Endovascular treatment for aneurysm repair has become a widely used method since the publication of results from the International Subarachnoid Aneurysm Trial (ISAT).23) The ISAT demonstrated the safety and efficacy of this technique for the treatment of aneurysms. In wide-necked aneurysms and those with a smaller dome to neck ratio, endovascular coil embolization has some limitations and obstacles to overcome. These include an unstable coil loop and/or coil herniation from the aneurysm to a parent artery or distal arterial branch. Various attempts at overcoming this problem have included, for example, balloon-assisted coil embolization,1)21)22)24)25) the double catheter technique,17) and stent-assisted coil embolization (SAC).2)3)4)5)12)18)20)27)28) Among them, use of an intracranial stent to treat ruptured intracranial aneurysms is controversial. Complications resulting from the use of an intracranial stent in the setting of acutely ruptured aneurysm repair include transient or permanent thromboembolic event provocation. To prevent these thromboembolic events, peri- procedural antiplatelet, heparin, or glycoprotein IIb/IIIa inhibitors are typically administered. Antiplatelet/anticoagulant administration in the setting of an acutely hemorrhagic state may lead to additional hemorrhagic complications including aneurysm re-bleeding, extra-ventricular drainage (EVD)-related hemorrhage. Currently, there are no publicly-available guidelines for the use of peri-procedural antiplatelet/anticoagulant medications, nor have any randomized controlled trials evaluated the proper administration of these medications in this context. Many studies2)3)4)5)12)14)18)20)27)28) have examined the use of aspirin, clopidogrel, heparin, or glycoprotein IIb/IIIa inhibitors as peri-procedural medications. However, to the best of our knowledge, there are no studies of glycoprotein IIb/IIIa inhibitor administration alone as a prophylactic for thromboembolic events following the SAC of ruptured aneurysm (in the three known studies12)19)28) where a glycoprotein IIb/IIIa inhibitor has been used, heparin was also used). There are, however, several randomized controlled trials10)11)13)26)30) that have evaluated glycoprotein IIb/IIIa inhibitor use in ischemic disease (e.g., cerebral infarction and myocardial infarction). There are currently no studies examining whether glycoprotein IIb/IIIa inhibitor use is suitable in the SAC of ruptured aneurysms. In this study, a glycoprotein IIb/IIIa inhibitor, tirofiban, was used alone to prevent thromboembolic events. Tirofiban is a nonpeptide tyrosine derivative that acts as a platelet glycoprotein IIb/IIIa receptor antagonist.9) Our aim here was to evaluate the safety and efficacy of SAC of ruptured wide-necked intracranial aneurysms using only a glycoprotein IIb/IIIa inhibitor.

