Research in context
Evidence before this study
Recent meta-analyses have shown that stereotaxis plus thrombolysis and other non-craniotomy surgical techniques could decrease mortality and poor functional outcome after intracerebral haemorrhage with approximate effect sizes of up to 0·50. However, high-quality evidence from well conducted stroke trials is limited, since only three of 14 studies identified in a recent meta-analysis met all Cochrane Review criteria. Available studies were mostly small, unblinded, did not use standardised surgical definitions or monitoring of the surgical task, and none assessed the generalisability of surgical performance or the association between performance and clinical outcome. Thus, we did a meta-analysis of multisite trials of catheter-based minimally invasive surgery plus thrombolysis in which outcomes were assessed using the modified Rankin scale (mRS) or extended Glasgow Outcome Scale at 180 days (appendix). The results of our meta-analysis found no significant benefit of minimally invasive surgery (odds ratio [OR] 0·61, 95% CI 0·29–1·26), which is consistent with current guidelines regarding the MISTIE intervention. The European Stroke Organisation and American Heart Association advise additional evidence is needed to recommend use of minimally invasive surgery plus thrombolysis in routine care. Biologically plausible mechanisms for surgical removal exist. Clinical injury from intracerebral haemorrhage is directly associated with clot size, with about 10% improvement in good outcomes for each 10 mL decrease in 10–50 mL clots (OR 1·4 per 10 mL). However, benefit from mechanical reduction of clot size has been difficult to demonstrate in humans. The International Surgical Trial in Intracerebral Haemorrhage (STICH) I and II studies provided strong indications that pragmatic use of open craniotomy does not yield an effect size of 10–15% in mortality or functional benefit. The MISTIE surgical task was designed to eliminate craniotomy-associated injury including cortical incision, electrocautery, toxic exposure to thrombin, and additional mechanical manipulations of brain tissue. This surgical procedure was rigorously standardised in a multisite study overseen by a core surgical laboratory. MISTIE II results provided evidence of safety of this non-craniotomy procedure, identified the best dose of thrombolytic drug to be used for clot volume reduction, and demonstrated a treatment effect for mRS 0–3 that was substantial (>10% absolute benefit) and was sustained for 1 year. The conclusions of MISTIE II required testing in a large population to assure generalisability, including the presence or absence of beneficial functional or mortality change, safety of this surgical-drug combination, and assessment of the range of performance of a standardised surgical technique and the impact of procedural performance on outcome.
Added value of this study
Despite the absence of benefit for our primary outcome in MISTIE III, data demonstrate that approximately 43% of all patients achieved a good functional outcome, even those with large intracerebral haemorrhage. These changes in functional outcome are consistent with a low frequency of withdrawal of care, guideline-driven intensive care unit care, and achievement of stability of haematoma growth. However, the fact that the proportion of all patients who achieved a good outcome was higher than expected is not solely because the patients were healthy; average patient severity matched or exceeded that of the patients included in the STICH trials. Accounting for all differences in functional outcome between randomised trials remains difficult. The secondary endpoints indicate acceptable safety and a slight decrease in mortality attributable to the MISTIE technique. The estimated mortality difference between the MISTIE and standard care treatment groups was modest, with a number needed to treat of 17 to preserve one life; however, mortality was not the primary outcome and as a result of multiple testing this estimate is exploratory. Our findings show the MISTIE technique can be safely adopted by a broad group of newly trained neurosurgeons. The exploratory secondary results suggest that clot size reduction to 15 mL or less in the MISTIE group was associated with better mRS scores at 365 days in patients who were stabilised. This finding identifies a threshold of procedural outcome, which would need to be evaluated in a future trial.
Implications of all the available evidence
The pragmatic use of MISTIE cannot be recommended. The overall functional results strongly support an active approach to care for patients with intracerebral haemorrhage who fit the enrolment criteria. For the entire trial cohort, around 43% of patients had good functional outcomes, and 80% of patients were living at home or in active rehabilitation 365 days after stroke with an acceptable quality of life. The data provide a sound basis to avoid limitation of care in patients with intracerebral haemorrhage. The MISTIE approach did not increase dependency and mortality might be decreased. The safety profile of the MISTIE procedure shows clot size reduction can be achieved with similar safety to standard medical care. Exploratory analyses also suggest that reduction in clot size to 15 mL or less is associated with functional improvement. These findings require further study of the MISTIE technique with a greater emphasis on consistently achieving clot reduction to 15 mL or less. A detailed analysis of elements of surgical performance in MISTIE III is ongoing.