Neurological outcomes of flow-diverter stent placement for middle cerebral artery aneurysms, with reference to the effects of argatroban on ischemic events: patient series

Abstract

BACKGROUND

A systematic review and meta-analysis of flow-diverter stents (FDSs) for the treatment of middle cerebral artery (MCA) aneurysms reported concerns about ischemic complications during treatment. The authors report on the intraoperative and postoperative complications of unruptured MCA aneurysms and their control strategies at their hospital, with detailed information on the aneurysms and a review of the previous literature.

OBSERVATIONS

Intraoperative and perioperative in-stent thrombus occlusion occurred in 3 (37.5%) of the 8 patients evaluated. In cases with in-stent thrombus formation, rapid administration of 10 mg argatroban led to improvement in blood flow, as seen on angiography. Only 1 patient (12.5%) had a symptomatic stroke postoperatively. This patient was admitted for rehabilitation and drug therapy but was discharged from the hospital 10 days postoperatively with a modified Rankin Scale (mRS) score of 1. The patient had an mRS score of 0 at 90 days after surgery and at the last observation.

LESSONS

Ischemic complications require attention during FDS treatment for MCA aneurysms. The use of argatroban in cases of in-stent thrombosis may contribute to a good neurological prognosis.

https://thejns.org/doi/10.3171/CASE24237

Flow-diverter stents (FDSs) are widely used in the treatment of intracranial aneurysms. A systematic review and meta-analysis of FDSs for the treatment of middle cerebral artery (MCA) aneurysms reported concerns about ischemic complications during FDS treatment for MCA aneurysms.¹ At our institution, we treated 8 cases of unruptured MCA aneurysms with FDSs, of which 3 cases were complicated by intraoperative in-stent thrombosis. However, all of the thromboses were successfully reopened with argatroban, resulting in good outcomes. We report on the intraoperative and postoperative complications of unruptured MCA aneurysms and their control strategies at our hospital, with detailed information on the aneurysms and a review of the literature.

Study Description

Methods of the Study

We investigated the details of intraoperative and postoperative in-stent thrombosis and ischemic events in 8 consecutive patients treated with FDSs for unruptured MCA aneurysms from November 2020 to August 2023. In addition, we examined age, gender, preoperative maximum aneurysm diameter, presence or absence of branching from the aneurysm, smoking history, medical history (e.g., hypertension, diabetes mellitus, dyslipidemia), results of preoperative antiplatelet drug efficacy assessed using the VerifyNOW system (Accriva Diagnostics), postoperative disappearance of branching vessels, and modified Rankin Scale (mRS) score at discharge, 90 days after surgery, and at the last observation.

Method of Treatment

All patients continued dual antiplatelet therapy (DAPT) with a P2Y12 receptor inhibitor (clopidogrel or prasugrel) and a cyclooxygenase (COX)–1 inhibitor (aspirin), which commenced 1 week before surgery. Preoperative evaluation with the VerifyNOW system was used to determine the efficacy of the antiplatelet agents. COX-1 inhibitors were judged to have an adequate response when their aspirin reaction units (ARUs) were < 550, and P2Y12 receptor inhibitors were deemed adequate when P2Y12 reaction units (PRUs) were < 208. Heparin was administered intraoperatively, and surgery was started after confirming an activated clotting time of > 250 seconds. The treatment devices used were an 8-Fr Roadmaster guiding catheter (Goodman) and a 6-Fr SOFIA SELECT (MicroVention-Terumo) intermediate catheter. The microcatheter used was Headway21 (MicroVention-Terumo), and the microguidewire was CHIKAI (Asahi Intecc). The flow redirection endoluminal device (FRED; MicroVention-Terumo) was used as the FDS in all cases, with the size selected according to the diameter of the patient’s vessels.

Postoperative Follow-Up and Management Methods

Cerebral angiography was performed between 6 months and 1 year after surgery to check the aneurysm obliteration rate. DAPT was continued until 6 months after surgery. To avoid hemorrhagic complications, DAPT was switched to single antiplatelet therapy (SAPT) in some cases 6 months postoperatively. For this, the VerifyNOW system was again used to measure ARUs and PRUs to confirm the effectiveness of DAPT, after which SAPT was continued. Antiplatelet medication was discontinued in cases in which it was not in the effective range as measured by the VerifyNOW system. If both drugs were in the effective range, 1 of the antiplatelet medications was discontinued at the doctor’s discretion.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

The median observation period in this study was 41 months. Details of the 8 patients are shown in Table 1. Intraoperative and perioperative in-stent thrombus occlusion occurred in 3 (37.5%) of the 8 patients. In cases with in-stent thrombus formation, rapid administration of argatroban 10 mg led to improvement in blood flow, as seen on angiography (Fig. 1). Only 1 patient (12.5%) had a symptomatic stroke postoperatively. This patient was admitted for rehabilitation and drug therapy but was discharged from the hospital 10 days postoperatively with an mRS score of 1; they had an mRS score of 0 at 90 days after surgery and at the last observation. Only 1 patient had cerebral infarction after the perioperative period. This was due to discontinuation of antiplatelet agents 6 months after surgery. Although diffusion-weighted imaging showed high signal intensity, the symptoms were transient and the patient had an mRS score of 0 at the time of discharge. There were no deaths during the observation period, no hemorrhagic complications, including rupture of the aneurysm, and no complications of perianeurysmal inflammation. The mRS score at 90 days after surgery was 0 in all patients. The mRS score at the last observation (median 41 months) was also 0 in all patients.

