▲Image source: Getty Image Bank.
[메디칼업저버 박선혜 기자] The possibility that parenteral anticoagulants may be effective in improving the prognosis of acute ischemic stroke patients presenting with early neurological deterioration (END) has been suggested.
Results from the randomized EASE trial conducted in China showed that intravenous administration of the anticoagulant agatroban along with standard antiplatelet agents to patients with acute ischemic stroke who experienced early neurologic deterioration is likely to improve functional outcome without further intracranial hemorrhage.
There is growing interest in whether this study will strengthen the use of anticoagulants to reduce disability after acute ischemic stroke. The results of the EASE study were published in the online edition of JAMA Neurology on January 8.
Patients who experience early neurological deterioration are at increased risk of worsening prognosis.
Patients with acute ischemic stroke commonly experience early neurologic deterioration within 48 hours of the onset of symptoms. Most patients who experience early neurologic deterioration have a high risk of worsening prognosis due to thrombus expansion, hemodynamic damage, and incomplete antiplatelet response even when antiplatelet drugs are administered.
Professor Ko Seong-ho (Neurology) of Guri Hospital of Hanyang University said: “For stroke patients who have suffered early neurological deterioration, the most dangerous period is the week after admission to hospital. This because not only do brain cells die due to poor blood circulation, but edema and inflammation also occur.” He explained: “Therefore, an important question is how to prevent the functional prognosis from worsening in patients who present with early neurological deterioration.”
In theory, it is assumed that the early use of anticoagulants in stroke patients can prevent the formation of thrombus in the intracranial arteries, reduce the volume of cerebral infarction and consequently reduce the risk of disability and death. The problem is that bleeding can occur while taking anticoagulants.
According to a Cochrane review published in 2021, anticoagulants may prevent recurrence in patients with acute ischemic stroke, but increase the risk of symptomatic intracranial hemorrhage (Cochrane Database Syst Rev 2021 Oct 22;10(10):CD000024).
Furthermore, early use of vitamin K antagonists such as warfarin in patients with transient ischemic attack or minor stroke was found to be associated with an increased risk of intracranial hemorrhage (Cochrane Database Syst Rev 2012;2012(9):CD001342 ). Consequently, guidelines do not recommend the use of emergency anticoagulants in patients with acute ischemic stroke.
Agatroban is the first direct synthetic thrombin inhibitor that blocks the activity of thrombin, a key factor in blood clotting. Because it works quickly and for a short period of time, it has a low risk of bleeding and is expected to have additional benefits by preventing the proliferation of blood clots when administered to patients with stroke or transient ischemic attack.
Accordingly, the randomized, open-label, blinded EASE study conducted in China was conducted to evaluate the efficacy and safety of agatroban administered within 48 hours of symptom onset in patients with acute ischemic stroke who experienced early deterioration. neurological.
Chance of mRS 0~3 points, 1.1 times higher in the Agatroban group than in the control group
Incidence of intracranial hemorrhage, agatroban group 0.9% compared to control group 0.7%
▲Image source: Getty Image Bank.
From April 4, 2020 to July 31, 2022, 628 patients with acute ischemic stroke who experienced early neurological deterioration were recruited into the study at 28 medical institutions in China.
Early neurological deterioration was defined as a National Institutes of Health Stroke Score (NIHSS) of 2 or greater within 48 hours of symptom onset. The average age was 65 years and 63.7% were male.
The entire group of patients was randomly assigned 1:1 into a group that received intravenous agatroban (agatroban group) or a group that did not receive (control group) standard antiplatelet drugs within 48 hours of receiving onset of symptoms. The agatroban treatment period was 7 days, with 60 mg administered intravenously daily for the first 2 days, followed by 20 mg daily for the remainder.
The primary endpoint was defined as the ratio of 0 to 3 points on the modified Rankin Scale (mRS), an indicator assessing disability prognosis, assessed at 90 days. The mRS score ranges from 0 to 6, with higher scores indicating more severe functional disability.
As a result of the analysis, the primary target percentage was 80.5% in the agatroban group and 73.3% in the control group, confirming a significant difference of 7.2%p between the two groups. The probability of improvement in mRS score assessed at 90 days was significantly 1.1 times greater in the agatroban group compared to the control group (RR 1.10; P=0.04).
The important finding is that the benefit of agatroban was observed without an increased risk of bleeding. The incidence of symptomatic intracranial hemorrhage was similar, 0.9% in the agatroban group and 0.7% in the control group (P=0.78).
Professor Min Lou of Zhejiang Medical University in China, who led the study, said: “Research to reduce early neurological deterioration has focused on new anticoagulants that can be used in combination with antiplatelet drugs. In this study, alteplase , a thrombolytic drug, “No risk signals from agatroban were observed in even one patient. This result suggests that the anticoagulant is safe,” she said.
Professor Ko said: “This study confirmed that administration of agatroban together with standard antiplatelet therapy may be better for patients with acute ischemic stroke who experienced early neurological deterioration. He added: “The patient group has been identified with stroke who should receive standard antiplatelet therapy. “It was an adventurous study that confirmed the possibility of the combined use of anticoagulants.”
It remains to be seen whether the results will also appear in races other than the Chinese one.
It has been suggested that the reason why no additional bleeding risk was observed with agatroban in the EASE study is because low doses were used.
According to the results of the ARAIS randomized trial published last year, when agatroban was administered to patients with acute ischemic stroke who received alteplase intravenously, neurological function did not significantly improve, but the risk of symptomatic intracranial hemorrhage was elevated.
In this study, agatroban was administered as a bolus intravenous injection of 100 μg/kg over 3 to 5 minutes, followed by 1.0 μg/kg per minute for 48 hours (JAMA 2023;329(8) :640-650).
Professor Brett Cucchiara of the University of Pennsylvania, who was not involved in the study, said in a comment: “Many questions remain about the use of anticoagulants such as agatroban,” adding: “This study will determine whether acute stroke patients should be treated with parenteral anticoagulants and when they should be administered.” “It will fuel the long-standing debate about whether or not to do this,” he said.
He added: “Research should be conducted to confirm the ideal time for anticoagulant treatment after experiencing early neurological deterioration,” and added: “We also need to confirm whether this outcome is observed in breeds other than Chinese.”
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