New data fail to support an advantage of endovascular therapy (EVT) over standard medical therapy among patients with basilar-artery-occlusion stroke.
In the trial, the likelihood of a favorable outcome was similar between patients randomly assigned to EVT (44.2%) and those who received medical treatment (37.7%). Further, researchers observed a trend toward higher risk for symptomatic intracranial hemorrhage among patients who received EVT vs medical treatment.
Dr Wouter Schonewille
Still, the researchers say they can’t rule out a benefit. “Our results suggest that EVT may be effective in basilar-artery occlusion, but less effective than it is in anterior-circulation stroke,” Wouter J. Schonewille, MD, PhD, a neurologist at St. Antonius Hospital in Nieuwegein, the Netherlands, told Medscape Medical News. “A larger trial might have shown a significant treatment effect.”
The data, from the Basilar Artery International Cooperation Study (BASICS), were published online May 20 in The New England Journal of Medicine.
Stroke resulting from occlusion of the basilar artery is associated with high rates of morbidity and mortality. Beginning in 2015, several studies showed a benefit of EVT for patients with ischemic stroke, but few patients with basilar-artery occlusion have been included in trials of EVT.
Stroke resulting from basilar-artery occlusion is different enough from stroke in the anterior cerebral circulation that trials of EVT among patients with basilar-artery stroke are justified, the researchers suggest.
Revision of Inclusion Criteria
In a prospective trial at 23 international centers, patients with stroke resulting from basilar-artery occlusion were randomly assigned to receive either EVT within 6 hours of stroke onset or medical therapy, which could include intravenous (IV) thrombolysis. Eligible patients were younger than 85 years and had a National Institutes of Health Stroke Scale (NIHSS) score of 10 or greater.
Enrollment was slow, and some enrolling physicians appeared to be unsure about the best treatment approach for particular subgroups of patients. For these reasons, the investigators revised the eligibility criteria 4 years after the trial had begun. They started to allow patients who were aged 85 years or older, those who had an NIHSS score lower than 10, and those with contraindications to IV thrombolysis.
The investigators chose favorable functional outcome, defined as a Modified Rankin Scale (mRS) score of 0 to 3, at 90 days as their primary endpoint. Primary safety endpoints were symptomatic intracranial hemorrhage (ICH) within 3 days of treatment and mortality at 90 days.
The researchers also examined secondary outcomes, including excellent clinical outcome (defined as an mRS score of 0 to 2), and NIHSS score at 24 hours.
During the study period, the investigators identified 424 eligible patients and randomly assigned 300 of them to treatment. The groups that were and that were not assigned to treatment were similar in age (mean, 66.8 years) and sex (38% women).
The researchers assigned 154 patients to EVT and 146 to medical treatment. Three patients in the EVT group and seven patients in the medical group crossed over into the opposite group.
The First Completed Trial
There was no significant difference between the two groups on the primary outcomes.
The rate of favorable functional outcome was 44.2% in the EVT arm and 37.7% in the medical arm (risk ratio, 1.18; 95% CI, 0.92 – 1.50; P = .19).
Within 3 days of treatment, the risk for symptomatic ICH was higher in the EVT arm (4.5%) than in the medical arm (0.7%), but this difference was not statistically significant.
The rate of mortality at 90 days was 38.3% in the EVT group and 43.2% in the medical group (risk ratio, 0.87; 95% CI, 0.68 – 1.12; P = .29).
The rate of excellent outcome was 35.1% in the EVT arm and 30.1% in the medical arm (risk ratio, 1.17; 95% CI, 0.87 – 1.57). NIHSS score at 24 hours was 11.0 in the EVT group and 15.0 in the medical group.
EVT was effective at opening the basilar artery. About 72% of patients in the EVT group achieved successful reperfusion. The rate of basilar-artery patency at 24 hours was 84.5% in the EVT group and 56.3% in the medical group.
“Ours is the first completed trial in patients with basilar-artery occlusion,” said Schonewille. “Other trials, such as AUST and BEST, have been halted prematurely due to a loss of perceived equipoise among investigators.”
In the setting of clinical research, equipoise refers to uncertainty over whether a treatment will provide benefit. The loss of equipoise among stroke centers around the world made it difficult to find centers willing to participate in this study as well as to recruit patients, said Schonewille.
Had the researchers used advanced imaging in patient selection, it could have affected the results as it did in trials of patients with anterior-circulation stroke, said Schonewille. “Including patients with a minor deficit certainly played a role, as these patients did better with standard therapy,” he said.
Thrombolysis might be more effective in basilar-artery occlusion than in anterior-circulation vessel occlusion, he suggested. Because collateral flow is greater in the posterior circulation than in the anterior circulation, basilar-artery occlusion may entail a lower degree of hypoperfusion. This factor could enable a longer time window for recanalization therapy, thus favoring EVT, and create a lower risk for hemorrhage after EVT, said Schonewille.
Absence of Equipoise
These results raise the question of why EVT is beneficial for large-vessel occlusion in the anterior circulation but is not clearly better than medical treatment for stroke resulting from basilar-artery occlusion, writes Marc Fisher, MD, a neurologist at Beth Israel Deaconess Medical Center, in Boston, Massachusetts, in an accompanying editorial. Patient selection may explain this discrepancy, he said.
