Comparison of Enterprise stent 2 with 1 in assisting coiling of ruptured aneurysms: a real-world study

The present study is an extension of previous research that evaluated the clinical effectiveness and safety of the first-generation Enterprise (E1) stent in the setting of acute subarachnoid hemorrhage attributable to ruptured intracranial aneurysm (IA). The same study protocol and data collection forms were used in the extension and the data collected from both stages were combined in the analysis. In brief, the study was a single-center, retrospective, observational study based at a tertiary hospital in China. The hospital's electronic medical information system was screened for patients presenting with subarachnoid hemorrhage and treated with E1 (from January 2013 to 2018) or the second-generation Enterprise (E2) stent (from 2018 to November 2020). Patients were included if they had been diagnosed with ruptured IAs and treated with E1 or E2 SAC and had had at least one post-procedural follow-up visit. The Hunt and Hess grading system and Fisher scales were used to rate the severity of subarachnoid hemorrhage [10,11]. Patients were excluded if they met any of the following exclusion criteria: comatose status (Hunt and Hess grade V) attributable to subarachnoid hemorrhage; subarachnoid hemorrhage caused by conditions other than IA such as brain arteriovenous malformation or arteriovenous fistula; and treatment with vascular reconstruction devices other than the Enterprise vascular reconstruction device and delivery system. The numbers of cases and causes of death were described if patients died during hospitalization.

The local institutional ethical review committee approved this study and waived informed consent, as the data were collected from routine patient care and analyzed retrospectively in an anonymous fashion.

Interventional embolization was the first choice for the treatment of ruptured aneurysms, including patients with hematoma without obvious space-occupying effect, especially simple coiling at the authors' institute. SAC was used primarily for wide-necked and dissecting aneurysms. Some patients underwent craniotomy due to rebleeding or vasospasm. For patients with multiple aneurysms, the responsible aneurysm was identified by experienced neurointerventional physicians and neurosurgeons according to the clinical and angiographic conditions. The responsible aneurysm was treated first. The rest of the aneurysms were also treated simultaneously if simple coiling could be achieved. Otherwise, they were treated at the second stage. If the responsible aneurysm was difficult to identify, all aneurysms with a high risk of rupture were treated simultaneously.

The anti-platelet regimens entailed several anti-platelet medications administered in the following sequence. A loading dose of aspirin and clopidogrel (300 mg each) are given either orally or by anus for patients with ruptured aneurysms planning stent placement before the procedure. At the beginning of the procedure, 60–80 units/kg of heparin were administered, followed by a half dose every 2 h. Dual anti-platelet drugs (aspirin 100 mg daily and clopidogrel 75 mg daily) were administered for 6 weeks followed by only aspirin, which patients were instructed to use indefinitely. If there was in-stent thrombosis during embolization, tirofiban was given through microcatheter or guiding catheter and pumped intravenously at the same time.

The following effectiveness end points were included in the outcomes evaluation: duration of the procedure, stent placement success rate, immediate embolism rate, patient functional outcomes at discharge and at 3 months and 6 months post-discharge and cumulative aneurysm recurrence at 6 months post-discharge. The degree of aneurysm treatment success was graded based on the digital subtraction angiography (DSA) images according to the revised Raymond–Roy occlusion classification (RROC) criteria [12] immediately after the procedure – class I: complete obliteration; class II: residual neck; class IIIa: residual aneurysm with contrast within coil interstices; and class IIIb: residual aneurysm with contrast along aneurysm wall. The recurrence of aneurysms was defined as at least one level worsening with respect to aneurysm occlusion as determined by the RROC during follow-up compared with that immediately post-surgery, regardless of the need for retreatment [13]. The authors used the Modified Rankin Scale (mRS) score to measure patient functional outcomes. The mRS is a six-point disability scale with possible scores ranging from 0 (no symptoms at all) through 5 (severe disability) [14]. Patients with mRS scores ≤2 were in general considered to have good functional outcomes and those with mRS scores ≥3 were considered to have functional impairment. The safety end point was examined by documented stent-related complications, which were defined as events that occurred during the procedure or hospitalization period such as reruptured aneurysms, hemorrhages associated with external drainage of the brain, in-scaffolding thrombosis and stent disposition. Thromboembolic complications were diagnosed intraoperatively on DSA or CT/MRI scans indicating new infarcts, performed in cases of unexpected neurological compromise.

The primary focus of the analysis was to compare the outcomes of interest between patients treated with E2 and those treated with E1. In univariate analysis, for continuous variables, the data were reported as means ± standard deviation (SD), and the two-sample t-test or Wilcoxon rank test was used for the group comparisons as appropriate. For categorical variables, the percentages were calculated with the denominator tabulated from non-missing data unless noted otherwise. The Chi-square or Fisher exact test was used to test the group differences where appropriate. Since the frequency and duration of patient follow-ups were at the discretion of the treating physicians, the cumulative recurrence rate of aneurysms was estimated using the life-table method, which accounts for the duration of follow-ups.

