Our post hoc analysis of the Earlydrain trial highlights three main findings. First, a per-year analysis revealed a consistent and balanced clipping/coiling ratio over the study duration. Accordingly, the Earlydrain trial as one of the most recent RCTs in SAH demonstrates that aneurysm clipping is still a frequently applied method in clinical practice across German-speaking countries. Second, explorative outcome rates after clipping and coiling, other than the rate of vasospasm, showed no statistically significant differences between the groups. Third, rates of TCD and angiographic vasospasm were higher after microsurgical clipping.

While the incidence of SAH has remained stable, the volume of endovascular treatment increased significantly in ruptured and non-ruptured aneurysms in the United States of America (USA) from 1993 to 2015 according to the Nationwide Inpatient Sample (NIS) database, whereas clipping decreased for ruptured aneurysms and slightly increased for non-ruptured aneurysms [10]. Shah et al. reported regional differences with a higher prevalence of surgical clipping in the West of the USA compared to other regions (18.8 vs. 11.6%; p < 0.0001) from 2009 to 2018 according to the Vizient Clinical Data Base, and surgical clipping was used in 13,866 (12.7%) patients, whereas endovascular coiling was used in 11,146 (10.2%) patients of the total cohort of 109,034 patients with primary ICD diagnosis of non-traumatic SAH (including non-aneurysmal SAH) [12]. Reports from Europe are limited to a few single-center studies, which showed a rapid shift to endovascular treatment nearly a decade later than in the USA [11, 18, 19]. To determine whether progressive technical developments in the endovascular field, including an expanding variety of coils, influenced treatment choices in mainly German-speaking countries during the study duration, we performed a per-year analysis of the Earlydrain cohort which showed a stable and balanced clipping/coiling ratio. According to these findings, aneurysm clipping is still a frequently used method in aneurysmal SAH. Of note, our data only extends up to the year 2016 and this ratio may have changed given the further developments since then. Data on patients requiring stent-assisted coiling was not available in our study, as these patients were excluded per protocol due to required double-platelet anticoagulation which prohibited insertion of a lumbar drain. Nevertheless, evidence supporting the use of stent-assisted coiling in SAH is limited and higher hemorrhagic and complication rates compared to coiling alone have been reported [20, 21]. Intrasaccular devices and coated stents that do not require dual anti-platelet therapy have only been developed and broadly applied in SAH within the last 5 years and were therefore not included in the study. The influence of these newer techniques on current practice has yet to be determined.

Our explorative outcome analysis of real-world clinical practice in predominantly German-speaking countries shows no significant differences in outcomes between the clipping and the coiling groups regarding mRS, infarction at discharge, requirement of VP-shunt, mortality, GOS-E or Barthel-Index. A recent Cochrane review mainly based on the ISAT trial stated, that for patients in good clinical condition with ruptured aneurysms of either the anterior or posterior circulation, coiling is associated with a better outcome if the aneurysm is suitable for both treatment methods [2]. During the recruitment of ISAT, only 22% of SAH patients treated at the participating centers were enrolled in the study. Furthermore, patients in poor clinical condition were underrepresented in the ISAT cohort as 88% of included patients were in good clinical condition (WFNS Grade 1–2) [6]. Thus, there is limited treatment evidence from RCTs that can be applied to SAH patients with poor clinical condition [2]. Furthermore, the advantage of coiling over clipping cannot be assumed for patients under 40 years old according to a post hoc analysis of the ISAT results [22]. The treatment choice should consider various factors, such as clinical condition, location and configuration of the aneurysm, as well as the skill level of the surgeon. Particularly for younger patients and those with aneurysms in certain locations, such as the middle cerebral artery (MCA), surgical clipping may still be the favorable treatment option due to its lower risk of aneurysm recurrence, rebleeding, and the need for retreatment [23, 24]. The ISAT trial randomized ruptured intracranial aneurysms considered to be suitable for both, microsurgical and endovascular treatment [6]. In contrast, aneurysms were treated according to the discretion of the local centers in the Earlydrain trial [13], constituting a substantial difference between these studies. Of note, our post hoc analysis does not have the same evidence level as prospective RCTs comparing clipping and coiling. Nevertheless, interdisciplinary treatment decisions as applied in the Earlydrain trial, in which advantages and risks of both treatment modalities were considered equally, represent a realistic and accurate scenario of real-world clinical practice. Our resulting exploratory outcome analysis included a representative patient cohort regarding WFNS and Hunt-Hess grades without differences between the clipping and coiling group, and clinical outcomes were without statistically significant difference. A meta-analysis and systematic review of three RCTs and 37 observational studies including ISAT [6] and the Barrow Ruptured Aneurysm Trial (BRAT) [25] (which has been excluded from the Cochrane Review) reported a better life quality (mRS 0–2) as well as a lower incidence of postprocedural complications after coiling, and a lower rate of mortality, rebleeding, hydrocephalus, and a higher rate of complete aneurysm occlusion after clipping [7]. Higher re-rupture rates after coiling were also reported in another recent meta-analysis (1.5% vs. 0.5%, p = 0.002; median follow-up of 6.1 years) [26]. Yet, properly designed and conducted RCTs are necessary to determine the optimal treatment strategy for intracranial aneurysms and to settle this ongoing controversy [27].

