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Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial

Lookup NU author(s): Emeritus Professor David Mendelow, Dr Barbara Gregson



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Background Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for dot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage.Methods MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0.3 mg or 1.0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with, number NCT00224770.Findings Between Feb 2,2006, and April 8,2013,96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9.5%, 95% CI 2.7-22.6] vs eight [14.8%, 6.6-27.1], p=0.542), 7 day mortality (zero [0%, 0-8.4] vs one [1.9%, 0-1-9.9], p=0.562), symptomatic bleeding (one [2.4%, 0.1-12.6] vs five [9.3%, 3.1-20.3], p=0.226), and brain bacterial infections (one [2.4%, 0.1-12.6] vs zero [0%, 0-6.6], p=0.438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22.2%; 95% CI 12.0-35.6] vs three [7.1%; 1.5-19.5]; p=0.051).Interpretation MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage.

Publication metadata

Author(s): Hanley DF, Thompson RE, Muschelli J, Rosenblum M, McBee N, Lane K, Bistran-Hall AJ, Mayo SW, Keyl P, Gandhi D, Morgan TC, Ullman N, Mould WA, Carhuapoma JR, Kase C, Ziai W, Thompson CB, Yenokyan G, Huang E, Broaddus WC, Graham RS, Aldrich EF, Dodd R, Wijman C, Caron JL, Huang J, Camarata P, Mendelow AD, Gregson B, Janis S, Vespa P, Martin N, Awad I, Zuccarello M, MISTIE Investigators

Publication type: Article

Publication status: Published

Journal: Lancet Neurology

Year: 2016

Volume: 15

Issue: 12

Pages: 1228–1237

Print publication date: 01/11/2016

Online publication date: 11/10/2016

Acceptance date: 02/04/2016

Date deposited: 25/01/2018

ISSN (print): 1474-4422

ISSN (electronic): 1474-4465

Publisher: Lancet Publishing Group / Elsevier BV


DOI: 10.1016/S1474-4422(16)30234-4


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