ENRICH

Clinical Context

The role of surgical intervention for spontaneous intracerebral hemorrhage (ICH) has been a subject of extensive research and debate for decades. While large hematomas cause significant mass effect and secondary injury, traditional open craniotomy has not consistently shown clear benefits over medical management in broad populations, as evidenced by trials like STICH and STICH-II, particularly for deep hematomas or when surgery is not performed very early for specific subtypes.

However, advancements in minimally invasive surgical (MIS) techniques have offered new hope. These approaches aim to achieve adequate hematoma evacuation with less iatrogenic injury to surrounding brain tissue compared to conventional craniotomy. The ENRICH (Early Minimally Invasive Removal of Intracerebral Hemorrhage) trial was designed to rigorously evaluate the efficacy and safety of one such MIS technique—stereotactically guided endoscopic parafascicular surgery—in patients with acute supratentorial ICH. The trial hypothesized that early hematoma removal using this approach would lead to improved functional outcomes.

Patient Population

The ENRICH trial enrolled 300 adult patients (aged 18 to 80 years) across 37 centers in the United States. Eligible patients had:

• Spontaneous supratentorial ICH (lobar or basal ganglia location) confirmed by CT.
• Hematoma volume between 30 and 80 mL.
• Glasgow Coma Scale (GCS) score between 5 and 14 (inclusive).
• Amenability to surgery within 24 hours of the last known well time.

Key exclusion criteria included infratentorial hemorrhage, significant intraventricular hemorrhage requiring pre-randomization EVD, ICH due to underlying structural lesions or coagulopathy, severe pre-existing disability (mRS > 2), or a moribund state (GCS 3 or 4).

The mean age of participants was approximately 62 years, and about 57% were male. Lobar hemorrhages constituted roughly 60-65% of cases, with the remainder being anterior basal ganglia hemorrhages. The median baseline hematoma volume was around 45-50 mL, and the median GCS was approximately 10-11.

Study Design

ENRICH was a multicenter, prospective, randomized, adaptive clinical trial. The adaptive design allowed for pre-specified interim analyses and sample size adjustments.

Protocol Details

Patients meeting eligibility criteria were randomized 1:1 to:

• Intervention Group (MIPS): Minimally invasive parafascicular surgery (MIPS) for hematoma evacuation performed within 24 hours of the last known well time, plus guideline-based medical management. The surgical technique involved using the NICO Myriad and BrainPath systems. The goal of surgery was to achieve at least 70% reduction in hematoma volume or a residual volume of less than 15 mL.
• Control Group (Medical Management): Guideline-based medical management alone. This included intensive care unit monitoring, blood pressure control, management of intracranial pressure, and other standard supportive care measures. Crossover from the medical management group to surgical intervention was allowed if deemed medically necessary by the treating physicians.

Outcome Assessment

Outcomes were assessed at 30, 90, 180, and 365 days. The primary outcome was assessed at 180 days. Outcome assessors were blinded to the treatment assignment.

Power Analysis & Statistical Approach

The trial used a Bayesian adaptive design. The primary outcome was the utility-weighted mRS score at 180 days. A pre-specified threshold for concluding superiority of MIPS was a Bayesian posterior probability of >0.975 for a positive treatment effect (utility-weighted mRS difference > 0). The trial planned to enroll up to 375 patients but was stopped early at 300 patients after an interim analysis met the pre-specified criteria for success.

Risk of Bias Analysis

(Content for this section needs to be added. Considerations: open-label nature of the intervention, potential for performance bias in surgical group, blinded outcome assessment is a strength, adaptive design features.)

Results

A total of 300 patients underwent randomization: 150 to MIPS and 150 to medical management. Baseline characteristics were generally well-balanced. In the MIPS group, surgery was performed at a median of 16.5 hours from last known well. The mean percentage reduction in hematoma volume at 24 hours was approximately 73%, with a mean residual volume of about 13 mL. About 19% of patients in the medical management group crossed over to receive surgery.

Primary Outcome: Utility-Weighted mRS at 180 Days

The mean utility-weighted mRS score at 180 days was significantly higher (better) in the MIPS group compared to the medical management group:

• MIPS group: 0.458
• Medical Management group: 0.374
  The mean difference was 0.084 (95% Credible Interval, 0.005 to 0.163). The Bayesian posterior probability of superiority for MIPS was 0.981, exceeding the pre-specified threshold of >0.975 for success.

Secondary Outcomes

Several key secondary outcomes also favored the MIPS group:

• Functional Independence (mRS 0-3) at 180 days: Achieved by 49% of MIPS patients vs. 32% of medical management patients (difference not explicitly reported with CI/p-value in abstract, but implied favorable).
• Mortality at 30 days: 9.3% in the MIPS group vs. 18.1% in the medical management group.
• Mortality at 180 days: 20.0% in the MIPS group vs. 23.3% in the medical management group.
• Change in NIHSS score: Greater improvement in the MIPS group.
• Length of ICU stay: Shorter in the MIPS group (median 6 days vs. 8 days).

Safety Outcomes

The rates of serious adverse events were generally similar between the groups, although specific types of AEs might differ (e.g., surgical site infections in MIPS vs. complications of prolonged immobility in medical management).

Final Thoughts & Critical Appraisal

The ENRICH trial is a significant positive trial in the field of ICH management, demonstrating a benefit for early minimally invasive surgical hematoma evacuation in a selected population of patients with spontaneous supratentorial hemorrhage.

Key takeaways:

• Benefit of Early MIPS: For patients with moderate-to-large (30-80 mL) lobar or anterior basal ganglia ICH and GCS 5-14, early MIPS (within 24 hours) resulted in improved functional outcomes (as measured by utility-weighted mRS) and reduced mortality at 30 days compared to standard medical management.
• Specific Technique and Population: The positive results are specific to the minimally invasive parafascicular technique used (NICO BrainPath system) and the patient population enrolled (volumes 30-80 mL, specific locations, GCS range). Extrapolation to other MIS techniques or significantly different patient groups should be done cautiously.
• Contrast with Previous Surgical Trials: Unlike STICH and STICH-II, which largely showed neutral results for conventional open craniotomy in broader ICH populations, ENRICH provides evidence supporting a specific surgical approach in a more targeted patient group. This suggests that the method and timing of surgery, along with patient selection, are critical.
• Adaptive Design Success: The trial’s Bayesian adaptive design allowed it to conclude efficacy with a smaller sample size than might have been required with a traditional frequentist design, once a clear benefit was established at an interim analysis.
• Future Directions: The ENRICH results are likely to influence clinical practice guidelines for selected ICH patients. Further research may explore the benefits of this technique in other ICH locations or volumes, optimal timing, and long-term outcomes beyond 180 days.

ENRICH represents an important step forward, suggesting that for the right patient with the right type of bleed, the right minimally invasive technique performed early can make a meaningful difference in outcomes.

How do we reconcile the results with other studies?

(Content for this section needs to be added, discussing ENRICH in the context of STICH, STICH-II, MISTIE trials, and the evolving landscape of ICH surgical intervention.)

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