TABLE 1.

Summary of patient characteristics

Characteristic	Value
Female sex, no. (%)	8 (100)
Age, yrs (SD)	64.6 (10.7)
Smoking, no. (%)	3 (37.5)
Hypertension, no. (%)	6 (75)
Diabetes, no. (%)	0 (0)
Dyslipidemia, no. (%)	4 (50)
Maximum size of aneurysm in mm (SD)	5.1 (0.2)
Branch vessels from aneurysm dome, no. (%)
None	1 (12.5)
Cortical branch	4 (50)
Lenticulostriate artery	1 (12.5)
Cortical branch & lenticulostriate artery	2 (25)
Preop antiplatelet drug efficacy w/ VerifyNOW system, no. units (SD)
ARU	409 (40.7)
PRU	150 (44.2)
Postop O’Kelly-Marotta grading scale, no. (%)
A	0 (0)
B	2 (25)
C	1 (12.5)
D	5 (62.5)
A + B	2 (25)
C + D	6 (75)
Intraop & periop in-stent occlusion, no. (%)	3 (37.5)
Postop symptomatic stroke, no. (%)	2 (25)
Cerebral infarction related to discontinuation of antiplatelet agents, no. (%)	1 (12.5)
Postop ruptured aneurysm, no. (%)	0 (0)
mRS score at discharge, no. (%)
0	7 (87.5)
1	1 (12.5)
2–6	0 (0)
mRS score after 90 days postop, no. (%)
0	8 (100)
1	0 (0)
2–6	0 (0)
Postop loss of branching vessels, no. (%)	2 (25)

FIG. 1.

A typical case of MCA occlusion due to intraoperative in-stent thrombus. Preoperatively, the efficacy of antiplatelet agents was determined using the VerifyNOW platelet testing system and confirmed to be satisfactory (PRUs: 163, ARUs: 425). Branching of a cortical branch from the dome of the aneurysm (A). The MCA was occluded 15 minutes after implantation of the FRED as an FDS (B). The stent was deployed to cover the aneurysm neck (C). Peripheral vascularity was well visualized after argatroban administration (D). On the day after surgery, the patient was asymptomatic, although high-intensity dot-like signals, indicative of ischemic changes, were observed on diffusion-weighted magnetic resonance imaging (E).

The median timing of postoperative follow-up cerebral angiography was 12 months. Although the aneurysm branch vessel was occluded in 2 cases (25%; Fig. 2), neither case presented ischemic symptoms or ischemic signals on magnetic resonance imaging. The aneurysm obliteration rate was better than 95% in 6 of the 8 patients (75%).

FIG. 2.

Typical case of asymptomatic branch vessel occlusion on cerebral angiography performed 1 year postoperatively in a case without intraoperative branch vessel occlusion. Preoperatively, the efficacy of antiplatelet agents was determined using the VerifyNOW platelet testing system and confirmed to be satisfactory (PRUs: 137, ARUs: 391). Branching of a cortical branch from the dome of the aneurysm (A). The MCA was occluded 10 minutes after implantation of the FRED as an FDS (B). The stent was deployed to cover the aneurysm neck (C). Cerebral angiography performed 1 year after surgery showed obliteration of the aneurysm and occlusion of the branch vessels from the aneurysm (D). No neurological symptoms were observed postoperatively.

Observations

In this study, 8 patients with unruptured MCA aneurysms were treated with FDSs. Although some patients developed ischemic complications immediately after surgery, all patients had a good mRS score of 0 at 90 days after surgery and at the last observation (median 41 months). Cagnazzo et al. conducted a systematic review and meta-analysis including 12 studies of FDS treatment for unruptured MCA aneurysms and concluded that FDS treatment for MCA aneurysms should be limited to cases in which conventional treatment is not feasible, because postoperative complications were seen in 20.7% of cases and permanent residual effects were seen in 10.3% of cases.¹ In our case series, argatroban was administered to 3 patients who developed perioperative in-stent thrombosis. Argatroban, a direct thrombin inhibitor, reportedly inhibits thrombus formation via its selective antithrombin activity.² It is reportedly fast-acting and short-acting, with a low bleeding rate.³ In a randomized clinical trial, the combination of argatroban and DAPT in the treatment of acute stroke did not increase the risk of bleeding and was safer than DAPT alone.⁴ Intravenous tirofiban, which is a selective platelet GPIIb/IIIa antagonist, has also been used for the treatment of in-stent thrombosis in FDSs, although its safety is questionable because of reports of intracerebral hemorrhage caused by tirofiban and the recurrence of in-stent thrombosis after discontinuation of its administration.⁵ There are also reports of the intraoperative disappearance of a thrombus in FDSs with argatroban.⁶ Although argatroban has no thrombolytic effect, it has been shown to induce a relative predominance of the fibrinolytic system by inhibiting coagulation.⁷ In our study, argatroban treatment of in-stent thrombosis resulted in the disappearance of the thrombus and good outcomes. Since there is no effective treatment for acute occlusion caused by an in-stent thrombus following FDS treatment, we hope that this study will be useful for guiding future research.

