Feasibility of single antiplatelet therapy after stent assisted coiling for ruptured intracranial aneurysms

Patient population

Cases of RIAs treated at our institute were retrospectively collected from January 2017 to December 2022 upon institutional review board approval. A total of 211 consecutive RIAs were treated with endovascular treatment.

Among them, we only enrolled patients who only had a single RIA treated with SAC. The following cases were excluded: RIAs treated without stent deployment, those treated with flow diverters, fusiform, blood-blister, or multiple aneurysms, and those with prior dual antiplatelet or anticoagulant medication. In total, 77 aneurysms in 77 patients were finally included and reviewed. All these patients received SAPT with aspirin following the procedure. This group was named the “SAPT-RIA group.”

For comparison, albeit not in a main-stream group, we also collected information on the patients who underwent DAPT following SAC for UIA during the same period. A total of 99 aneurysms in 99 patients were included and reviewed in this group. This group was named the “DAPT-UIA group”. Similar to the SAPT-RIA group, only cases with a single treated aneurysm were enrolled, with the same exclusion criteria applied. All treated aneurysms in both groups were packed at least above Raymond-Roy occlusion class 2.

Patient information was collected including age, sex, underlying disease, history of previous medication, aneurysm size, and location. Information related to thromboembolism such as high signal on the post-procedural diffusion-weighted image (DWI) magnetic resonance imaging (MRI), identification of acute in-stent thrombosis during the procedure and symptomatic cause of thromboembolic infarction was also included and reviewed.

Peri-procedural antiplatelet and anticoagulation management

In the case of UIA, DAPT (aspirin and clopidogrel) was administered at doses of 100 mg and 75 mg, respectively, for 5 days before the procedure. After the procedure, patients who underwent SAC were administered DAPT for 3 months. Thereafter, single aspirin medication was maintained for 9 months.

On the contrary, in the case of RIA, no pre-procedural antiplatelet medication was administered. Furthermore, no intravenous heparin injection was administered during the procedure. Without loading dose administration, only 100mg daily aspirin was administered immediately following the procedure with two doses of low molecular heparin injection at 12-hour intervals and thereafter, only SAPT was maintained for a year.

Endovascular procedure

Under general anesthesia, all the procedures were performed by an experienced neuro-interventionist. Contrary to the UIA procedure, no initial bolus heparin injection was administered intravenously at the beginning of the procedure. However, all the catheters were flushed by using a continuous irrigation system to avoid embolism caused by air bubbles. All flushed saline was heparinized (1000 IU/100 mL), and the guiding catheters and microcatheters were exposed to a continuous heparinized drip.

Standard approaches were generally performed through the right common femoral artery. A 6-French guiding catheter was advanced into the internal carotid artery or vertebral artery. After placing a microcatheter into the sac, embolization coils were inserted. A variety of coils were used to fill the sac. All the cases of aneurysms enrolled in this study were treated using stent-assisted techniques. Stent types varied based on the situation; however, open-cell stents such as Neuroform EZ and Neuroform Atlas (Stryker Neurovascular, Kalamazoo, MI, USA) were more commonly used than closed-cell stents such as Enterprise (Cerenovus, Miami, FL, USA) and low-profile visualized intraluminal support [LVIS] (MicroVention, Aliso Viejo, CA, USA). After completing the procedures, post-procedural angiography was performed to determine evidence for the presence of parent or perforating artery occlusion. After completing the procedure, all the patients were closely monitored in the neurosurgical intensive care unit.

When hyperacute thrombosis occurred during the procedure, including in-stent thrombosis, localized intra-arterial (IA) tirofiban injection was administered. We injected tirofiban via a microcatheter located near the thrombus to deliver the smallest effective dose of the drug, a maximum of 0.5 mg, to the closest sites of the clot, which was administered only when sufficient aneurysm protection was identified.

