Article In Brief
Revascularization treatments may be less effective in patients with acute ischemic stroke and COVID-19, thanks to coronavirus-related inflammation and other factors.
Patients with acute ischemic stroke and COVID-19 experienced greater rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than counterparts who did not have COVID-19, a new study found.
COVID-related inflammation, endothelial dysfunction, and coagulopathy may elevate the bleeding risk and decrease the efficacy of revascularization treatments in patients with acute ischemic stroke, the authors noted.
Until now, not enough data existed to determine whether revascularization treatments were safe and effective in COVID-19 patients or to establish treatment recommendations in this subgroup of patients with ischemic stroke.
“Our findings can be taken into consideration for treatment decisions, patient monitoring, and establishing prognosis,” the authors wrote in the study published online in Neurology on Nov. 9.
“The idea to conduct this study came from the clinical observation that patients with acute ischemic stroke and COVID-19 raised particular challenges,” said the study's corresponding author, João Pedro Marto, MD, a stroke neurologist at the Hospital de Egas Moniz in Lisbon, Portugal, who also is a fellow of the European Stroke Organization.
The patients in the study presented with severe strokes and poor outcomes even when known risk factors or predictors were absent, Dr. Marto told Neurology Today.
“We observed unexpected hemorrhagic transformations and challenging endovascular procedures with low recanalization rates, the need for multiple device passes, and vessel re-occlusion,” he said. “After successful recanalization, patients continued to have poor neurological outcomes at higher rates than expected.”
He noted that this is the largest study to assess safety and outcomes of revascularization treatments in patients with ischemic stroke and COVID-19 and the first to investigate three-month outcomes.
“This large sample size allowed us to conduct a robust analysis,” Dr. Marto said, adding that the quality of the statistical analysis allowed for the adjustment of multiple confounders.
The retrospective and observational study design were study limitations, Dr. Marto acknowledged, and even after its best efforts, the research team could not exclude reporting or registration biases.
“We must not forget that COVID-19 can have multiple systemic complications that by themselves will contribute to poorer outcomes in patients with ischemic stroke and COVID-19,” Dr. Marto cautioned. “Virus variants, pandemic waves, and vaccination status were not assessed and could have influenced our results. We can't also say if more recent COVID-19 treatments (not available during most of the study period) would have influenced patients' outcomes.”
Dr. Marto said the research team hopes to conduct additional analysis to better understand COVID-19 in patients with acute ischemic stroke and that its work “will contribute to improved stroke care during this pandemic.”
The multicenter study reviewed data on patients with acute ischemic stroke receiving IVT and/or EVT between March 2020 and June 2021 and who tested positive for SARS-CoV-2 infection. A total of 15,128 patients were included from 105 centers across five continents: 5.6 percent (853) were diagnosed with COVID-19, 38.7 percent (5,848) received intravenous thrombolysis (IVT), and 61.3 percent (9,280) received endovascular therapy (EVT), with or without IVT.
Applying both propensity score weighting and multivariate regression, they examined the association of COVID-19 with intracranial bleeding complications and clinical outcomes. The researchers conducted subgroup analyses according to treatment groups (IVT-only and EVT).
The investigators found that those who were comorbid for COVID-19 and stroke had higher rates of symptomatic intracranial hemorrhage, symptomatic subarachnoid hemorrhage, and 24-hour mortality. And they had worse functional outcome at three months.
Patients with COVID-19 incurred a higher rate of symptomatic intracerebral hemorrhage (adjusted odds ratio [OR] 1.53), symptomatic subarachnoid hemorrhage (OR 1.80), and/or symptomatic intracerebral hemorrhage and symptomatic subarachnoid hemorrhage combined (OR 1.56). They also were more likely to die at 24 hours (OR 2.47) and at three months (OR 1.88).
Adam de Havenon, MD, MS, associate professor of neurology at Yale School of Medicine, praised the study's international scope and inclusion of more granular details than previous large cohorts, which have on administrative data or registries such as the Get with the Guidelines-Stroke program.
The findings are consistent with other analyses that have shown a higher risk of death and poor outcomes in patients who have a stroke while infected with COVID-19. However, the authors went a step further by looking specifically at rates of intracranial hemorrhage and other complications following IVT or EVT, Dr. de Havenon said.
Dr. de Havenon pointed out the inclusion of data on the procedural aspects of endovascular therapy, including the recanalization score and time from stroke onset to arterial puncture, was a strength of the study, as was providing three-month functional outcomes.
