MISTIE III

Clinical Context

Intracerebral hemorrhage (ICH) remains a stroke subtype with high morbidity and mortality, and effective treatments are limited. Surgical evacuation of the hematoma is theoretically beneficial by reducing mass effect and limiting secondary injury from blood products. However, large trials of traditional open craniotomy (like STICH and STICH-II) did not show consistent benefits for broad populations. Minimally invasive surgery (MIS) techniques, which aim to remove the hematoma with less disruption to surrounding brain tissue, have been developed as potentially safer and more effective alternatives.

The MISTIE (Minimally Invasive Surgery Plus rt-PA for ICH Evacuation) program investigated one such approach: stereotactic catheter placement into the hematoma followed by local instillation of alteplase (rt-PA) to liquefy the clot for aspiration. Phase II results (MISTIE II) suggested that this technique was safe and could effectively reduce hematoma volume, with a signal towards improved functional outcomes if substantial clot removal (to a residual volume ≤15 mL) was achieved. MISTIE III was the definitive phase 3 trial designed to confirm these findings.

Patient Population

MISTIE III enrolled 506 adult patients (aged 18–80 years) from 76 sites in North America, Europe, and Asia. Eligible patients had:

• Spontaneous supratentorial ICH confirmed by CT.
• Hematoma volume ≥30 mL.
• Glasgow Coma Scale (GCS) score between 4 and 14.
• A stable hematoma, defined as no more than 5 mL growth on a CT scan performed at least 6 hours after the initial diagnostic CT.
• The ability to receive the first dose of alteplase (or sham procedure in the medical arm, though the trial was open-label for the active intervention) between 12 and 72 hours after the diagnostic CT scan.

Exclusions included infratentorial hemorrhage, significant intraventricular hemorrhage requiring treatment, known secondary causes of ICH, irreversible anticoagulation, severe pre-existing disability (mRS >2), or conditions making survival or follow-up unlikely.

The mean age of participants was approximately 62 years, and about 60% were male. The median GCS at enrollment was 10-11. The median baseline hematoma volume was substantial, around 45-50 mL.

Study Design

MISTIE III was an international, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE-like) phase 3 superiority trial.

Protocol Details

Patients were randomized 1:1 to:

• Intervention Group (MISTIE Procedure): Minimally invasive surgery consisting of stereotactic or image-guided catheter placement into the hematoma, followed by instillation of alteplase (1 mg in 1 mL saline) directly into the hematoma cavity. Alteplase could be administered up to every 8 hours for a maximum of 9 doses (or 72 hours), or until the hematoma volume was reduced to ≤15 mL as assessed by CT. This was in addition to standard medical care.
• Control Group (Standard Medical Care): Received standard medical care alone, according to established local and international guidelines. This included intensive monitoring, blood pressure management, intracranial pressure control if needed, and other supportive therapies. Crossover to surgical intervention was not permitted unless for life-saving indications.

Outcome Assessment

The primary outcome was assessed at 365 days. Assessment of the modified Rankin Scale (mRS) was performed by trained, certified evaluators who were blinded to the treatment assignment.

Power Analysis & Statistical Approach

The trial was designed to have 80% power to detect an absolute difference of 12.5% in the proportion of patients achieving a good functional outcome (mRS 0–3) at 365 days, assuming a rate of 30% in the medical care group and 42.5% in the MISTIE group, with a two-sided alpha of 0.05. The primary analysis was based on intention-to-treat.

Risk of Bias Analysis

(Content for this section needs to be added. Considerations: open-label nature of the intervention, blinded outcome assessment is a strength, potential for learning curve with the surgical procedure, adherence to the surgical protocol.)

Results

A total of 506 patients were randomized: 255 to the MISTIE procedure and 251 to standard medical care. Baseline characteristics were well-matched. In the MISTIE group, the median time from ICH onset to the first dose of alteplase was approximately 48 hours. The surgical goal of achieving a residual hematoma volume of ≤15 mL was achieved in 70% of patients who completed the MISTIE procedure. The mean percentage reduction in hematoma volume was significantly greater in the MISTIE group.

