Safety of Abciximab injection during endovascular treatment of ruptured aneurysms

Abstract

Background and purpose

We aimed to determine the safety of intra-arterial Abciximab injection in the management of thromboembolic complications during endovascular treatment of ruptured cerebral aneurysms.

Methods

In a monocentric consecutive series of endovascular treatment of 783 ruptured aneurysms, 42 (5.3%) patients received Abciximab after the aneurysm was secured. Bleeding complications were registered and dichotomized as follows: new intracranial hemorrhage and peripheral bleeding. For each patient, World Federation of Neurosurgery (WFNS) subarachnoid hemorrhage (SAH) grade, shunting, and clinical outcomes in the post-operative period and at 3–6 months were recorded.

Results

SAH WFNS grades were as follows: grade I n = 14, grade II n = 10, grade III n = 11, grade IV n = 4, grade V n = 3. Ten patients had intracranial hematoma additionally to the SAH prior to embolization. Four patients (9.5%) presented more blood on the post-embolization CT but only one suffered a new clinically relevant intracranial hemorrhage. Two patients (4.8%) experienced significant peripheral bleeding but none were associated with long-term disabilities. Fourteen patients had a shunt installed less than 24 h prior to Abciximab injection and one less than 48 h later. At 3–6-month follow-up, 31 patients (74%) achieved a modified Rankin Scale score (mRS) of 2 or less, six patients (14%) had a mRS of 3–5, three were dead (7%), and two were lost at follow-up.

Conclusion

When the aneurysm is secured, intra-arterial Abciximab injection is a low complication rate treatment modality for thromboembolic events during embolization of cerebral ruptured aneurysm.

Introduction

Reported rates of angiographic thromboembolic complications occurring during cerebral aneurysm embolization vary, ranging from 9–28%.^1,2 Recent magnetic resonance (MR) studies indicate that these events probably occur at a much higher rate.³ Symptomatic complications are less frequent, probably around 5%.¹ In endovascular treatment of cerebral aneurysms, the two mainly used molecules with high affinity for the platelet glycoprotein IIb/IIIa receptor are Abciximab and Tirofiban. With Abciximab, the effect occurs within 10 min, and though it may be reduced, it persists for as long as 48 h after the cessation of treatment.⁴ Data have been published^5–10 but only a small series focused on the safety of this use in the case of ruptured aneurysm.¹¹ The injection of Abciximab is not free of risk, and in the cardiologic literature the rate of major bleeding in a meta-analysis is 2.5%.¹² In the neurologic literature, in case of acute ischemic stroke, symptomatic intracranial hemorrhage occurs in 5.5% of patients.¹³ The purpose of this study is to assess the safety of the use of Abciximab in the context of aneurismal subarachnoid hemorrhage (SAH) by recording the rates of intracranial and peripheral bleeding complications and the safety of ventricular shunting.

Material and methods

Procedures

Procedures with Abciximab (Reopro; Eli Lilly, Indianapolis, IN) injections were prospectively and consecutively recorded from November 2004 (start of Abciximab use) to November 2012. During this period, 783 patients with ruptured aneurysms were treated endovascularly in our institution. All procedures were performed under general anesthesia and patients were given an initial loading dose of 5000 IU of heparin followed by continuous infusion to maintain an activated clotting time between 250 and 300  seconds. In 42 (5.3%) procedures, a thromboembolic event occurred and Abciximab was injected (Figure 1).

Figure 1.

Example of the use of Abciximab in a grade III SAH for non-occlusive and growing clot at the coil/parent artery interface of a right Pcom ruptured aneurysm (1(a) and 1(b)).

Thromboembolism event

Thromboembolism was defined as presence and/or progression of a thrombus, an antegrade flow disturbance and/or a missing branch. The thrombus could be located at the coil/parent artery interface or in the more distal circulation. We use the term “proximal thrombus” when it arises at the coil/parent artery interface and “distal thrombus” when its location is distal to the aneurysm but within the same vascular territory. Considering that thrombi in these procedures often occurred at the coil/artery interface and did not lead to downstream flow perturbation in all cases, the TIMI/TICI flow grades scale has not been used.

