Initial Experience with the Use of Intravenous Eptifibatide Bolus during Endovascular Treatment of Intracranial Aneurysms

Procedure

All procedures were performed with the patients under general anesthesia with intraoperative neurophysiologic monitoring (spectral electroencephalography, somatosensory evoked potential, and/or brain stem auditory evoked potential). A 6F guide catheter was placed in the cervical target artery proximal to the aneurysm. Systemic heparinization was routinely achieved before catheterization of all aneurysms to maintain activated clotting time at 250–300 seconds. A microcatheter and microwire were gently navigated into the aneurysm. All coils were introduced into the aneurysms using simultaneous biplane imaging with road-mapping until angiographically complete obliteration was achieved or until the risk of occluding a normal arterial branch adjacent to the aneurysm seemed imminent. Heparin was not reversed postprocedure, and when eptifibatide was given as a bolus, patients were not maintained on continuous intravenous heparin infusion for the usual 12–24 hours postprocedure. Eptifibatide was used during 84 procedures for various reasons (Table 1), with a bolus dose of 180 μg/kg administered intravenously. No patient received continuous infusions postprocedure.

The rationale for eptifibatide infusion in this cohort was as follows: (1) The rate of thromboembolic events in the literature based on small case series during placement of a Neuroform stent (Boston Scientific, Natick, Mass) is 7%–10%.^16,17 (2) Broad-necked and larger aneurysms have a higher likelihood of asymptomatic MR imaging/diffusion-weighted imaging hyperintensities¹⁸ as a result of either longer procedure times, more sophisticated techniques (dual catheter technique, balloon remodeling), higher risk of coil protrusion in the parent vessel, or higher likelihood of unorganized thrombus formation.¹⁹ (3) Coil prolapse into the parent vessel has been shown to be an independent risk of a postprocedural ischemic event.⁶ This may be due to embolization of metal fragments or platelets from the protruding coil mass.^20,21 Likewise, coil fracture within the parent vessel is a risk of thromboembolic events. (4) Recoiling of a previously embolized aneurysm may carry higher rate of thromboembolic events² during deposition of coils into a coil mass with likely unorganized thrombus within the aneurysm. Recanalized aneurysms probably have early invasion of clot and are thus less likely to form a stable fibrin matrix.²² During recoiling, some loose clot may theoretically dislodge into the parent vessel. (5) Multilobed aneurysms and aneurysms with interstitial filling were believed to be at higher risk for ischemic events as a result of the potential for thrombotic material to exit the coil mass because of incomplete stagnation of flow.

Eptifibatide was not reversed with platelet transfusion unless a bleeding complication was noted. The femoral artery puncture site was closed using a suture-mediated closure device (Perclose; Abbott Vascular Devices, Redwood City, Calif). Postprocedure, patients with ruptured aneurysms were managed in the neurosurgical intensive care unit. Patients with unruptured aneurysms treated without complication were observed in a neurosurgical stepdown unit for 24 hours before discharge. In cases of placement of a Neuroform stent, patients were loaded with 300 mg of clopidogrel and then placed on 75 mg/day clopidogrel and 325 mg/day aspirin postprocedurally for 30 days and then 325 mg/day aspirin indefinitely.

An external ventricular drainage (EVD) system was placed in patients with hydrocephalus preprocedure secondary to a ruptured cerebral aneurysm (n = 14). Only 1 patient required an EVD postprocedure. This was performed 14 hours after coil embolization.

Cases in which eptifibatide-related complications and procedure-related complications occurred were identified. Any bleeding or thromboembolic complication or change in neurologic status was recorded. In addition, any instances of thrombocytopenia (platelet count <100,000/mL) were recorded.

Clinical Outcome

Overall, there were 4 deaths (4.7%) and 3 persistent neurologic deteriorations (3.6%). Of 4 patients who died, 2 patients were Hunt and Hess grade V, 1 was grade III, and 1 was grade 0. Two grade V patients died from diffuse cerebral edema on the 1st and 5th postoperative days, respectively. One grade III patient died from increased bleeding after an intraprocedural aneurysm rupture, and 1 grade 0 patient died 6 months later secondary to a contralateral middle cerebral artery (MCA) stroke and pneumonia. Only 1 of these deaths was felt to be partially attributable to the use of eptifibatide (patient with intraprocedural aneurysm rupture).

