A Neurosurgical Call to Arms: Lessons from ARUBA, Mr. Clean, and the Hydrocephalus Clinical Research Network

Abstract

Neurosurgeons have traditionally been at the forefront of investigations into clinical, translational, and basic science research to improve the quality of neurologic care. The pioneering work of Drs. Kassell and Gerk in the early versus late treatment of ruptured cerebral aneurysms (11) stands as a testament to our specialty’s long and illustrious history of critical examination of the problems of the time. However, the publication of certain randomized controlled trials (RCTs) has left the field in a more reactive posture of late. The past 12 months have provided neurosurgeons with the results of two large RCTs, ARUBA (14) and Mr. Clean (3), with the potential for diametrically different results on the field of neurosurgery. These trials demonstrated how quickly the care of neurosurgical patients can be impacted, for better or worse, in the modern age (Table 1). Although the goal of a prospective RCT is one to which we should all aspire (2), it can be difficult in many instances to ethically conduct the research “gold standard” in the face of previous large, well-conducted, experiential studies. Furthermore, the variability of disease within the central nervous system has also made some RCTs difficult to design and has produced results that have been subject to vociferous debate within the medical community. ARUBA, an RCT of medical management of brain arteriovenous malformations (bAVMs) versus surgical intervention, concluded that medical management alone was superior to intervention for the preventionofdeathorstroke(14).Theseresultshavebeentrumpeted inthemediaasthenewstandardofcareforpatientswithbAVMs.The widespreaddisseminationofthisstudymaylimitapatient’sabilityto consult with neurosurgeons, the subject matter experts on this disorder, as referring providers discount the role of any surgical intervention for these patients. Significant criticism of ARUBA’s design and execution question the validity and generalizability of the results from this trial (1, 21), but as the only National Institutes of Healthefunded RCT on bAVMs, this study’s impact may potentially carry more influence than any well-designed, new or historical, retrospective surgical series (19). Given this significant, ongoing controversy, it is evident that the final word on the best treatment for patients with bAVMs is yet to be spoken. Mr. Clean, an RCT comparing the standard-of-care medical management with or without intra-arterial treatment for largevessel anterior circulation strokes, concluded that intra-arterial treatment was superior to medical management alone (3). These findings have been supported with the reporting of additional RCTs of intra-arterial stroke treatments (5, 10). These additional studies were terminated after midterm analyses favored the intraarterial treatment arm (5, 10). In contrast to the findings from ARUBA, these results have been accepted with little to no criticism because of their well thought-out design and execution. These two examples stand in stark contrast to one another and serve to illustrate how RCTs of neurosurgical diseases performed by specialists outside of neurosurgery can significantly impact our field. As in most aspects of life, the “devil” is often found in the details of these trials. Study design and execution are critical to the validity and acceptance of any results. But regardless of the quality