A new scientific advisory from the American Heart Association (AHA)—published recently in the journal Stroke—has reviewed clinical data from six randomised controlled trials evaluating endovascular therapy (EVT) in the treatment of ischaemic strokes caused by large-core infarctions, and ultimately concludes that these data “reframe” the role for reperfusion therapies in this patient population.
The advisory details that the six trials in question—ANGEL-ASPECT, LASTE, RESCUE-Japan LIMIT, SELECT2, TENSION and TESLA—provide “strong evidence” supporting the benefits of EVT in patients with a good pre-stroke functional status and significant stroke severity, as per initial imaging assessments of the extent of their ischaemia. In addition to summarising the results of the trials, the advisory analyses similarities and differences between them, as well as outlining their overall generalisability when considered collectively.
“The results of these six trials reframe current evidence regarding the role of reperfusion therapies in those with larger areas of presumed irreversible ischaemia,” the authors state. “The benefit of EVT in this setting may reflect the prevention of further infarct expansion or potentially improved tissue outcomes within ischaemic beds. Further research is needed to elucidate the mechanisms at play.”
The six aforementioned trials enrolled a total of 1,887 patients across a number of global geographies, including Australia, Canada, China, Japan, New Zealand, the USA and several countries in Europe. And, notwithstanding some subtle discrepancies between the trials in terms of their designs, eligibility criteria and methods of analysis, they all intended to evaluate the efficacy of EVT alongside standard medical management, as compared to medical management alone, in large-core ischaemic stroke patients—a population within which thrombectomy treatments have remained a point of uncertainty despite the procedure’s expansion over the past decade.
“The [previous] idea was that, maybe, patients that have very large-core strokes would not benefit from endovascular interventions,” says Nestor Gonzalez (Cedars-Sinai Medical Center, Los Angeles, USA), chair of the scientific advisory committee, speaking in a video accompanying the AHA paper. “In the last two years, six clinical trials have changed our perspective on the benefit that endovascular techniques have for these patients. The scientific advisory that we prepared was commissioned to review these data, to present them in a condensed way, and to provide some fundamental guidance from the American Heart Association regarding the management of patients with acute ischaemic stroke.”
He notes that the group reviewed all available data, including eligibility criteria and patient outcomes, to present a concise yet detailed overview of these trials.
“All of the clinical trials have very good designs,” Gonzalez also comments. “From a methodological perspective, they were randomised with blinded-endpoint [assessments], and have generally low levels of deviation, which gives us a lot of confidence in the level of evidence that they provide.”
Touching on the primary endpoints of the trials, Gonzalez relays that they collectively demonstrate benefits in patients treated via EVT—as per significant improvements in rates of 90-day functional independence (19.5%) when compared to those who only received medical management (7.9%). The speaker goes on to highlight the fact that a key secondary endpoint across the trials—independent ambulation—improved even more notably with EVT compared to medical management (36% vs 19%, respectively).
“Regarding complications, symptomatic haemorrhages were seen to different degrees in the different clinical trials,” Gonzalez continues. “In four, they were nominally lower; in two, they were nominally higher, in the endovascular group compared to the medical management group. However, this did not reach any statistical significance and, clearly, did not affect the clinical outcomes of the patients at 90 days, which were favourable for the endovascular groups.”
Gonzalez further states that rates of decompressive craniectomy were comparable between groups across the board, while the majority of the trials suggested a benefit with EVT versus medical management in terms of 90-day mortality rates.
“In summary, the results of these six clinical trials are very positive for the application of endovascular thrombectomy in patients with large-core stroke,” he adds. “The improvement in functional independence was significant. However, it’s important to note that this functional independence is still limited—roughly, only 20% of the patients reached that level. There was a little bit of a bigger impact on the ability of these patients to walk but, still, patients with large-core stroke have significant morbidity that needs to be considered.”
With a calculated number needed to treat of eight (to prevent one patient from experiencing an outcome of functional dependence), it is “clear” that these trials demonstrate the benefits of EVT, according to Gonzalez.
However, in the view of the scientific advisory committee, there are some “important” factors that may be seen to curb the generalisability of the data—for example, the trials’ enrolment of predominantly younger stroke patients and a limited inclusion of people older than 85 years of age. Gonzalez goes on to highlight different time windows from stroke onset (for example, within versus beyond six hours) and varying degrees of infarction (for example, Alberta stroke programme early computed tomography scores [ASPECTS] 0–2 versus 3–5) as patient subgroups warranting further clinical research. Another factor he alludes to is the preponderance of patients enrolled with minimal pre-stroke disability (modified Rankin scale [mRS] 0–1) across most of the trials, potentially limiting their applicability in populations with higher initial mRS scores.
“Additional clinical data and analyses are pending from recently completed trials,” the advisory details. “Patient-level pooled clinical and imaging data might provide important insights that were not elucidated by individual trials, such as the role of advanced imaging, considerations for patient prognostication, and communication with families. Upcoming secondary endpoint data on quality of life will offer a further assessment of a patient’s wellbeing after treatment, covering dimensions not captured by the mRS. Related analyses are also needed to quantify the cost-effectiveness of thrombectomy in this patient population. Post-hoc studies to assess the degree of hypodensity in the large-core region as a prognostic indicator or effect modifier are also awaited.”
The advisory committee’s belief is that the results from these six clinical trials provide supportive evidence on the benefits of EVT in patients who have a good pre-stroke functional status (mRS 0–1) and substantial stroke severity (National Institutes of Health stroke scale [NIHSS] score ≥6) with occlusion of the internal carotid or proximal middle cerebral artery, and a large ischaemic core (ASPECTS 3–5), on initial imaging. However, the authors also aver that—in large-core stroke populations—data remain “limited” on EVT outcomes between different imaging protocols (for example, matched core/perfusion), and in patients with advanced age or very large ischaemic cores (ASPECTS 0–2), as well as in those presenting beyond six hours from last known well.
“The results [of these trials] change the framework in which we have been applying [endovascular thrombectomy] for patients with acute ischaemia—and question the reversibility or effects of the traditional, presumed core in those patients,” Gonzalez concludes. “We look forward to the development of guidelines that include these concepts, as well as future research that clarifies—in those patients that were [underrepresented] in these trials—the potential benefit of using endovascular thrombectomy for the treatment of their acute ischaemic strokes.”
In a commentary piece on the same topic, published shortly after the release of the AHA’s scientific advisory, Joseph Broderick (University of Cincinnati College of Medicine, Cincinnati, USA) writes: “Effective stroke treatment has once again expanded to include some of the sickest ischaemic stroke patients as determined by brain imaging. Implementation of the new scientific data will require a change in mindset for those interventionalists and stroke physicians who previously excluded these patients from treatment because of their poorer prognosis, and lack of evidence for EVT. There is no doubt that patients with large ischaemic cores will generally have poorer functional outcomes after EVT than less sick patients, but there is also no doubt that EVT in a good majority of these patients provides the best chance to improve their odds of a better outcome.”
