Elsevier

The Lancet

Volume 393, Issue 10175, 9–15 March 2019, Pages 1021-1032
The Lancet

Articles
Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial

https://doi.org/10.1016/S0140-6736(19)30195-3Get rights and content

Summary

Background

Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage.

Methods

MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0–3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046.

Findings

Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0–3 at 365 days (adjusted risk difference 4% [95% CI −4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012).

Interpretation

For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons.

Funding

National Institute of Neurological Disorders and Stroke and Genentech.

Introduction

Worldwide, more than 5 million brain haemorrhages occur annually.1 Intracerebral haemorrhage has greater morbidity and mortality than ischaemic stroke;1, 2, 3 however, no evidence-based primary treatment exists.2, 4 Large, pragmatic trials of craniotomy,5, 6 a therapy used in routine practice, have not improved functional outcome or mortality. Findings from non-surgical trials of aggressive, early haemostasis4 and early blood pressure reduction7, 8 showed volume stabilisation of haematoma growth (1–5 mL), but no change in functional outcome or mortality. We designed the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE) III trial to assess whether image-guided, minimally invasive surgery followed by gentle thrombolytic irrigation of the catheterised intracerebral haemorrhage clot alters functional outcome.9, 10, 11, 12 The aim of our trial was to determine whether the MISTIE procedure could achieve the benefits of clot evacuation and improve functional outcome at 365 days after stroke without procedure-related safety events or additional brain injury beyond the risks associated with standard care in an intensive care unit.

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.

Section snippets

Study design and patients

MISTIE III was a randomised, controlled, open-label, blinded endpoint, phase 3 explanatory trial13, 14 of image-guided,11 catheter-based10 removal of intracerebral haemorrhage of 30 mL or more, measured with the ABC/2 method,15 done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia (appendix).

Each hospital obtained local institutional review board or ethics committee approval. Eligible patients were aged 18 years or older with a spontaneous, non-traumatic, supratentorial

Results

Between Dec 30, 2013, and Aug 15, 2017, 19 942 patients were assessed for eligibility, of whom 506 patients were randomly assigned to the two study groups: 255 patients to receive MISTIE and 251 to receive standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set (figure 1). 305 (61%) of 499 patients were men and 194 (39%) were women (median age 62 years [IQR 52–71]). 307 (62%) of 499

Discussion

In the MISTIE III trial, aspiration and thrombolytic irrigation of the intracerebral haematoma with alteplase via an image-guided catheter did not improve functional outcomes compared with standard medical care in patients with large intracerebral haemorrhage. Our secondary analyses were not adjusted for multiplicity and should be interpreted as exploratory. Mortality at 365 days seemed to be lower in the MISTIE group than the standard medical care group, without a net increase in the

Data sharing

The MISTIE III trial data, including de-identified participant data, will be made available indefinitely at the National Institute of Neurological Disorders and Stroke data archive (https://www.ninds.nih.gov/) and the Virtual International Stroke Trials Archive (http://www.virtualtrialsarchives.org/vista/) by Dec 31, 2019. To gain access, requesters will need to sign a data-access agreement. The study protocol, statistical analysis plan, and informed consent form will be included, but are also

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