Historical Reference Page
This is a historical reference page. This trial preceded the modern evidence base. It is presented as a predecessor reference. See ENRICH (2024) for the modern successor trial that established minimally invasive evacuation for selected lobar intracerebral hemorrhage.
MISTIE III Trial: Minimally Invasive Surgery Plus rt-PA for ICH Evacuation
In patients with supratentorial intracerebral hemorrhage of 30 mL or larger, does image-guided catheter placement plus intermittent alteplase improve 1-year functional outcome compared with standard medical management?
Hanley et al. (Lancet 2019) · doi:10.1016/S0140-6736(19)30195-3 · 506 patients
Population
Included
- Supratentorial spontaneous ICH 30 mL or larger on baseline CT
- Age 18 years or older
- Clot stability: growth under 5 mL for at least 6 hours after the diagnostic CT, within a 72-hour eligibility window
- Hematoma accessible for stereotactic catheter placement
- GCS 14 or less or NIHSS 6 or higher
Age and diagnosis
- Aged 18 years or older
- Spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more
Severity markers
- Glasgow Coma Scale (GCS) score of 14 or less or National Institutes of Health Stroke Scale (NIHSS) score of 6 or higher
Baseline function
- Modified Rankin Scale (mRS) score of 0 or 1 before the bleed
Clot stability
- An intracerebral haemorrhage that remained the same size (growth less than 5 mL) for at least 6 hours after diagnostic CT
Baseline coagulation and blood pressure
- 6 hours or more after diagnostic CT, an international normalised ratio of 1.3 or less, a normal activated partial thromboplastin time, and blood pressure stability
Excluded
- Infratentorial (posterior fossa) hemorrhage
- ICH secondary to anticoagulation, AVM, aneurysm, or tumor
- Planned early craniotomy within 24 hours
- Intraventricular hemorrhage causing obstructive hydrocephalus requiring immediate intervention
- Platelet count below 100,000 or INR above 1.4, or any coagulopathy or clotting disorder (per registration); the publication additionally required an INR of 1.3 or less and a normal activated partial thromboplastin time before treatment
Stated in the publication
- Expressed care limitations
- Deemed to have life-threatening mass effect requiring surgery
- The full list of inclusion and exclusion criteria is in the appendix; the complete exclusion list is not reproduced in the main publication text
Source: Hanley et al., Lancet 2019· Retrieved 2026-06-09
Primary Outcome: mRS 0-3 at 1 Year
506 patients; image-guided catheter + alteplase vs standard medical management; supratentorial ICH ≥30 mL
In 506 patients with supratentorial ICH 30 mL or larger randomized to image-guided catheter plus alteplase or standard medical management, MISTIE did not significantly improve functional independence (mRS 0-3) at 1 year. In the modified intention-to-treat set of 499 treated patients (250 MISTIE, 249 standard care), the adjusted primary analysis estimated mRS 0-3 in 45% of the MISTIE group versus 41% of the standard care group (adjusted risk difference 4 percentage points, 95% CI -4 to 12, P=0.33). Among the 489 patients with an available 365-day mRS, the observed counts were 110 of 249 (44%) versus 100 of 240 (42%). An as-treated analysis of patients who reached the surgical aim of end-of-treatment hematoma 15 mL or less showed a risk difference of +10.5 percentage points (95% CI 1.0 to 20.0, P=0.03), suggesting that the degree of hematoma reduction, not just the technique, may be the critical determinant of outcome; the authors label this analysis exploratory and not adjusted for multiplicity.
Visualization not shown for predecessor reference pages. See source paper for figures.
Trial Design
MISTIE III was an international phase 3 RCT at 78 hospitals enrolling patients with supratentorial ICH 30 mL or larger whose clot had remained stable (growth under 5 mL) for at least 6 hours after the diagnostic CT. A CT-guided stereotactic catheter was placed into the hematoma and alteplase (1 mg every 8 hours, up to 9 doses over approximately 72 hours) was instilled to lyse the clot; fluid was drained passively. The target was residual hematoma 15 mL or less before catheter removal. The 1-year follow-up was longer than most surgical ICH trials. MISTIE differed fundamentally from ENRICH in technique: catheter-based lysis versus trans-sulcal surgical aspiration, with the latter achieving faster and more complete evacuation.
Safety
Symptomatic bleeding within 72 hours of the last alteplase dose occurred in 6 of 255 MISTIE patients (2%) versus 3 of 251 standard care patients (1%), P=0.33. Brain bacterial infection occurred in 2 of 255 MISTIE patients (1%) versus none in the standard care group, P=0.16. Asymptomatic bleeding was substantially more common with MISTIE (81 of 255, 32%, vs 21 of 251, 8%; P<0.0001). All-cause mortality was lower with MISTIE at 180 days (39 of 255, 15%, vs 57 of 251, 23%; P=0.033), and at 365 days the severity-adjusted Cox hazard ratio was 0.67 (95% CI 0.45 to 0.98, P=0.037); the unadjusted log-rank comparison across the 365-day period was not significant (P=0.08). Mortality was a secondary outcome among 54 pre-planned analyses with no study-wide multiplicity control, so read it as supportive rather than confirmatory. The primary functional endpoint was not met.