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Table 2 Randomized controlled trials comparing hematoma evacuation vs. conservative medical management or placebo

From: Surgery for spontaneous intracerebral hemorrhage

StudyDesignSurgical techniqueIncluded patients (conservative/surgery)CrossoverTiming of surgery (h)Outcome definition and timing of assessmentFindings
McKissock et al. (1961) [31]Double-center, prospective randomized clinical trialCraniotomy180 (91/89)1 patient72 (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 trialEndoscopic-guided evacuation100 (50/50)Not reported48- 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 trialCraniotomy52 (26/26)Not reported48- 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 trialCraniotomy- Total = 21
- 9 best medical management
- 4 best medical management + intracranial pressure monitoring
- 8 surgical evacuation
None241 (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 trialCraniotomy41 (34/7)None12- 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 trialCraniotomy
CT-guided stereotaxic placement of a catheter
20 (11/9)
- 5 craniotomy
- 4 stereotaxic evacuation
- 11 best medical therapy
1 patient24- 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 cohortUltra-early craniotomy11 (all surgical)None4- 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 injection71 (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 trialStereotactic evacuation242 (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 trialCraniotomy108 (54/54)2 patients8- 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 trialStereotactic-guided evacuation387 (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 injection377 (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 Surgery24None48- 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)None72- 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)None72- 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).
  1. †Minimally invasive procedures were burrhole with endoscopic evacuation in two patients and keyhole evacuation in one patient. *Grade 1—patient leads a full and independent life without neurological deficit; Grade 2—patient leads a full and independent life with minimal neurological deficit; Grade 3—patient has neurological or intellectual impairment, but is independent and able to work part-time; Grade 4—patient has neurological deficit, is unable to work but is capable of self-care; Grade 5—conscious patient totally dependent on others for activities of the day; Grade 6—dead