Primary Outcome: Good Functional Outcome (mRS 0–3) at 365 Days

The proportion of patients achieving a good functional outcome (mRS score of 0–3) at 365 days was:

• 45% in the MISTIE group (115 of 255 patients)
• 39% in the standard medical care group (98 of 251 patients)

This difference was not statistically significant (risk difference, 5.5 percentage points [95% CI, –3.0 to 13.9]; relative risk, 1.14 [95% CI, 0.90 to 1.44]; p=0.20).

Secondary Outcomes

• Ordinal analysis of mRS scores at 365 days: Showed a non-significant trend towards a favorable shift with the MISTIE procedure (adjusted common OR 1.26, 95% CI 0.89–1.79; p=0.19).
• Mortality at 365 days: 23% in the MISTIE group versus 28% in the medical care group (p=0.24).
• Mortality at 30 days: Was lower in the MISTIE group (10%) compared to the medical care group (17%; p=0.03).

Pre-specified Subgroup/Per-Protocol Analysis

A pre-specified analysis looked at patients in the MISTIE group who achieved the surgical goal of a residual hematoma volume of ≤15 mL. In this “successful surgery” group, the rate of good functional outcome was higher (49%) compared to the medical care group (39%), and also higher than in MISTIE patients who did not achieve this surgical goal (36%). This suggests that effective clot removal might be key to potential benefit.

Safety Outcomes

Symptomatic bleeding associated with alteplase occurred in 3% of MISTIE patients. The overall rates of serious adverse events were similar between the groups, though infections were numerically higher in the MISTIE group.

Final Thoughts & Critical Appraisal

MISTIE III was a rigorously conducted phase 3 trial that aimed to provide definitive evidence on the efficacy of minimally invasive catheter evacuation with alteplase for supratentorial ICH. While the trial did not meet its primary endpoint of a statistically significant improvement in the proportion of patients achieving good functional outcome (mRS 0-3) at 365 days in the intention-to-treat analysis, several aspects are noteworthy.

Key considerations:

• Primary Endpoint Not Met: The main conclusion is that the MISTIE procedure, as applied in this trial, did not significantly improve functional outcomes at one year compared to standard medical care in the overall study population.
• Signal of Benefit in “Successful Surgery” Group: The pre-specified analysis showing better outcomes in patients where the surgical goal (residual volume ≤15 mL) was achieved is hypothesis-generating. It suggests that the effectiveness of clot removal might be a critical determinant of benefit. However, this is an as-treated/per-protocol type of analysis and should be interpreted with caution.
• Early Mortality Reduction: The observed reduction in 30-day mortality in the MISTIE group is a potentially important finding, though the primary outcome was at 365 days.
• Challenges of the Procedure: Achieving the target clot reduction was not universal, and the procedure involves multiple alteplase instillations over several days, which has logistical implications and potential risks (like infection).
• Comparison with ENRICH: The more recent ENRICH trial, which also tested a minimally invasive surgical approach (endoscopic parafascicular surgery without alteplase) but with a different primary outcome (utility-weighted mRS) and slightly different patient selection (e.g., surgery within 24 hours, specific hematoma locations), did show a significant benefit. The differences in technique, timing, patient selection, and primary outcome measures make direct comparisons complex but highlight the evolving nature of this field.

MISTIE III contributed valuable data to the field of ICH surgery. While not a definitively positive trial for its primary endpoint, its findings, particularly regarding the importance of achieving substantial clot evacuation and the early mortality signal, have informed ongoing research and the design of subsequent trials. It underscores that the success of MIS for ICH likely depends on optimizing the technique, patient selection, and achieving efficient and safe clot removal.

How do we reconcile the results with other studies?

(Content for this section needs to be added, comparing MISTIE III with ENRICH, STICH trials, and other MIS approaches, and discussing the role of alteplase, timing, and extent of evacuation.)

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