A major study weakness, he said, was the fact that the researchers did not compare patients with COVID-19 and stroke who received these treatments with patients with COVID-19 and stroke who did not. The study design only allowed for comparison to patients who did not have COVID-19, he noted.
“Effectively, what the study can tell us is that having COVID-19 leads to worse outcomes, but it doesn't tell us anything about the potential benefit or risk of these treatments versus withholding them in patients with COVID-19,” Dr. de Havenon said. “While this article doesn't change clinical care, it does help physicians and providers to both prognosticate and understand the potential risks and outcomes of ischemic stroke patients that they're treating who have COVID-19.”
Because of the relatively large margin of benefit from revascularization treatments, such as EVT, and the small absolute numbers of symptomatic hemorrhage in patients with acute ischemic stroke and COVID-19, it is likely that revascularization treatments remain useful for these patients, said José Biller, MD, FACP, FAAN, FANA, FAHA, professor and chair of neurology at Loyola University Stritch School of Medicine in Chicago.
“The authors suggest that these treatments continue to be given as rapidly as possible to COVID-19 patents using the current treatment recommendations for acute ischemic stroke,” he said, adding that the study was “scientifically robust and enlightening” and had a “low proportion of missing data.”
It was interesting that the mortality rate did not differ after 24 hours in patients with COVID-19 and those without COVID-19 who received thrombolysis, said Alexis N. Simpkins, MD, PhD, MSCR, FAHA, director of vascular neurology research at Cedars-Sinai Medical Center in Los Angeles.
“Acute ischemic stroke patients with COVID-19 were less likely to be functionally independent at 90 days treated with either revascularization therapy than acute ischemic stroke patients treated similarly without COVID-19,” Dr. Simpkins said. “Also, there was a higher mortality rate at 90 days in patients with COVID-19.
“Of note, 10.2 percent of COVID-19 patients who received intravenous thrombolysis and or thrombectomy had a symptomatic intracranial bleed,” she added. “In comparison, the three-month mortality rate and proportion of COVID-19-positive acute ischemic stroke patients that received intravenous thrombolysis and or thrombectomy who were not functionally independent at three months were 32.2 percent and 63.7 percent, respectively.”
Selection bias related to the retrospective nature of the study is another caveat to consider, Dr. Simpkins said. While the study included many variables in a vigorous statistical analysis, many other variables associated with acute ischemic stroke treatment outcomes and COVID-19 were not factored into the analysis, including a comparative analysis with acute ischemic stroke patients not treated with revascularization therapy. For example, the proportion of acute ischemic stroke COVID-19 patients with a poor clinical outcome treated with thrombolysis or thrombectomy was much higher than the proportion of those patients with symptomatic hemorrhagic conversion, she said.
In addition, the difference in the percentage of patients with or without COVID-19 in which TICI2B (reperfusions) was obtained amounted to only 5.9 percent.
“Thus, additional factors may have also influenced long-term clinical outcomes, such as stroke volume, intracranial atherosclerosis, collateral blood flow, and medical complications associated with COVID-19,” Dr. Simpkins said.
“It is also still unclear how long-COVID symptoms could also influence clinical outcomes post-stroke independent of an acute stroke intervention and rates of hemorrhagic conversion,” she added. “Lastly, patients in this study pre-date community spread of the omicron variant and widespread administration of COVID-19 vaccinations and boosting.”
Future studies should be undertaken to confirm the results in more recent cohorts, considering the continual emergence of new COVID-19 variants and evolving clinical practice during the pandemic, Dr. Simpkins said. She added that more translational studies are necessary to determine how COVID-19-induced inflammation could potentially influence bleeding risks associated with thrombolysis and thrombus characteristics in the context of acute ischemic stroke and confirm if any of these findings directly relate to clinical outcomes.
Because of the inclusion of both asymptomatic and symptomatic COVID-19 patients, especially in the absence of a non-treated cohort in the analysis, more research also is needed to determine if the severity of COVID-19 infection is more influential regarding clinical outcome post-acute stroke treatment than a positive test for COVID-19 in an individual who is otherwise asymptomatic or received treatment early to prevent severe COVID-19, Dr. Simpkins said.
Drs. Parto, Biller, and Simpkins had no disclosures.
Dr. de Havenon has received consultant fees from Integra and Novo Nordisk and royalty fees from UpToDate, and he has equity in Titin KM Biomedical Corp. and Certus