MISTIE III
(2019)Objective
Evaluate whether image-guided minimally invasive surgery with catheter-based alteplase administration improves functional outcomes in patients with spontaneous supratentorial intracerebral hemorrhage (ICH) compared to standard medical care.
Study Summary
• In patients with moderate to large spontaneous supratentorial ICH, minimally invasive surgery with alteplase (MISTIE) did not significantly improve the proportion achieving mRS 0–3 at 365 days compared to medical care. However, clot reduction to <15 mL was associated with better outcomes. MISTIE significantly reduced mortality and was found to be safe with no increase in severe adverse events.
Intervention
Phase 3, open-label, blinded-endpoint RCT at 78 hospitals globally. Adults with spontaneous supratentorial ICH ≥30 mL were randomized to MISTIE (surgical catheter placement + alteplase 1.0 mg q8h x9 doses max) vs. standard medical care. Patients had to be clinically and radiographically stable before randomization. Primary outcome: mRS 0–3 at 365 days.
Study Design
Arms: Array
Outcome
• Primary outcome (mRS 0–3 at 365 days): 45% (MISTIE) vs. 41% (control); adjusted risk difference 4% (95% CI –4 to 12); p=0.33
• Mortality at 365 days: 15% vs. 23%; HR 0.67 (95% CI 0.45–0.98); p=0.037
• Achieving clot size <15 mL associated with better outcomes; 10.5% increase in mRS 0–3 vs. control (p=0.03)
• Serious adverse events: 30% (MISTIE) vs. 33% (control); p=0.012
• Symptomatic bleeding and infection rates similar; asymptomatic bleeding more frequent in MISTIE
• No difference in quality of life or secondary outcomes like eGOS or ICU metrics
• Mortality at 365 days: 15% vs. 23%; HR 0.67 (95% CI 0.45–0.98); p=0.037
• Achieving clot size <15 mL associated with better outcomes; 10.5% increase in mRS 0–3 vs. control (p=0.03)
• Serious adverse events: 30% (MISTIE) vs. 33% (control); p=0.012
• Symptomatic bleeding and infection rates similar; asymptomatic bleeding more frequent in MISTIE
• No difference in quality of life or secondary outcomes like eGOS or ICU metrics
Bottom Line
MISTIE III did not significantly improve good functional outcome (mRS 0–3 at 365 days) compared with standard medical care (45% vs 41%, adjusted risk difference 4%, 95% CI −4 to 12; p=0.33). However, the procedure was safe, was associated with significantly lower 365-day mortality (severity-adjusted HR 0.67, 95% CI 0.45–0.98; p=0.037), and as-treated analyses showed that achieving the surgical goal of ≤15 mL residual hematoma was associated with a 10.5% absolute increase in good outcome.
Major Points
- MISTIE III enrolled 506 patients (255 MISTIE, 251 standard care) between December 2013 and August 2017 at 78 hospitals across the USA, Canada, Europe, Australia, and Asia — the largest minimally invasive surgery trial for ICH to date.
- The primary outcome (mRS 0–3 at 365 days, mITT population n=499) was not met: 45% MISTIE vs 41% standard care (adjusted risk difference 4%, 95% CI −4 to 12; p=0.33). On the unadjusted analysis, 110/249 (44.2%) MISTIE vs 100/240 (41.7%) standard care reached mRS 0–3.
- The MISTIE procedure achieved dramatic hematoma reduction: mean residual ICH volume was 16 mL (SD 13) in the MISTIE group vs 47 mL (SD 18) in standard care (mean difference 32 mL, 95% CI 30–34; p<0.0001). The surgical goal of ≤15 mL residual clot was achieved by 146/250 (58%) of MISTIE patients vs 2/249 (<1%) of standard care patients.
- Alteplase was delivered at 1.0 mg in 1 mL via the catheter every 8 hours for up to 9 doses. Median number of doses given was 4 (IQR 2–6). Clot reduction was more consistent in surgeons who had performed ≥10 procedures.
- Severity-adjusted all-cause mortality at 365 days was significantly lower in MISTIE (HR 0.67, 95% CI 0.45–0.98; p=0.037), though the log-rank test did not reach significance (p=0.084). At 7 days: 2 (0.8%) vs 10 (4.0%) (p=0.018); at 30 days: 24 (9.4%) vs 37 (14.7%) (p=0.066); at 180 days: 39 (15.3%) vs 57 (22.7%) (p=0.033).
- As-treated analysis: patients who achieved the surgical goal of ≤15 mL residual clot had a 10.5% absolute increase in mRS 0–3 at 365 days vs standard care (95% CI 1.0–20.0; p=0.03), adjusting for initial severity — suggesting the procedure is beneficial when technically successful.
- Clot volume removal correlated with functional outcome: each unit decrease in residual clot was associated with improved mRS 0–3 (OR 0.68 per mL, 95% CI 0.59–0.78; p<0.0001), supporting a dose-response relationship between hematoma reduction and recovery.
