Randomized clinical trials for endovascular spasm therapies?—call for action!

Aneurysmal subarachnoid hemorrhage (aSAH) remains a major global health burden, with a global incidence of approximately six cases per 100,000 person-years. In recent decades, age-standardized incidence and mortality rates have declined, mainly due to advances in lowering blood pressure and smoking rates (1,2). On the other hand, however, there has been no positive development in case fatality rates among individuals with SAH over the last 20 to 30 years, and in this context the results regarding temporal trends in functional outcomes also remain inconclusive (3). In cases where the bleeding event is survived, the development of delayed cerebral ischemia (DCI)-related infarction is significantly correlated with unfavorable outcome (4). In particular, the prevalence of DCI continues to be reported at 29%, with no relevant changes over the last 20 years (5).

It is well recognized that the secondary brain damage phase following aSAH is multifactorial and complex. However, symptomatic cerebral vasospasm remains the most important diagnostic criterion in the post-hemorrhagic phase, with routine transcranial Doppler ultrasound examinations, invasive measurement of brain tissue oxygenation, and angiographic and perfusion imaging. Therapy of DCI is also primarily based on treating symptomatic vasospasm, although DCI can occur without vasospasm and even severe angiographic vasospasms can remain asymptomatic (6-8). This mismatch between DCI and vasospasm may be a main reason for the failure of past trials without benefits for endovascular spasm treatment. Angiographic outcomes may have been an insufficient endpoint and future trials should prioritize functional outcomes to answer the question that matters most.

To date, only systemic administration of calcium channel blockers has been shown to be evidently beneficial in preventing DCI and improving functional outcome, but the required number needed to treat of 19 is quite high (9,10). Regarding the further medical management of DCI after aneurysmal SAH, maintaining euvolemia can also be beneficial in preventing DCI and improving functional outcome—however, only with a weak strength of recommendation (class 2b). In addition, induced hypertension with elevating systolic blood pressure values may be reasonable to reduce the progression and severity of DCI (9).

In case of refractory DCI, endovascular spasm therapies (EST) are widely used with a range of different intra-arterial vasodilators, doses and treatment durations and also mechanical options: in Germany alone, more than 7,600 EST were documented between 2021 and 2024, although this figure is likely to be significantly higher due to incomplete documentation, as registration is not mandatory (11). In the vast majority of cases, only intra-arterial drug treatments are performed, with nimodipine, nicardipine, verapamil, papaverine, or nitroglycerin being used. These agents have been described as predominantly effective in reducing angiographic vasospasm (12). Mechanical EST promise longer-term effects and are mainly performed with balloon catheters (compliant or non-compliant), but recently also with stent retrievers or novel non-occlusive stent dilatation devices such as pRELAX^® (WallabyPhenox, China/USA), NeVa™ VS (Vesalio, USA) or Comaneci™ (Rapid Medical, Israel) (8). The combined use of calcium channel blockers and balloon catheters was recently investigated in a meta-analysis by Musmar et al. and appears to have advantages over intra-arterial monotherapy (as local medication or balloon angioplasty) (12).

Despite widespread clinical adoption, the evidence base for EST remains limited, relying primarily on single-arm observational studies, with even repeatedly treated patients achieving satisfactory clinical outcomes (13,14). On the other hand, there are also sobering results associated with balloon angioplasty, particularly with regard to complication rates (up to 17% for thromboembolic infarction in a single-center study) and mortality (20% in a meta-analysis) (12,15).

All in all, however, the question arises if the results achieved so far with EST are simply too good to be compared with best medical DCI-treatment? One could even say that the benefits of EST demonstrated so far are also its curse. True equipoise remains elusive because EST use is variable, outcome data is inconsistent and complications non-negligible; therefore failing to conduct a definite randomized controlled trial (RCT) may itself be ethically problematic.

Even long held therapeutic beliefs can and must be called into question and be toppled if necessary. For example, surgical appendectomy has been challenged by conservative treatment with the advent of antibiotics. In the endovascular realm, for intracranial vessel occlusion adjunct mechanical thrombectomy finally proved to be more effective than intravenous thrombolysis alone which in turn ended decades of therapeutic nihilism in acute ischemic stroke treatment some 20 years earlier. In both diseases, RCTs lead to more nuanced approaches with respect to therapy regarding different clinical presentation and disease course (16-18).

