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Clinical Trial
. 2019 Jun 1;84(6):1157-1168.
doi: 10.1093/neuros/nyz077.

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

Issam A Awad  1 , Sean P Polster  1 , Julián Carrión-Penagos  1 , Richard E Thompson  2 , Ying Cao  1 , Agnieszka Stadnik  1 , Patricia Lynn Money  3 , Maged D Fam  1 , Janne Koskimäki  1 , Romuald Girard  1 , Karen Lane  2 , Nichol McBee  2 , Wendy Ziai  2 , Yi Hao  2 , Robert Dodd  4 , Andrew P Carlson  5 , Paul J Camarata  6 , Jean-Louis Caron  7 , Mark R Harrigan  8 , Barbara A Gregson  9 , A David Mendelow  9 , Mario Zuccarello  3 , Daniel F Hanley  2 ; MISTIE III Trial Investigators
Affiliations
Clinical Trial

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

Issam A Awad et al. Neurosurgery. .

Abstract

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.

Keywords: Intracranial hemorrhage; Intraparenchymal hemorrhage; MISTIE; Minimally invasive surgery; Recombinant tissue plasminogen activator.

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Figures

FIGURE 1.
FIGURE 1.
A , Axial CT scan showing ICH of 37 mL with demonstrated stability. B , Subsequent MISTIE frontal catheter placed (trajectory A) by a surgeon qualified with probation*, with surgical center grading catheter placement as good*. C , Hematoma evacuated to final volume of 1 mL after 3 doses of alteplase and achieving mRS 2 after 1 yr. *See methods for detailed definitions.
FIGURE 2.
FIGURE 2.
Volume reduction for each patient randomized to the MISTIE procedure expressed as percent evacuation. Efficacy of hematoma evacuation over the course of the trial as demonstrated by average hematoma evacuation rate and percent of subjects reaching target EOT volume of ≤15 mL. Cases that underwent craniotomy are denoted in red. Cases with negative percent evacuation included rebleeds and ICH expansions.
FIGURE 3.
FIGURE 3.
Cubic spline regression analyses (blue line) and linear spline regression analyses (black line) showing the relationship of hematoma reduction (EOT ICH Volume) to the probability of having a good outcome, mRS 0 to 3, at 1 yr. This is created by classifying dichotomized outcome as 1 or 0 (green dots at 1 = mRS 0 to 3, red dots at 0 = mRS 4 to 6). Further reduction beyond the 15 mL threshold (OR 0.09, P = .002) increased the chance of having a good outcome by 10% for each additional mL of hematoma removed (green shading showing statistically significant area of curve). Volume reductions to >15 mL threshold did not significantly impact the likelihood of achieving a good outcome.
FIGURE 4.
FIGURE 4.
Cubic Spline regression analyses (blue line) and linear spline regression analyses (black line) showing the relationship of percent hematoma reduction (EOT ICH Volume) to the probability of having a good outcome, mRS 0 to 3, at 1 yr. This is created by classifying dichotomized outcome as 1 or 0 (green dots at 1 = mRS 0 to 3, red dots at 0 = mRS 4 to 6). Hematoma reduction beyond 70% increasing the chance of achieving a good outcome. Each additional mL beyond 70% carries a 6% improvement in the chance of achieving a good outcome (OR 1.06, P = .002) (green shading showing statistically significant area of curve). Percent reduction below the 70% threshold did not significantly impact the probability of achieving a good outcome.
FIGURE 5.
FIGURE 5.
EOT ICH volumes for all MISTIE enrolled patients, excluding craniotomy (n = 6). EOT of ≤30 mL were achieved in 216 cases (89.2%), ≤20 mL in 182 cases (75.2%), and ≤15 mL in 145 cases (59.9%).
FIGURE 6.
FIGURE 6.
A, Surgeon andB, site experience depicting the number of prior cases performed in the MISTIE trial until the date of the index case, in cohorts where EOT ICH volume was ≤ or >30 mL (significant variable in univariate analysis). (Whiskers represent the 3rd and the 1st quartiles with box line representing the median). No surgeon with experience >4 MISTIE procedures or a site with >7 MISTIE procedures had a patient with >30 mL EOT ICH volume. This difference was present at the 30 mL EOT volume threshold, but not at 20 or 15 mL EOT thresholds (not shown).
FIGURE 7.
FIGURE 7.
Three example scenarios of failure to achieve the desired surgical evacuation. In Scenarios 1 and 2, surgical experience and protocol adherence could have achieved the desired outcome. In Scenario 3, inherent limitations related to the type of hematoma prevented the desired outcome, despite optimal surgical performance and protocol adherence. A and B , Scenario 1. A , Initial catheter placement was suboptimal (purple outline of catheter perforations and hematoma interface) but deemed suitable for dosing. B , After 9 doses of alteplase, there was 72.6 mL residual hematoma eccentric to the catheter. Replacing the catheter during dosing was suggested to the site in contemporaneous notes, but was not pursued. Instead, the site investigators administered all 9 doses through the eccentric catheter location despite evidence of suboptimal clearance. C and D , Scenario 2. C, Catheter was dislodged before completion of dosing. D, Surgical Center query could not verify that the catheter was properly secured at three points, as mandated in the protocol and emphasized in surgical education module/webinars (arrows highlight optimal catheter fixation in another case, arrowhead shows proper use of stopcock and star denotes proper labeling of MISTIE from EVD catheter). The site team aborted the procedure and declined replacing the catheter. Scenario 3. E and F: E, Despite excellent catheter placement, F, there was 24.1 mL residual hematoma in fragmented satellite configuration not amenable to further evacuation.
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