Stroke Snapshot: Intracerebral Hemorrhage—Surgery and the Future of Clinical Trials

Intracerebral hemorrhage (ICH), a devastating form of stroke caused by bleeding into the brain parenchyma, accounts for ~10% of strokes in the United States and affects >5 million people globally.^1,2 Despite its lower incidence compared with ischemic stroke, ICH carries a disproportionately high mortality rate, with up to 50% of individuals with ICH dying within 30 days; ICH also accounts for more than half of stroke-related disability. Although the field has seen remarkable progress in improving ischemic stroke management, advancements in hemorrhagic stroke have lagged.³

Current ICH therapies primarily aim to prevent hematoma expansion through aggressive blood pressure control and pharmacologic strategies to enhance coagulation. These efforts have spurred initiatives (eg, “Code ICH”) designed to streamline triage and accelerate specialty care for this critical population.⁴

Few advances have been made in medical therapy for ICH, but surgical intervention is entering a new era. Although earlier clinical trials in ICH failed to show consistent outcome improvements, results from more recent studies have demonstrated improvements. Whereas earlier clinical trials failed to show consistent outcome improvements, more recent studies have begun to shift this narrative. The Minimally Invasive Surgery Plus rt-PA for Intracerebral Hemorrhage Evacuation (MISTIE) III trial (NCT01827046) established a high level and class of evidence for mortality benefit, and the Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH) trial (NCT02880878) further supported the potential for functional improvement in individuals with lobar ICH.^1,2 Both trials highlighted that surgical efficacy is a key aspect of improving functional outcomes with identified volume thresholds of evacuations that ultimately confer functional benefit.^5,6 The studies also demonstrated that successful removal of more blood is associated with better functional outcomes (Figure 1). In addition, over the past decade substantial progress has been made in the treatment of ICH as evidenced by improvements in favorable functional outcomes—from 26% and 41% in the era of Surgical Trial in Intracerebral Hemorrhage (STICH) I and STICH II trials, respectively, to 50% demonstrated by the MISTIE III and ENRICH trials.^1,2,7,8

With the lessons of the past decade and the advent of novel tools and treatment frameworks, there is a compelling rationale to reexamine and refine how to apply surgical strategies in ICH, with a focus on optimizing technique and patient selection to realize the full potential of these interventions.

Figure 1. Artistic representation of surgical strategies of landmark trials in intracerebral hemorrhage (ICH) evacuation. In Surgical Trial in Intracerebral Hemorrhage (STICH), open craniotomy for ICH evacuation was tested, without benefit (A). Minimally Invasive Surgery Plus rt-PA for ICH Evacuation (MISTIE) III tested catheter-based ICH evacuation, with a mortality benefit and signal toward functional improvement (B). Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH) tested a tubular access system, with functional benefit in lobar bleeds only (C). Results of these trials have led to an emphasis on volume reduction of the hematoma by the least invasive means.
Images are AI-generated and adapted with permission from Awad IA, Polster SP, Carrión-Penagos J, et al. Surgical performance determines functional outcome benefit in the
minimally invasive surgery plus recombinant tissue plasminogen activator for intracerebral hemorrhage evacuation (MISTIE) procedure. Neurosurgery. 2019;84(6):1157-1168. doi:10.1093/neuros/nyz077

Historical Studies of ICH Evacuation

Early attempts at hematoma evacuation were often met with skepticism because surgical interventions failed to demonstrate clear survival or functional benefits. This sentiment was largely shaped by 2 landmark trials—STICH I and STICH II—which evaluated open craniotomy for ICH evacuation.^7,8 STICH I included a broad range of spontaneous supratentorial ICH cases and found no significant overall advantage of surgery compared with medical management. However, the study identified a potential signal of benefit in individuals with superficial hematomas (≤1 cm from the cortical surface), suggesting that surgical benefit might be location-dependent. This hypothesis formed the basis for STICH II, which selected lobar hemorrhages with similar superficial location criteria. Although STICH II also failed to demonstrate statistically significant functional improvement with surgical compared with medical management, there was a trend toward better survival in selected subgroups, reinforcing the need for more nuanced patient selection.⁸