Advanced imaging was used to select patients in all but one of the trials of EVT in patients with large-vessel occlusion in the anterior circulation, but it was not used in the current study. Similarly, the investigators did not examine the extent of collateral circulation and thrombus when selecting patients. In addition, the mRS is an insufficiently sensitive instrument in this context, Fisher concludes.
“It is very difficult to conduct randomized trials of stroke due to basilar artery occlusion, especially after the 2015 trials,” said Tudor G. Jovin, MD, director of Cooper Neurological Institute, in Camden, New Jersey, who commented on the findings for Medscape Medical News. “The authors should be congratulated for their persistence and perseverance.”
But the study’s main weakness is the fundamental problem facing randomized trials in basilar large-vessel-occlusion stroke, which is the absence of perfect equipoise, said Jovin. “That’s evident from the fact that it took them so long to enroll so few patients,” he said.
Subgroup analysis showed little difference in outcome between patients assigned to treatment before 2017 and those assigned afterward. This finding is dubious, said Jovin, because registry data suggest that outcomes of EVT have improved with improvements in the devices and in systems of care. The outcomes of medical care have not changed.
“In my mind, this is not about what is better, medical therapy versus EVT,” said Jovin. “The fundamental question is what is better, leaving a vessel occluded versus not occluded?” More than half of patients who received medical treatment were successfully recanalized. But the study does not address the question of how to treat patients in whom IV thrombolysis does not work, said Jovin.
In addition, the results do not show that EVT in addition to medical therapy does not work. Rather, they fail to show that EVT works, said Jovin. The authors acknowledge the possibility that EVT is effective in this patient population. “To me, this was an underpowered trial,” said Jovin. “I don’t think it has necessarily answered the question.”
To reach the sample size that they finally achieved, the investigators had to change the study’s inclusion criteria. “This underscores the challenges that we have with this disease,” said Jovin. If the researchers had maintained their original inclusion criteria, the results might well have shown a benefit of EVT, he added.
“My hope is that a meta-analysis will shed some more light into the benefit of this procedure, because I think that it’s going to be very challenging in the future to randomize patients,” said Jovin.
“Cherry Picking” of Patients?
The main contribution of the BASICS trial is that it provides crucial information about the relatively high efficacy of IV thrombolysis in basilar-artery occlusion, said Raul Nogueira, MD, professor of neurology, neurosurgery, and radiology at Emory University School of Medicine, in Atlanta, Georgia, who commented on the findings for Medscape Medical News.
The investigators also provided important data about the use of IV thrombolysis on the basis of the estimated time of basilar-artery occlusion, rather than time from symptom onset. This decision allowed for IV tPA treatment in an additional 10% of the patients, said Nogueira. “While the study was underpowered and had many limitations, it still provides the largest number of randomized patients treated with EVT thus far,” he noted.
The slow pace of recruitment and low number of participants may reflect selection bias, said Nogueira. There seems to have been “cherry picking of the patients that were less likely to benefit from EVT, as many of those who were more likely to benefit were then treated outside the trial,” he added. The participation of many centers with low clinical volumes, and consequently more limited endovascular expertise, also may explain the pace of recruitment.
“It is important to acknowledge the Herculean effort of the BASICS investigators, which clearly represents one of the best studies about basilar-artery occlusion,” said Nogueira. Nevertheless, the reason few high-volume centers participated in the trial, and why many qualifying patients were excluded from it was “poor equipoise, which is critical to the successful completion of any clinical trial.”
The protocol modifications that the investigators made were not enacted to improve the trial, but to ensure that it could be completed. But these modifications were made at the cost of assumptions that had been based on the investigators’ own preliminary findings, said Nogueira. They had the paradoxical result of diluting the treatment effect and increasing the expected effect size.
“I do not believe BASICS should raise any questions about the efficacy of EVT in basilar-artery occlusion patients of moderate to severe clinical severity—even more so in those who are not candidates for IV thrombolysis—as these patients are well known to have a dismal prognosis in the absence of reperfusion,” said Nogueira. The pooled analysis of data from the BASICS and BEST trials that he presented at the International Stroke Conference 2021 indicated a significant benefit of EVT in patients presenting with an NIHSS score of 10 or greater.
“The BASICS trial elegantly highlights how efficacious IV thrombolysis can be for basilar-artery occlusion patients and calls for new studies aimed to expand the time window for IV thrombolysis in this patient population,” Nogueira concluded.
The study was supported by the Dutch Heart Foundation, the Swiss Heart Foundation, the São Paulo Research Foundation, the National Council for Scientific and Technological Development in Brazil, the University Medical Center Utrecht, and St. Antonius Hospital Nieuwegein. Schonewille has disclosed no relevant financial relationships. Fisher has received personal fees from AstraZeneca, Simere USA, Lumosa, and ALLM for unrelated work. Jovin was a principal investigator of a previous randomized trial of EVT in basilar-artery occlusion. Nogueira had no disclosures that were directly related to the BASICS trial.
N Engl J Med. 2021;384:1910-1920. Abstract, Editorial
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This post originally appeared on Medscape Medical News Headlines