Fatal Hemorrhagic Transformation of Acute Cerebral Infarction After the Use of Abciximab
To the Editor:
The Abciximab in Ischemic Stroke Investigators reported the encouraging results of their randomized, double-blind, placebo-controlled, dose-escalation trial.1 Of 74 eligible and consenting patients presenting within 24 hours of onset of their ischemic stroke, 54 patients were treated with 4 escalating doses of intravenous abciximab and 20 patients with placebo. The scheduled post-study CT brain scan detected asymptomatic parenchymal hemorrhages in 7% of abciximab-treated patients and 5% of placebo-treated patients; another 11% of abciximab-treated patients had asymptomatic parenchymal hemorrhages on unscheduled brain imaging (CT or MRI) performed on days 2 through 35. Symptomatic hemorrhagic transformation was not seen, while asymptomatic parenchymal hemorrhages were associated with a higher baseline National Institute of Health Stroke Scale (NIHSS) score. We would raise the following issue for clarification by the authors and report our limited experience of using abciximab in Chinese stroke patients.
Concomitant use of antithrombotic medications during the time period of diagnosing parenchymal hemorrhage was listed in Table 3 of the article.1 The scheduled CT brain scan detected asymptomatic parenchymal hemorrhages in patients A, D, G, H, and I, who also received concomitant antithrombotic medications, such as systemic heparin, low-dose heparin, aspirin, and warfarin sodium. Nevertheless, the study protocol required that antiplatelet agents or anticoagulants not be administered until the results of the scheduled CT brain scan became available (as stated in the subsection on Ancillary Care within Subjects and Methods).1 The investigators stated that they were not certain whether these agents were administered before or at the time of hemorrhage. While it is perceivable that some patients might be taking regular aspirin at the time of admission, the administration of systemic, low-dose, and low-molecular-weight heparin could only be in-hospital, and so their commencement time should be well documented in the study.
With a background similar to that indicated in the article by the Abciximab in Ischemic Stroke Investigators,1 we designed a pilot study to evaluate the safety issue of administering intravenous abciximab in Chinese patients within 6 hours of symptom onset. Our regimen was a 0.22-mg/kg intravenous bolus of abciximab followed by intravenous infusion at 9 μg/min for 12 hours. Concomitant use of oral antiplatelet agents was permitted. Of 2 consenting patients who received intravenous abciximab, the second patient had a fatal hemorrhagic transformation of his acute cerebral infarction.
This patient was a 65-year-old man with a history of hypertension, ischemic heart disease, peripheral vascular disease, hypercholesterolemia, mild bilateral carotid artery stenosis, and right vertebral artery occlusion. He had 2 previous episodes of nondisabling ischemic stroke and was taking aspirin and ticlopidine. He was admitted for percutaneous angioplasty to his stenotic left subclavian artery. On the morning of the day of the scheduled angioplasty, he developed right-sided weakness, with an NIHSS score of 8 and a Glasgow Coma Scale (GCS) score of 15. The clinical diagnosis was a recurrent lacunar infarction. The initial CT brain scan revealed old infarcts over the left middle cerebral artery territory, with no interval change when compared with the last CT brain scan performed 6 months before. Informed consent was obtained from the patient and his relatives, and intravenous abciximab was commenced at 5 hours after symptom onset. He was allowed to continue his oral medications, including enteric-coated aspirin (at 100 mg QD) and ticlopidine (which was reduced from 250 mg BID to 250 mg QD). Reassessment at 10 hours after onset showed an NIHSS of 6, but his relatives noted dramatic recovery at 14 hours after onset. Nevertheless, he deteriorated at 10 hours after commencement of intravenous infusion of abciximab (ie, at 15 hours after onset). He had dense right hemiplegia; his GCS score was 9. Repeat CT brain scan revealed massive hemorrhagic transformation involving both the presumed site of acute cerebral infarction and the old cerebral infarcts (Figure). Transfusion of platelet concentrates was given, and the neurosurgeon recommended conservative treatment. He became comatose and died 12 hours after onset of the sudden deterioration (ie, at 27 hours after onset, or at 22 hours after intravenous abciximab). Further recruitment of stroke patients into this safety study was stopped. After reading the encouraging results from the Abciximab in Ischemic Stroke Investigators, we will seek the approval of our Ethics Committee to modify our protocol and continue our safety study in Chinese patients with acute ischemic stroke. We will use a lower dose of intravenous abciximab for the 12-hour infusion and will avoid concomitant use of other antithrombotic medications such as aspirin.
Abciximab (ReoPro) was kindly provided by Eli Lilly Asia Inc.
- Copyright © 2000 by American Heart Association
The Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, dose-escalating study. Stroke.. 2000;31:601–609.
I thank Drs Cheung and Ho for their letter and for the opportunity to clarify the information included in Table 3 of the dose escalation study of abciximab.R1 Our data collection forms listed all ancillary agents given during the first 5 days after enrollment, and that information is included in Table 3. Obviously, this material spans the time of the mandated CT examination, performed at approximately 24 to 36 hours after entry. As Drs Cheung and Ho noted, the protocol stated that antiplatelet agents and anticoagulants could not be started until after the completion of the CT study. To ensure the accuracy of the information, we contacted the sites that enrolled the 5 patients in question (A, D, G, H, and I) to reconfirm that treatment with an anticoagulant or antiplatelet agent was not started before the scan was obtained. The sites report that no stroke-preventive medications had been started in these 5 cases before the CT was performed.
Abciximab is a potent antiplatelet agent, and some cases of symptomatic hemorrhagic transformation are possible. The report by Drs Cheung and Ho of a case of fatal intracranial hemorrhage following administration of abciximab is sobering. They point out that their patient had received ticlopidine and aspirin in conjunction with the abciximab. I recognize that our trial might have been very fortunate that we had no such serious bleeding event. The dose escalation study of abciximab enrolled patients with a wide spectrum of moderate-to-severe strokes, and many cases were treated more than 12 hours after stroke. Presumably, some of these patients should have been at very high risk for symptomatic hemorrhage. Still, the study made every effort to avoid situations that might have been associated with a high bleeding risk. Because the dose escalation study was primarily focusing on safety, we wanted to avoid any concomitant medications that might cause bleeding. The experience of Drs Cheung and Ho emphasizes the importance of determining the potential risks before testing the efficacy of any new therapy for stroke. Their experience also should prompt care about giving other medications that affect coagulation simultaneously with abciximab to patients with acute ischemic stroke.
The Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, dose-escalation study. Stroke.. 2000;31:601–609.