Table 2 Randomized controlled trials comparing hematoma evacuation vs. conservative medical management or placebo
Study | Design | Surgical technique | Included patients (conservative/surgery) | Crossover | Timing of surgery (h) | Outcome definition and timing of assessment | Findings |
|---|---|---|---|---|---|---|---|
McKissock et al. (1961) [31] | Double-center, prospective randomized clinical trial | Craniotomy | 180 (91/89) | 1 patient | 72 (most patients were treated within 48 h) | - Full work; partial disability; total disability - 6 months | The authors were “unable to demonstrate any benefit from surgery in regard either to mortality or morbidity” |
Auer et al. (1989) [32] | Prospective single-center randomized clinical trial | Endoscopic-guided evacuation | 100 (50/50) | Not reported | 48 | - 6 Grades Outcome* - 6 months | Lower mortality (30 vs. 70%, p < 0.05) and higher rates of favorable outcome (40 vs. 25%, p < 0.01) in the surgical group. These results were limited to patients with subcortical hemorrhages, who were alert or somnolent perioperatively. The outcome was not improved by surgery in putaminal or thalamic hemorrhages. |
Juvela et al. (1989) [33] | Prospective single-center randomized clinical trial | Craniotomy | 52 (26/26) | Not reported | 48 | - Glasgow Outcome Scale - 1, 6, and 12 months | Surgery did not offer any advantage over conservative treatment. Additionally, in comatose patients (GCS = 7–10), surgery decreased mortality, but patients survived with poor quality of life. |
Batjer et al. (1990) [34] | Prospective single-center randomized clinical trial | Craniotomy | - Total = 21 - 9 best medical management - 4 best medical management + intracranial pressure monitoring - 8 surgical evacuation | None | 24 | 1 (dead or vegetative) 2 (dependent) 3 (independent at home) 4 (return to prestrike activity) - 6 months | - 4 out of 8 patients died in the surgical group - 2 were capable of independent life. - Surgery was ineffective compared with best medical management or best medical management + ICP monitoring |
Morgenstern et al. (1998) [35] | Prospective single-center randomized clinical trial | Craniotomy | 41 (34/7) | None | 12 | - Barthel score and mortality - 1 and 6 months | - 6-month mortality rate and functional outcome favor conservative group |
Zuccarello M et al. (1999) [36] | Prospective three centers randomized clinical trial | Craniotomy CT-guided stereotaxic placement of a catheter | 20 (11/9) - 5 craniotomy - 4 stereotaxic evacuation - 11 best medical therapy | 1 patient | 24 | - Glasgow Outcome Scale - 3 months | No difference in the likelihood of a good outcome or mortality at 3 months. |
Morgenstern et al. (2001) [37] | Prospective single-center cohort | Ultra-early craniotomy | 11 (all surgical) | None | 4 | - Barthel score, modified Rankin Scale and mortality - 6 months | - Interrupted after planned interim analysis, because of increased rates of rebleeding with ultra-early craniotomy |
Teernstra et al. (2003) [38] | Multicenter randomized controlled trial (13 centers) | Stereotactic aspiration combined with urokinase injection | 71 (35/36) | - One crossover from medical to craniotomy - One patient from stereotactic group underwent craniotomy - Four patients received no stereotactic drainage | 72 | - Death - 6 months | - The trial was prematurely stopped due to slow recruitment - Mortality 3-months was not statistically significant, 56% in the surgical group vs. 59% in the nonsurgical group |
Hattori et al. (2004) [39] | Prospective single-center randomized clinical trial | Stereotactic evacuation | 242 (121/121) | None | - Modified Rankin Scale - 12 months | Stereotactic evacuation reduced mortality and improved functional outcomes in patients with neurological Grade 3 (eyes closed but open to strong stimuli) | |
STICH (2005) [40] | Multicenter randomized controlled trial (83 centers in 27 countries) | Craniotomy 75% Burrhole 8% Endoscopy 7% Stereotaxy 7% Other 3% Not recorded | 1033 (530/503) | 26% | 72 h of ictus and 24 h of randomization | - Extended Glasgow Outcome Scale according to a prognosis-based methodology - 6 months | No overall benefit in mortality or functional outcome mortality was found with surgery |
Pantazis et al. (2006) [41] | Prospective single-center randomized clinical trial | Craniotomy | 108 (54/54) | 2 patients | 8 | - Glasgow Outcome Scale - 12 months | - 33% of patients in the surgical group vs. only 9% of patients in the conservative group had a Glasgow Outcome Scale > 3 (p < 0.05). - There is no mortality benefit with surgery. - When functional outcome was stratified by neurological status on admission, hematoma volume and location, no benefit with surgery was seen for patients with GCS < 8 or ICH ≥ 80 ml at enrollment |