Abciximab treatment

The treatment of angiographic thromboembolic events was performed via a bolus of IA Abciximab (0.25 mg/kg) through coil delivery microcatheter or guiding catheter followed by a 12-h IV infusion (0.125 µg/kg/min) when judged necessary (one case) and/or when neurological deficits were present immediately after the procedure and not related to hemorrhage by emergency computed tomography (CT) (three cases).

Ventricular shunting

Patients were dichotomized in two groups: cerebral spinal fluid (CSF) shunts placed prior to Abciximab injection and after.

Demographic data

The study comprised 42 patients (age range 35–78 years, mean age +/− standard deviation, 54 years ± 11). There were 13 men (age range 43–72 years, mean age, 55 years ± 9.8) and 29 women (age range 35–78 years; mean age, 53 years ± 10.9).

Data analysis

Data were prospectively recorded and retrospectively analyzed. Non-enhanced CT was performed the day after the procedure in all cases, and has been retrospectively analyzed and compared with the CT before treatment by two readers to research new hemorrhage and new ischemic infarction related to the thrombus. New intracranial hemorrhage was defined as any new blood on CT or MR in the 48 h following Abciximab administration. Any hypodensity in the concerned vessel territory was defined as an ischemic infarction. Peripheral bleeding was defined as “requiring any specific imaging test or treatment.”

Post-procedural neurological morbidity was defined as any worsening of clinical status noticed in the 48 h post-embolization compared with pre-embolization clinical neurological status. Initial SAH World Federation of Neurosurgery (WFNS) scores were collected in all patients, as well as the modified Rankin Scale (mRS) score at 3 months.

Results

Clinical and radiological SAH presentation

The WFNS at hospital admission was 1 in 14 of the 42 patients (33%), 2 in 10 patients (24%), 3 in 11 patients (26%), 4 in four patients (10%), and 5 in three patients (7%). Ten of the 42 patients presented an intra-parenchymatous hematoma on the pre-treatment CT scan.

Angiographic indications for Abciximab use

Of the thromboembolic complications, 34 (81%) were at or near the coil/parent artery junction and eight cases were distal emboli (19%).

Post-operative imaging

New intracranial hemorrhage

Four patients (9.5%) suffered a new intracranial hemorrhage as defined above; however, only one appeared to be clinically relevant and greater than 1.5 cm in long axis. In the 10 patients with intra-parenchymatous hematoma additionally to SAH, one experienced an enlargement of the hematoma (Figure 2).

Figure 2.

Pre-treatment CT with diffuse SAH and a small internal temporal hematoma (same patient as in Figure 1) (a). Facing decline of level of consciousness and right mydriasis, CT shows the increase of the temporal hematoma and intraventricular hemorrhage (b). Re-bleeding has been ruled out by a cerebral angiography (not shown), surgical evacuation and ventricular shunting has been performed. CT shows large ischemic changes in the MCA and PCA territories (c). Patient mRS 4, 4 months later.

In the 15 patients who needed ventricular shunting, 14 were placed less than 24 h prior to the embolization and Abciximab injection and one in the 48 h following. Two patients experienced small new intracranial hemorrhage.

“Thrombus-related” infarction

Ischemic changes were observed on CT in 14 patients (33%), including eight post-procedure new deficit patients (19%).

Post-Abciximab injection peripheral bleeding

Two patients (4.8%) experienced peripheral bleeding as defined above, but none were associated with long-term disabilities.

Neurological outcome

Post-procedural outcome

Immediate post-procedural clinical examination showed six (14%) cases of worsening of neurological clinical exam compared with initial clinical status.