Several factors may have contributed to the equivocal results of these early trials. First, there was considerable heterogeneity in patient populations, timing of surgery, surgical technique, and perioperative management. In addition, the surgical methods used (ie, open craniotomies) were often associated with substantial trauma to adjacent brain tissue, potentially offsetting the benefits of hematoma removal. These trials did not assess or consider a volume threshold of ICH removal in relation to outcome.

In retrospect, the STICH trials helped reframe the research agenda: rather than broadly comparing “surgery versus medicine,” subsequent efforts began focusing on how, when, and in whom surgical intervention might be beneficial. These lessons laid the groundwork for the next generation of studies emphasizing minimally invasive surgical (MIS) techniques, more refined inclusion criteria, and standardized surgical goals.

Advances in ICH Evacuation and Lessons Learned

The limitations of traditional craniotomy and disappointing outcomes from earlier trials have encouraged exploration into MIS approaches for ICH evacuation. Recent pivotal trials, notably MISTIE III and ENRICH, have shifted the perception of surgical evacuation from a generalized procedure to one defined by measurable endpoints. 

MISTIE III

The MISTIE III trial examined the effectiveness of catheter-based clot removal combined with recombinant tissue plasminogen activator administration.² Study results demonstrated a significant reduction in mortality and perihematomal injury and a strong trend toward improved functional outcomes measured by the modified Rankin Scale (mRS). However, the primary outcome analysis failed to show a statistically significant difference in functional outcome between the surgical and nonsurgical groups. A post hoc analysis revealed that achieving an end-of-treatment hematoma volume <15 cc conferred clear functional benefits in both deep and superficial hemorrhages. This key finding, in addition to surgical performance, will be important in future trials. Overall, despite being considered a negative trial due to its predefined primary endpoint, MISTIE III also underscored crucial surgical insights including the necessity of thorough etiology screening using advanced vascular imaging (eg, CT angiography, MRI, magnetic resonance angiography, digital subtraction angiography) and the importance of confirming hematoma stability through serial imaging (ie, 2 scans at least 6 hours apart showing no hematoma expansion).⁹

The MISTIE III trial results emphasized the necessity for rigorous protocol adherence and surgical performance to prevent additional bleeding and reach end-of-treatment volume goals. Analyses suggested that strict adherence to the surgical protocol and hematoma-removal goals would have significantly shifted the trial outcomes to favor surgical intervention. Future trials must emphasize extensive training and procedural adherence to realize improved outcomes.

ENRICH 

The ENRICH trial, initiated in December 2016, was a multicenter randomized study evaluating MIS evacuation using a tubular retractor system (BrainPath; Stryker, Portage, MI) versus best medical management.¹ Using adaptive randomization, utility-weighted mRS outcomes, and Bayesian inference methodologies, results of the ENRICH trial demonstrated improved functional outcomes at 180 days in surgically treated patients with lobar hemorrhages. Although innovative, the unique methodologic approach—particularly the absence of conventional P values and reliance on Bayesian statistics—has introduced skepticism regarding the broader clinical impact, somewhat limiting widespread adoption of this technique.