Kim et al. (2009) [42] | Prospective single-center randomized clinical trial | Stereotactic-guided evacuation | 387 (183/204) | 23 patients (they were excluded from the analysis) | 12 h up to 5 days | - Modified Barthel Indices (MBI) and the modified Rankin Scale - 6 months | - Stereotactic-guided evacuation had a significant effect on a functional recovery - MBI was 90.9 in the surgical group vs. 62.4 in conservative group (p < 0.05) - mRS was 1.2 in the surgical group vs. 3.0 in the conservative group (p < 0.05) |
Wang et al. (2009) [43] | Multicenter randomized controlled trial (42 centers) | Minimally invasive craniopuncture combined with urokinase injection | 377 (182/195) | - 16 patients (7 patients randomized to craniopuncture therapy refused operation, and 9 patients randomized to conservative treatment crossover to surgery) - they were excluded from the analysis | Mean time in hours from stroke onset to operation (SD) = 21.1 (15.9) | - Modified Rankin Scale and Barthel Index - 3 months | - No significant difference in activities of daily living score - The proportion of dependent survival patients (modified Rankin scale > 2) in the craniopuncture group (40.9%) was significantly lower than that in the conservative group (63.0%) - No significant difference in the cumulative fatality rates |
STICH II (2013) [44] | Multicenter randomized controlled trial (78 centers) | Craniotomy 99% Craniectomy < 1% †Minimally invasive 1% | 601 (294/307) | 21% | 48 h of ictus and 12 h of randomization | - Extended Glasgow Outcome Scale according to a prognosis-based methodology - 6 months | - 59% of the surgery group had an unfavorable outcome versus 62% in the initial conservative group (absolute difference = 3.7%, 95% CI = − 4.3–11.6, OR = 0.86, 95% CI = 0.62–1.20, p = 0.367). - No overall benefit in functional outcome or mortality was found |
MISTIE (2016) [45] | Randomized, controlled, open-label, phase 2 trial (26 centers) | Image-guided, catheter-based, stereotactic aspiration and thrombolysis (alteplase 0.3 mg or 1.0 mg every 8 h for up to nine doses) | 96 (42/54) | - 4 patients in the conservative group and 2 in the minimally invasive surgery plus alteplase underwent craniotomy | - 57% underwent surgery within 36 h, while 43% underwent surgery beyond 36 h | - Primary outcomes: 30-day mortality; 7-day procedure-related mortality; 30-day bacterial brain infection; symptomatic bleeding within 72 h after the last dose. | - Primary outcomes did not differ between the two groups - Asymptomatic hemorrhages were more common in the surgical group |
Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery for Brain Hemorrhage (2016) [46] | Multicenter randomized controlled trial (78 centers) | Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery | 24 | None | 48 | - Modified Rankin Scale - 6 and 12 months | - Early computerized tomographic image-guided endoscopic surgery is a safe and effective - One bleed occurred peri-operatively - The surgical intervention group had a greater percentage of patients with favorable neurological outcome |
CLEAR III (2017) [24] | Randomized, multicenter, multiregional, placebo-controlled trial (73 centers) | Thrombolytic removal of intraventricular hemorrhage (alteplase 1 mg through an EVD, every 8 h, to a max. 12 doses) | 500 (251 placebo/ 249 alteplase) | None | 72 | - Modified Rankin Scale - 6 months | - The injection of intrathecal alteplase did not improve functional outcomes in IVH patients - 6-month modified Rankin scale (mRS) of 0–3 was not significantly different between the r-tPA and saline groups - Treatment was associated with lower case, to the cost of a higher proportion of patients in a vegetative state |
MISTIE III (2019) [47] | Randomized, controlled, open-label, blinded endpoint phase 3 trial (78 centers) | Minimally invasive catheter evacuation followed by thrombolysis (alteplase 1.0 mg every 8 h for up to nine doses) | 506 (251/255) | None | 72 | - Modified Rankin Scale - 12 months | - MISTIE did not improve long-term outcome - 110 patients (45%) in the MISTIE group vs. 100 patients (41%) in the conservative group achieved a favorable outcome [adjusted risk difference 4% (95% CI − 4 to 12); p = 0.33] - Meta-analysis including only multisite trials of MISTIE was performed by the authors and no significant benefit of MISTIE was found (OR 0.61, 95% CI 0.29–1.26). |