Most of the FDSs used in the studies analyzed by Cagnazzo et al. were the Pipeline embolization device (Covidien) or the Silk flow diverter device (Balt Extrusion).¹ All FDSs used in our study were FREDs. The FRED is a two-layered stent consisting of an inner mesh with low porosity and an outer stent with high porosity. Only 80% of the central part is double-layered, with the inner mesh mainly exerting flow-diversion effects on the neck of the aneurysm.⁸ The remaining 20% of the outer portion, at the proximal and distal ends, has the advantage of consisting of a single outer stent layer to protect the perforating vessel from the mother vessel.⁹ The use of FREDs, which have a different structure from that of conventional FDSs, may also contribute to the low ischemic complication rate. However, FREDs have a higher thrombogenic potential than other FDSs; hence, the use of clopidogrel, a P2Y12 inhibitor, is recommended.¹⁰ We also used P2Y12 inhibitors preoperatively in our cases and confirmed their efficacy using the VerifyNOW system before surgery. Although we used FREDs at our facility, FRED X has recently been introduced worldwide. FRED X is a new version of the FRED, with the application of a specific antithrombotic surface treatment to the stent. Although this stent is reported to have fewer thrombotic complications, a previous multicenter study reported that ischemic complications occurred in 4.3% of patients, 2.4% of patients had intraoperative in-stent occlusion, and postinterventional neurological morbidity and mortality rates were 1.9% and 1.2%, respectively.⁵ Thus, intraoperative stent occlusion remains a serious complication that might occur regardless of the type of FDS used.

In the present study, FRED was used as the FDS for MCA aneurysms, but coil embolization and the Woven EndoBridge (WEB; MicroVention-Terumo) device are other options for endovascular treatment of MCA aneurysms. However, since lenticulostriate arteries and branching vessels were observed from the aneurysm and aneurysm neck in 7 of our 8 cases, there was concern about coil occlusion and subsequent ischemic complications. In addition, all of the aneurysms originated from the lateral aspect of the mother vessel, making it difficult to deploy the WEB. Hence, we used FDSs in our cases.

Seven of the 8 patients in the present study had branching vessels from the aneurysm dome. In this case series, 2 patients developed postoperative occlusion, both of whom were asymptomatic. In their review, Cagnazzo et al. also reported that 26% of the side branches of the MCA were occluded or had reduced blood flow, but only 2.7% of them were symptomatic.¹ The vessels affected in our study were all cortical branches, which were early bifurcations,¹¹ with branching into the cortex from the M1 portion of the MCA. Complementarity between cortical vessels has been demonstrated in leptomeningeal anastomoses,¹² and it has been reported that ischemic complications do not usually occur following FDS treatment in patients with complementary collateral vessels even if the vessels imprisoned by the FDS are subsequently stenosed or occluded.¹³ It is thus possible that the complementarity of intracranial vessels works to prevent symptomatic ischemic complications.

Lessons

Although ischemic complications require attention during FDS treatment for MCA aneurysms, antiplatelet therapy with a P2Y12 inhibitor before surgery and the use of argatroban in case of in-stent thrombosis may contribute to a good neurological prognosis. FDS treatment of aneurysms at early bifurcations may be associated with a relatively low occurrence of postoperative ischemic complications due to the complementarity of the bifurcating vessels.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Yoshida, Kamatani, Maruyama, Hashiguchi, Go. Acquisition of data: Yoshida, Hashiguchi. Analysis and interpretation of data: Yoshida, Hashiguchi, Yasaka. Drafting the article: Yoshida, Tashiro, Hashiguchi, Yasaka. Critically revising the article: Yoshida, Tashiro, Hashiguchi, Yasaka. Reviewed submitted version of manuscript: Yoshida, Tashiro, Hashiguchi, Yasaka, Go. Approved the final version of the manuscript on behalf of all authors: Yoshida. Statistical analysis: Yoshida, Hashiguchi. Administrative/technical/material support: Yoshida, Takigawa, Hashiguchi, Aikawa. Study supervision: Yoshida, Kazekawa, Hashiguchi, Yasaka, Go.

Correspondence

Shinichiro Yoshida: Fukuoka Neurosurgical Hospital, Fukuoka, Japan. fkewk902@gmail.com.