To adjust for the baseline variables that could confound the findings (including age, gender, diabetes, high blood pressure, smoking, Hunt and Hess grade, Glasgow Coma Scale [GCS] score, Fisher scale score, presence of hematoma, aneurysm size, aneurysm width, aneurysm neck width, aneurysm height and stenting technique) in univariate analysis, multivariate logistic regression analysis was fitted by the backward stepwise approach, with all potential confounding factors being included at the initial step. In all analyses, two-tailed p-values were reported for the null hypothesis of no difference between the E1 and E2 stents, and the threshold for statistical significance was p < 0.05. All statistical analyses were conducted using the R version 3.5.3.

A total of 360 patients met the study criteria and were included in this analysis; of those, 270 received first-generation Enterprise (E1) and 90 patients were treated with second-generation Enterprise (E2).

Table 1 highlights the patients' demographic characteristics, current smoking and drinking status, notable medical history and clinical presentations at hospital admission. In both E1 and E2 groups, the mean age was near 60 years old, with females accounting for more than two-thirds of the study population; fewer than 10% were current alcohol drinkers or cigarette smokers. When admitted to the hospital, three-quarters of the patients in both groups presented with high blood pressure, and the patients in both groups had nearly identical GCS scores (13.5 ± 2.6 vs 13.5 ± 2.8). However, the patients in the E2 group had significantly higher grades on both the Hunt and Hess scale (p < 0.001) and the Fisher scale (p = 0.002). The presence of intracranial hematomas, acute hydrocephalus and multiple aneurysms was similar between the two groups.

The distribution of aneurysm locations was similar, with slightly more than half of all aneurysms located at the posterior or anterior communicating artery in both groups (E1:57.1%; E2:50.9%), followed by the middle cerebral artery (E1:13.0%; E2:16.4%) and posterior cerebral artery (E1:8.4%; E2:6.4%). The measurements of aneurysms were comparable across the two groups as well, with mean aneurysm widths of 4.6 ± 2.8 mm (E1) and 4.8 ± 2.8 mm (E2) and height at 4.7 ± 2.9 mm (E1) and 4.9 ± 2.7 mm (E2), respectively. Tabulated by aneurysm size, about half of the aneurysms were considered small (<5 mm) and the remaining were medium (5–15 mm) in both groups.

The univariate perioperative outcomes are displayed in Table 2. The operation time was significantly shorter for the E2 group than for the E1 group (166.3 vs 190.3 min; p = 0.008), and the length of the hospital stay was shorter for the E2 group, but the difference did not reach statistical significance. For both E1 and E2, all stents were successfully deployed during the procedure, with a 100% technical success rate of stent placement. Post-procedural arteriography confirmed that slightly over 75% of the patients achieved complete obliteration (class I) in both groups.

Overall, 16.4% and 7.8% of the patients in the E1 and E2 groups, respectively, encountered procedure-related complications (p = 0.044). In both groups, in-stent thrombosis was the most common procedure-related complication (E1:11.9%; E2:7.8%), and all but one patient in each group was successfully managed with infusion of thrombolytics. Three patients in the E1 group died during hospitalization due to gastrointestinal bleeding, rerupture of the aneurysm and respiratory and circulatory failure. One patient in the E2 group died due to cerebral herniation secondary to intracranial bleeding.

At discharge, 81.1% and 78.7% of the patients in the E1 and E2 groups, respectively, exhibited good functional outcomes (mRS ≤2; p = 0.612).

By 3 months post-discharge, six patients from the E1 group and two patients from the E2 group experienced aneurysm recurrence based on RROC. By 6 months post-discharge,an additional ten patients from the E1 group and two patients from the E2 group had aneurysm recurrence, resulting in estimated 6-month cumulative recurrence rates of 14.9% and 13.3%, respectively, after accounting for loss to follow-up using the life-table method.

By 6 months post-discharge, about four of five patients in both groups experienced good functional outcomes (E1:81.9%; E2:80.2%; p = 0.875).

The findings from stepwise multivariate logistical regression analysis in assessing the predictors for aneurysm complete obliteration and patient functional outcomes after the procedure indicated that E2 was comparable to E1 after adjusting for potential confounding factors (all p > 0.05). However, the patients treated with E2 had significantly fewer procedure-related complications (Table 3), which is consistent with the results of univariate analysis. After adjusting for the effects of age, the presence of hypertension and aneurysm width and height, the risk of complications associated with E2 was 64% lower compared with E2 (odds ratio [OR]: 0.36; 95% CI: 0.15–0.91). The model also indicates that increased age (OR: 2.48; 95% CI: 1.29–4.77), the presence of hypertension (OR: 2.83; 95% CI: 1.13–7.09) and a large aneurysm width (OR: 1.22; 95% CI: 1.02–1.45) were all independently associated with risk of procedure-related complications.