Landmark Trials in Intracerebral Hemorrhage (ICH)

A. BLOOD PRESSURE MANAGEMENT

1. INTERACT2 (2013)

• Full name: Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial 2
• Design: RCT, ~2,800 patients; acute ICH with SBP 150-220 mmHg within 6 hours of onset
• Intervention: Intensive BP lowering (target SBP <140 mmHg within 1 hour) vs. standard care (target <180 mmHg)
• Primary outcome: Death or major disability (mRS 3-6) at 90 days
• Result: Primary outcome was NOT significantly different (52.0% vs 55.6%; OR 0.87, p=0.06), but ordinal analysis of the full mRS showed a significant improvement in functional outcome with intensive treatment
• Significance: Established that acute intensive BP lowering is safe and suggested modest functional benefit; shifted practice toward targeting SBP <140 mmHg

2. ATACH-2 (2016)

• Full name: Antihypertensive Treatment of Acute Cerebral Hemorrhage II
• Design: RCT, ~1,000 patients; acute ICH, SBP ≥180 mmHg within 4.5 hours
• Intervention: Intensive (SBP 110-139 mmHg) vs. standard (SBP 140-179 mmHg) using IV nicardipine
• Primary outcome: Death or disability (mRS 4-6) at 3 months
• Result: No benefit - primary outcome 38.7% vs 37.7% (RR 1.04, p=0.72); trial stopped early for futility
• Significance: Intensive lowering below 140 mmHg did not further improve outcomes vs. standard <180 mmHg; more renal adverse events in intensive group

3. INTERACT3 (2023)

• Design: Stepped-wedge cluster RCT in 144 hospitals in 10 countries
• Intervention: Comprehensive care bundle: intensive BP lowering + glucose management + temperature management + reversal of anticoagulation
• Result: Significant improvement in functional outcome (mRS shift toward better outcomes) with the bundle
• Significance: First trial to show benefit of a bundled care protocol rather than a single intervention

B. SURGICAL EVACUATION

4. STICH I (2005)

• Full name: Surgical Trial in Intracerebral Haemorrhage
• Design: RCT, 1,033 patients; spontaneous supratentorial ICH
• Intervention: Early surgery (within 96 hours) vs. initial conservative treatment
• Primary outcome: Death or disability (extended Glasgow Outcome Scale) at 6 months
• Result: No benefit - unfavorable outcome 74% surgery vs 76% conservative (p=0.414)
• Subgroup finding: Hematomas <1 cm from the cortical surface showed a trend toward benefit with surgery
• Significance: Established that routine early surgery for supratentorial ICH has no proven benefit - Bradley & Daroff's Neurology, p.1029

5. STICH II (2013)

• Design: RCT, ~600 patients; superficial lobar ICH (<1 cm from cortex), no IVH
• Intervention: Early surgery vs. initial conservative treatment
• Result: No significant difference in unfavorable outcome (59% surgery vs 62% conservative; OR 0.86, p=0.367)
• Post-hoc analysis: Suggested possible benefit in patients with predicted poor prognosis (those already expected to do badly may benefit from surgery)
• Significance: Confirmed STICH I findings even for the "favorable" subgroup; surgery remains unproven as routine - Bradley & Daroff's Neurology, p.1029

6. MISTIE III (2019)

• Full name: Minimally Invasive Surgery Plus Alteplase for ICH Evacuation III
• Design: RCT, 506 patients; large ICH (≥30 mL), minimally invasive catheter aspiration + tPA to dissolve clot
• Primary outcome: Functional independence (mRS 0-3) at 365 days
• Result: Primary outcome negative (45% vs 41%; adjusted difference 4%, p=0.30); reduced 30-day mortality (9% vs 18%)
• Exploratory finding: Patients in whom residual hematoma was reduced to ≤15 mL had significantly better outcomes, suggesting a volume-reduction threshold effect
• Significance: Did not show benefit on the primary outcome, but the mortality signal and volume-reduction relationship prompted further MIS research - Bradley & Daroff's Neurology, p.1029

7. ENRICH Trial (2024 - NEJM) 🔴 Most Recent Positive Trial

• Full name: Early MiNimally-invasive Removal of ICH
• Design: Multicenter, adaptive RCT; 300 patients; supratentorial ICH (lobar or anterior basal ganglia), volume 30-80 mL, GCS 5-14
• Intervention: Early minimally invasive parafascicular surgery (MIPS) using BrainPath + Myriad device vs. guideline-based medical management; surgery within 24 hours of onset
• Primary outcome: Utility-weighted mRS (UWmRS) at 180 days
• Result: POSITIVE - UWmRS 0.458 (MIPS) vs 0.374 (MM); difference 0.084 (95% CI 0.005-0.163); posterior probability of superiority 98.1%
• By location: Benefit driven by lobar hemorrhages (UWmRS 0.513 vs 0.371; difference 0.127). Anterior basal ganglia: neutral (basal ganglia enrollment halted for futility)
• Mortality: 30-day mortality 9.3% surgery vs 18.1% control; 180-day mortality 20% vs 23%
• ICU LOS: Reduced by 2.8 days; hospital LOS reduced by 3.1 days
• Published: NEJM 2024;390:1277-1289 (DOI: 10.1056/NEJMoa2308440)
• Significance: First positive RCT to improve functional outcomes in ICH - a landmark result, specifically for early MIPS in lobar hemorrhages

C. HEMOSTASIS / ANTICOAGULATION REVERSAL

8. FAST Trial (2008) - rFVIIa

• Design: RCT, ~841 patients; recombinant Factor VIIa (rFVIIa) given within 4 hours of ICH onset
• Result: No benefit in functional outcome despite reducing hematoma growth; increased thromboembolic events
• Significance: Established that rFVIIa is not recommended for routine spontaneous ICH

9. TICH-2 (2018) - Tranexamic Acid

• Design: RCT, ~2,325 patients; tranexamic acid 1g IV bolus + 1g IV over 8 hours within 8 hours
• Result: Reduced early death and hematoma expansion at 24 hours, but no improvement in functional outcome (mRS 0-3) at 90 days
• Significance: Tranexamic acid not routinely recommended for spontaneous ICH

10. INCH Trial (2016) - PCC vs FFP in Warfarin-ICH

• Design: RCT; prothrombin complex concentrate (PCC) vs fresh frozen plasma in VKA-related ICH
• Result: PCC was superior to FFP in achieving INR normalization within 3 hours; better hematoma control
• Significance: Established PCC as the preferred agent for warfarin reversal in ICH; now standard of care - Bradley & Daroff's Neurology, p.1030

D. INTRAVENTRICULAR HEMORRHAGE

11. CLEAR III (2017) - Intraventricular tPA

• Design: RCT, ~500 patients; IVH with obstructive hydrocephalus; intraventricular alteplase vs saline via EVD
• Result: No improvement in favorable functional outcome (mRS 0-3) at 180 days; reduced mortality but increased survivors with severe disability
• Significance: IVH thrombolysis does not improve functional outcomes despite clearing clot

Summary Table