Surgical Performance Determines Functional Outcome Benefit in the Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) Procedure

RESEARCH—HUMAN—CLINICAL TRIALS ∗ Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois; ‡ Division of Brain Injury Outcomes, Department of Neurology, Johns Hopkins University Medical Institutions, Baltimore, Maryland; § Department of Neurosurgery, University of Cincinnati Medical Center, Cincinnati, Ohio; ¶ Department of Neurosurgery, Stanford University School of Medicine, Stanford, California; || Department of Neurosurgery, University of New Mexico School of Medicine, Albuquerque, New Mexico; # Department of Neurosurgery, University of Kansas School of Medicine, Kansas City, Kansas; ∗∗ Department of Neurosurgery, University of Texas, San Antonio, Texas; ‡‡ Division of Neurosurgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama; §§ Neurosurgical Trials Group, Newcastle University, Newcastle upon Tyne, United Kingdom This material was presented as an abstract at the American Heart Association’s International Stroke Conference on February 7, 2019 in Honolulu, Hawaii. Correspondence: Issam A. Awad, MD, MSc, Section of Neurosurgery, University of Chicago Medicine, 5841 S. Maryland, MC3026/Neurosurgery J341, Chicago, IL 60637. Email: Received, January 4, 2019. Accepted, February 14, 2019. Published Online, March 20, 2019. C 2019 by the Copyright  Congress of Neurological Surgeons NEUROSURGERY Surgical Performance Determines Functional Outcome Benefit in the Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) Procedure BACKGROUND: Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). OBJECTIVE: To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. METHODS: Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. RESULTS: Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. CONCLUSION: This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal. KEY WORDS: MISTIE, Minimally invasive surgery, Intracranial hemorrhage, Intraparenchymal hemorrhage, Recombinant tissue plasminogen activator Neurosurgery 84:1157–1168, 2019 I DOI:10.1093/neuros/nyz077 ntracerebral Hemorrhage (ICH) is the most devastating type of stroke, affecting more than 2 million people annually.1 The ABBREVIATIONS: CT, computed tomography; EOT, end of treatment; IVH, intraventricular hemorrhage Neurosurgery Speaks! Audio abstracts available for this article at www.neurosurgery-online.com. Supplemental digital content is available for this article at www.neurosurgery-online.com. www.neurosurgery-online.com evolution of ICH management has yet to lead to concrete interventions significantly impacting functional outcomes.2-4 Procedures aimed at reducing hematoma expansion have had only limited or no benefit on the ultimate functional outcome in this disease.5,6 There has long been an interest in the surgical evacuation of ICH, with the aim of mitigating secondary effects of large-volume bleeds on the brain. However, recent well-conducted trials of craniotomy for supratentorial ICH failed to realize significant VOLUME 84 | NUMBER 6 | JUNE 2019 | 1157 Issam A. Awad, MD∗ Sean P. Polster, MD∗ Julián Carrión-Penagos, MD∗ Richard E. Thompson, PhD‡ Ying Cao, MS∗ Agnieszka Stadnik, MS∗ Patricia Lynn Money, NP§ Maged D. Fam, MD∗ Janne Koskimäki, MD, PhD∗ Romuald Girard, PhD∗ Karen Lane, CMA‡ Nichol McBee, MPH‡ Wendy Ziai, MD‡ Yi Hao, PhD‡ Robert Dodd, MD, PhD¶ Andrew P. Carlson, MD|| Paul J. Camarata, MD# Jean-Louis Caron, MD∗∗ Mark R. Harrigan, MD‡‡ Barbara A. Gregson, PhD§§ A. David Mendelow, MD§§ Mario Zuccarello, MD§ Daniel F. Hanley, MD‡ on behalf of the MISTIE III Trial Investigators AWAD ET AL benefits in functional outcome.7,8 Minimally invasive interventions for ICH evacuation have held more promise, presumably by sparing the brain added damage of surgical manipulations. But most studies to date have been small and the quality of evidence suboptimal by Cochrane criteria.9 One such technique, the minimally invasive surgery plus recombinant tissue plasminogen activator for ICH evacuation (MISTIE), was subjected to rigorous optimization in a Phase II trial.10 This led to a recently completed Phase III trial, randomizing 506 cases prospectively to best medical therapy per current guidelines with or without the MISTIE procedure, with blinded assessment of outcome at one year.11 The procedure involved planning of the surgical approach and image-guided cannulation of an ICH through which initial aspiration of the hematoma is performed. A catheter is then secured in the remaining hematoma, which is then further dissolved and drained passively with serial doses of thrombolytic agent (Figure 1). Goals of the intervention were the reduction of the ICH volume to 10 to 15 mL at end of treatment (EOT) or until a maximum of 9 doses of alteplase (1 mg every 8 h) were administered. Each catheter is placed using image guidance along 1 of 3 trajectories depending on the anatomical location of the hematoma. These factors allowed standardization of the surgical task. Validation of the final catheter placement was assessed in real time by the trial’s Surgical Center. Each catheter placement not receiving a passing grade required replacement, as further defined in the methods. From a surgical standpoint, the trial evaluated an explicitly defined technique that utilizes widelyavailable tools (Computed tomography [CT] scan, triage system, and image guidance). The trial midpoint ana (...truncated)