Aspirin and Heparin Increase Bleeding Risk During EVT
Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.
In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.
“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, in Rotterdam, the Netherlands, told Medscape Medical News. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.
The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said van der Steen.
He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
Trial Stopped for Safety
Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.
Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.
The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of ≥2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.
Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.
ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5000 IU followed by 1250 IU/h for 6 hours.
The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.
An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.
After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.
After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
Increased Risk for sICH
In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.
The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.
The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR [aOR], 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs 7.2%; aOR, 1.95).
Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.
The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs 7.4%; aOR, 2.00).
Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.
The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).
There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
“A Unique Trial”
“MR CLEAN-MED is a unique trial because it investigated a widely used treatment, but until now without any proof of effectiveness,” said van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.
“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, told Medscape Medical News. “However, to make more definite statements, we will have to do more in-depth analyses.”
It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said van der Steen.
To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.
Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for Medscape Medical News.
At least three strategies are available: the use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.
“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”
The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Van der Steen and Fisher have disclosed no relevant financial relationships.
European Stroke Organisation Conference (ESOC) 2021: Presented September 1, 2021.
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