Post-procedural MRI and thromboembolism detections

DWI MRI was routinely performed on the day following the procedure, usually approximately 24 hours after the procedure. DWI-positive lesions were measured manually on the axial images in the institutional picture archiving and communication system (PACS, INFINITT Healthcare, South Korea). A positive sign on follow-up DWI was defined as a high signal intensity lesion regardless of the side of the coiled aneurysm. We did not count a single tiny lesion; only an area of more than 3 mm2 was considered as DWI positive.

We only identified the post-procedural complications related to thromboembolism. Symptoms that occurred immediately after the procedure were considered thromboembolic complications. In contrast, symptoms related to subarachnoid hemorrhage such as delayed ischemia due to vasospasm and certain disorders caused by hydrocephalus were not included as complications.

Statistical Analysis

Statistical analysis was performed using SPSS version 26.0 (SPSS Inc., IBM Corp., Armonk, NY, USA). We performed Fisher’s exact test to analyze the normal variables. Mann-Whitney U test was employed for the analysis of the numerical variables. Statistical differences were considered significant at p-values <0.05.

Patient characteristics in the SAPT-RIA and DAPT-UIA group

The SAPT-RIA and DAPT-UIA groups were compared in all the suggested tables. The baseline characteristics of both groups were summarized in Table 1. In the SAPT-RIA group, there were 62 women and 15 men with a mean age of 67.6. In the DAPT-UIA group, there were 81 women and 18 men with a mean age of 61.9. All the baseline characteristics of the patients between the two groups were statistically insignificant, except for age. The average age of patients was higher in the SAPT-RIA group (67.6±11.5) than in the DAPT-UIA group 61.9±10.8).

Table 1.

Patient characteristics of the SAPT-RIA and DAPT-UIA group

The characteristics of the aneurysms are summarized in Table 2. A total of 77 saccular aneurysms were included in the SAPT-RIA group. 62 internal carotid arteries, three middle cerebral arteries, four anterior cerebral arteries, and eight posterior circulation artery aneurysms (six basilar top, one vertebral, one posteroinferior cerebellar artery) were included. The mean maximum diameter of the aneurysms in this group was 8.07 mm. In the DAPT group, 99 aneurysms were included, 81 internal carotid artery, five middle cerebral artery, three anterior cerebral artery, and 10 posterior circulation artery aneurysms (nine basilar top, one posteroinferior cerebellar artery) were included. The mean maximum diameter of the aneurysms in this group was 6.32 mm.

Table 2.

Patient characteristics of the SAPT-RIA and DAPT-UIA group

Thromboembolic complications

Thromboembolic complications were summarized in Table 3. DWI positive sign, hyperacute thrombosis, and symptomatic thromboembolism were compared between two groups. There were no significant differences in the proportion of DWI positivity between the two groups. However, the incidence of hyperacute thrombosis during the procedure was significantly higher in the SAPT-RIA group (10.4%). On the contrary, in the DAPT-UIA group, there were no cases of hyperacute thrombosis. The number of the symptomatic complications was only one in each group.

Table 3.

Summary of thromboembolic complications of SAPT-RIA and DAPT-UIA group

Additionally, the types of the stent and thromboembolic complications are reviewed in SAPT-RIA group in Table 4. Incidence of hyperacute thrombosis and post-procedural DWI positivity was slightly higher in the closed-cell type group. However, none of the items showed statistical significant difference between the groups, including thromboembolic symptom. In the subgroup analysis of the SAPT-RIA group using Neuroform stents, the incidence of hyperacute thrombosis was 9.3% for the Neuroform Atlas and 10% for the Neuroform EZ, with no statistically significant difference between the two groups. (p=0.999)

Table 4.

Types of the stent and thromboembolic complications in SAPT-RIA group

Overall findings of this study

In contrast to the UIA cases, ruptured cases can be accompanied with concomitant hydrocephalus, severe cerebral edema, and pulmonary edema, which might require further invasive management such as ventriculostomy, decompressive surgery, tracheostomy, and ventriculoperitoneal shunt. In such clinical conditions, DAPT could result in catastrophic hemorrhagic complications. Prolonged DAPT have been shown to increase the risk of both intra- and extracranial hemorrhages. In addition, the risk of hemorrhagic complication is known to be more dangerous when the DAPT is initially loaded despite being more protective against ischemic events [3,5,22].