Three patients suffered persistent (>24 hour) clinical deterioration. The first patient became permanently hemiparetic after intentional ICA sacrifice for a ruptured paraclinoid aneurysm. The patient suffered an infarct as a result of hemodynamic impairment as seen on MR imaging perfusion/diffusion imaging. The second patient underwent unsuccessful clipping of a ruptured posterior communicating aneurysm but underwent craniectomy for a swollen brain. Endovascular coiling was then attempted, but the aneurysm was perforated during coiling and thus therapeutic carotid occlusion was performed. Eptifibatide was administered after successful sacrifice of the carotid was performed. The patient has remained hemiparetic from the hemorrhage secondary to the perforation of the aneurysm at 6-month follow-up. The third patient had a ruptured MCA bifurcation aneurysm that was coiled using Neuroform stent assistance. A subsequent thromboembolism to an MCA division occurred despite eptifibatide prophylaxis. Postprocedure head CT showed hemorrhagic conversion of the infarct that was probably caused or worsened by the eptifibatide. The patient underwent decompressive craniectomy and survived but has not regained independent function. This was the only patient with a thromboembolic complication despite eptifibatide prophylaxis and intracranial hemorrhage as a result of eptifibatide in combination with clopidogrel and aspirin.

Complications

During the 38-month period reviewed, of the 84 procedures performed with eptifibatide, 2 patients (2.4%) had an intraprocedural aneurysm rupture. In both of these patients, an EVD was inserted preprocedure. In the 77 procedures in which eptifibatide was given prophylactically, only 1 patient (1.3%) developed a thromboembolic event. There were 5 overall (5.9% [total cohort]) bleeding complications attributable to eptifibatide. Intracranial hemorrhages attributable to eptifibatide occurred in 2 patients (2.4% [total cohort]/6.3% [ruptured aneurysm group]) with ruptured aneurysms (Table 3). A third patient with an intraprocedural rupture of an aneurysm was given eptifibatide after sacrifice of the ICA as described above. In this patient, it is unlikely that eptifibatide contributed to the intracranial hemorrhage because the drug was administered after emergent sacrifice of the ICA as a result of aneurysm rerupture. In addition, no bleeding complications were noted along the catheter tract in the 14 patients receiving EVDs preprocedure. The 1 patient treated with an EVD after embolization also had no intracranial bleeding complications as a result of EVD placement.

Vascular access site hematoma occurred in 3 (3.6% [total cohort]) procedures. All 3 patients were managed with conservative measures and blood transfusions.

Characteristics of GP IIb/IIIa Antagonists

GP IIb/IIIa inhibitors can potentially enhance thrombolysis via the following mechanisms: (1) prevention of platelet aggregation, leading to reduction both in thrombus mass and the platform for further thrombin generation; (2) inhibition of release of local thrombolysis inhibitors of by platelets; and (3) weakening of the clot structure by decreasing the binding of factor XIII, fibrin, and α-2 plasminogen inhibition.²⁴

Currently, there are 3 FDA-approved GP IIb/IIIa receptor antagonists: abciximab, tirofiban, and eptifibatide (Table 5). Abciximab (ReoPro), a large compound, has a strong receptor affinity, long plasma half-life, and low plasma concentrations, making it difficult to reverse bleeding complications with platelet transfusions.²⁵ Eptifibatide (Integrilin) and tirofiban (Aggrastat) are small compounds that have lower receptor affinity and higher plasma levels and are shorter-acting than abciximab.²⁶

Eptifibatide has theoretical advantages over abciximab in patients undergoing coil embolization procedures. First, it is less likely to induce thrombocytopenia because of its small molecular weight.²⁷ Second, it is less antigenic and thus has a lower probability of causing an adverse immune response such as that has been reported after abciximab administration.²⁸ Third, it has a low GP IIb/IIIa receptor affinity and is thus quickly reversible within 2–4 hours.²⁶ This factor is important in patients who harbor ruptured aneurysms and may require procedures in the intensive care unit including EVD systems. Despite its short half-life, the potential for significant hemorrhagic complications resulting from procedures performed within hours after its administration is of greatest concern and we currently administer eptifibatide in patients with ruptured cerebral aneurysms only if an EVD is already in place.

There are several limitations to this retrospective study and considerations to the use of eptifibatide in endovascular procedures: (1) We included 8 patients with poor Hunt-Hess grades in whom it may have been difficult to detect postcoiling focal neurologic deficits consistent with a thromboembolic event. In an attempt to account for this issue, all surviving patients with SAH had serial head CT scans that were used as a surrogate to determine whether new ischemic insults had occurred. (2) Small, clinically silent thromboembolic events can occur, and postprocedure MR imaging scans were not obtained; these would probably have been more sensitive in detecting such events. (3) Eptifibatide was ordered by the treating physician whenever it was thought that the drug was clinically indicated but without any prospectively established criteria. This makes an accurate assessment of who stands to benefit from this therapy difficult. Nonetheless, this study does provide a framework for a prospective randomized trial investigating the role of eptifibatide in reduction of morbidity associated with thromboembolic events after endovascular procedures both for unruptured and possibly for ruptured aneurysms.