAN trial but may have influenced
patient selection. Hence, positive results in the MR CLEAN trial may not be entirely
attributable to imaging selection on the basis of vessel occlusion alone. The interval
between the initiation of alteplase and randomization was 30 minutes in this study,
as compared with 100 minutes in the MR CLEAN trial, because of this approach of identifying
patients with the greatest potential to benefit from reperfusion and then maximizing
early reperfusion with the use of combined alteplase and endovascular therapy, rather
than waiting to assess clinical response to alteplase. As a result, the time from
stroke onset to the initiation of the endovascular procedure was a median of 50 minutes
shorter than the similar interval in the MR CLEAN trial, which may also have contributed
to the substantially higher pro-portion of patients with independent functional outcomes
observed in this study.
Limitations of this study include the inability to perform subgroup analyses, given
the small number of patients. Such analyses will require individual patient meta-analysis
of multiple trials. The patients who were excluded from the trial on the basis of
a large ischaemic core or absence of significant salvageable ischaemic brain tissue
might have benefited from endovascular therapy. Purely volume-based criteria do not
account for the location of the core, which is also relevant to the clinical outcome.[10] The early termination of the trial does create potential for overestimation of the
effect size. However, the investigators believed that the new information from the
MR CLEAN trial ethically mandated review by the independent data and safety monitoring
board.
The authors conclude that patients with ischaemic stroke with a proximal cerebral
arterial occlusion and salvageable tissue on CT perfusion imaging had improved reperfusion,
early neurologic recovery, and functional outcome if endovascular thrombectomy with
the Solitaire FR stent retriever was performed without delay after the initiation
of intravenous alteplase. Further studies will be needed to clarify remaining uncertainties
regarding the benefit in patients with more distal occlusions, later time windows,
and the influence of the type of device that is used and variability in the endovascular
technique.