In this sense, hemorrhagic complications were implicated in having more significant impact on clinical outcome. Thus, our institution applied SAPT rather than DAPT in cases of SAC for ruptured aneurysms to avoid the aforementioned complications. However, reduction of antiplatelet medication from DAPT to SAPT may increase the risk of thromboembolic complications. So, we focused our attention on the hypothesis that SAPT might not increase thromboembolic complications. Consequently, based on our results, we carefully opinioned that compared to DAPT, SAPT in SAC might not increase the incidence of thromboembolic complications as we expected. Although DAPT is currently the mainstream treatment strategy for SAC, tailored modification of these antiplatelet agents might be needed to reduce hemorrhagic or ischemic complications if necessary and SAPT can be a viable option among these tailored modifications.

Hyperacute thrombosis and the role of local IA tirofiban

In our series, the incidence of hyperacute thrombosis in the SAPT group was higher than that in the DAPT group. We probably assumed that the lack of pre-procedural antiplatelet medication and IV heparin injection during the procedure may have affected these results.

However, despite the incidence of hyperacute thrombosis being quite higher in the SAPT group than in the DAPT group, all thrombosis successfully dissolved after IA tirofiban injection. DWI positivity and the presence of thromboembolic symptoms did not reach statistical significance between the two groups. Considering thromboembolic complications, the overall outcome of the SAPT group was not inferior to that of DAPT group. Therefore, we believe that appropriate IA tirofiban injection could be of sufficient help to overcome the limitations of SAPT.

Several studies have already reported that proper injection of IA tirofiban for hyperacute thrombosis in a ruptured aneurysm is safe and efficient and has a high rate of successful recanalization and a low risk of bleeding complication [6,7]. Moreover, the plasma half-life is quite short (two hours) and platelet function is nearly normalized within four hours following the injection. Therefore, additional procedures such as ventriculostomy and decompressive surgery are not significantly hindered by the injection.

Stent type and the risk of thromboembolism in SAC-RIA

All the open-cell type stents used in this study were Neuroform EZ and Neuroform Atlas (Stryker Neurovascular, Kalamazoo, MI, USA). We assumed that thromboembolic complications were less likely to occur when applying open-cell type stent than closed-cell type stents because the open-cell type stents were supposed to be better with regard to wall apposition. As we assumed, the incidence of acute thrombosis that required IA tirofiban injection was slightly higher in the closed-cell type group. However, the statistical results did not confirm our hypothesis.

Russo et al. suggested that SAC using Neuroform stents in patients with ruptured aneurysm was feasible and effective. Although the reports stated that the overall complications, both ischemic and hemorrhagic, were more frequent in cases of SAPT; however, in the mid-term, the thrombogenic potential of the stent rapidly reduced, allowing SAPT to be comparable with DAPT [28].

Katsaridis et al. also reported that SAC with the Neuroform2 stent is effective and safe. They even performed the procedure without pretreatment with antiplatelets, similar to our study, and the results were excellent. No thromboembolic events occurred in the postoperative period ranging from 10 days to 18 months [15].

Limitations

There are several limitations in this study. First, this was a non-randomized, single-center retrospective study. Therefore, the results may be influenced by the limitations of the study design related to inherent treatment bias. Second, the absence of an exact control group is an additional limitation. For an accurate comparison, SAPT and DAPT should be compared in the same ruptured aneurysm patient group. However, the number of cases of DAPT in patient with ruptured aneurysm was too small for the analysis. Accordingly, we were reluctant to set a patient group for SAPT in the ruptured cases and DAPT in the unruptured cases. Comparison between the UIA and RIA groups might not be appropriate. Therefore, further prospective randomized controlled studies seem necessary to clarify the present topic.