Volume Considerations

Post hoc analyses from MISTIE III highlight the significance of precise hematoma volume reduction. Results demonstrated an association between achieving an end-of-treatment hematoma volume ≤30 cc and improved survival, and volumes ≤15 cc were associated with markedly better functional outcomes (mRS 0–3). Deep hematomas required an even lower volume threshold to confer functional benefit. Results of the ENRICH trial also demonstrated surgical effectiveness with reduced hematoma volumes to a mean of 14.9±21.7 cc, and achieved reduction to <15 cc in ~73% of treated cases. Notably, the ENRICH trial reached futility for deep hemorrhages after enrolling only 48 surgical patients, reinforcing the critical interplay between hematoma location and volume reduction efficacy.¹

In a pooled analysis of surgical cases from the MISTIE III trial involving lobar bleeds and the STICH II trial involving superficial bleeds, a clear relationship emerged between hematoma volume and outcomes that was shared between the 2 studies regardless of surgical technique (STICH I did not provide end-of-treatment hematoma volumes and hence could not be analyzed for volume-based outcomes). Hematoma volume reduction to an end-of-treatment volume of ≤30 cc increased the probability of achieving a favorable outcome (mRS score of 0-3) at 180 days after multivariable adjustment (Figure 2, A and B).⁶ This threshold for lobar hematoma evacuation is consistent across studies, with a more stringent threshold for deeper locations.^10,11 An identical shift in mRS was observed in MISTIE III and ENRICH study participants with lobar cases, highlighting the similarity of outcome in the same types of patients when ICH evacuation was accomplished using different techniques.¹²

Timing of Intervention

Optimal timing for surgical intervention remains an area in need of further clarification. Trials to date have not implemented any clear data-driven cutoffs for the timing of ICH surgical intervention. Data from MISTIE III and STICH I and II indicate a stable 40% to 50% absolute benefit (mRS 0–3) for surgical intervention occurring between 12 and 48 hours postictus, with the possibility of harm for ultraearly interventions, especially if key medical protocols are not followed to ensure hematoma stability and to confirm underlying etiology (Figure 2, C and D).^6,12 The ENRICH trial used a narrower median timeframe of 16.75 hours (interquartile range, 10.70–21.25) from ictus. Furthermore, the estimated effect sizes observed in the as-treated analysis from MISTIE III (10.5%) closely match those from ENRICH (9.0%), despite MISTIE procedures being performed up to 72 hours postictus.^1,2 This pragmatic finding emphasizes the possibility of a longer effective time window for ICH interventions. 

Neither ENRICH nor other randomized trials have definitively shown that earlier intervention consistently leads to better outcomes. Given that not all individuals can access experienced minimally invasive surgery centers within 24 hours, it is important to determine if there is a benefit for individuals who are treated in the 24- to 48-hour window. A well-powered clinical trial including substantial cohorts at various timeframes is needed to effectively answer this essential clinical question, which has major implications for generalizability in real-world practice and infrastructure.¹²

Figure 2 . Cubic spline modeling of the dichotomized outcomes (modified Rankin Scale [mRS] score 0–3 vs 4–6) in Minimally Invasive Surgery Plus rt-PA for Intracerebral Hemorrhage Evacuation (MISTIE) III showing a key threshold at 15 mL end-of-treatment (EOT) volume, where the probability of a good outcome drastically emerges (green shading shows significance) (A). A similar analysis was done in the Surgical Trial in Intracerebral Hemorrhage (STICH) II trial, showing a threshold of 30 mL for the EOT volume for lobar hematoma, confirming a good functional outcome. In MISTIE III, a similar threshold was identified at 28.8 mL (data not shown) (B). The timing of intervention did not show a clear correlation to functional outcomes in MISTIE III (C), with pooled analysis of STICH I and II (D) showing a significant spline model from ictus up to 62 hours.
Reproduced with permission from Polster SP, Carrión-Penagos J, Lyne SB, et al. Intracerebral hemorrhage volume reduction and timing of intervention versus functional benefit and survival in the MISTIE III and STICH trials. Neurosurgery. 2021;88(5):961-970.6