The publication of the randomized controlled ISAT23) established EVT as a safe and effective therapeutic option. Therefore, treatment of aneurysms by EVT experienced increased popularity. However, when performing EVT, the catheter may act as a contact activator of the coagulation cascade, leading to thromboembolic events and significant thromboembolic risk.8) The same is true of cases of subarachnoid hemorrhage due to a ruptured aneurysm. In the acute phase of subarachnoid hemorrhage, a hypercoagulable state occurs.27) Unlike in EVT of unruptured aneurysms, pre-procedure antiplatelet medications are not administered to these patients, leading to an elevated risk of thromboembolic events. The use of stents in the treatment of wide-necked aneurysms increases the likelihood of thromboembolic events, such as in-stent thrombosis formation. Multiple studies2)3)4)5)7)12)18)20)27)28) of the peri-procedural administration of aspirin, clopidogrel, heparin, or a glycoprotein IIb/IIIa inhibitor during EVT to prevent the occurrence of a thromboembolic event have been conducted, but there are no established guidelines for the use of these drugs in this surgical context. In most studies, systemic heparinization was performed with pre and/or intra-procedural aspirin and clopidogrel for the prevention of thromboembolic events. Glycoprotein IIb/IIIa inhibitors have also been used systemically to prevent thromboembolic events.12)19)28) Bruening et al.5) describe intravenous or intra-arterial injection of glycoprotein IIb/IIIa inhibitors upon the occurrence of thromboembolic events such as in-stent thrombosis or defective parent artery filling. However, as far as are aware, the present study was the first to examine tirofiban administration in SAC without pre- or intra-procedural aspirin, clopidogrel, or systemic heparinization. Although Liang et al.19) reported on the safety and efficacy of tirofiban administration in coil embolization of ruptured aneurysms, they included single coiling without stent deployment. The present study examines only coil embolization with stent deployment. Furthermore, in the present study there was no pre- or intra-procedural aspirin or clopidogrel administration. Tirofiban was loaded just before stent deployment and its administration was maintained for 24 hours. Tirofiban loading and procedures such as stent deployment, additional coil packing were simultaneously performed. Since onset time of tirofiban is rapid, it seems to be enough to prevent the thromboembolic event with tirofiban. While intra-procedural administration of tirofiban may reduce thromboembolic events, it seems likely to increase the likelihood of intra-procedural rupture. However, in the present study, there were no intra-procedural aneurysm ruptures reported. When bleeding occurs due to an aneurysm rupture, platelets aggregate and form a thrombus at the aneurysm rupture site which can stop bleeding. A platelet-rich thrombus might dissolve upon tirofiban administration when the aneurysm is not secured as tirofiban acts to break the dihydrogen sulfate bonds between platelets.29) This eventually contributes to an increased risk for aneurysm re-bleeding. To avoid this potentially catastrophic outcome, in the present study, tirofiban was loaded just prior to stent deployment but after the coil was packed in the rupture site to ensure against re-bleeding. As such, we concluded that no intra-procedural ruptures of aneurysms occurred in our cohort of patients because of tirofiban inhibitor loading prior to securing of aneurysms. If tirofiban had been administered prior to this, aneurysm re-bleeding would have occurred. On the other hand, if tirofiban was administered late, thromboembolic event would have occurred. Tirofiban has some practical advantages over other preventive medications. When used as pre-procedural medications, antiplatelet agents (aspirin and clopidogrel) have to be administered enterally. Alert, conscious patients can take an antiplatelet agent orally, though this requires consumption of a small amount of water. Consumption of any foods or liquids prior to receiving general anesthesia, which can lead to vomiting during intubation or extubation, is associated with an increased risk of aspiration pneumonia. However, if the procedure is delayed to allow for sufficient fasting time before general anesthesia administration, aneurysm re-bleeding risk increases. Additionally, to achieve intra-procedural administration of these drugs, an additional, troublesome nasogastric tube must be inserted. In unconscious patients, nasogastric tube insertion prior to the procedure is necessary for administration of an antiplatelet agent. Nasogastric tube insertion induces the gag reflex and consequently increases blood pressure and intracranial pressure. This also leads to an increased risk of aneurysm re-bleeding. Unlike the difficulties faced in administering these drugs, tirofiban can be simply and conveniently administered intravenously. The short, 1.5-hour half-life of tirofiban9)16) provides an additional practical advantage over other, longer-lived antiplatelet and anticoagulant agents. Should hemorrhagic complications occur during or after the procedure, this shorter half-life allows for decreased exacerbation of hemorrhagic complications. When thromboembolic complications do occur, there is an advantage in applying the same substance previously infused intravenously via intra-arterial injection to treat thromboembolisms. Alurkar et al.2) previously reported two cases with intra-procedural, in-stent thrombosis treated by intra-arterial injection of glycoprotein IIb/IIIa inhibitor without any resultant neurologic deficits. Cho et al.6) and Kim et al.15) have also reported on the safety and efficacy of intra-arterial tirofiban injection to treat thromboembolic events during EVT of ruptured aneurysms. Likewise, when intra-procedural thromboembolic events occurred in the present study cohort, we also obtained good results from the use of intra-arterial tirofiban injection—only five cases of intra-procedure thromboembolic events despite tirofiban use were identified. All of these events comprised in-stent thrombosis, where intra-arterial glycoprotein IIb/IIIa inhibitor injection was done on a case-by-case basis. When delayed contrast filling occurred due to thrombosis formation in one patient, vessel patency was restored with intra-arterial injection of tirofiban. Although just one case, this evidences the safety and efficacy of intra-arterial injection of tirofiban.

While there were no cases of intra-procedural aneurysm rupture reported here, it is critical to note that hemorrhagic complications beyond aneurysm re-bleeding may occur with anticoagulant use. Extra-cranial hemorrhagic complication such as complicated hematoma or gastro-intestinal bleeding may occur. In the present study, there were no cases of complicated hematoma, though one case of upper gastro-intestinal bleeding and one case of delayed intracerebral hemorrhage which was not related to aneurysm were reported. Despite the concern that tirofiban use in the acute phase of SAH may lead to intra-procedural rupture of aneurysms, tirofiban proved to be a relatively safe and efficacious medication for the prevention of thromboembolic complications.

This study has several limitations. First, it uses a retrospective design and is therefore subject to selection bias. Second, it results from data collected at a single center study with a relatively small patient population which does not provide the power to ensure the broader safety and efficacy of tirofiban. Finally, this study faces the limitation that it contains no true control group as all patients were prescribed tirofiban, as is dictated by best clinical practice guidelines at our institution. While other medical centers may use a glycoprotein IIb/IIIa inhibitor, centers cannot universally treat patients identically as various procedural and clinical factors (e.g., endovascular procedure technique used, neuro-interventionist competence and experience, etc.) will differ.

There is concern about the exclusive use of tirofiban to prevent thromboembolic events in stent-assisted coil embolization. However, in the present study, we report the outcomes of ruptured wide-necked intracranial aneurysms treated with SAC with tirofiban alone and conclude that its use is both relatively safe and therapeutically efficient.