- Sensitivity analyses using generalised ordered logistic regression showed ORs for mRS >5 vs ≤5: 0.60 (p=0.03); >4 vs ≤4: 0.84 (p=0.42); >3 vs ≤3: 0.87 (p=0.49); >2 vs ≤2: 0.82 (p=0.44) — consistent directionality toward MISTIE but none individually significant.
- ICP elevation and CPP depression were significantly less common in MISTIE: ICP ≥20 mmHg readings 3.3% vs 9.4% (p=0.01); CPP <70 mmHg readings 9.3% vs 22.4% (p=0.04). Total serious adverse events within 30 days: 126 (MISTIE) vs 142 (standard care) (p=0.012).
- Safety was acceptable: symptomatic bleeding within 72 h of last dose 6/255 (2.4%) vs 3/251 (1.2%) (p=0.325); bacterial brain infection within 30 days 2/255 (0.8%) vs 0/251 (0.0%) (p=0.160). Asymptomatic brain bleeds were higher in MISTIE: 81 (31.8%) vs 21 (8.4%) (p<0.0001).
- At 365 days, 314/379 (83%) patients across both groups were living at home or in active rehabilitation. Overall ~43% achieved good functional outcome — higher than expected historically, suggesting that guideline-adherent intensive care (aggressive BP management, avoiding withdrawal of care) may independently improve ICH prognosis.
Study Design
- Study Type
- Randomised, controlled, open-label, phase 3 trial with blinded endpoint (PROBE design)
- Randomization
- Yes
- Blinding
- Open-label treatment; outcomes adjudicated by independent committee masked to treatment allocation; mRS interviews recorded and scored at University of Glasgow
- Sample Size
- 506
- Follow-up
- 365 days (clinic visits days 30, 180, 365; telephone contact days 90, 270)
- Centers
- 78
- Countries
- United States, Canada, Europe (United Kingdom, Germany, Spain, Hungary, Israel), Australia, China
Primary Outcome
Definition: Good functional outcome defined as mRS 0–3 at 365 days, adjusted for prespecified baseline covariates (stability ICH size, age, GCS, stability IVH size, clot location) using longitudinal TMLE
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | 0.33 |
Limitations & Criticisms
- The primary endpoint was not met — MISTIE cannot be recommended for routine use in all patients with ICH ≥30 mL. The neutral result likely reflects the fact that only 58% of MISTIE patients achieved the surgical goal of ≤15 mL residual clot, which was associated with benefit in exploratory analyses.
- Open-label surgical design (inherent to surgical trials) means caregiver bias cannot be fully excluded; however, blinded outcome adjudication by an independent masked committee and independent jury scoring at University of Glasgow substantially limits this concern.
- Protocol adherence (achieving ≤15 mL clot) improved with surgeon experience (≥10 procedures) — the neutral primary result may partly reflect suboptimal technique in inexperienced centres. This limits generalisability to centres without dedicated neurosurgical training programmes.
- Conducted exclusively at tertiary referral centres with 78 hospitals, 114 surgeons, and a dedicated core surgical laboratory — limits generalisability to community hospitals without neurosurgical expertise or dedicated surgical oversight.
- The as-treated analysis showing 10.5% benefit in patients achieving surgical goal is exploratory and potentially confounded by unmeasured confounders — patients with haemorrhage shape or location more amenable to clot reduction may have better prognoses independent of treatment.
- Stability inclusion criterion (no growth ≥5 mL over ≥6 hours) excluded patients with haematoma expansion and those with life-threatening mass effect — selecting a more stable, potentially better-prognosis population. This likely explains the unexpectedly low overall 30-day mortality (~12%) compared to STICH I (37%) and STICH II (21%).
- Mortality benefit at 365 days (HR 0.67, p=0.037) was a secondary endpoint not adjusted for multiplicity (54 pre-planned analyses) and the log-rank test did not reach conventional significance (p=0.084) — should be interpreted as exploratory, not confirmatory.
- Higher anticoagulation rate in MISTIE group at baseline (9.6% vs 4.0%) — while groups were otherwise well-balanced, this imbalance may affect bleeding risk interpretations.
- Asymptomatic brain bleeds were markedly higher in MISTIE (31.8% vs 8.4%) — though classified as asymptomatic and not associated with worse clinical outcomes in this trial, the long-term significance of subclinical bleeding events is uncertain.
- The trial was powered to detect a 13% absolute difference (25% vs 38%) in mRS 0–3, based on MISTIE II data. The actual observed difference was only 4%, suggesting the treatment effect was substantially smaller than anticipated — this may indicate inadequate precision in the phase 2 effect size estimate used for sample size calculation.
Citation
Hanley DF, Thompson RE, Rosenblum M, et al. Minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label phase 3 trial with blinded endpoint. Lancet. 2019;393(10175):1021–1032. doi:10.1016/S0140-6736(19)30195-3.