Anatomic Considerations

The interaction between hemorrhage location and surgical efficacy is an emerging focal point for future trials. Results from the ENRICH trial demonstrated a functional benefit in cases of lobar hemorrhages versus deep hemorrhages which had variable outcomes and early futility was perceived. ENRICH reached futility in intervening on deep hemorrhages after 48 procedures. The anatomic location of ICH substantially influences outcome, highlighting the importance for future surgical strategies and thresholds to be based on precise anatomic criteria. The STICH I trial included a substantial number of individuals with basal ganglia/thalamic hematomas (42%, with 19% considered both deep and lobar). The MISTIE III trial included individuals with deep hemorrhages, defined as “theputamen or thalamus,” with the final location adjudicated by a single neuroradiologist.^5,6 The ENRICH trial defined deep as “the anterior basal ganglia includ[ing] the caudate, putamen, and pallidum to the capsula externa and exclud[ing] the thalamus.”¹ These definitions are likely unsatisfactory to capture anatomic considerations for patient selection and outcomes prognostication. CT resolution and ICH workflow make more precise determination impractical, but advances in imaging along with the potential role of artificial intelligence in image processing will likely be a key area of interest in the future.¹³ Anatomic location may be the most important factor in ICH outcomes, and identifying involved fiber tracks that can be correlated to function or fiber tracks deemed salvageable would be a useful tool in patient selection and surgical strategy. At present, the best anatomic surrogate uses broad, ill-defined terms of lobar vs deep, along with quantitative volume. Image processing platforms in which volumetrics are automated and reliable have become widely available, which is a step forward from previous trials that used manual calculations.

The Future of ICH Evacuation

Advances in neuroimaging, surgical robotics, and precision medicine are poised to shape the future of ICH evacuation. Emerging technologies that improve clot evacuation and novel neuroprotective strategies may enhance outcomes by minimizing secondary injury. Future clinical trials will continue to refine the optimal timing, patient selection criteria, and techniques for surgical intervention, with the goal of improving both survival and functional recovery in people with ICH.

Advancements in the understanding of ICH, including results from recent clinical trials, has resulted in a shift toward minimally invasive surgery to evacuate clots, with a goal end-of-treatment volume of ≤15 cc. This is a starting point for future trials with good preliminary evidence to test and reenforce this threshold. However, an unequivocal trial that shows functional benefits for both deep and lobar hemorrhage types, as well as a better understanding of the timing of such interventions, is urgently needed.¹² The MISTIE and ENRICH trials have set the stage to answer these questions, and the time is right to move forward with a large pragmatic trial. 

A future trial will undoubtedly benefit from recent advancements in technology, neurocritical care, and surgical techniques. The next phase of innovation will rely on refining patient selection, optimizing minimally invasive approaches, and harmonizing the surgical task across centers and providers to improve outcomes. Lessons learned from clinical trials on ischemic stroke are instructive for future trials on ICH in that they lead researchers to ask the proper questions based on biology (eg, volume, location, timing) to improve functional outcomes, rather than testing different tools to complete a task. For example, in ischemic stroke, a series of endovascular studies have made clear that what matters for patient outcomes is not the specific tool chosen, but the degree of procedural success in restoring blood flow.¹² Similarly it is becoming clear that the focus of ICH research should be less on proving the advantage of one device over another and more on achieving target hematoma volumes using the variety of tools available. In addition, in ischemic stroke, timing windows for intervention were initially strictly controlled, but once efficacy was demonstrated in a tight window, subsequent trials expanded windows of intervention based on better understanding of biology and cerebral salvageability.¹²

Conclusion

The future of ICH evacuation will be shaped by a multidisciplinary approach that combines surgical innovation, advanced imaging, artificial intelligence–driven decision support, and neuroprotective strategies.^3,10-12,14 By refining patient selection, expanding minimally invasive techniques, and integrating novel therapeutics, the next generation of ICH treatment has the potential to shift outcomes from high mortality and disability toward improved survival and functional independence. Continued research, collaboration, and equitable health care implementation will be imperative in translating these advancements into widespread clinical practice. Multidisciplinary, multi-institutional collaboration will be necessary to plan, implement, and test interventions in forthcoming clinical trials.