Three to six-month follow-up

In total, 31 patients (74%) achieved a mRS score of 2 or less, six patients (14%) had a mRS of 3–5, three were dead (7%), and two were lost at follow-up.

Discussion

In the literature, the rate of thrombus formation during the coiling of cerebral aneurysm varies from 9–20%.^1,2,10 In ruptured aneurysm, Pierot et al. reported a higher rate of thromboembolic events in patients with aneurysms larger than 10 mm, in smokers and in patients with aneurysms with a neck larger than 4 mm.²

The sequence of events leading to the clot starts with the adhesion of platelets. Platelets become “activated” and glycoprotein lIb/IIIa receptors on the platelet surface assume an active conformation that binds circulating adhesive proteins and ultimately leads to thrombosis.

Facing an acute intra-arterial clot, no consensus on optimal management exists. Neuro-interventionists have several options: abstention and observation of the evolution, arterial or IV injection of antiplatelet agents, and/or mechanical intervention.⁹

Abciximab is not the only drug available in order to attempt lysis of an acute intra-arterial clot during neuro-interventional procedures.⁹ Cronqvist et al.¹⁴ described the use of Urokinase to manage thromboembolic events encountered during coil embolization. In this small case series of six patients with acutely ruptured aneurysms, three experienced symptomatic hemorrhagic complications after thrombolysis leading to a poor outcome (GOS score of 5).¹⁴ Hähnel et al.¹⁵ described the use of recombinant tPA in a case series of nine patients. The authors observed a 22% recanalization rate and reported significant morbidity and mortality, (two deaths and three morbidities).¹⁵ Following those publications and the appearance of antiplatelet agents as inhibitors of the glycoprotein IIb/IIIa receptor, lytic agents as Urokinase or tPA are no longer used as first-line therapy by most teams facing an acute thromboembolic complication.

In the past 10 years, several series have shown that Abciximab injection for thromboembolic complication during coiling was associated with a low complication rate. However, a large number of the aneurysms treated in these papers were unruptured, and most of the papers included ruptured and unruptured aneurysms.^{8,10,11,16,17} Tirofiban is a shorter-acting and reversible glycoprotein IIb/IIIa receptor inhibitor. According to Jeon et al. and Bruening et al., intra-arterial Tirofiban and Abciximab exhibited similar safety and recanalization rates.^18,19

In our series, we used Abciximab injection in 5.3% of our ruptured aneurysm treatment cases; 81% of the clots appeared at the coil/artery interface. We generally injected the Abciximab via the microcatheter already in place in order to be as close as possible to the clot, as suggested by Duncan et al.²⁰ Some authors have advocated that local IA delivery of Abciximab by a microcatheter, placed in the parent vessel, may require smaller doses of the agent and therefore may decrease the risk of hemorrhagic complications.⁶ However, this is not proven and was not our strategy; likewise, the benefit of injecting Abciximab via the microcatheter rather than through the guiding catheter or intravenously is also unproven, despite some data from the cardiologic literature.¹²

On the early post-operative imaging, we observed new onset of bleeding in four patients (9.5%). These numbers may seem high, but three-quarters of the new instances of intracranial bleeding were minimal and not clinically relevant. The only concerning bleeding we observed was an important extension of a pre-existing hematoma versus a re-bleeding of the aneurysm (Figure 2). Regarding ischemic changes, we observed new lesions in 14 patients (33%). However, 74% of our population still achieved a mRS score of 2 or less at 3–6 months, which is comparable with the 3–6 months follow-up mRS of ISAT patients.²¹ In any case this is a retrospective study not designed and not powerful enough to discuss the efficacy of Abciximab.

Conclusion

The use of Abciximab as a first-line treatment in thrombotic complications during coil embolization of ruptured cerebral aneurysm seems safe. In this series we did not observe concerning bleeding around the ventricular shunt trajectory even though shunts were placed less than 24 h prior to Abciximab injection 14 times.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

None declared.