So far, there are only two randomized controlled studies comparing conservative DCI-treatment with EST: Vatter et al. from Germany prospectively included patients from three university centers. Conservative treatment included induced arterial hypertension for seven days and continued for another week if deemed necessary. The primary outcome was defined as the size of new infarcts relatable to DCI. EST included intraarterial infusion of nimodipine and transluminal balloon angioplasty at the discretion of the treating neurointerventionist. The authors reported significantly larger infarcts and worse functional outcomes (defined as a secondary outcome parameter) in patients who received intra-arterial therapies for DCI (19).

A study of Yindeedej et al. from Thailand, prospectively included 68 patients from a single university center. The primary outcome was defined as the short term (24 hours and discharge) motor function and functional outcome on the basis of the modified Rankin Scale (mRS). However, no power analysis was made to estimate the effect size. All patients received best medical treatment including induced arterial hypertension. Patients allocated to the EST group (n=38) additionally received intraarterial nimodipine infusion in a standardized manner if tapering of the brain supplying arteries was present on a screening digital subtraction angiography within 14 days after the index SAH. The authors could demonstrate significant positive effects of EST on motor function compared to the conservatively treated control group (20).

However, criticism can be leveled at the study design in both cases, as these studies have significant shortcomings: Vatter and coworkers performed screening using magnetic resonance imaging, which may have led to selection bias, and terminated their study prematurely after only 16 patients had been enrolled in the EST group (19). The study by Yindeedej et al. only considered short-term effects and defined vasospasm solely on the basis of radiological findings (20).

However, without meaningful results from well-powered prospective multicenter RCT, EST will not achieve a sufficient level of evidence and cannot be clearly recommended. If high-quality evidence continues to be lacking in the future, a paradoxical effect must be considered: patients might be denied EST in cases of doubt.

This is likely to be a problem in smaller hospitals in particular, where the spread of thrombectomy has led to the availability of angiography facilities and suitable neurointerventionists, but where typically scarce human resources could mean that EST is refused although it would make perfect sense. This strategy is also pursued by centers with high treatment volumes, where endovascular vasospasm treatment may be avoided under unclear circumstances (21).

Refraining from initiating a large-scale RCT on EST would, in case of doubt, cause more harm than good. Furthermore, an intelligent study design could provide more insight into earlier and more aggressive EST for selected patients. It is important not to treat EST as a single entity, despite meaningful differences between local vasodilator infusion, balloon/stent angioplasty and repeated vs. single-session endovascular treatment. Thus, in the future, RCT may need to be stratified or modular, rather than testing EST as a monolith.

For example, in an evolving, increasingly comprehensive landscape of aSAH-therapy it is also worth mentioning that according to the results of a recently published meta-analysis the systemic application of clazosentan effectively prevents cerebral vasospasm, in particular at higher doses in surgically treated patients, but its clinical utility must be weighed against significant systemic adverse effects. These findings support selective use of this agent in high-risk patients while highlighting the need for careful monitoring and individualized treatment approaches also in the overall context (22). Furthermore, other non-endovascular emerging therapies (e.g., neuroinflammation-targeted strategies) are important to mention and to contextualize EST within the broader landscape of DCI-treatment (23).

An RCT should address the following unanswered question to close the evidence gap:

• Do EST strategies improve patient centered outcomes (90 days mRS, cognition, quality of life, etc.) and not just surrogate parameters (reduction of angiographic vasospasm)?
• Which EST approach (IA vasodilator vs. mechanical vasodilation) or what combination or sequence of approaches is optimal and in which patients?
• What is the net clinical benefit of EST when balancing potential efficacy against procedural complications and downstream burden for intensive care units?

A future RCT would avoid the above mentioned shortcomings of past trials and fill the knowledge and evidence gaps that clearly exist. The included population needs to be clearly defined, optimally all patients with symptomatic DCI after acute SAH should be potentially included to avoid selection bias. The intervention design should be stratified or modular to allow for a nuanced endovascular approach and rescue-crossover as a comparator. Most importantly, the primary endpoint has to be a patient centered outcome parameter, e.g. shift of mRS at 90 days or a functional outcome composite with secondary endpoints such as angiographic vasospasm resolution, length of hospital stay etc. Ideally, such a trial should be designed as a multicenter trial with blinded outcome adjudication.

Because one thing must be certain: the best treatment method must be available to all affected patients without exception after the life-threatening event of aSAH. To conclude, we would like to state quite clearly: we consider high-quality randomized data on EST, despite its widespread use, to be absolutely required for the treatment of DCI.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Neurointervention. The article has undergone external peer review.

Peer Review File: Available at https://jni.amegroups.com/article/view/10.21037/jni-25-66/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jni.amegroups.com/article/view/10.21037/jni-25-66/coif). A.N. serves as an unpaid editorial board member of Journal of Neurointervention from September 2025 to December 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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