The only significant difference between the groups was the rate of vasospasm. At total of 60.2% of clipped versus 42.6% of coiled patients showed signs of elevated TCD criteria (p = 0.007). Notably, TCD measurements come with limitations, including unreliability and variability across different examiners [28,29,30]. TCD is also technically easier and more reliable in the anterior compared to the posterior circulation [28, 29]. Since the coiling group had a higher proportion of patients with posterior circulation aneurysms, there is a risk of underestimating TCD vasospasm in this group, constituting a notable limitation when comparing the clipping and coiling groups. Nevertheless, this finding was reflected in the higher rates of angiographic vasospasm in the clipping group and has been confirmed in the meta-analysis conducted by Peng et al. which analyzed 13 publications with a total of 2857 patients regarding vasospasm. Here, postprocedural vasospasm occurred less frequently in the coiling than in the clipping group (20.5% vs. 24.8%; OR = 0.787; CI = 0.649 – 0.954; p < 0.05) [7]. Furthermore, a meta‐analysis conducted by Zhu et al. showed a 45% increase in the risk of vasospasm if patients were treated by clipping (RR: 1.45, 95% CI: 1.23 – 1.71, p < 0.001) [8]. Angiographic vasospasm contributes to poor outcomes [9]. Consequently, further development of periprocedural treatment modalities for clipped aneurysms in SAH to reduce vasospasm is warranted. Promising results have been reported, for example, in a randomized controlled phase IIA/B study assessing the safety and tolerability of NicaPlant®, a modified prolonged release formulation of the calcium channel blocker nicardipine. In this approach, nicardipine implants are applied locally in patients with aneurysmal SAH undergoing microsurgical clipping, potentially reducing systemic side effects and improving outcomes. The placement of nicardipine implants during clipping raised no safety concerns [31], and a recently published RCT confirmed that this approach can safely and effectively prevent vasospasm after aneurysmal SAH [32]. Given these promising results, a phase III clinical trial to investigate the impact on clinical outcomes may now be justified.

The Earlydrain trial has not been designed for a direct comparison between clipping and coiling, and the statistical analyses should therefore be treated with caution. As a consequence, the explorative outcome analysis may lack sufficient statistical power and does not claim to answer the question whether aneurysms should be clipped or coiled. Yet our data shows that a careful interdisciplinary treatment decision can produce a balanced clinical outcome. Another limitation is the lack of long-term outcome data exceeding 6 months, which could offer a more thorough comprehension of the therapeutic impact over an extended duration. Nevertheless, the Earlydrain study is one of the most recently published multicenter RCT in SAH and the data provide a representative real-world scenario of clinical practice regarding clipping versus coiling in SAH.